Regioselective one-pot protection, protection-glycosylation and protection-glycosylation-glycosylation of carbohydrates: A case study with d-glucose

Article abstract of DOI:10.1039/c3ob42097c

Well-defined oligosaccharides are important requirements in evaluating structure-activity relationships to decipher the roles of carbohydrates in various physiological processes. These oligosaccharides are accessed mainly through chemical synthesis, which

Full text of DOI:10.1039/c3ob42097c

Organic &
Biomolecular Chemistry
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Regioselective one-pot protection, protection–
glycosylation and protection–glycosylation–
glycosylation of carbohydrates: a case study with
D-glucose†
Cite this: Org. Biomol. Chem., 2014,
12, 376
Teng-Yi Huang, Medel Manuel L. Zulueta and Shang-Cheng Hung*
Well-defined oligosaccharides are important requirements in evaluating structure–activity relationships to
decipher the roles of carbohydrates in various physiological processes. These oligosaccharides are
accessed mainly through chemical synthesis, which nonetheless remains a huge undertaking despite the
many advances in recent years. A combinatorial and regioselective one-pot protection strategy was pre-
viously disclosed by us to reduce the effort and wastes associated with carbohydrate synthesis. With the
tetra-trimethylsilylated 4-methylphenyl thioglucoside as the starting material, we herein show the one-
pot preparations of diols, triols and fully protected derivatives of thioglucosides, and, more importantly,
we generated building blocks in situ that effectively acted as glycosyl donors and glycosyl acceptors for
further coupling with other monosaccharide building blocks. Our one-pot protection–glycosylation and
protection–glycosylation–glycosylation approaches made use of the perceived reactivity differences
between thioglycoside donors to conveniently supply disaccharide and trisaccharide skeletons as well as
the backbone of a recently discovered compatible solute from two thermophilic bacteria of the Petrotoga
species. The demonstrated protocol is another step in reducing the enormous work in carbohydrate syn-
thesis and efficiently delivering sugar constructs for application in other areas of glycobiology.
Received 21st October 2013,
Accepted 7th November 2013
DOI: 10.1039/c3ob42097c
www.rsc.org/obc
and efficient preparations of diverse monosaccharide building
blocks and their assembly into oligosaccharides as well as the
Introduction
Carbohydrates, including free or conjugated mono-, oligo- and stereoselective control of glycosidic bond formation are major
polysaccharides, are essential for the operation, structural challenges in carbohydrate synthesis.5
integrity and interactions of biological systems.1 Unlike
In current practice, monosaccharide building blocks can be
nucleotides and amino acids, monosaccharide units have mul- designed to act as glycosyl acceptors, glycosyl donors or both.
tiple linkage potentials and form assemblies that may be Acceptors have a strategically positioned free hydroxyl group
linear or branched. These features, together with the (or other nucleophile) to allow glycosidic bond formation with
occasional chain substitutions, contribute to the vast a donor. Donors, on the other hand, are conventionally charac-
embedded information within sugar scaffolds. The ardent terised by the presence of a leaving group at the anomeric
interest in understanding how Nature exploits such infor- center. However, the availability of leaving groups amenable to
mation promoted glycobiology into an intense and exciting chemoselective activation6 as well as preactivation7 and the
field of study.2 The nontemplate-driven biosynthesis of carbo- recent appreciation of the diverse donor reactivity differences8
hydrates gives rise to closely related microheterogeneous struc- enabled the application of monosaccharide donor–acceptor
tures, complicating the access to pure and adequate materials hybrids in oligosaccharide assembly. These monosaccharide
needed for structure–activity relationship evaluations.3 Chemi- building blocks are especially useful in sequential one-pot gly-
cal methods to synthesise these function-oriented domains cosylations. The effective use of these materials is highly
have, therefore, acquired immense importance.4 The rapid dependent on protecting groups, which are installed not only
to influence regio- and stereoselectivity during glycosylations
but also to tune donor reactivity.4c,5
Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road,
One-pot approaches minimise the time, effort and wastes
Taipei 115, Taiwan. E-mail: schung@gate.sinica.edu.tw
