Total Synthesis of Legionaminic Acid as Basis for Serological Studies

Article abstract of DOI:10.1021/jacs.5b00455

Legionaminic acid is a nine-carbon diamino monosaccharide that is found coating the surface of various bacterial human pathogens. Its unique structure makes it a valuable biological probe, but access via isolation is difficult and no practical synthesis h

Full text of DOI:10.1021/jacs.5b00455

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Communication
Total Synthesis of Legionaminic Acid as Basis for Serological Studies
Stefan Matthies, Pierre Stallforth, and Peter H Seeberger
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b00455 • Publication Date (Web): 10 Feb 2015
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Total Synthesis of Legionaminic Acid as Basis for Serological
Studies
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Stefan Matthies,†,‡ Pierre Stallforth,†,§ and Peter H. Seeberger*,†,‡
†Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems, Am Mühlenberg 1, 14476
Potsdam, Germany
‡Freie Universität Berlin, Department of Biology, Chemistry, Pharmacy, Arnimallee 22, 14195 Berlin, Germany
Supporting Information Placeholder
baumannii9, Enterobacter cloacae10 and Campylobacter je-
ABSTRACT: Legionaminic acid is a 9-carbon diamino
monosaccharide that is found coating the surface of various
juni.3,11
bacterial human pathogens. Its unique structure makes it a
valuable biological probe but access via isolation is difficult
and no practical synthesis has been reported. We describe a
stereoselective synthesis that yields a legionaminic acid
building block as well as linker-equipped conjugation-ready
legionaminic acid, starting from cheap D-threonine. To set
the desired amino and hydroxyl group pattern of the target
we designed a concise sequence of stereoselective reactions.
The key transformations rely on chelation-controlled
organometallic additions and a Petasis multi-component
reaction. The legionaminic acid was synthesized in a form
that enables attachment to surfaces. Glycan microarray
containing legionaminic acid revealed that human antibodies
bind the synthetic glycoside. The synthetic bacterial
monosaccharide is a valuable probe to detect an immune
response to bacterial pathogens such as Legionella
pneumophila, the causative agent of Legionnaires’ disease.
The structural complexity of legionaminic acids that ren-
ders them exquisite biological probes has a major drawback:
the total synthesis of these compounds is notoriously diffi-
cult. So far no synthetic strategy has been described to access
fully functionalized legionaminic acid 2 and 3 glycosylating
agents3,8,12-14 for the construction of oligosaccharides or for
the conjugation to slides or carrier proteins.15,16
Here, we provide a versatile synthetic route to legionamin-
ic acid building block 5 and linker-equipped legionaminic
acid 4. We describe a de novo strategy17-27 starting from inex-
pensive and commercially available D-threonine 8.
The retrosynthetic disconnection of linker-LegA 4 is
shown in Scheme 1 with hemiketal 5 as universal building
block. The latter is accessible by a sequence of an oxidation
and an indium-mediated allylation of aminol 6. Acetamide 6
is derived from α-hydroxy aldehyde 7 via a Petasis-borono-
Mannich reaction. Aldehyde 7 in turn originates from
D-threonine 8 via an intramolecular inversion and a chela-
tion-controlled organometallic addition reaction.
The human immune system can identify bacterial patho-
gens by interacting with specific carbohydrates on the outer
membrane of the microbe.1 In particular, homopolymers
built from sialic acid monomers (1-3) are key players involved
in recognition processes.2,3 While N-acetylneuraminic acid 1
is ubiquitous in both mammalian and bacterial glycomes,
legionaminic acids 2 and 3 are specific to bacteria.3,4 Struc-
turally, they differ from their closest mammalian relative,
N-acetylneuraminic acid 1, by lacking one oxygen at C9 and
by exhibiting an amine in place of an oxygen at C7 (Scheme
1).
Scheme 1. A) Structures of N-Acetylneuraminic acid 1,
Legionaminic acid 2 and 4-Epi-legionaminic acid 3; B)
Retrosynthesis of Legionaminic Acid Building Block
5
as well as Conjugation-Ready LegA 4.
