Multigram-scale synthesis of L,D-heptoside using a Fleming-Tamao oxidation promoted by mercuric trifluoroacetate

Article abstract of DOI:10.1016/j.carres.2016.07.010

An efficient multigram-scale synthesis of methyl 2,3,4,6-tetra-O-benzyl-L-glycero-α-D-manno-heptopyranoside from methyl 2,3,4-tri-O-benzyl-α-D-mannopyranoside is reported. It involves a sequence of Swern oxidation, Grignard addition and Fleming-Tamao reac

Full text of DOI:10.1016/j.carres.2016.07.010

Accepted Manuscript
Multigram-scale synthesis of L,D-heptoside using a Fleming-Tamao oxidation
promoted by mercuric trifluoroacetate
Tianlei Li, Abdellatif Tikad, Maxime Durka, Weidong Pan, Stéphane P. Vincent
PII:
S0008-6215(16)30241-5
10.1016/j.carres.2016.07.010
CAR 7230
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 30 May 2016
Revised Date: 5 July 2016
Accepted Date: 6 July 2016
Please cite this article as: T. Li, A. Tikad, M. Durka, W. Pan, S.P. Vincent, Multigram-scale synthesis of
L,D-heptoside using a Fleming-Tamao oxidation promoted by mercuric trifluoroacetate, Carbohydrate
Research (2016), doi: 10.1016/j.carres.2016.07.010.
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ACCEPTED MANUSCRIPT
2
Graphical Abstract
Multigram-scale Synthesis of L, D-heptoside
Using a Fleming-Tamao Oxidation promoted
by Mercuric Trifluoroacetate
Tianlei Li, Abdellatif Tikad, Maxime Durka, Weidong Pan and Stéphane P. Vincent

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ACCEPTED MANUSCRIPT
Multigram-scale Synthesis of L,D-heptoside Using a
Fleming-Tamao Oxidation promoted by Mercuric
Trifluoroacetate
Tianlei Li,a Abdellatif Tikad,a Maxime Durka,a Weidong Pan,b and Stéphane P. Vincent,a,
a Department of Chemistry, University of Namur, Rue de Bruxelles 61, 5000 Namur, Belgium.
b The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences 202, Sha-chong South Road,
Guiyang 550002, P. R. China.
Keywords: Heptose, Fleming-Tamao oxiadation, Homologation, Grignard addition,
Lipopolysaccharide.
Abstract: An efficient multigram-scale synthesis of methyl 2,3,4,6-tetra-O-benzyl-
L-glycero-
α- -manno-heptopyranoside from methyl 2,3,4-tri-O-benzyl-α- -mannopyranoside is
D
D
reported. It involves a sequence of Swern oxidation, Grignard addition and Fleming-Tamao
reactions. The resulting scaffold was used as a precursor to design a small library of clickable
L
-heptosides. This study shows that the use of mercuric bistrifluoroacetate is required both to
accelerate and to cleanly perform the Fleming-Tamao oxidation, without side-reactions.
Introduction
The preparation of ‘‘higher-carbon sugars’’ such as heptoses has been investigated for more
than a century. L,D-heptosides (L-glycero-D-manno-heptopyranosides) are found in important
bacterial glycolipids such as lipopolysaccharide (LPS) but they are not commercially
available. The biological relevance of this carbohydrate is illustrated by the fact that its
biosynthesis is targeted for the development of novel antibacterial agents. Indeed, Gram-
negative bacteria lacking the heptose units display the deep rough phenotype1 and show a
reduction in outer membrane protein content, an increased sensitivity towards detergents or
hydrophobic antibiotics and are much more susceptible to phagocytosis by macrophages.2
Molecules 1-3 represented in Figure 1 are typical examples of L,D-heptosides designed to
inhibit heptosyl processing enzymes : 1 is a conformational probe,3 2 a donor substrate
Corresponding author. Tel.: +32 (0) 81724521; fax: +32 (0) 81724517; e-mail: stephane.vincent@unamur.be

