Desymmetrization of trehalose via regioselective DIBAL reductive ring opening of benzylidene and substituted benzylidene acetals

Article abstract of DOI:10.1039/c3ob41389f

Trehalose dibenzylidene and substituted dibenzylidene acetals were reductively opened either at O6 or O4 in a regioselective manner by using a DIBAL stock solution prepared in toluene or dichloromethane, respectively, to achieve desymmetrization of the trehalose core. The method was applied to synthesize various biologically important unsymmetrically substituted trehalose glycoconjugates, including a mycobacterial trisaccharide, a 4-epi-trehalosamine analog and a maradolipid.

Full text of DOI:10.1039/c3ob41389f

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Desymmetrization of trehalose via regioselective DIBAL
reductive ring opening of benzylidene and substituted
benzylidene acetals†
Cite this: Org. Biomol. Chem., 2013, 11,
6460
Received 6th July 2013,
Accepted 12th August 2013
Vikram A. Sarpe and Suvarn S. Kulkarni*
DOI: 10.1039/c3ob41389f
www.rsc.org/obc
Trehalose dibenzylidene and substituted dibenzylidene acetals Trehalose glycolipids and lipooligosaccharides form an impor-
were reductively opened either at O6 or O4 in a regioselective tant class of biologically active compounds, most of which are
manner by using a DIBAL stock solution prepared in toluene or related to M. tuberculosis1–5 while some are found in fungi and
dichloromethane, respectively, to achieve desymmetrization of worms. These glycoconjugates are challenging synthetic
the trehalose core. The method was applied to synthesize various targets due to their highly amphiphilic character and struc-
biologically important unsymmetrically substituted trehalose tural diversity, which includes additional functional groups,
glycoconjugates, including a mycobacterial trisaccharide, a 4-epi- chiral centres of the side chains and, most importantly, the
trehalosamine analog and a maradolipid.
point of attachments to the trehalose core. Some of them com-
prise a non-symmetrically substituted trehalose core with sub-
stituents attached at O4 or O6. For example (Fig. 1), a
maradolipid 2 was recently isolated6 from C. elegans and it has
been correlated with the dauer larvae resistance. It is the first
diacylated trehalose glycolipid found in the animal kingdom
and also the first 6,6′-unsymmetrically substituted trehalose
glycolipid reported so far.
Trehalose 1 [α-D-Glc-(1 → 1)-α-D-Glc] (Fig. 1) is a C2 symmetric,
non-reducing disaccharide present in several organisms.
Likewise, trisaccharide 3 from M. fortuitum7 and M. smeg-
matis,8 consisting of a β-linked D-glucosyl unit attached to one
of the O6 of the trehalose, is a representative member of a
group of O4/O6 linked trehalose based oligosaccharides which
are thought to impart stability to mycobacteria during stress
and latency. Trisaccharide 3 was earlier isolated from yeast as
well.9 Several trehalosamine derivatives have been evaluated
for their potential antibiotic activity.10,11 The C4 epimer of the
4-amino-4-deoxy-α,α-trehalose 4 is an attractive target.12 Very
recently, a unique trehalose glycolipid fusaroside 5 was iso-
lated13 from an endophytic fungus, Fusarium sp. LN-11. It is
composed of a trehalose unit attached at O4 to the carboxylic
carbon of a rare, branched long-chain fatty acid (C20 : 4) com-
prising a conjugated diene moiety and a conjugated ketone
moiety. Fusaroside 5 has been shown to be moderately active
against brine shrimp larvae. Similarly, several other unsymme-
trical trehalose glycoconjugates are shown to be involved in a
wide range of biological activities.1,2
Fig. 1 Various biologically important glycans containing unsymmetric treha-
lose core.