A key virulence factor involved in Legionnaire’s disease, a
devastating form of pneumonia in humans, is the lipopoly-
saccharide (LPS) of Legionella pneumophila.3,5 Legionaminic
acid 2 is the major component of the LPS, a homopolymer of
5-N-acetimidoyl-7-N-acetyl legionaminic acids.4,6-8
The presence of legionaminic acids 2 and 3 (LegA) within
glycoconjugates of bacterial pathogens3,4 makes them ideal
targets for pathogen detection and for the development of
vaccines. Interestingly, legionaminic acid is also found in
other prominent human pathogens such as Acinetobacter
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The total synthesis of legionaminic acid commenced with
in 80% yield. Since the oxidation of the furan moiety failed
preparation of aldehyde 9 setting the required stereogenic
information at C7 and C8 in the final building block (Scheme
2). Since D-allo-threonine methyl ester is prohibitively ex-
pensive, aldehyde 9 was synthesized from D-threonine 8 via a
slightly modified literature procedure.28 The necessary C3-
epimerization was achieved by anchimeric assistance. Methyl
ester formation, N-benzoylation, followed by thionyl chlo-
ride-induced cyclization, acidic hydrolysis of the intermedi-
ate oxazoline and esterification yielded D-allo-threonine
methyl ester in 98% over five steps without chromatographic
purification. The latter was transformed to the correspond-
ing N-toluenesulfonamide, followed by an acetalization and
DIBAL-H reduction of the intermediate ester provided D-
allo-threoninal 9 in 84% overall yield.29
using ruthenium-based protocols,30 we treated alcohol 10
with ozone followed by methylation to give methyl ester 11 in
59% yield. The conversion of ester 11 to diol 12 employing
lithium borohydride in THF31 proceeded in 92% yield. X-ray
crystallographic analysis of diol 12 confirmed the stereo-
chemical assignment (see SI).32
α-Hydroxy aldehyde 7 was required as precursor to intro-
duce a protected amine via a Petasis-borono-Mannich reac-
tion.33,34 Careful optimization of the chemoselective oxida-
tion of diol 12 to aldehyde 7 was crucial in circumventing the
notorious propensity of α-hydroxy aldehydes to decompose
or epimerize. Subjecting alcohol 12 to Dess-Martin
oxidation35 resulted in low conversion, while TEMPO-
mediated oxidation employing trichloroisocyanuric acid as
the stoichiometric oxidant36 did not proceed reproducibly.
Finally, when using Anelli’s modification of the TEMPO
oxidation,37 the desired aldehyde 7 was obtained in quantita-
tive yield without loss of stereochemical purity.38
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Scheme 2. Synthesis of Hemiketal Donor 5.a
To access protected diamines 13 or 14, a Petasis-borono-
Mannich reaction between aldehyde 7, (E)-styrylboronic acid
and an amine component was used (Table 1). The newly
formed stereocenter displays anti-configuration relative to
the directing free hydroxyl group. The high degree of stere-
ocontrol reported by Petasis and Zavialov34 arises from two
energetically different conformations of the intermediate ate
complexes (not shown, for review see33).
