Stereoselective Synthesis of 2-(β-C-Glycosyl)glycals: Access to Unusual β-C-Glycosides from 3-Deoxyglycals

Article abstract of DOI:10.1021/acs.joc.5b02879

A novel method for the highly stereoselective synthesis of β-(1→2)-C-saccharides employing 3-deoxy- and 3-C-branched glycals as hermaphroditic substrates is revealed. The generality of the C-C bond formation reaction between the two sugar units is evaluated. The developed methodology is successfully applied to the synthesis of biologically significant subunits that are present in various natural products, which include mixed C-disaccharides with adjacent THP-THF rings, C-aryl glycosides, and highly functionalized β-C-glycosides.

Full text of DOI:10.1021/acs.joc.5b02879

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Article
Stereoselective synthesis of 2-(beta-C-glycosyl)-glycals: An
access to the unusual beta-C-glycosides from 3-deoxy-glycals
Gadi Madhusudhan Reddy, Boddu Uma Maheswara Rao, and Perali Ramu Sridhar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02879 • Publication Date (Web): 29 Feb 2016
Downloaded from http://pubs.acs.org on February 29, 2016
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Stereoselective synthesis of 2ꢀ(βꢀCꢀglycosyl)ꢀglycals: An access to the unusual βꢀCꢀ
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glycosides from 3ꢀdeoxyꢀglycals
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Gadi Madhusudhan Reddy, Boddu Uma Maheswara Rao and Perali Ramu Sridhar*
School of Chemistry, University of Hyderabad, Hyderabad – 500 046, INDIA
p_ramu_sridhar@uohyd.ac.in
ABSTRACT
A novel method for the highly stereoselective synthesis of βꢀ(1→2)ꢀCꢀsaccharides employing 3ꢀ
deoxy and 3ꢀCꢀbranched glycals as hermaphroditic substrates is revealed. The generality of the
CꢀC bond formation reaction between the two sugar units is evaluated. The developed
methodology is successfully applied to the synthesis of biologically significant subunits that are
present in various natural products, which include mixed Cꢀdisaccharides with adjacent THPꢀ
THF rings, Cꢀaryl glycosides and highly functionalized βꢀCꢀglycosides.
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Introduction
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The stability of Cꢀglycosides1 to the acids and carbohydrate processing enzymes had attracted
many synthetic organic chemists and biologists worldwide for their exploration as potential
mimics to the biologically active Oꢀglycosides.2 This has intensified the search for new Cꢀ
glycosidic structures for the discovery of potential drug candidates in the treatment of various
diseases and immunological disorders.3
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Reaction of glycals with carbon nucleophiles in the presence of a Lewis acid is one of the most
widely used method for the synthesis of 2,3ꢀunsaturataed Cꢀglycosides.1g Recently, palladium
catalyzed Heckꢀtype glycosylation of glycals4 and allylic alkylation5 have also been reported.
However, very few methodologies are available for the synthesis of Cꢀsaccharides,6
disaccharides and higher homologues, owing to the difficulties associated in their preparation.
Compared to Oꢀglycosides, absence of exoꢀanomeric effect and the nonꢀpredominant
neighbouring group participation are the major drawbacks in the stereoselective synthesis of Cꢀ
glycosides.7 Further, selective modification of one of the sugar parts in Cꢀsaccharides is an
arduous and important task for the transformation of Cꢀsaccharides to complex glycosides,
natural products and biologically important skeletons. The insufficient availability of pure Cꢀ
glycosidic compounds from the natural sources to study their biological profile provided a strong
motivation for the development of synthetic approaches using abundant natural sugars and their
derivatives.
Our investigation towards the synthesis of Cꢀsaccharides started from the observation of 3,4,6ꢀ
triꢀOꢀacetylꢀ
D
ꢀglucal 1 dimerization using BF3.Et2O to provide the 2,3ꢀunsaturated αꢀ(1→2)ꢀCꢀ
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disaccharide 3 in moderate yield.8 This reaction is feasible only in presence of an effective
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leaving group at the Cꢀ3 position of a glycal. On the other hand, 3,4,6ꢀtriꢀOꢀbenzylꢀDꢀglucal 2
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was reported to provide the benzyl glycoside 49 under similar reaction conditions. Interestingly,
using acetyl perchlorate as the Lewis acid, glucal 2 was converted to the bicyclicꢀacetal 5
through an unprecedented 1,7ꢀhydrogen shift10 (Scheme 1).
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Scheme 1: Reactivity of glycal under Lewis acid conditions.
Surprisingly, to the best of our knowledge, there was no report documented in the
literature on the reactivity of 3ꢀdeoxy glycals under Lewis acid conditions. The probable
reason might be due to the unpredictability in the formation and the fate of the formed
oxocarbenium ion in 3ꢀdeoxyꢀglycals. These observations made us curious to investigate the
reactivity of 3ꢀdeoxy glycals in presence of a Lewis acid. We envisaged that the presence of a
leaving group at Cꢀ3 position might facilitate the Ferrier rearrangement11 but, its absence
might not hinder the general electrophilic addition reaction to give
Cꢀsaccharides.
Additionally, the reaction could be driven stereoselectively by the substituents present at
C4 and C5 via stabilizing the generated oxocarbenium ion intermediate. Thus, herein, we
report the reactions of 3ꢀdeoxy glycals, under a Lewis acid, to produce 2ꢀ(βꢀCꢀglycosyl)ꢀ
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glycals or βꢀ(1→2)ꢀCꢀsaccharides (Scheme 1) in an unusual and highly stereoselective
fashion. Further, we also reveal the selective modification of a single sugar unit of the
synthesized novel Cꢀsaccharides to obtain various biologically important Cꢀglycoside
architectures.
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Results and Discussion
To obtain the appropriately protected 3ꢀdeoxy glycal derivative, 3ꢀCꢀbranched glycal 612 was
reduced to the alcohol 7 followed by benzylation provided the glycal 8. When 3ꢀdeoxyꢀ3ꢀCꢀ
branched glycal 8 in anhydrous CH2Cl2 upon treating with BF3.Et2O (1 equiv.) at ꢀ50 oC, most of
the starting material was consumed and a new compound, which is slightly more polar than
glycal 8, and a complex polar mixture at the bottom of the TLC were observed. On structural
analysis, the new compound was found as the diastereomerically pure βꢀ(1→2)ꢀCꢀdisaccharide 9
(65% isolated yield, Scheme 2). The stereochemistry at the anomeric center was assigned based
on positive correlation between Hꢀ1/Hꢀ5 in 2DꢀNOSEY experiment. 13 (Scheme 2).
Scheme 2. Lewis acid mediated dimerization of 3ꢀdeoxy 3ꢀCꢀbranched glycal.