Synthesis of unsymmetrically substituted trehalose glyco-
conjugates is a formidable task as it requires either the
differentiation of eight hydroxyl groups of trehalose 15 or
stereoselective construction of 1,1-α,α-linkage between the two
appropriately protected glucose units.14 Installation of this
α,α-1,1-linkage via coupling of protected D-glucose derivatives
Department of Chemistry, Indian Institute of Technology Bombay, Powai,
Mumbai-400076, India. E-mail: suvarn@chem.iitb.ac.in; Fax: (+)(91-22) 2576 7152;
Tel: (+)(91-22) 2576 7166
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ob41389f
6460 | Org. Biomol. Chem., 2013, 11, 6460–6465
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is very difficult, as not one but two anomeric linkages are the regioselectivity of the DIBAL reductive ring opening can be
formed simultaneously. To tackle this problem, Bertozzi and controlled by using DIBAL stock solutions prepared in
coworkers developed an intramolecular aglycon delivery (IAD) different solvents. Thus, in the case of methyl 2,3-di-O-benzyl-
approach for stereoselective formation of α,α-1,1-linkage.15,16 4,6-benzylidene-α-D-glucoside, the reaction with DIBAL in
An alternative approach is to use commercially available treha- toluene gives predominantly the corresponding 6-OH product,
lose. However, desymmetrization of the C2 symmetrical disac- whereas the 4-OH product was obtained as a major product
charide trehalose 1 via regioselective protection is again a when the same reaction was carried out in dichloromethane
challenge. Most of the trehalose glycoconjugates have modifi- stock solution. With this background, we conducted a series of
cations at C4 or C6 positions of trehalose. A number of experiments on trehalose di-benzylidene acetals. Our results
methods have been reported for selective O6 mono-protection indicate that by carefully tuning the temperature conditions
of trehalose5,17–21 whereas reports on selective O4 and equivalents of the DIBAL stock solution prepared in
functionalization22–24 are rare and involve longer protection toluene or dichloromethane, desymmetrization of the C2 sym-
deprotection sequences.
metric trehalose core can be achieved to access the 4-OH or
Regioselective reductive ring opening of 4,6-O-benzylidene 6-OH trehalose derivatives, respectively.
and substituted 4,6-O-benzylidene acetals is routinely used to
We began our experiments with the known di-O-benzyl-
obtain the 6-OH or 4-OH derivatives of various sugars.25–34 We idene derivative 639 (Scheme 1) which was conveniently pre-
envisioned that a selective ring opening of only one of the 4,6- pared by di-benzylidenation of trehalose 1,40 followed by
O-benzylidene groups of the trehalose dibenzylidene acetals, benzylation (90%, 2 steps). A systematic study of the regioselec-
carried out under controlled conditions, would give access to tive ring opening of 6 using DIBAL in toluene or dichloro-
unsymmetrically substituted trehalose derivatives. Although methane to obtain the corresponding 6-OH 7 and 4-OH 8 was
seemingly straightforward, this approach has not been devel- conducted first. The regioselectivity of ring opening was deter-
oped for desymmetrization of trehalose. As such, there are only mined by analyzing the 2D NMR spectra of 7 and 8. Their
a few reports on the reductive ring opening of symmetrical COSY spectra showed a correlation of the OH proton with
4,6,4′,6′-di-O-benzylidene derivatives of trehalose to obtain the either H6 or H4. This was also confirmed by carrying out the
corresponding symmetric diols.11,16,35–37 For the mono- acetylation of 6-OH 7 and 4-OH 8 and observing the downward
opening of bis-acetals, Wessel and Minder reported that in the movement of two (CH2) or one (CH) proton in 1H NMR, by
case of an unsymmetrical 3-deoxy 4,6,4′,6′-di-O-benzylidene ∼0.5 or 1.5 ppm, respectively. This general procedure was fol-
trehalose derivative, the benzylidene acetal close to the deoxy lowed for characterization of all the ring opening products
centre is found to be more reactive under NaCNBH3/HCl con- reported in the study (see ESI†). The reaction conditions and
ditions, leading to the corresponding 4-OH (51%) as a major results are summarized in Table 1. First, compound 6 in
product along with the minor 6-OH (22%).38 However, this toluene was treated with 10 equiv. of 1.5 M DIBAL (supplied as
method does not apply to naturally occurring C2 symmetric a 25 wt% stock solution in toluene) at −10 °C (entry 1). The
trehalose. Recently, Bertozzi and coworkers observed that the starting material was consumed in 1 h and two new, clearly
reaction of a 4,6,4′,6′-di-O-dibenzylidene derivative with the separable spots were seen on TLC, the proportion of which
NaCNBH3–TfOH combination led to an inseparable mixture of remained unchanged even after 24 h. From this reaction, we
4-mono and 4,4′-di opened products in modest yields.35 To obtained the non-symmetric 6-OH derivative 7 in 61% yield
the best of our knowledge, there are no reports on the regio- along with the C2 symmetric 6,6′-di-OH trehalose derivative 941
selective O6 mono-opening of trehalose dibenzylidene acetals. (29%). In order to suppress the formation of 9, resulting from
Herein, we present the first systematic study to establish the ring opening of the second benzylidene acetal, the reaction
the reaction conditions of regioselective DIBAL reductive ring was conducted at −18 °C using 8 equiv. DIBAL (entry 2).