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analogue of bacterial heptosyl transferase WaaC4 and glycofullerenes 3 was shown to inhibit
WaaC in a multivalent manner.5
Synthetic LPS fragments containing heptosides have also been used to develop synthetic
vaccines or diagnostic tools.6 Such an approach may aid the design of a protective
immunization against many pathogenic gram negative bacteria.7
NH2
OH
O
P
N
N
N
HO
HO
HO
H
O- O-
O
O
O
F
HO
O
O
N
O
HO
O
P
P
OMe
OH
O
O
O
HO
OH
OH
2
1
R
R
R
R
O
O
O
O
O
O
O
O
OH
OH
O
O
O
O
R
HO
HO
R
O
O
O
O
O
N
HO
N
O
O
R
3
R
N
n
O
O
O
O
O
n= 1 or 4
O
O
R
R
R
R
Figure 1 Typical L,D-heptosides designed as inhibitors of heptosyl processing enzymes.
Due to their biological interests, heptosides and their glycomimetics have attracted the
attention of synthetic chemists. Among other methods (see our recent review8), the one carbon
homologation via a Grignard approach from an aldehyde generated at C-6 of
mannopyranosides usually affords heptose derivatives in good yields and high
stereoselectivity in favor of the
-glycero-isomers (Scheme 1).9 It must be stressed that
D-
L
alkoxy-methyl Grignard reagents easily decompose and high yields of reactions depend
strongly on the quality of the chloromethyl ethers used. Alternately, α-silylmethyl Grignard
reagents are stable under standard conditions and exhibited the highest L-selectivity especially
when they are hindered.10 In addition, organosilanes have broad application in total synthesis
and are used as "masked hydroxy groups" thanks to the Fleming-Tamao oxidation.11
In the late 1980’s, a convenient diastereoselective hydroxymethylation of a suitably protected

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pyranoside was developed by van Boom and collaborators. 9e, 10, 12 As an example, treatment
of perbenzylated α- -manno-hexodialdo-1,5-pyranoside 4 with the Grignard reagent
D
generated from dimethylphenylsilylmethyl chloride gave diastereoselectively the silane 7.
Cleavage of the carbon-silicon bond in 7 by a Fleming-Tamao oxidation, in the presence of
peracetic acid and potassium bromide, afforded the diol displaying the
6.12c
L-configuration at C-
Scheme 1
L,D-Heptose synthesis via a Grignard homologation.
For instance, this strategy was used to synthesize a trisaccharide from the inner core region of
Nesseria meningitidis LPS,12a and ADP-heptopyranose derivatives.13 However, during our
own synthetic investigations, several problems were encountered during the Fleming-Tamao
oxidative cleavage of the C-Si bond. Several by-products such as the Peterson elimination
product appeared under the usual conditions, sometimes in substantial amount. Using this
procedure, we observed that the yields were very dependent on the scale of the reaction, and
generally were lower on a large scale.
Here we describe the large scale synthesis of
L-glycero-D-manno-heptosides 13 designed as a
precursor to generate clickable -heptoside derivatives displaying an azido or an alkyne
L
group. Our procedure involves the van Boom’s sequence: a Grignard addition followed by a
Fleming-Tamao oxidation catalyzed by mercury trifluoroacetate. The targeted molecules have
been designed to generate libraries of heptose glycomimetics as ligands or inhibitors of
heptose processing enzymes and heptose binding lectins.

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Results and Discussion
As mentioned above, we privileged, for this study, the van Boom’s strategy9e, 10a, 12a, 12c
depicted in Scheme 1. This sequence employs (phenyldimethylsilyl)-methylmagnesium
chloride 8 (Table 1, entry 2) as a very convenient reagent for the one-carbon elongation.
Ethynylmagnesium bromide 9 (entry 3) was also used as nucleophilic Grignard reagent to
construct the alkyne heptoses which could directly serve as potentially clickable building
block. The organomagnesium 8 was freshly prepared following the procedure detailed in the
supporting informations, while ethynylmagnesium bromide 9 is commercially available.
Alcohol 4 was prepared following literature’s procedures.14
The synthesis begins with a Swern oxidation of primary alcohols 4 to afford the
corresponding aldehyde 5. We observed that it is important to assess the purity of aldehyde 5
by 1H NMR is required before engaging it into the next step. Moreover, aldehyde 5 is unstable
and decomposes during silica gel chromatography. For this reason, the vacuum-dried crude
aldehyde was directly engaged without further purification. In addition, when the temperature
is higher than -60 °C during the Swern oxidation, a significant amount of side-products was
observed, which dramatically decreased the yield.
Then, aldehyde 5 was reacted with the above-mentioned Grignard reagents to obtain the
homologated glycosides 6 and 7 in 89 and 82% yields, respectively (Table 1, entries 1-2). The
L
-stereoselectivity of these additions is in agreement with the Cram chelate model,15 in which
the pyranose ring oxygen O-5 and the exocyclic oxygen of the aldehyde are assumed to
chelate the magnesium cation. The silylated Grignard reagent 8 provided the highest
stereoselectivity (L/D = 15:1) compared to ethylnylmagnesium bromide 9 (Table 1, entries 1-
2). In order to scale up the synthesis of homologated glycosides 6 and 7 and to improve the
yield, it was necessary to control the addition rate of the solution of aldehyde 2 and the
reaction temperature. This protocol could be scaled up from 100 mg scale to 20 g with
reproducible yields (Table 1, entries 3-4).