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Exhilarated by this result, the formation of disaccharide 9 was examined under various Lewis
acid conditions at different temperatures (Table 1). Trifluoromethanesulfonates of Sc, Ag and Cu
were found to be ineffective in catalyzing the reaction at ꢀ78 oC. However, the reaction of 8 with
1 equiv. of Sc(OTf)3 at 0 oC afforded 9 in 68% yield. Whereas, AgOTf and Cu(OTf)2 were found
to be
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Table 1. Lewis acid catalyzed electrophilic addition of glycals.
[a] Yield refers to the pure isolated product. [b] Recovered starting material. [c] Equiv. calculated by w%.
o
ineffective from ꢀ78 C to room temperature (Table 1, Entry 2ꢀ4). Gratifyingly, when the
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reaction was conducted using 0.3 equiv. of TMSOTf at ꢀ78 C in anhydrous CH2Cl2 provided
90% of 9 as a single diastereomer (Table 1, Entry 5). Although, the reaction proceeded with
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Montmorillonite K10 at room temperature, the yield was found to be only 60% (Table 1, Entry
6). Lewis acids InCl3 and BiCl3 were found to be ineffective in catalyzing the reaction even at 25
oC (Table 1, Entry 7ꢀ8). Therefore, catalytic TMSOTf was preferred to be the better Lewis acid
for the electrophilic addition of deoxyꢀglycals to produce βꢀ(1→2)ꢀCꢀsaccharides.
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In contrast to the carbonꢀFerrier rearrangement1g of glycals, which mostly produce 2,3ꢀ
unsaturated αꢀCꢀglycosides, it is surprising to observe the exclusive formation of 2ꢀ(βꢀCꢀ
glycosyl)ꢀglycals from 3ꢀdeoxy glycals under various Lewis acid conditions. The formation of
the single diastereomer 9 from 8 could be explained by considering the approach of the
nucleophile towards the substituted tetrahydropyran derived oxocarbenium ion. Glycal derived
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oxocarbenium ions will adopt halfꢀchair conformations of H4 and H3.14 Mostly, nucleophiles
are likely to approach the cation in a pseudoaxial trajectory to attain the maximum orbital
overlap.15 In the case of 4H3 conformer 10, the approach of nucleophile suffers from unfavorable
1,3ꢀdiaxial interactions between the Cꢀ3 substituent and the incoming nucleophile. Similarly, in
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the case of H4 conformer 11, 1,3ꢀdiaxial interactions between the incoming nucleophile and the
Cꢀ6 substituent hinders the nucleophilic approach. However, due to the electrostatic stabilization
of oxocarbenium ions by axial 4ꢀOBn,14 the reaction proceeds through the oxocarbenium ion
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possessing the H4 conformation to provide exclusively the βꢀ(1→2)ꢀCꢀdisaccharide 13 (Figure
1).
Figure 1. Halfꢀchair conformers of glycal derived oxocarbenium ions and preferred nucleophilic
approach to provide the corresponding glycosides.
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After having the optimized reaction conditions in hand, the substrate scope of the reaction was
investigated. Thus, 3ꢀdeoxy 3ꢀCꢀbranched glycals 15 and 18 were synthesized by benzylation of
the corresponding alcohols 14 and 1712 respectively, and subjected to catalytic TMSOTf
mediated electrophilic addition reaction. Both the glycals underwent a smooth dimerization
reaction providing the diastereomerically pure βꢀ(1→2)ꢀCꢀdisaccharides 16 and 19, respectively,
in good yield (Scheme 3).
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Scheme 3: Synthesis of βꢀ(1→2)ꢀCꢀdisaccharides derived from 3ꢀdeoxyꢀ3ꢀCꢀbranched sugars.
To investigate the regioselectivity of the endocyclic double bond over an isolated olefin as well
as an electron deficient olefin, compounds 21 and 23 were synthesized. Thus, the 3ꢀCꢀbranched
glycal aldehyde 6 was treated with vinylmagnesium bromide followed by acetylation to provide
the allyl acetate substituted glycal 20. On the other hand, Wittig olefination16 of 6 provided the
α,βꢀunsaturated ester derived glycal 22. Subjecting compounds 20 and 21 to TMSOTf mediated
CꢀC bond formation reaction afforded the βꢀ(1→2)ꢀCꢀdisaccharides 21 and 23, respectively, as
the only products in which the isolated olefins were intact (Scheme 4). This study clearly
supports the requirement of an oxocarbenium ion formation for the reaction to proceed.
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Scheme 4: Synthesis of βꢀ(1→2)ꢀCꢀdisaccharides in presence of an external olefin.
Subsequently, to study the importance of the steric effects, 3ꢀdeoxy glycals17 such as 24 and 26
were synthesized and subjected to the optimized Cꢀdisaccharide formation reaction conditions.
Interestingly, in the absence of the 3ꢀCꢀbranch (ꢀCH2CH2OBn), both the glucose and galactose
derived 3ꢀdeoxy glycals 24 and 26 provided exclusively the βꢀ (1→2)ꢀCꢀdisaccharides 25 and
27, respectively in good yield. These results provide sufficient evidence that the electrostatic
effect is mainly driving the stereochemical outcome of the reaction. Additionally, to explore the
inherited glycalic double bond present in the formed disaccharide, towards the formation of a
trisaccharide, glycal 24 was loaded in gram scale and subjected to TMSOTf (0.3 eq) in CH2Cl2.
Excitingly, the βꢀ(1→2)ꢀCꢀβꢀ(1→2)ꢀCꢀtrisaccharide 28 was isolated in 15% yield as a single
diastereomer along with the disaccharide 25 in 65% yield (Scheme 5).
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TMSOTf (0.3 equiv.)
OBn
OBn
O
OBn
4 Å MS, CH2Cl2
O
OBn
O
BnO
-78 oC, 86%
BnO
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OBn
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TMSOTf (0.3 equiv.)
4 Å MS, CH2Cl2
OBn
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BnO
BnO
OBn
OBn
O
O
-78 oC, 88%
O
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27
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OBn
TMSOTf (0.3 equiv.)
4 Å MS, CH2Cl2
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BnO
-78 oC
O
24 (6.4 mmol
25 (65%)
scale)
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Scheme 5: TMSOTf catalyzed stereoselective synthesis of βꢀ(1→2)ꢀCꢀdisaccharides from 3ꢀ
deoxy glycals.