incurred during the intervening work-up and purifications of
†Electronic supplementary information (ESI) available: Detailed experimental
the exceptionally multistep synthesis of carbohydrates.9 For
procedures and the 1H and 13C NMR spectra for relevant compounds. See DOI:
10.1039/c3ob42097c
building block preparations, the careful differentiation of
376 | Org. Biomol. Chem., 2014, 12, 376–382
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multiple hydroxyl groups was addressed in our trimethylsilyl donors. Different disaccharide and trisaccharide skeletons
trifluoromethanesulfonate (TMSOTf)-mediated one-pot protec- were generated starting from the per-trimethylsilylated thioglu-
tion strategy.10 This regioselective and combinatorial protocol coside 1.10 Because this topic integrates our various efforts on
facilitated the efficient accumulation of hundreds of building one-pot preparations, similar synthesis of a few monosacchar-
blocks from per-trimethylsilylated starting materials. Per- ides featured here have been disclosed previously.12,14a,e
trimethylsilylation improves saccharide solubility in common
organic solvents and also provides steric and thermodynamic
leverage for regioselective protecting group installation.9b First
Results and discussion
Regioselective one-pot synthesis of D-glucosyl diol and fully
demonstrated for D-glucose, the strategy was extended to syn-
thesise derivatives of D-glucosamine,11 D-galactose, D-xylose12
and D-mannose.13 The generated building blocks have since
protected diacetyl derivatives
been applied in the assembly of various essential gly- 4,6-O-Arylmethylidene acetal formation followed by regioselec-
cans.10a,12,14 Notable one-pot protection strategies promoted tive reductive 3-O-arylmethyl group installation are pivotal
by copper trifluoromethanesulfonate (Cu(OTf)2),15 FeCl3 16 and steps in our established one-pot protection strategy. They gen-
cyanuric chloride17 were also reported by others.
erally set the stage for the succeeding transformations. With
In this paper, we further developed our one-pot approach to per-trimethylsilylated starting materials, acetalation is flexible
carbohydrate synthesis to cater to the preparations of a variety enough to be carried out at 0 °C or lower, whereas subzero
of sugar structures. Additions of a broad range of reactants in temperatures are needed for 3-O-arylmethylation. We pre-
already complicated mixtures present challenges in the expan- viously identified Cu(OTf)2 as the best catalyst among other
sions of these one-pot processes. Our previous reports exten- metal trifluoromethanesulfonates for reductive 3-O-etherifica-
sively covered the preparations of 2-, 3-, 4- and 6-alcohols and tion under similar systems.18 However, in our hands, TMSOTf
arylmethylidene-containing fully protected derivatives.10 The was found to be a superior catalyst, especially when working
present goal is to synthesise several diol and triol glucoside with molecular sieves, which displayed a tendency to reduce
derivatives carrying benzyl (Bn)- and ester-type protecting the catalytic activity of Cu(OTf)2. The flexibility of the acetal
groups and further generate fully protected glycosyl donors with respect to regioselective ring opening19 and acidic depro-
through them in one pot (Fig. 1). Herein, we chose the β-thio- tection together with the availability of selectively cleavable
toluenyl (β-STol) group as the masking group for the anomeric arylmethyl groups are highly advantageous in generating
center to afford glycosyl donors and, more importantly, donor– various diols from compound 1 in one pot.
acceptor hybrids. Finally, the one-pot process was extended
Scheme 1 illustrates our one-pot diol preparations. The
from regioselective one-pot protection to glycosylation, taking solution of the tetrasilylated glucoside 1 in CH2Cl2 was treated
advantage of the presumed reactivity differences between the with 1.1 equiv. of benzaldehyde and catalytic TMSOTf to
Fig. 1 Combinatorial and regioselective monosaccharide protection and protection–glycosylation in a one-pot manner. Arrows with broken lines
point to targets in the present work. TMS: trimethylsilyl.
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Scheme 2 Preparation of fully protected diacetylated thioglucosides.
Reagents and conditions: (a) benzaldehyde, cat. TMSOTf, 3 Å molecular
sieves, CH2Cl2, −78 °C, 2 h; (b) benzaldehyde, Et3SiH, cat. TMSOTf,
−78 °C, 2.5 h; (c) BH3·THF, cat. TMSOTf, 0 °C, 5 h, then, MeOH, 0 °C,
30 min; (d) Ac2O, Et3N, cat. DMAP, rt, 12 h; (e) Me2EtSiH, cat. TMSOTf,
CH3CN, 0 °C, 1 h; (f) Ac2O, cat. TMSOTf, 0 °C, 12 h; (g) Ac2O, cat.
TMSOTf, 0 °C, 1 h.