Table 1. Optimization of the Petasis Multi Compo-
nent Reaction
Entry
Amine
Solvent
EtOH
Temp. Time Yield
rt 36 h 49%
120°C[f] 0.5 h <10%
[a]
1
NHAll2
NHAll2
NHAll2
NHAll2
NHAll2
NHAll2
[b]
[b]
[b]
[b]
[b]
2
3
4
5
6
7
DCM
DCM/HFIP[c]
DCM/HFIP[d]
EtOH/water[e]
DCM
40°C
40°C
40°C
rt
24 h
24 h
2 h
46%
57%
23%
aReagents and conditions: a) SOCl2, MeOH, reflux, 1 h,
quant.; BzCl, NEt3, MeOH, 0°C, 4 h, quant.; SOCl2, 0°C, 5
days, 99%; 6N HCl, reflux, 5 h; SOCl2, MeOH, reflux, 1 h,
99%; TsCl, NEt3, DCM, 0°C, 4 h, 99%; 2,2-DMP, p-TsOH,
Toluene, 120°C, 4 h, 98%; DIBAL-H, Toluene, -78°C, 2 h, 87%;
b) n-BuLi, furan, MgBr2·OEt2, DME, -78°C, 4 h, d.r.=5:1
(syn/anti), 80% (syn) ; c) O3, DCM, MeOH, -78°C, 1 h, then
PPh3 and TMSCHN2, 0°C, 59%; d) LiBH4, THF, 0°C → rt, 12
h, 92%; e) NaOCl, cat. TEMPO, KBr, DCM, sat. aq. NaHCO3,
0°C, 10 min, quant.; f) (E)-styrylboronic acid, HNR2, d.r.>19:1
(anti/syn), yield and conditions see: Table 1; g) DMBA,
Pd(PPh3)4, DCM, 35°C, 2 h, then Ac2O, NaHCO3, MeOH, rt, 5
h, 99%; h) O3, PPh3 (resin, crosslinked), then i) In, methyl 2-
(bromomethyl)-acrylate, EtOH, sat. aq. NH4Cl, rt, sonication,
30 min, 99%, d.r.=2.5:1 (syn/anti); j) O3, MeOH, -78°C, 15
min, then Me2S, rt, 4 h, 46% (syn), 15% (anti); k) Ac2O, pyr,
24 h 0%[f]
NH2All[a]
EtOH
rt
24 h
76%
1:1:1.
[a]Equivalents
(7:(E)-styrylboronic
acid:amine)
[b]Equivalents (7:(E)-styrylboronic acid:amine) 1:1.5:1.5, [c]3:1,
[d]9:1, [e]4:1, [f]microwave irradiation, [f]N,O-Isopropylidene
hydrolyzed. HFIP = 1,1,1,3,3,3-Hexafluoro-2-propanol
Table 1 summarizes the optimization process of the key
Petasis-borono-Mannich reaction. Initially, we applied
standard reaction conditions using ethanol as the solvent
and equimolar amounts of all reactants as well as a reaction
time of 36 h (entry 1).34 Despite quantitative conversion of 7,
the isolated yield of aminol 13 was low (49%). Microwave
irradiation is known to accelerate and facilitate Petasis reac-
tions.38,39 However, in our hands it did not result in accepta-
ble rates of conversion (entry 2). Polar, protic solvents such
as hexafluoroisopropanol are known to increase reaction
rates and improve yields for this transformation. Unfortu-
nately, the yields were comparable to the initial trials (entries
3 and 4). Using an ethanol-water mixture, as well as di-
chloromethane as solvent resulted in N,O-isopropylidene
DMAP, DCM, 0°C
toluenesulfonic acid, Bz
→
rt, 12 h, 82%. p-TsOH
Benzoyl, DMBA
=
p-
1,3-
=
=
dimethylbarbituric acid, DMP = Dimethoxypropane, Ts =
Tosyl.
With threoninal 9 in hand, a Cram-chelate organometallic
addition reaction of 2-lithiofuran to threoninal 9 resulted in
the formation of the desired syn-configured alcohol 10
(Scheme 2).29 Crystallization gave diastereomerically pure 10
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cleavage rather than improved yields (entries 5 and 6). Even-
ment (selective, coupled, 1D 1H-13C-HMBC) was performed to
determine the heteronuclear coupling constant. With
tually, the use of monoallyl amine provided aminol 14 in 76%
yield (entry 7). As desired, the exclusive formation of the
anti-diastereomers 13 and 14 with a d.r.>19:1 was observed in
all cases.
3JC-1 H-3ax
= 1.9 Hz the anomeric configuration proved the β-
,
anomeric center.46 Starting from thioether 20, acetate re-
moval gave alcohol 21 in close to quantitative yield. Hydroly-
sis of the methyl ester, using 20 equivalents of lithium hy-
droxide to prevent the formation of elimination by-products,
gave carboxylate 22 in quantitative yield.