To investigate the mechanism of the reaction, the deuterated 3ꢀdeoxy glucal 31 was planned to
synthesize from the deuterated glucal derivative 29.18 Thus, Ferrier rearrangement of deuterated
glucal 29 with ethanol provided the 2,3ꢀunsaturated glycoside 30. Deprotection of the acetyl
groups followed by subjecting the obtained diol to LAH17 under reflux conditions provided the
3ꢀdeoxyglucal which was benzylated to afford the required deuterated 3ꢀdeoxy glucal derivative
31. Subjecting 31 to TMSOTf mediated Cꢀsaccharide formation reaction provided the
deuterated Cꢀdisaccharide 32 in 60% yield and deuterated Cꢀtrisaccharide 33 in 30% yield
(Scheme 6). The increased yield in the formation of Cꢀtrisaccharide 33 could be attributed due to
the kinetic isotopic effect. The formation of diꢀdeuterated Cꢀdisaccharide 32 clearly indicates
that the hydrogen present at the 2ꢀposition of the starting 3ꢀdeoxy glucal 31 is the source of the
H+ in the Cꢀsaccharide formation.
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Scheme 6: Synthesis of isotope labelled di and trisaccharides from the deuterated 3ꢀdeoxy
glucal.
Based on the above observations, a possible mechanism is proposed for the formation of βꢀCꢀ
disaccharide under TMSOTf catalysis conditions (Figure 2). Accordingly, glucal 31 upon
reaction with TMSOTf could form the 2ꢀtrimethylsilyl glucal derivative 34 and TfOD. Addition
of TfOD on glucal 31 would lead to the formation of oxocarbenium ion intermediates 35a and
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35b possessing H3 and H4 conformations, respectively. Approach of the 34 on to the
intermediate 35b, which is stabilized by the stereoꢀelectronic effect due to the presence of 4ꢀOBn
in pseudoꢀaxial position, in an axial trajectory would provide the disaccharide derived
oxocarbenium ion intermediates 36a and 36b. On regeneration of the catalyst, TMSOTf, would
provide the observed C-disaccharide 32. Akin, uninterrupted addition of another molecule of 34
on 32 followed by termination would provide the Cꢀtrisaccharide 33 (Figure 2).
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Figure 2. Proposed mechanism for the βꢀCꢀsaccharide formation.
To further demonstrate the importance of the novel oneꢀstep Cꢀsaccharide formation from 3ꢀ
deoxy glycals, we turned our attention to explore the synthetic applications of glycalic double
bond in the synthesized 2ꢀ(βꢀCꢀglycosyl)ꢀglycals. In this context, annonaceous acetogenins are a
class of natural products isolated from the Annonaceae species and they have been highly
recognized for their potent biological properties, most importantly hailed for their cytotoxicity.19
An important subclass of these natural products possess the carbon linked adjacent THPꢀTHF
rings, for example jimenezin (37), muconin (38) (Figure 3) etc.
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Figure 3: Cytotoxic annonaceous acetogenins from Rollinia mucosa seeds.
Various groups had previously reported the total synthesis of these natural products but, using a
multiꢀstep protocol for the formation of adjacent bicyclic core skeleton (adjacent THPꢀTHF
rings).20 However, we had planned to convert the obtained 2ꢀ(βꢀCꢀglycosyl)ꢀglycals to the core
skeletons present in these natural products in comparatively less synthetic steps. Towards this,
compounds 9, 25 and 27 were subjected to ozonolysis12a,21 followed by deformylation with
OBn
OBn
OBn
OBn
HO
O
O
O
O
A
B
9
BnO
BnO
BnO
BnO
OBn
OBn
OBn
OBn
40 (90%)
39 (85%)
OBn
OBn
OBn
OBn
HO
O
O
O
O
A
A
B
B
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27
BnO
OBn
BnO
OBn
OBn
OBn
OBn
OBn
41 (91%)
42 (98%)
HO
O
O
O
O
BnO
BnO
OBn
OBn
43 (80%)
44 (92%)
Condition A: i) O3, CH2Cl2,DMS, -78 oC, ii) NaHCO3, MeOH
Condition B: i) Et3SiH, BF3.OEt2, -78 oC, CH2Cl2
Scheme 7: Synthesis of a mixed Cꢀdisaccharides possessing adjacent THPꢀTHF rings.
NaHCO3 in MeOH to provide the Cꢀdisaccharide derived hemiꢀketals 39, 41 and 43 in good
yield.22 These hemiꢀketals upon dehydroxylation with Et3SiH and BF3.Et2O afforded the targeted
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βꢀ(1→2)ꢀCꢀpyranofuranosides or adjacent THPꢀTHF rings 40, 42 and 44, respectively, as single
diastereomers (Scheme 7).6h Further, functional group modification of these adjacent THPꢀTHF
rings to natural acetogenins and their analogs is in progress.
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The stereochemistry at the newly formed stereocentre in the obtained adjacent THPꢀTHF rings
was assigned based on the 2D COSY and NOESY experiment. For example, in the case of
compound 42, positive correlations between Hꢀ1/Hꢀ5, Hꢀ1/Hꢀ3, Hꢀ1'/Hꢀ4' were observed (Figure
4)13. The stereochemistry for the other two bicycles were assigned based on the COSY and
NOESY correlations and their spectra are presented in the supporting information.
Figure 4: Through space correlations observed in compound 42 using 2D NOESY experiment.
Another important subclass of Cꢀglycoside family of natural products is Cꢀaryl glycosides which
are known for their antibiotic properties.23 Therefore, a notable approach, from βꢀ(1→2)ꢀCꢀ
saccharides, for the synthesis of βꢀCꢀaryl glycosides with functionalized furan moieties would be
very interesting. Towards this, the hemiꢀketal derivatives 41 and 43 were treated with
trifluoroacetic acid in CH2Cl2 to provide the corresponding βꢀCꢀglycosyl furan derivatives 45
and 46, respectively, in excellent yield (Scheme 8).24 On the other hand, methodologies to
synthesize the densely functionalized Cꢀglycosides1 is of great importance because of their high
structural resemblance to the pharmacologically undermined glycolipids. Hence, NaBH4
mediated reduction of the hemiꢀketal 43 provided the highly functionalized βꢀCꢀglycoside 47 as
a single diastereomer in excellent yield (Scheme 8).
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Scheme 8. Synthesis of βꢀCꢀglycosyl furans and βꢀCꢀglycosides from Cꢀdisaccharide
derivatives.
Conclusion
In conclusion, a facile protocol for the highly stereoselective synthesis of βꢀ(1→2)ꢀCꢀsaccharides
or 2ꢀ(βꢀCꢀglycosyl)ꢀglycals by TMSOTf mediated dimerization of 3ꢀdeoxy glycals is revealed.
The generality and the stereoselectivity for the βꢀCꢀsaccharide formation is investigated. In
addition, the developed methodology was extended to prepare a diversity of mixed Cꢀ
disaccharides, Cꢀglycosyl furans and a highly functionalized βꢀCꢀglycoside. Further functional
group transformations to achieve the total synthesis of bioꢀactive natural products is in progress.