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Table 1. Homologation of methyl mannoside 4 by Swern oxidation followed by Grignard
addition.
Amount of
Grignard
reagent
Yield Ratio
Entry
1
Product
Time
12 h
(%)b
(L/D)
Alcohol 4
1.6 g
4.0 g
82
9:1
2
15 h
89
15:1
3
4
10.0 g
20.0 g
15 h
20 h
90
85
15:1
15:1
8
8
7
7
a Grignard reagent 8 was freshly prepared; b Isolated yields in pure L-heptoside.
Optimization of the Fleming-Tamao reaction
In order to generate the L-heptosides, the cleavage of the C-Si bond by the Fleming-
Tamao oxidation was then investigated. In particular, the effect of the C-6 protecting group on
this oxidative cleavage was also investigated. To do so, the hydroxyl group at C-6 position of
the silane 7 was protected under classical conditions as a benzyl ether 10 and an acetyl ester
11 in excellent yields. As shown in Table 2, the first experiments were carried out using silane
10 as a starting material under standard conditions10b, 12a-c, 16 in the presence of KBr (1.5
equiv.), AcOK (10 equiv.), AcO2H (30 equiv.) in AcOH (0.4 M) (Table 2, entry 1). After 2
1
hours, analysis of the crude H NMR spectrum showed that silane 7 had not completely
disappeared and that the desired product 13 had been formed in 44% yield along with 46% of
alkene 15 as a side product (Table 2, entry 1). Increasing the reaction time to 5 hours was
required for the reaction to go to completion but it did not improve the yield because the
Peterson elimination became predominant (Table 2, entry 2). Interestingly, Ley et al.
described, for the total synthesis of Azadirachtin, that the use of mercuric salts could
accelerate the oxidation of dimethylphenylsilanes.17 Inspired by these impressive results, we

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employed Hg(OAc)2, instead of KBr, under the previous conditions. Rewardingly, this
protocol modification prevented the side-products formation and the desired L-heptoside 13
was isolated in 90% after 15 hours (Table 2, entry 3). Excellent results were also obtained
with Hg(TFA)2 which significantly decreased the reaction time to 2 hours (Table 2, entry 4).
Table 2. Optimization of the Fleming-Tamao oxidation.
product (yield (%))
starting material
entry
additive
time (h)
7, 10
or11
(mass (g))
12-14
15
1d
2d
3e
4e
5e
6e
7e
8e
9e
10 (0.1)
10 (0.1)
10 (0.1)
10 (0.1)
7 (0.1)
KBr
2
5
7 (10)
13 (44)
13 (44)
13 (90)
13 (90)
12 (85)
14 (78)
13 (89)
12 (66)
14 (71)
13 (92)
13 (90)
13 (86)
46
56
-
KBr
-
-
-
-
-
-
-
-
-
-
-
Hg(OAc)2
15
2
Hg(OCOCF3)2
Hg(OCOCF3)2
Hg(OCOCF3)2
Hg(OCOCF3)2
Hg(OCOCF3)2
Hg(OCOCF3)2
Hg(OCOCF3)2
Hg(OCOCF3)2
Hg(OCOCF3)2
-
4
-
11 (0.1)
10 (0.5)
7 (0.5)
5
-
2
-
5
-
11 (0.5)
10 (5)
7
-
10e
11e
12e
4
-
10 (10)
10 (15)
5
-
5
-
Reagents and conditions: (a) BnBr, NaH, DMF, 0 °C-r.t., 15h, 92%; (b) Ac2O, DMAP,
pyridine, 0 °C-r.t., 12h, 95%; (c) All reactions were carried out in the presence of: AcOK (10
equiv.), AcO2H (30 equiv.), AcOH (0.4 M), additives: [KBr (1.5 equiv.), Hg(OAc)2 (2.5
equiv.) and Hg(OCOCF3)2 (2.5 equiv)], at 7 °C for 30 min, then warmed at room temperature.
Under these optimized conditions, the Fleming-Tamao oxidation was also performed
starting from 7, 10 and 11. The results reported in entries 4-9 indicate that protecting groups
at C-6 does influence the C-Si bond oxidative cleavage. Indeed, lower yields and longer