opening of benzylidene and substituted benzylidene acetals Although this reaction generated the 6-mono opened product
of trehalose to give facile access to the corresponding 7 exclusively, it was sluggish and led to the recovery of the
6-OH or 4-OH derivatives of trehalose. Application of this
method to the synthesis of trehalose glycoconjugates 2–4 is
demonstrated.
From the array of reagent combinations available for the
ring opening of benzylidene acetals, we opted for DIBAL owing
to its operational simplicity and the flexibility to change the
course of the reaction to obtain either 6-OH or 4-OH deriva-
tives by merely changing the solvent and temperature con-
ditions. Takano et al.32 first employed DIBAL for the regio-
selective ring opening of benzylidene acetals. Subsequently,
Mitsunobu and coworkers33 extended these studies to carbo-
hydrates and found that the bulk and orientation of the C3
protecting group play a crucial role in determining the mode
of regioselection. Nokami and coworkers34 further showed that Scheme 1 Preparation and ring opening of trehalose dibenzylidene acetal 6.
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Table 1 Regioselective ring opening of benzylidene acetal in 6
Yield (%)
Entry
Reagent (equiv.)
DIBAL (equiv.)
Solvent (mL per 0.1 g)
T (°C)
Time (h)
6
7
8
9
1
DIBAL in toluene
DIBAL in toluene
DIBAL in toluene
DIBAL in toluene
DIBAL in CH2Cl2
DIBAL in CH2Cl2
DIBAL in CH2Cl2
10
8
8
5
5
5
5
Toluene
Toluene
Toluene
Toluene
Neat
Neat
Neat
−10
24
5
1
1.5
1
1
—
36
—
—
—
—
90
61
40
78
89
70
25
—
—
—
—
—
—
60
Trace
29
—
19
Trace
14
2
−18
3a
4a
5
−18 to rt
−18 to rt
rt
6
7
0
—
—
−18 to −10
1
a DIBAL was added at −18 °C and the reaction was immediately moved to rt.
unreacted starting material to the extent of 36%. There was no obtained using similar conditions from trehalose 1 in excellent
progress in the reaction after 1 h. To alleviate the reactivity, the yield (93%, 2 steps). The results of the regioselective DIBAL
DIBAL addition was carried out at −18 °C and the reaction was reductive ring opening of p-methoxybenzylidene acetals in 10
immediately moved to rt. Under these conditions the desired 7 are summarized in Table 2. Since p-methoxybenzyl (PMB)
was obtained in 78% yield but the di-opened product 9 (19%) ethers are more electron donating, as anticipated, compound
was encountered again as a minor product (entry 3). Finally, 10 proved to be more reactive than 6. Thus, reaction of 10 with
reducing the amount of DIBAL to 5 equiv. under the same con- 1.5 M DIBAL (supplied as 25 wt% in toluene) under the con-
ditions circumvented the formation of the di-opened product ditions earlier optimized for 6 for selective mono opening
giving 7 in 89% yield (entry 4). With such success in selective (−18 °C to rt, 1.5 h) in fact furnished the diol 12 (90%) in a
O6 mono opening of 6, we turned our attention to the rapid manner (entry 1). Conducting the same reaction with a
O4 mono opening. We first conducted the ring opening reac- lesser amount of DIBAL (3 equiv.) allowed isolation of the
tion using DIBAL stock solution (1 M in dichloromethane) at desired 6-OH 11 (34%) along with major 6,6′-diol (61%) (entry 2).
rt. To our surprise, the reaction generated the 6-opened The best results were obtained when the DIBAL (3 equiv.)
product 7 (70%) along with the 6,6′-diol 9 (14%). However, the addition was carried out in an ice-salt bath at −18 °C and the
regioselectivity of the reaction was reversed when the same reaction was quenched after 15 min without moving it to rt.