Scheme 1 Regioselective one-pot synthesis of D-glucosyl diol deriva-
tives. Reagents and conditions: (a) benzaldehyde, cat. TMSOTf, 3 Å
molecular sieves, CH2Cl2, −78 °C, 2 h; (b) benzaldehyde, Et3SiH, cat.
TMSOTf, −78 °C, 2.5 h; (c) BH3·THF, cat. TMSOTf, 0 °C, 5 h; (d) Me2EtSiH,
The usefulness of the one-pot protection protocol in achiev-
ing the diacetyl derivatives was tested by plainly extending the
steps utilised to prepare the diols. We targeted the diacetyl
derivatives 8 and 9 (Scheme 2) to benefit from the neighbour-
ing group assistance provided by ester-type groups installed at
O2 during glycosylation. After the respective 4,6-O-benzylidena-
tion and 3-O-benzylation of compound 1, the regioselective
6-O-ring opening with BH3·THF was carried out, followed by
slow quenching with methanol at 0 °C. The solution was sub-
sequently made basic by adding Et3N, and acetylation was con-
ducted under N,N-dimethyl-4-aminopyridine (DMAP) catalysis
to generate the 2,6-diacetate 812 (77%, 4 steps). Me2EtSiH, on
the other hand, supplied the 4-O-ring opening product, which
was diacetylated to produce the 2,4-diacetate 9 (42%, 4 steps).
A variation of this preparation, wherein separate acetylations
were conducted before and after 4-O-ring opening, gave 9 in a
higher one-pot yield of 65% (5 steps).
cat. TMSOTf, CH3CN,
0 °C, 1 h; (e) 2-NaphCHO, Et3SiH, cat.
TMSOTf, −78 °C, 3 h; (f) Ac2O, TMSOTf, 0 °C, 1 h; (g) DDQ, H2O, rt, 3 h;
(h) benzaldehyde, cat. TMSOTf, 3 Å molecular sieves, CH2Cl2, 0 °C, 2 h;
(i) Bz2O, TMSOTf, 0 °C to rt, 18 h; ( j) TFA, H2O, rt, 1 h. Ac: acetyl;
Bz: benzoyl.
install the benzylidene acetal. Afterwards, stoichiometric
Et3SiH, another equivalent of benzaldehyde, and TMSOTf were
added to the same flask to afford the 3-O-benzylated inter-
mediate. From here, the regioselective ring opening of the
acetal should provide the 2,6-diol 2 and 2,4-diol 3. Conse-
quently, additions of borane–tetrahydrofuran complex
(BH3·THF) and TMSOTf successfully delivered 214a in 86%
yield (3 steps) whereas Me2EtSiH and TMSOTf with added
CH3CN solvent19a led to the reverse opening and 3 in 72%
yield (3 steps). We next tackled the synthesis of 3,6-diol and
3,4-diol. In this case, the 2-naphthylmethyl group was chosen
Regioselective one-pot synthesis of D-glucosyl triol and fully
protected triacetyl derivatives
as temporary protection at O3. Full protection was carried out The synthesis of Bn- or ester-type monoprotected glycosides,
through the usual 4,6-O-benzylidenation, 2-naphthylmethyl while appearing simpler at first glance, is occasionally as intri-
ether formation using 2-naphthaldehyde (2-NaphCHO), Et3SiH
cate as the preparation of fully protected building blocks. We,
and TMSOTf reagents, and acetylation with acetic anhydride therefore, decided to apply the relevant steps in our one-pot
(Ac2O) and TMSOTf at the O2 position. The reductive ring procedure in affording some monoprotected thioglucosides
opening mediated by BH3·THF or Me2EtSiH as described
(Scheme 3). The regioselective ring opening of the 4,6-O-benzy-
above followed by the addition of 2,3-dichloro-5,6-dicyano-1,4- lidene acetal could directly lead to the 2,3,6-triol 1021 and
benzoquinone (DDQ) at room temperature to cleave the
2,3,4-triol 11. Consequently, compound 1 was benzylidenated.