Conversion of the N-allyl group of 14 into the correspond-
ing N-acetate was achieved by Pd(0)-catalyzed deallylation
followed by chemoselective N-acetylation to give amide 6 in
99% yield (Scheme 2).38 Oxidative cleavage of N-
cinnamylacetamide 6 to give aldehyde 15 required careful
optimization of the ozonolytic conditions to prevent epimer-
ization and decomposition of the labile α-aminoaldehyde
moiety.27,40 Zinc and dimethyl sulfide reduced the ozonide
but the transformation required long reaction times.27 The
use of resin-bound triphenyl phosphine41 resulted in com-
plete reduction of the intermediate ozonide without epimer-
ization. Thus, quantitative conversion of hydroxylamine 6 to
N-acetamide aldehyde 15 was achieved. Indium-mediated
allylation of aldehyde 15 to enoate 16 is an established meth-
od to introduce a masked pyruvate unit.42-44 While other
potential methods such as the Cornforth synthesis45 are
performed using harsh conditions, the In-mediated allylation
offers mild reaction conditions and can be performed in
aqueous media.43 Quantitative conversion of aldehyde 15 to
the desired allylic alcohol 16 was achieved using sonication
and a solvent mixture consisting of ethanol and aqueous
ammonium chloride. Ammonium chloride was used as alter-
native to aqueous hydrogen chloride,44 which would hydro-
lyze the N,O-isopropylidene acetal. Labile enoate 16 was
isolated in high yield (99%) in favor of the syn-configuration
(d.r.=2.5:1 (syn/anti)). Oxidative cleavage of the double bond
on enoate 16, proved problematic, initially leading to decom-
position or low yields. The use of a reductive workup (dime-
thyl sulfide) after ozonolytic cleavage of the alkene moiety in
methanol to provide legionaminic acid 17 and
4-epilegionaminic acid derivative 18 in good yield.
9
Scheme 3. Synthesis of Glycoside 4.a
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aReagents and conditions: a) Ph2SO, Tf2O, HOC2H4SBn, 4Å
MS, -78°C → -50°C, 2.5 h; then b) DCM, TFA, H2O (10:3:1
v/v), 0°C, 5min 63%; c) NaOMe, MeOH, rt, 12 h, 95%; d) 20
eq. LiOH, MeOH/H2O (1:1 v/v), rt, 15 h, 99%; e) Na(s), NH3(l), -
78°C, 45 min, then O2 atmosphere, 99%; f) NaOH, Ac2O,
H2O, 0°C, 60 min, then MeOH, 2 h, rt, 98%.
Global deprotection by reductive cleavage of the thioether
and the N-sulfonamide moiety was achieved by Birch reduc-
tion (Scheme 3). Carboxylate 22 was treated with sodium in
liquid ammonia without co-solvent to provide the desired
amine 23 as the disulfide in quantitative yield. Amide 4 was
finally obtained by treatment of amine 23 with sodium hy-
droxide and acetic anhydride. Starting from D-threonine, the
overall yield of N-acetamide 4 was 6%.
To obtain linker-equipped legionaminic acid 4, the instal-
lation of an anomeric linker via glycosidation of a suitable
legionaminic acid building block was required. Screening of
protocols for the glycosidation of sialic acid building blocks46
(e.g. anomeric chlorides, acetates and phosphites, thioglyco-
sides and N-phenyl-trifluoroacetimidate, results not shown)
were irreproducible. Finally, we found that a dehydrative
glycosylation protocol47 furnished the desired linker-
conjugate. Thus, diol 17 yet had to be elaborated into C4-OAc
hemiketal donor 5 by selective acylation. Careful optimiza-
tion allowed for selective C4-O-acetylation when using 2
equivalents of acetic anhydride and pyridine in the presence
of catalytic amounts of DMAP to yield monoacetylated
hemiketal 5 in high yield.44 Starting from D-threonine, the
overall yield of acetate 5 was 10%. To confirm the stereo-
chemical configuration of diol 17, the corresponding C2/C4-
OAc derivate was characterized (see SI).