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reaction times were observed either when an acetate was used as a protecting group instead of
a benzyl ether or when the alcohol was not protected (entries 5-10).
Multigram syntheses of
yields were always reproducible, demonstrating that 10 is the best starting material for this
reaction (entries 10-12). In addition, molecule 13 could serve as a central -heptose scaffold
for the construction of -heptose glycomimetics. The functionalization at the 7-position was
L-heptoside 13 were realized starting from 5 to 15 g of 7. The
L
L
chosen based on the fact that the 3D-structure of heptosyltransferase WaaC in complex with
the fluorinated analogue 2 (Figure 1) shows that WaaC does not interact with the 7-position of
the heptose donor substrate.2e,4a
Scheme 2. Synthesis of clickable heptosides using 13 as a central precursor. Reagents and
conditions: (a) TEMPO, PhI(OAc)2, CH2Cl2/H2O, 0 °C-r.t., overnight, 68%; (b) 3-
azidopropylamine, HBTU, DIPEA, THF, r.t., 12 h, 62%; (c) But-3-yn-1-amine, HBTU,
DIPEA, THF, r.t., 12 h, 82%; (d) Dess-Marin Periodinane, CH2Cl2, r.t., 4 h; (e) Dimethyl (1-
diazo-2-oxopropyl) phosphonate, K2CO3, MeOH, 0 °C-r.t., 5 h, 60% over two steps.
In order to synthesize clickable heptose analogues, we then tried to install different
clickable functional groups at the heptose 7-position. The heptoside 13 was used as a central
scaffold to generate three clickable derivatives which displayed an azido-group or an alkyne
at C-7 position with different spacers (Scheme 2). For the synthesis of heptosides 17 and 18
bearing a propyl linker, the primary alcohol 13 was oxidized by TEMPO18 to give the
carboxylic acid 16 which was reacted with primary amines under peptide coupling conditions
to afford clickable heptosides 17 and 18 in 62% and 82% yields, respectively (Scheme 2). In
parallel, alkyne-glycosides 6 and 20 were prepared by two complementary methods: the first

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one, described in Table 1, was based on the addition of ethynylmagnesium bromide to
aldehyde 5 giving access to alkyne 6 as a 9:1 diastereomeric mixture. The second one was
L/D
performed from alcohol 13 in 60% yield over two steps after a Dess-Martin periodinane
oxidation followed by a Seyferth-Gilbert reaction.
In conclusion, the efficient access to 2,3,4,6-tetra-O-benzyl-L-glycero-α-D-manno-
heptopyranoside 13 from primary alcohol 4 was realized through a van Boom’s sequence
consisting in a Swern oxidation immediately followed by a Grignard addition and a Fleming-
Tamao oxidation. The latter step was optimized and it was found that the use of mercuric
trifluoroacetate instead of sodium bromide was a key parameter to efficiently and
reproducibly obtain the desired heptosides, whatever the scale. Moreover,
L-heptoside 13 was
exploited as a precursor to generate clickable -heptoside derivatives bearing an azido or an
L
alkyne group. These clickable molecules can now be exploited to generate libraries of
potential inhibitors of heptosyl processing enzymes and heptose-binding lectins.
Acknowledgments
The authors are grateful to China Scholarship Council (Ph.D. grant No. 2010667003 to T.L.)
and to the Fonds National de la Recherche Scientifique (FNRS) (Mandat de Chargé de
Recherche for A. T.).
Supplementary Material
Detailed experimental procedures and NMR spectra for all new compounds are available in
the supplementary material.
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ACCEPTED MANUSCRIPT
Professor Stéphane VINCENT
University of Namur
Director of the
Laboratory of Bio-Organic Chemistry
Rue de Bruxelles, 61
B-5000 Namur, Belgique
Tél : +32 (0)81 72 45 21
Fax : +32 (0)81 72 45 17
Stephane.Vincent@unamur.be
Highlights
manuscript entitled “Multigram-scale Synthesis of L-heptoside Using a Fleming-Tamao
Oxidation Catalyzed by Mercuric Trifluoroacetate”.


Heptosides are important bacterial carbohydrates associated with key cellular functions.
Heptosides are involved in the pathogenicity and the virulence of some important
infectious agents.



Multi-gram scale synthesis of L,D-mannoheptose,
Lipopolysaccharide
a
key component of
Clickable heptosides as interesting molecular tools for generating libraries of heptose
mimetics.
Heptose glycomimetics