2-naphthylmethyl group supplied the 3,6-diol 4 (41%, 5 steps)
The subsequent ring opening worked as expected but was
and 3,4-diol 5 (47%, 5 steps), respectively. For the 4,6-diol 6, much easier for the 6-O-ring opening with BH3·THF, which
4,6-O-benzylidenation and reductive 3-O-benzylation left O2
readily amenable to benzoylation in one pot. After treatment
gave 10 in 81% yield, than for 4-O-ring opening with
Me2EtSiH, which provided 11 in 51% yield. The one-pot prepa-
with benzoic anhydride (Bz2O) and TMSOTf, exposure to tri- ration of the 3-O-benzylated thioglucoside 12 (62%, 3 steps)
fluoroacetic acid (TFA) subsequently furnished 614e in 75%
was readily achieved from 1 via 4,6-O-benzylidenation, regio-
yield (4 steps). If the 2,3-diacetate 7 is desired, 4,6-O-benzylide-
nation and 2,3-di-O-acetylation both catalysed by TMSOTf, and of the benzylidene acetal. The 2-acetate 13 was, on the other
selective reductive 3-O-benzylation and TFA-mediated hydrolysis
lastly TFA-mediated hydrolysis of the benzylidene acetal can be
performed. This 3-step transformation generated compound
7
hand, acquired in 4 steps through a fully protected derivative.
Here, a 2-naphthylmethyl group was temporarily positioned at
O3 prior to acidic 2-O-acetylation. The final addition of TFA
20 in 70% yield.
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materials. Our earlier work related to this technique involved
partially protected starting materials apart from the labile TMS
groups.22 The intermediate generated by the reductive benzyla-
tion step acted as an acceptor for the trichloroacetimidate
donor that was subsequently added to form α1 → 2-linked di-
saccharides. A single catalyst (i.e., TMSOTf) was utilised in this
two-step one-pot procedure. Subsequently, a number of papers
have reported glycosylation carried out in tandem with protect-
ing group manipulation, such as benzylidenation,15b benzyli-
dene ring opening,23 acidic desilylation12 and Fmoc removal,24
in a single vessel. For the present work, we examined the capa-
bility of the extended one-pot protection–glycosylation strategy
starting from the tetrasilylated starting material 1. N-Iodosuc-
cinimide (NIS) and trifluoromethanesulfonic acid (TfOH)—the
typical activator tandem for thioglycosides—were utilised to
induce building block couplings. Given that protections of
compound 1 generate thioglycoside donors or donor–acceptor
hybrids, we also took advantage of the current understanding
of relative reactivities to form some representative disacchar-
ides and trisaccharides.
Numerous biologically active β-glucans of assorted linkage
patterns occur in Nature.25 The types of linkages found in
these biomolecules are suitable targets in evaluating glycosyla-
tion using a fully protected donor intermediate in one pot.
Accordingly, we decided to synthesise glucan disaccharides
with β1 → 6 and β1 → 4 linkages (Scheme 5). The 1,2-trans gly-
cosidic bond required the installation of an ester group at the
O2 position for neighbouring group assistance. A 4,6-O-benzy-
lidene, on the other hand, is an access point for any further
elongations. Thus, we pursued compound 16 as our glycosyl
donor intermediate. Using our developed procedures, the thio-
glycoside 1 underwent 4,6-O-benzylidenation, reductive 3-O-
benzylation and acidic 2-O-acetylation to afford 16. Then
Scheme 3 Regioselective one-pot synthesis of D-glucosyl triol deriva-
tives. Reagents and conditions: (a) benzaldehyde, cat. TMSOTf, 3 Å
molecular sieves, CH2Cl2, 0 °C, 2 h; (b) BH3·THF, cat. TMSOTf, 0 °C, 5 h;
(c) Me2EtSiH, cat. TMSOTf, CH3CN, 0 °C, 1 h; (d) benzaldehyde, cat.
TMSOTf, 3 Å molecular sieves, CH2Cl2, −78 °C, 2 h; (e) benzaldehyde,
Et3SiH, cat. TMSOTf, −78 °C, 2.5 h; (f) TFA, H2O, rt, 1 h; (g) 2-NaphCHO,
Et3SiH, cat. TMSOTf, −78 °C, 3 h; (h) Ac2O, cat. TMSOTf, 0 °C, 1 h.
cleaved both the benzylidene acetal and the 2-naphthylmethyl
group to furnish the 3,4,6-triol 13 in 53% yield.
In a similar vein as the diacetylated derivatives, we carried
out the preparations of some triacetylated thioglucosides by
applying the same steps used in the previous triol synthesis
(Scheme 4). The 2,3,6-tri-O-acetyl thioglucoside 14 was
obtained from 1 in 77% yield by the 6-O-ring opening of the
initially installed benzylidene acetal followed by full acetyl-
ation. Alternatively, the reverse 4-O-ring opening and full
acetylation supplied the 2,3,4-tri-O-acetyl thioglucoside 15 in
47% yield (3 steps). Again, separate acetylations before and
after the 4-O-benzylidene ring opening supplied 15 in a better
65% yield (4 steps).