Experimental Section
General Methods: All reactions were carried out under an inert atmosphere with dry solvents
under anhydrous conditions unless otherwise mentioned. Dichloromethane, methanol, THF,
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dimethoxyethane, dichloroethane, dioxane, and DMF were initially dried and stored in suitable
conditions. TLC was run on silica gel 60 F254 plates, and the spots were detected by staining
with H2SO4 in methanol (5%, V/V) or phosphomolybdic acid in ethanol (5%, W/V) and heating.
Silica gel (100ꢀ200 mesh) was used as a stationary phase for column chromatography. Yield is
referred to the isolated products unless otherwise stated. NMR spectra were recorded at 25 oC on
a 400 MHz spectrometer (400 MHz for 1H and 100 MHz for 13C) or 500 MHz spectrometer (500
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MHz for 1H and 125 MHz for C) instrument in CDCl3, using residual CHCl3 (δH = 7.26 ppm)
1
13
as internal standard for H, and CDCl3 (δC = 77.0 ppm) as internal standard for C. Chemical
shifts are given in δ (ppm) and coupling constants (J) in Hz. IR spectra were recorded with a
FTIRꢀ5300 instrument. High resolution mass spectra were recorded on ESIꢀTOF spectrometer. A
Welsbach Ozoniser was used for all ozonolysis reactions.
(2R,3S,4S)-3-(benzyloxy)-4-(2-benzyloxyethyl)-2-(benzyloxymethyl)-3,4-dihydro-2H-
pyran
(
8
): Alcoholꢀderivative 712 (0.5g, 1.41 mmol) was dissolved in anhydrous THF (10
o
mL). To this solution, at 0 C, NaH (68 mg, 2.8 mmol) was added portionwise over 10
min with stirring. After continuous stirring for further 1
2.11 mmol) and TBAI (cat) we added and the mixture was stirred until completion (12 h) at
25 °C. The eaction was quenched with slow addition of cold water and extracted with
CH2Cl2. The combined organic layers were dried with anh ous Na SO and concentrated
h at 0 °C, benzyl bromide (0.36 g,
re
r
ydr
2
4
under reduced pressure to obtain crude benzylated derivative. Purification of the crude product
by column chromatography over silica gel (hexanes/ethyl acetate) provided pure glycal
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derivative 8 (0.56 g, 90%) as colourless liquid. Rf = 0.8 (20% EtOAc in Hexanes). 1H NMR (400
MHz, CDCl3): δ = 7.33ꢀ7.30 (m, 15H), 6.34 (d, J = 6.0 Hz, 1H), 4.69 (t, J = 4.8 Hz, 1H), 4.64ꢀ
4.60 (m, 3H), 4.53ꢀ4.51 (m, 3H), 4.13ꢀ4.09 (m, 1H), 3.82ꢀ3.79 (m, 1H), 3.75 (d, J = 4.0 Hz, 2H),
3.57 (t, J = 6.0 Hz, 2H), 2.63 (dd, J = 4.8, 9.2 Hz, 1H), 2.12ꢀ2.104 (m, 1H), 1.58ꢀ1.49 (m, 1H)
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43
44
45
46
47
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60
13
ppm. C NMR (100 MHz, CDCl3): δ = 142.1, 138.5, 138.1, 138.0, 128.3, 127.8, 127.7, 127.5,
101.6, 73.5, 73.0, 72.9, 72.8, 71.1, 69.4. 67.8, 30.9, 29.6 ppm. IR (neat): ν͂ = 2974, 2920, 2860,
2363, 2334, 1647, 1454, 1362 cmꢀ1. HRMS (ESI): Calcd. for C29H33O4 [M + H]+ 445.2379;
found 445.2377.
(2R,3S,4S)-3-(benzyloxy)-5-(2R,4S,5S,6R)-5-(benzyloxy)-4-(2-(benzyloxyethyl)-6-
(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)-4-(2-benzyloxyethyl)-2-(benzyloxymethyl)-
3,4-dihydro-2H-pyran (9): Glycal 8 was dried over vacuum for 1 h prior to use. Glycal 8 (0.13
g, 0.3 mmol) was dissolved in freshly distilled dry dichloromethane (10 mL). To this solution,
powdered 4 Å molecular sieves (100 mg) was added and stirred for 1 h at room temperature. The
o
solution was cooled to ꢀ78 C and stirred for 15 min at the same temperature. Freshly distilled
o
TMSOTf (16.4 ꢀL, 0.09 mmol) was added at ꢀ78 C and stirred until completion of the reaction
o
(1 h). Triethylamine (12.5 ꢀL, 0.09 mmol) was added at ꢀ78 C to quench the reaction and
allowed to reach the room temperature. Dichloromethane was evaporated under reduced pressure
and the obtained crude was purified by column chromatography over silica gel (hexanes/ethyl
acetate) to obtain the disaccharide
9 (0.12 g, 90%) as a colourless liquid. Rf = 0.45 (20%
EtOAc in Hexanes). 1H NMR (500 MHz, CDCl3): δ = 7.36ꢀ7.23 (m, 30H, Ar(OBn)), 6.39 (s, 1H,
Hꢀ1'), 4.64ꢀ4.63 (m, 1H, OCH2Ph), 4.61ꢀ4.57 (m, 3H, OCH2Ph), 4.58 (d, J = 12.0 Hz, 1H,
OCH2Ph), 4.53 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.52ꢀ4.51 (m, 1H, OCH2Ph) 4.45ꢀ4.43 (m, 2H,
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OCH2Ph), 4.40ꢀ4.38 (m, 1H, OCH2Ph), 4.37 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.36 (d, J = 11.5 Hz,
1H, OCH2Ph), 4.08 (br. d, J = 10.5 Hz, 1H, Hꢀ1), 4.05ꢀ4.02 (m, 1H, Hꢀ5'), 3.81ꢀ3.62 (m, 7H, Hꢀ
4, 5, 6a, 6b, 3', 6a', 6b'), 3.56ꢀ3.53 (m, 4H, Hꢀ8a, 8b, 8a', 8b'), 2.90 (q, J = 5.0 Hz, 1H, Hꢀ3'), 2.47ꢀ
2.45 (m, 1H, Hꢀ7a), 2.11ꢀ2.09 (m, 1H, Hꢀ3), 2.02 (dd, J = 6.0, 13.5 Hz, 1H, Hꢀ7a'), 1.80ꢀ1.72 (m,
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13
3H, Hꢀ2a, 2b, 7b), 1.24 (t, J = 7.0 Hz. 1H, Hꢀ7b') ppm. C NMR (100 MHz, CDCl3): δ = 140.4,
138.8, 138.7, 138.5, 138.4, 138.1, 138.0, 128.2, 127.7, 127.6, 127.5, 127.5, 127.3, 114.6, 75.5,
75.4, 73.6, 73.5, 73.3, 73.0, 72.8, 72.5, 71.2, 71.1, 70.5, 70.4, 69.6, 69.4, 68.9, 31.9, 31.0, 30.3,
29.8, 25.2 ppm. IR (neat): ν͂
= 3651, 2980, 2888, 1657, 1492, 1454 cmꢀ1. HRMS (ESI): Calcd.
for C58H64O8Na [M + Na]+ 911.4499; found 911.4499.