reaction was conducted at 0 °C (entry 6) leading to 4-OH 8 Under these conditions, the desired 6-OH 11 was obtained in
(60%) as a major product and 6-OH 7 (25%) as a minor 83% yield (entry 3). Our attempts to open the PMP acetal in 10
product. Further reducing the reaction temperature to −18 °C in an O4 selective manner, however, met with little success
to −10 °C did not help and the starting material was recovered (entries 4–6). The corresponding 4-OH compound could not be
to the extent of 90% (entry 7). Compound 8 had been prepared obtained; instead 11 and 12 were generated each time. The
earlier in 25% overall yield from 6 via regioselective benzylidene reaction was too sluggish at −78 °C to allow any conversion.
hydrolysis followed by tin mediated benzylation.24 1H NMR
We next tested the 2-naphthylidene acetal 14 which was
data of 8 was in complete agreement with the reported data.
efficiently prepared from the known per-O-TMS trehalose
In order to expand the scope of the reaction, we turned our 1336,42 via bis-naphthylidenation using 2-naphthaldehyde and
attention to the substituted benzylidene acetals. For this TMSOTf43 catalyst followed by removal of TMS groups using
purpose, the p-methoxybenzylidene acetal 10 (Scheme 2) was TBAF and its subsequent PMB protection in excellent yield
(Scheme 3). The reaction conditions and results of the
naphthylidene ring opening reactions of 14 with DIBAL in
toluene or CH2Cl2 to access the corresponding 6-OH 15 and
4-OH 16 are summarized in Table 3. The conditions earlier opti-
mized for the benzylidene acetal 6 equally worked well for the
6-opening of acetal in 14 using 1.5 M DIBAL in toluene
(5 equiv., −18 °C to rt, 1 h) leading to the desired 6-OH 15 in
81% yield (entry 1). For the O4 opening of acetal in 14, 1 M
DIBAL in CH2Cl2 was added at 0 °C. However, this reaction
afforded 6-OH 15 in 76% yield. Conducting the reaction at
−20 °C led to generation of the 4-OH 16 in minor amounts
along with major 6-OH 15. The best results were obtained
when the reaction was conducted at −30 °C (entry 4) giving the
desired 4-OH 16 (52%) as a major product along with 6-OH 15
(8%) in minor proportions; substantial starting material was
Scheme 2 Preparation and ring opening studies of Di-PMP acetal 10.
6462 | Org. Biomol. Chem., 2013, 11, 6460–6465
recovered (29%).
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Table 2 Regioselective ring opening of p-OMe-benzylidene acetal in 10
Yield (%)
Entry
Reagent (equiv.)
DIBAL (equiv.)
Solvent (mL per 0.1 g)
T (°C)
Time (h)
11
12
1a
2a
3
DIBAL in toluene
DIBAL in toluene
DIBAL in toluene
DIBAL in CH2Cl2
DIBAL in CH2Cl2
DIBAL in CH2Cl2
5
3
3
3
3
3
Toluene
Toluene
Toluene
Neat
Neat
Neat
−18 to rt
−18 to rt
−18
1.5
1.5
0.25
0.5
0.75
2
—
34
83
38
25
—
90
61
Trace
45
60
4
0
5
−45
−78
6b
—
a DIBAL was added at −18 °C and the reaction was immediately moved to rt. b Starting material was recovered quantitatively.
Table 3 Regioselective ring opening of 2-Naph acetal in 14
Yield (%)
Entry
Reagent (equiv.)
DIBAL (equiv.)
Solvent (mL per 0.1 g)
T (°C)
Time (h)
14
15
16
1a
2
3
DIBAL in toluene
DIBAL in CH2Cl2
DIBAL in CH2Cl2
DIBAL in CH2Cl2
5
5
5
5
Toluene
Neat
Neat
−18 to rt
0
−20
−30
1
1.5
2
2
7
—
—
29
81
76
53
8
—
—
28
52
4
Neat
a DIBAL was added at −18 °C and the reaction was immediately moved to rt.