Tandem one-pot regioselective protection and glycosylations to
synthesise disaccharides and trisaccharides
The monosaccharide building blocks delivered by our regio-
selective one-pot protection strategy could be used directly as
donors or acceptors in glycosylation. Accommodating glycosy-
lation as an added step in the one-pot process should further
reduce the labour and wastes associated with preparing glycan
Scheme 4 Preparation of fully protected triacetylated thioglucosides.
Reagents and conditions: (a) benzaldehyde, cat. TMSOTf, 3 Å molecular
sieves, CH2Cl2, 0 °C, 2 h; (b) BH3·THF, cat. TMSOTf, 0 °C, 5 h, then,
MeOH, 0 °C, 30 min; (c) Ac2O, Et3N, cat. DMAP, rt, 12 h; (d) Me2EtSiH,
cat. TMSOTf, CH3CN, 0 °C, 1 h; (e) Ac2O, cat. TMSOTf, 0 °C, 12 h; (f)
Ac2O, cat. TMSOTf, 0 °C, 1 h.
Scheme 5 Regioselective one-pot protection–glycosylation towards β1
→ 6 and β1 → 4 glucans. Reagents and conditions: (a) benzaldehyde, cat.
TMSOTf, 3 Å molecular sieves, CH2Cl2, −78 °C, 2 h; (b) benzaldehyde,
Et3SiH, cat. TMSOTf, −78 °C, 2.5 h; (c) Ac2O, cat. TMSOTf, 0 °C, 1 h; (d)
NIS, cat. TfOH, CH2Cl2, −78 °C to 0 °C, 2 h.
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without quenching, glycosylation in one pot was attempted by compound 21 entailed 4,6-O-benzylidenation and reductive
adding methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (17)19a 3-O-benzylation with the usual reagents both carried out at
dissolved in CH2Cl2, followed by NIS and catalytic TfOH. −78 °C. It should be made clear that the structure of the inter-
Because the 6-hydroxyl group of 17 is relatively unhindered, mediate that would act as an acceptor for the ensuing glycosy-
the β1 → 6-linked disaccharide 18 was expected to form easily. lation step is only represented here by 219b,10 as other
Sadly, 18 was obtained only in 21% yield over four steps. Here, equivalent forms present in solution are not ruled out. The
we also isolated the 6-O-acetylated and 6-O-silylated glucoside relative reactivities of these species were not afforded in good
byproducts. Reducing the amount of Ac2O from 1.2 equiv. to confidence, but our measurements26 of related compounds
1.05 equiv. and increasing the amount of 6-alcohol 17 from 1.2 showed that the 4,6-O-benzylidenated thioglucosides27 has
equiv. to 1.5 equiv. under the same one-pot procedure fortu- roughly one order of magnitude lower reactivity than their 4,6-
nately gave the disaccharide 18 in an improved 41% yield. di-O-benzylated counterparts.14b The first donor evaluated is
With a suitable one-pot protection–glycosylation method to the mannoside 22. The tetrabenzylated thiomannoside is more
synthesise the β1 → 6-linked glucan 18, the preparation of the reactive than the tetrabenzylated thioglucoside4c and a silyl
β1 → 4-linked glucan 20 was carried out under identical con- group was already shown to exert arming influence on the
ditions, this time using the 4-alcohol 1919a as an acceptor. In donor wherever it is located.14b Moreover, the tert-butyldiphe-
this case, 20 was obtained in a satisfactory 52% yield (4 steps) nylsilyl (TBDPS) group at O6 could assist in gaining α-selecti-
in one pot.
vity during glycosylation.14e As anticipated, the coupling step
After achieving fully protected donor generation and acti- mediated by NIS and TfOH delivered the desired disaccharide
vation in the presence of a glycosyl acceptor in one pot, the 23 in a one-pot yield of 72% (3 steps). Compound 23 is still
synthesis of an intermediate acceptor followed by glycosylation amenable to further activation to achieve a trisaccharide.
with a donor was next examined. Here, we aimed to make the Thus, the same one-pot protection–glycosylation protocol was
thioglycoside acceptor 21 from compound 1 and then selec- repeated. Additional molecular sieves were added in the pre-
tively activate a donor that also carries a STol leaving group in vious step to ensure a constantly dry solution during the
the same flask (Scheme 6). The success of such coupling assembly. Without quenching, the 6-alcohol 17, NIS, and
depends on familiarity with the relative reactivities between TfOH were added to the mixture, which provided the tri-
the donor and the would-be acceptor. The preparation of saccharide 24 in 52% yield (4 steps).