OBn
BnO
OBn
BnO
NaH, BnBr
O
O
THF, 0 oC - rt
95%
HO
BnO
14
15
(2R,3R,4S)-3-(benzyloxy)-4-(2-benzyloxyethyl)-2-(benzyloxymethyl)-3,4-dihydro-2H-
pyran
(
15):
A
lcoholꢀderivative 1412 (0.5g, 1.41 mmol) was dissolved in anhydrous THF
o
(10 mL). To this solution, at 0 C, NaH (68 mg, 2.8 mmol) was added portionwise over
10 min with stirring. After continuous stirring for further 1
g, 2.11 mmol) and TBAI (cat) we added and the mixture was stirred at 25 °C until
completion of the reaction (12 h). The eaction was quenched with slow addition of cold water
and extracted with CH2Cl2. The combined organic layers were dried over anh ous Na2SO4
h at 0 °C, benzyl bromide (0.36
re
r
ydr
and concentrated under reduced pressure to obtain crude benzylated derivative. Purification of
the crude product by column chromatography over silica gel (hexanes/ethyl acetate) provided
pure glycal derivative 15 (0.56 g, 95%) as a colourless liquid. Rf = 0.4 (10% EtOAc in Hexanes).
1H NMR (400 MHz, CDCl3): δ = 7.36ꢀ7.28 (m, 15H), 6.44 (d, J = 6.0 Hz, 1H), 4.72 (t, J = 5.6
Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.52ꢀ4.44 (m, 4H), 4.05ꢀ4.02 (m,
1H), 3.78 (dd, J = 7.6, 10.0 Hz, 1H), 3.60 (dd, J = 4.8, 10.0 Hz, 1H), 3.55ꢀ3.53 (m, 3H), 2.42 (br.
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s, 1H), 1.72ꢀ1.64 (m, 1H), 1.61 (dd, J = 6.8, 13.6 Hz, 1H) ppm. C NMR (100 MHz, CDCl3): δ
6
7
= 142.5, 138.2, 138.0, 137.9, 128.3, 128.0, 127.8, 127.7, 127.6, 102.4, 74.4, 73.4, 73.0, 72.6,
8
9
71.2, 69.2, 67.4, 35.3, 31.2 ppm. IR (neat): ν͂ = 3046, 2926, 2857, 2350, 2318, 1650, 1492, 1454
cmꢀ1. HRMS (ESI): Calcd. for C29H32O4Na [M + Na]+ 467.2199; found 467.2201.
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(2R,3R,4S)-3-(benzyloxy)-5-(2R,4S,5R,6R)-5-(benzyloxy)-4-(2-benzyloxyethyl)-6-
(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)-4-(2-benzyloxyethyl)-2-(benzyloxymethyl)-
3,4-dihydro-2H-pyran (16): Glycal 15 was dried over vacuum for 1 h prior to use. Glycal 15
(0.13 g, 0.3 mmol) was dissolved in freshly distilled dry dichloromethane (10 mL). To this
solution, powdered 4 Å molecular sieves (100 mg) was added and stirred for 1 h at room
o
temperature. The solution was cooled to ꢀ78 C and stirred for 15 min at the same temperature.
Freshly distilled TMSOTf (16.4 ꢀL, 0.09 mmol) was added at ꢀ78 oC and stirred until completion
o
of the reaction (1 h). Triethylamine (12.5 ꢀL, 0.09 mmol) was added at ꢀ78 C to quench the
reaction and allowed to reach the room temperature. Dichloromethane was evaporated under
reduced pressure and the obtained crude was purified by column chromatography over silica
gel (hexanes/ethyl acetate) to obtain the disaccharide 16 (0.11 g, 85%) as a colourless
1
liquid. H NMR (500 MHz, CDCl3): δ = 7.38ꢀ7.24 (m, 30H, Ar(OBn)), 6.57 (s, 1H, Hꢀ1'), 4.63
(d, J = 12.0 Hz, 1H, OCH2Ph), 4.62 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.57ꢀ4.53 (m, 4H, OCH2Ph),
4.49 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.51 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.42 (d, J = 12.0 Hz,
1H, OCH2Ph), 4.46 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.41 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.39 (d, J
= 10.5 Hz, 1H, OCH2Ph), 4.07 (d, J = 11.0 Hz, 1H, Hꢀ1), 4.02 (t, J = 6.0 Hz, 1H, Hꢀ5'), 3.87 (dt,
J = 1.0, 6.0 Hz, 1H, Hꢀ5), 3.75 (dd, J = 6.5, 10.0 Hz, 1H, Hꢀ4'), 3.67 (br. s, 1H, Hꢀ8a'), 3.63 (dd, J
= 2.0, 6.0 Hz, 2H, Hꢀ6a, 6b), 3.56ꢀ3.51 (m, 5H, Hꢀ6a', 6a', 8b', 8a, 8b), 3.29 (s, 1H, Hꢀ4), 2.65 (d, J
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= 8.0 Hz, 1H, Hꢀ3'), 2.38ꢀ2.37 (m, 1H, Hꢀ3), 2.26ꢀ2.20 (m, 2H, Hꢀ2a, 7a'), 1.81ꢀ1.76 (m, 2H, Hꢀ
7a, 7b), 1.38ꢀ1.33 (m, 2H, Hꢀ2b, 7b') ppm. 13C NMR (100 MHz, CDCl3): δ = 141.6, 138.9, 138.6,
138.4, 138.3, 138.2, 138.0, 128.4, 128.3, 128.2, 127.6, 127.5, 127.4, 127.3, 127.3, 114.4, 74.5,
74.2, 73.3, 73.2, 73.0, 72.8, 72.5, 72.2, 71.0, 70.8, 70.4, 69.8, 68.6, 68.3, 34.0, 31.2, 30.2, 28.8
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60
ppm. IR (neat): ν͂
= 3028, 2977, 2917, 2857, 2380, 2354, 1660, 1480 cmꢀ1. HRMS (ESI): Calcd.
for C58H64O8Na [M + Na]+ 911.4499; found 911.4499.