Recent mechanistic studies44–46 have indicated that the
regioselectivity of the ring opening reaction depends on a
complex interplay of several factors including the solvent,
temperature, time, steric factors and the nature of the reducing
agent as well as the Lewis acid catalyst.31 The exact reasons for
the observed reversal of selectivity, upon changing the solvent,
in the absence of Lewis acid, remain obscure. From a purely
practical point of view, this study gives rapid access to the
6-OH (7, 11 and 15) and 4-OH (8 and 16) derivatives of treha-
lose in which a benzylidene or substituted acetal is present at
one terminus and the remaining hydroxyls are protected as
benzyl or substituted benzyl ethers. These unsymmetrically
substituted derivatives can be used for synthesizing a variety
of trehalose glycoconjugates as exemplified by the synthesis
of 2–4.
Scheme 4 Synthesis of a 4-epi-trehalosamine analog.
Scheme 4 delineates a short synthesis of the 4-epi-trehalos-
amine analog 4 from 8. The 4-OH group of 8 was converted
into a mesylate group, which was subsequently displaced by
sodium azide to obtain the 4-azido trehalose derivative 17
Hydrogenolysis of 17 furnished the 4-amino trehalose deriva-
tive 4 which was characterized as its per-acetate derivative 18.
The structure of compound 18 was confirmed by comparison
of its 1H NMR and 13C NMR with the literature data.12
An efficient synthesis of the trisaccharide 3 found in Myco-
bacterium smegmatis,7 Mycobacterium fortuitum8 and yeast9 is
presented in Scheme 5. Known D-glucosyl per-O-benzoate 19
was first converted into the corresponding glycosyl bromide
20, which was coupled as such with 6-OH 7 as an acceptor
using silver triflate as a promoter to afford the protected trisac-
charide 21 (91%). Hydrogenolysis followed by debenzoylation
afforded the target trisaccharide 3 in excellent yields. The spec-
tral data of 3 were in perfect agreement with the data of the
isolated one.9 Compound 3 has been earlier synthesized by a
different route.47
(79%,
2 steps) with inversion of configuration at C4.
Scheme 3 Preparation and ring opening of Di-2-Naph acetal 14.
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fusaroside 5. Efforts in this direction are currently underway in
our laboratory.
Conclusions
In conclusion, we have established the conditions for desym-
metrization of the trehalose core via DIBAL reductive ring
opening of benzylidene and substituted benzylidene acetals,
for the first time, by controlling the reagent stoichiometry,
solvent and temperature. The methodology is applied for the
synthesis of unsymmetrically substituted trehalose glycolipids
and oligosaccharides. The short and convenient method
would certainly find its use in the synthesis of complex treha-
lose glycoconjugates.
Scheme 5 Synthesis of trisaccharide 3.
Maradolipid 2 has gained considerable attention from the
synthetic community since its isolation in 2010.6 We reported
the first synthesis of 242 using regioselective acylation of the
6,6′-diol trehalose hexa-O-TMS derivative as a key step. Sub-
sequently, other groups reported the syntheses of 248–50 and its
thioglycoside analog51 along similar lines employing regiose-
lective acylation as a symmetry breaking step. Herein we report
a conceptually different route for synthesis of compound 2
using regioselective reductive ring opening of PMB acetal as a
key step (Scheme 6). Benzyl groups are rendered unsuitable for
the synthesis of trehalose glycolipids containing lipid chains
with unsaturation, because the double bond and the acyl func-
tion are susceptible to hydrogenolysis or Birch reduction con-
ditions, respectively. PMB groups on the other hand are
orthogonal to these functionalities, as they can be easily
cleaved under oxidative conditions by using CAN or DDQ.
Accordingly the 6-OH 11 was acylated with oleic acid using
DCC and DMAP to obtain 22 (83%). The p-methoxybenzylidene
acetal in 22 was selectively hydrolyzed using 80% acetic acid
and the freed 4,6-diol was regioselectively acylated with
13-methyl myristic acid under DCC conditions to afford 23 (65%).
The PMB groups in 23 were removed using DDQ in a facile
manner to deliver a maradolipid 2. The data of 2 corroborated
well the earlier reported data of the maradolipid.6,42 It is
expected that coupling of the 4-OH derivative 16 with the
appropriate long chain acid can be utilized for the synthesis of
Acknowledgements
This work was supported by the Department of Science and
Technology (grant no. SR/S1/OC-40/2009). V. A. S. thanks the
CSIR-New Delhi for a fellowship.
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