To evaluate whether a legionaminic acid monosaccharide
is a sufficient epitope for antibody recognition, human sera
were screened against the synthetic structures using glycan
microarrays (Scheme 4).48-51 Carbohydrates 4 and 23 were
immobilized via their thiol linker on maleimide coated glass
slides. Treatment with pooled human sera revealed that
legionaminic acids 4 and 23 were recognized, presumably as
a result of previous immune responses to bacterial pathogens
displaying a legionaminic acid motif. IgG serum antibody
levels against acetamide 4 were substantially higher than
against amine 23 (Scheme 4). This side chain modification
appears to be crucial for the specificity of antibody recogni-
tion. Since no bacterial glycans isolated so far display free
amino groups on C7, we chose amine 23 as negative control
to exclude unspecific binding. We further confirmed the
preferential binding of human antibodies to antigen 4 using
two other pooled human antisera (CDC199252 and anti-Hib
human reference serum53, results not shown). Legionaminic
acid-binding antibodies in human sera show that this rare
Dehydrative glycosylation of 4Ac5NAcLeg donor 5 provid-
ed crude thioether 19 (Scheme 3).47 Surprisingly, attempts to
purify crude 19 all failed due to decomposition of the materi-
al. Thus, acetal hydrolysis using aqueous TFA was performed
prior to purification to provide glycoside 20 (63% β-anomer).
Although the α-anomer was formed, it proved to be insepa-
rable from minor decomposition products by means of silica
gel chromatography. A 1D heteronuclear correlation experi-
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(2)
Mühlenhoff, M.; Eckhardt, M.; Gerardy-Schahn, R. Curr.
carbohydrate from bacterial pathogen origin is recognized by
the human immune system. Conjugate 4 is a valuable tool for
the production of novel pathogen detection systems or vac-
cines.
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Scheme 4. Microarray analysis of synthetic LegA.
Cazalet, C.; Jarraud, S.; Ghavi-Helm, Y.; Kunst, F.; Glaser,
A
B
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A: Printing Pattern. Legionaminic acid structures (4 and 23)
printed in concentration from 1 mM to 0.0016 mM. B: Repre-
sentative microarray scan representing IgG antibodies to
LegA 4 and 23 after incubation with Human Reference Serum
007sp.
Filatov, A. V.; Wang, M.; Wang, W.; Perepelov, A. V.;
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In summary, we have completed the de novo synthesis of
orthogonally protected legionaminic acid 5. This building
block served as a glycosylating agent in the synthesis of link-
er-equipped legionaminic acid 4. Glycan arrays containing
synthetic antigen 4 showed that this epitope is recognized by
human antibodies present in blood sera. Immunization stud-
ies and additional binding studies are currently ongoing.
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AUTHOR INFORMATION
Chemical Society: 2008; Vol. 990, p 3.
Corresponding Author
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Brasholz, M.; Reissig, H.-U. Angew. Chem. Int. Ed. 2007,
peter.seeberger@mpikg.mpg.de
Leonori, D.; Seeberger, P. H. Beilstein J. Org. Chem. 2013,
Present Addresses
§ Leibniz Institute for Natural Product Research and Infec-
tion Biology e.V. (HKI), Department of Chemistry of Micro-
bial Communication, Beutenbergstr. 11, 07745 Jena, Germany
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The authors declare no competing financial interests.
Szechner, B.; Achmatowicz, O.; Galdecki, Z.; Fruzinski, A.
ACKNOWLEDGMENT
Kasai, M.; Ziffer, H. J. Org. Chem. 1983, 48, 2346.
Watanabe, A.; Kiyota, N.; Yamasaki, T.; Tanda, K.;
We thank the Max Planck Society and the Studienstiftung
des deutschen Volkes (Fellowship to P.S.) for generous fund-
ing. The authors would like to thank Dr. A. Schäfer (FU Ber-
lin) for NMR analysis, Dr. A. Hagenbach (FU Berlin) for X-
ray crystallographic analysis and Dr. F. Pfrengle for critical
comments to the manuscript and A. Geissner for help with
microarray experiments.
CCDC
1019693
contains
the
supplementary
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