(2R,3S,4S)-3-(benzyloxy)-4-(2-benzyloxyethyl)-2-methyl-3,4-dihydro-2H-pyran
(18):
A
lcoholꢀderivative 1712 (0.43 g, 1.73 mmol) was dissolved in anhydrous THF (15 mL).
o
To this solution, at 0 C, NaH (83 mg, 3.46 mmol) was added portionwise over 10 min
with stirring. After continuous stirring for further 1 at 0 °C, benzyl bromide (0.59 g, 3.46
mmol) and TBAI (cat) we added and the mixture was stirred at 25 °C until completion of the
reaction (12 h). The eaction was quenched with slow addition of cold water and extracted with
CH2Cl2. The combined organic layers were dried with anh ous Na SO and concentrated
h
re
r
ydr
2
4
under reduced pressure to obtain crude benzylated derivative. Purification of the crude product
by column chromatography over silica gel (hexanes/ethyl acetate) provided pure glycal
1
derivative 18 (0.56 g, 96%) as a colourless liquid. Rf = 0.6 (10% EtOAc in Hexanes). H NMR
(400 MHz, CDCl3): δ = 7.37ꢀ7.29 (m, 10H), 6.27 (dd, J = 1.2, 6.0 Hz, 1H), 4.67ꢀ4.55 (m, 3H),
4.52(s, 2H), 4.09ꢀ4.02 (m, 1H), 3.57 (t, J = 5.6 Hz, 2H), 3.42 (dd, J = 5.2, 7.2 Hz, 1H), 2.68ꢀ2.62
13
(m, 1H), 2.10ꢀ2.02 (m, 1H), 1.59ꢀ1.50 (m, 1H), 1.32 (d, J = 6.4 Hz, 3H) ppm. C NMR (100
MHz, CDCl3): δ = 141.9, 138.6, 138.1, 138.3, 127.8, 127.6, 127.5, 101.6, 77.4, 72.8, 71.1, 69.7,
67.9, 30.8, 29.4, 17.7 ppm. IR (neat): ν͂
= 3056, 3024, 2926, 2857, 1723, 1644, 1489, 1454 cmꢀ1.
HRMS (ESI): Calcd. for C22H26O3Na [M + Na]+ 361.1780; found 361.1774.
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(2R,3S,4S)-3-(benzyloxy)-5-(2R,4S,5S,6R)-5-(benzyloxy)-4-(2-benzyloxyethyl)-6-methyl
tetrahydro-2H-pyran-2-yl)-4-(2-benzyloxyethyl)-2-methyl-3,4-dihydro-2H-pyran (19): Glycal 18
was dried over vacuum for 1 h prior to use. Glycal 18 (0.11 g, 0.32 mmol) was dissolved in
freshly distilled dry dichloromethane (10 mL). To this solution, powdered 4 Å molecular sieves
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o
(100 mg) was added and stirred for 1 h at room temperature. The solution was cooled to ꢀ78 C
and stirred for 15 min at the same temperature. Freshly distilled TMSOTf (17.7 ꢀL, 0.09 mmol)
was added at ꢀ78 oC and stirred until completion (1 h). Triethylamine (13.4 ꢀL, 0.09 mmol) was
o
added at ꢀ78 C to quench the reaction and allowed to reach the room temperature.
Dichloromethane was evaporated under reduced pressure and the obtained crude was purified by
column chromatography over silica gel (hexanes/ethyl acetate) to obtain the disaccharide 19
1
(0.07 g, 65%) as a colourless liquid. Rf = 0.4 (10% EtOAc in Hexanes). H NMR (400 MHz,
CDCl3): δ = 7.34ꢀ7.24 (m, 20H, Ar(OBn)), 6.29 (s, 1H, Hꢀ1'), 4.64 (d, J = 11.6 Hz, 1H,
OCH2Ph), 4.61 (d, J = 11.6 Hz, 1H, OCH2Ph), 4.52ꢀ4.49 (m, 3H, OCH2Ph), 4.43 (d, J = 12.0 Hz,
2H, OCH2Ph), 4.36 (d, J = 11.6 Hz, 1H, OCH2Ph), 4.04 (t, J = 6.8 Hz, 1H, Hꢀ1), 3.93 (dd, J =
6.0, 8.8 Hz, 1H, Hꢀ5'), 3.58ꢀ3.48 (m, 5H, Hꢀ8a, 8b, 8a', 8b', 5), 3.38 (dd, J = 5.2, 8.8 Hz, 1H, Hꢀ
4'), 3.14 (dd, J = 5.2, 9.2 Hz, 1H, Hꢀ4), 2.83 (q, J = 5.2 Hz, 1H, Hꢀ3'). 2.45ꢀ2.40 (m, 1H, Hꢀ7a),
2.11ꢀ2.02 (m, 1H, Hꢀ3), 1.98 (dd, J = 6.4, 14.0 Hz, 1H, Hꢀ7a'), 1.75ꢀ1.65 (m, 4H, Hꢀ2, 2, 7b', 7b),
1.29 (d, J = 6.0 Hz, 3H, Hꢀ6'), 1.23 (d, J = 6.0 Hz, 3H, Hꢀ6) ppm. 13C NMR (100 MHz, CDCl3):
δ = 140.2, 138.8, 138.6, 138.4, 138.2, 128.4, 128.3, 127.8, 127.7, 127.6, 127.5, 127.5, 127.4,
114.8, 81.1, 78.6, 77.3, 72.8, 72.6, 71.7, 71.3, 70.8, 70.4, 69.8, 69.5, 69.0, 32.2, 31.1, 30.4, 30.4,
30.0, 25.3, 19.0. 18.2 ppm. IR (neat): ν͂
= 3651, 2984, 2972, 2882, 2354, 2333, 1657, 1451 cmꢀ1.
HRMS (ESI): Calcd. for C44H52O6Na [M + Na]+ 699.3662; found 699.3662.
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1-(2R,3S,4S)-3-(benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyran-4-yl)but-3-en-2-yl
10
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acetate (20): To a solution of aldehyde 612 (0.3 g, 0.85 mmol) in anhydrous THF at ꢀ78 C was
slowly added vinylmagnesium bromide (3.41 mL, 1M sol.) and stirred until completion (3 h).
The reaction was quenched with aq. NH4Cl (2 mL) and brought to the room temperature. The
reaction mixture was diluted with EtOAc (20 mL) and washed with aq. NH4Cl and brine. The
separated organic phase was dried over anhydrous sodium sulphate and concentrated in vacuo.
The crude compound was taken forward without purification.
o
The crude alcohol (0.3 g, 0.78 mmol) was dissolved in pyridine (5 mL) and cooled to 0 C.
Acetic anhydride (0.4 mL, 3.94 mmol) was slowly added and stirred at room temperature for 8 h.
The organic phase was evaporated in vacuo and purified by column chromatography over silica
gel (hexanes/ethyl acetate) to provide the colourless liquid of acetylated derivative 20 (0.3 g,
85%) as an inseparable mixture of diastereomers. Rf = 0.5 (10% EtOAc in Hexanes). IR (neat):
ν͂
= 3062, 2933, 2366, 2321, 1793, 1647, 1457 cmꢀ1. HRMS (ESI): Calcd. for C26H30O5Na [M +
Na]+ 445.1991; found 445.1991.