Scheme 6 Tandem one-pot regioselective protection and glycosylations toward disaccharides and trisaccharides. Reagents and conditions: (a)
benzaldehyde, cat. TMSOTf, 3 Å molecular sieves, CH2Cl2, −78 °C, 2 h; (b) benzaldehyde, Et3SiH, cat. TMSOTf, −78 °C, 2.5 h; (c) NIS, cat. TfOH,
CH2Cl2, AW-300 molecular sieves, −78 °C to −40 °C, 3 h; (d) 17, NIS, cat. TfOH, CH2Cl2, −40 °C to 0 °C, 2 h; (e) NIS, cat. TfOH, CH2Cl2,
AW-300 molecular sieves, −78 °C to −60 °C, 3 h; (f) 17, NIS, cat. TfOH, CH2Cl2, −60 °C to 0 °C, 2 h. The α/β ratios were determined from the 1H
NMR of the crude products.
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acquisition of disaccharide and trisaccharide skeletons using
donors and acceptors prepared in situ. Compared to traditional
stepwise synthesis, which takes several days to weeks, our pro-
tocol, including purification, could be accomplished in several
hours to no more than 2 days. The effectiveness of our
approach was demonstrated by the one-pot synthesis of the
MMG skeleton. As the demand for well-defined carbohydrate
constructs continues to surge, these one-pot methods to oligo-
saccharides should permit the expeditious assembly of core
and peripheral structures and benefit the expansion of the
glycobiology field.
Acknowledgements
This work was supported by the National Science Council
(NSC 100-2113-M-001-019-MY3, NSC 101-2628-M-001-006-
MY3), National Health Research Institutes (NHRI-EX101-
10146NI), and Academia Sinica.
Scheme 7 One-pot synthesis of the MMG skeleton. Reagents and con-
ditions: (a) benzaldehyde, cat. TMSOTf, 3 Å molecular sieves, CH2Cl2,
−78 °C, 2 h; (b) benzaldehyde, Et3SiH, cat. TMSOTf, −78 °C, 2.5 h; (c) 22,
NIS, cat. TfOH, CH2Cl2, AW-300 molecular sieves, −78 °C to −40 °C, 3 h;
(d) NIS, cat. TfOH, CH2Cl2, −40 °C to 0 °C, 2 h.
To achieve β1 → 2-linked disaccharides, the thioglucoside
25 and thiogalactoside 28 having benzoyl groups at their O2
positions were utilised in place of donor 22. Both of these
donors have relative reactivities14b that are expected to be way
higher than that of compound 21. Consequently, the one-pot
protection followed by glycosylation with 25 or 28 in the same
vessel went smoothly and generated the desired β-linked com-
pounds 26 (70%) and 29 (63%), respectively. Extension of the
one-pot process by another glycosylation with acceptor 17 sup-
plied the trisaccharides 27 and 30 in satisfactory yields. These
results show a remarkable capability in targeted manipulation
of the intermediates and their tolerance to the wide range of
materials available in the reaction mixture.
Notes and references
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Following the above strategy, the natural solute α-D-manno-
pyranosyl-(1 → 2)-α-D-glucopyranosyl-(1 → 2)-D-glycerate (MGG)
backbone 32 was synthesised in one pot as depicted in
Scheme 7. The thermophilic bacteria Petrotoga miotherma28
and Petrotoga mobilis29 utilise MMG as a compatible solute
against osmotic and/or thermal stresses. Moreover, MMG was
shown as an effective protector of pig malate dehydrogenase
from heat inactivation and freeze drying.28
A synthetic
approach to MMG was recently reported.30 TMSOTf-catalysed
protection to generate the glycosyl acceptor intermediate, fol-
lowed by selective activation of the thiomannoside 22 gave the
α1 → 2-linked disaccharide 23 as the glycosyl donor for further
coupling. Finally, addition of the glycerate 31,30 NIS, and TfOH
to the reaction mixture delivered the desired MMG skeleton 32
in a one-pot yield of 34% (4 steps).
12 T.-Y. Huang, M. M. L. Zulueta and S.-C. Hung, Org. Lett.,
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382 | Org. Biomol. Chem., 2014, 12, 376–382
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