1-(2R,3S,4S,6R)-6-(2R,3S,4S)-4-(2-acetoxybut-3-en-1-yl)-3-(benzyloxy)-2-(benzyloxymethyl)-
3,4-dihydro-2H-pyran-5-yl)-3-(benzyloxy)-2-(benzyloxymethyl) tetrahydro-2H-pyran-4-yl)but-3-
en-2-yl acetate (21): Glycal 20 was dried over vacuum for 1 h prior to use. Glycal 20 (0.1 g, 0.23
mmol) was dissolved in freshly distilled dry dichloromethane (10 mL). To this solution,
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powdered 4 Å molecular sieves (100 mg) was added and stirred for 1 h at room temperature. The
o
solution was cooled to ꢀ78 C and stirred for 15 min at the same temperature. Freshly distilled
o
TMSOTf (12.2 ꢀL, 0.07 mmol) was added at ꢀ78 C and stirred until completion (1 h).
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Triethylamine (9.7 ꢀL, 0.07 mmol) was added at ꢀ78 C to quench the reaction and allowed to
reach the room temperature. Dichloromethane was evaporated under reduced pressure and the
obtained crude was purified by column chromatography over silica gel (hexanes/ethyl acetate)
to obtain the disaccharide 21 (0.82 g, 82%) as a colourless liquid. Rf = 0.4 (10% EtOAc in
Hexanes). IR (neat): ν͂
= 2986, 2926, 2872, 2366, 2321, 1733, 1650, 1454 cmꢀ1. HRMS (ESI):
Calcd. for C52H64O10N [M + NH4]+ 862.4530; found 862.4537.
(E)-methyl 4-(2R,3S,4S)-3-(benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyran-4-yl)
but-2-enoate (
22): To a solution of aldehyde 612 (0.4 g, 1.14 mmol) in dimethoxyethane
(20 mL) was added methyl(triphenylphosphoranylidene)acetate (0.95 g, 2.86 mmol) at
room temperature and stirred until completion (16 h). The solvent was evaporated under
reduced pressure and the obtained crude was purified by column chromatography over silica
gel (hexanes/ethyl acetate) to obtain the pure compound 22 (0.42 g, 92%, E:Z (86:14)) as
1
a colourless liquid. Rf = 0.65 (10% EtOAc in Hexanes). For E isomer, H NMR (500 MHz,
CDCl3): δ = 7.35ꢀ7.30 (m, 10H), 7.01ꢀ6.94 (m, 1H), 6.35 (d, J = 6.0 Hz, 1H), 5.87 (d, J = 15.5
Hz, 1H), 4.63 (dd, J = 5.0, 6.0 Hz, 1H), 4.60ꢀ4.53 (m, 4H), 4.11ꢀ4.07 (m, 1H), 3.86 (dd, J = 5.5,
8.0 Hz, 1H), 3.75ꢀ3.72 (m, 5H), 2.61ꢀ2.56 (m, 1H), 2.53ꢀ2.49 (m, 1H), 2.18ꢀ2.12 (m, 1H) ppm.
13C NMR (125 MHz, CDCl3): δ = 166.6, 147.2, 142.6, 137.8, 137.6, 127.9, 127.8, 127.7, 127.5,
122.3, 100.8, 73.4, 72.7, 72.7, 71.5, 68.0, 51.2, 33.9, 32.6 ppm. IR (neat): ν
͂
= 3059, 3028, 2942,
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2857, 2907, 2366, 2328, 1723, 1641, 1498, 1454 cmꢀ1. HRMS (ESI): Calcd. for C25H32O5N [M +
NH4]+ 426.2280; found 426.2283.
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(E)-methyl4-(2R,3S,4S)-3-(benzyloxy)-5-(2R,4S,5S,6R)-5-(benzyloxy)-6-((benzyloxyme-
thyl)-4-(E)-4-methoxy-4-oxobut-2-en-1-yl)tetrahydro-2H-pyran-2-yl)-2-(benzyloxymet-
hyl)-3,4-dihydro-2H-pyran-4-yl)but-2-enoate (23): Glycal 22 was dried over vacuum for 1 h
prior to use. Glycal 22 (0.1 g, 0.24 mmol) was dissolved in freshly distilled dry dichloromethane
(10 mL). To this solution, powdered 4 Å molecular sieves (100 mg) was added and stirred for 1 h
o
at room temperature. The solution was cooled to ꢀ78 C and stirred for 15 min at the same
o
temperature. Freshly distilled TMSOTf (12.7 ꢀL, 0.07 mmol) was added at ꢀ78 C and stirred
o
until completion (1 h). Triethylamine (10.0 ꢀL, 0.07 mmol) was added at ꢀ78 C to quench the
reaction and allowed to reach the room temperature. Dichloromethane was evaporated under
reduced pressure and the obtained crude was purified by column chromatography over silica
gel (hexanes/ethyl acetate) to obtain the disaccharide 23 (0.80 g, 80%) as a colourless
liquid. Rf = 0.3 (20% EtOAc in Hexanes). 1H NMR (400 MHz, CDCl3): δ = 7.36ꢀ7.27 (m, 20H),
7.15ꢀ7.07 (m, 1H), 6.97ꢀ6.89 (m, 1H), 6.40 (s, 1H), 5.87 (dd, J = 6.8, 15.6 Hz, 2H), 4.63ꢀ4.55
(m, 6H), 4.47 (d, J = 11.2 Hz, 1H), 4.44 (d, J = 11.6 Hz, 1H), 4.06 (d, J = 10.8 Hz, 1H), 4.02ꢀ
4.00 (m, 1H), 3.84 (dd, J = 5.2, 9.2 Hz, 1H), 3.76 (s, 6H), 3.70ꢀ3.67 (m, 6H), 2.93 (q, J = 5.6 Hz,
1H), 2.68ꢀ2.59 (m, 2H), 2.49 (dd, J = 7.2, 14.0 Hz, 1H), 2.44ꢀ2.31 (m, 2H), 1.76ꢀ1.67 (m, 2H)
13
ppm. C NMR (100 MHz, CDCl3): δ = 166.9, 166.7, 149.5, 148.2, 141.1, 138.5, 138.0, 137.9,
137.6, 128.3, 128.2, 127.8, 127.7, 127.6, 127.4. 122.4. 121.5, 112.8, 75.2, 75.0, 73.5, 73.3, 73.2,
73.0, 71.6, 71.0, 70.8, 70.2, 60.2, 51.4. 51.3, 33.8, 33.1, 33.0, 31.2, 28.3 ppm. IR (neat): ν
͂
=
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3664, 2993, 2971, 2961, 2885, 2347, 1717, 1650, 1460 cmꢀ1. HRMS (ESI): Calcd. for
C50H56O10Na [M + Na]+ 839.3771; found 839.3770.
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(2R,3S)-3-(benzyloxy)-5-(2R,5S,6R)-5-(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-
yl)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyran (25): Glycal 24 was dried over vacuum for 1 h
prior to use. Glycal 24 (0.11 g, 0.35 mmol) was dissolved in freshly distilled dry
dichloromethane (10 mL). To this solution, powdered 4 Å molecular sieves (100 mg) was added
and stirred for 1 h at room temperature. The solution was cooled to ꢀ78 oC and stirred for 15 min
o
at the same temperature. Freshly distilled TMSOTf (19.3 ꢀL, 0.10 mmol) was added at ꢀ78 C
o
and stirred until completion (1 h). Triethylamine (14.0 ꢀL, 0.10 mmol) was added at ꢀ78 C to
quench the reaction and allowed to reach the room temperature. Dichloromethane was
evaporated under reduced pressure and the obtained crude was purified by column
chromatography over silica gel (hexanes/ethyl acetate) to obtain the disaccharide 25 (0.09 g,
86%) as a colourless liquid. Rf = 0.4 (20% EtOAc in Hexanes). 1H NMR (400 MHz, CDCl3): δ
= 7.37ꢀ7.28 (m, 20H, Ar(OBn)), 6.51 (s, 1H, Hꢀ1'), 4.70ꢀ4.65 (m, 3H, OCH2Ph), 4.63ꢀ4.58 (m,
3H, OCH2Ph), 4.53 (d, J = 11.6 Hz, 1H, OCH2Ph), 4.48 (d, J = 11.6 Hz, 1H, OCH2Ph), 3.95ꢀ
3.93 (m, 1H, Hꢀ5'), 3.85ꢀ3.76 (m, 6H, Hꢀ1, 6a, 6b, 4', 6a', 6b'), 3.52ꢀ3.50 (m, 1H, Hꢀ5), 3.46 (dd, J
= 4.0, 9.6 Hz, 1H, Hꢀ4), 2.55 (dd, J = 5.6, 16.0 Hz, 1H, Hꢀ3a'), 2.35ꢀ2.30 (m, 1H, Hꢀ3a), 2.16 (dd,
13
J = 8.4, 16.4 Hz, 1H, Hꢀ3b'), 1.78ꢀ1.74 (m, 1H, Hꢀ2a), 1.63ꢀ1.52 (m, 2H, Hꢀ2b, 3b) ppm. C
NMR (100 MHz, CDCl3): δ = 139.9, 138.6, 138.4, 138.1, 138.1, 128.3, 128.3, 128.2, 127.7,
127.6, 127.5, 127.4, 110.7, 80.8, 77.7, 76.6, 73.4, 73.4, 73.2, 71.0, 70.9, 70.1, 69.9. 68.9, 29.4,
29.1, 26.7 ppm. IR (neat): ν͂
= 3040, 2929, 2888, 2356, 2334, 1679, 1492 cmꢀ1. HRMS (ESI):
Calcd. for C40H44O6Na [M + Na]+ 643.3036; found 643.3033.
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(2R,3R)-3-(benzyloxy)-5-(2R,5R,6R)-5-(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-
yl)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyran (27): Glycal 26 was dried over vacuum for 1 h
prior to use. Glycal 26 (0.1 g, 0.24 mmol) was dissolved in freshly distilled dry dichloromethane
(10 mL). To this solution, powdered 4 Å molecular sieves (100 mg) was added and stirred for 1 h
o
at room temperature. The solution was cooled to ꢀ78 C and stirred for 15 min at the same
o
temperature. Freshly distilled TMSOTf (12.7 ꢀL, 0.07 mmol) was added at ꢀ78 C and stirred
o
until completion (1 h). Triethylamine (10.0 ꢀL, 0.07 mmol) was added at ꢀ78 C to quench the
reaction and allowed to reach the room temperature. Dichloromethane was evaporated under
reduced pressure and the obtained crude was purified by column chromatography over silica
gel (hexanes/ethyl acetate) to obtain the disaccharide 27 (0.88 g, 88%) as a colourless
liquid. Rf = 0.4 (20% EtOAc in Hexanes). 1H NMR (500 MHz, CDCl3): δ = 7.39ꢀ7.31 (m, 20H,
Ar(OBn)), 6.55 (s, 1H, Hꢀ1'), 4.69 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.68 (d, J = 12.0 Hz, 1H,
OCH2Ph), 4.61 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.58 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.53ꢀ4.51 (m,
3H, OCH2Ph), 4.47 (d, J = 12.0 Hz, 1H, OCH2Ph), 4.16 (t, J = 5.5 Hz, 1H, Hꢀ5'), 3.92 (q, J = 4.0
Hz, 1H, Hꢀ4'), 3.84 (d, J = 11.5 Hz, 1H, Hꢀ1), 3.76ꢀ3.64 (m, 5H, Hꢀ5, 6a, 6b, 6a', 6b'), 3.56 (s, 1H,
Hꢀ4), 2.37ꢀ2.27 (m, 2H, Hꢀ3a', 3b'), 2.20 (dd, J = 2.5, 14.0 Hz, 1H, Hꢀ3a), 2.02ꢀ1.93 (m, 1H, Hꢀ
2a), 1.61ꢀ1.54 (m, 1H, Hꢀ3b), 1.38 (d, J = 13.0 Hz, 1 H, Hꢀ2b) ppm. 13C NMR (100 MHz,
CDCl3): δ = 139.8, 138.6, 138.2, 138.1, 138.0, 128.2, 128.2, 128.1, 127.9, 127.8, 127.7, 127.6,
127.5, 127.5, 127.4, 127.4. 111.1, 78.7, 78.6, 75.0, 73.3, 73.2, 70.9, 70.6, 70.2, 70.1. 69.4, 68.4,
26.2, 24.5, 23.9 ppm. IR (neat): ν͂
= 3664, 2974, 2882, 2369, 2340, 1669, 1448, 1384 cmꢀ1.
HRMS (ESI): Calcd. for C40H44O6Na [M + Na]+ 643.3036; found 643.3033.
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OBn
OBn
TMSOTf (0.3 equiv.)
4'
6'
6
3'
2'
4
OBn
O
CH2Cl2
OBn
5
O
OBn
OBn
BnO
5'
2
O
1
OBn
3
O
O
2"
BnO
1'
3" OBn
BnO
24
4 Å MS
-78 oC,
4"
6"
1"
O 5"
(6.4 mmol
scale)
OBn
25
28
(15%)
(65%)
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(2R,2'R,3'S,5S,5'S,6R,6'R)-5,5'-bis(benzyloxy)-2'-((2R,3S)-3-(benzyloxy)-2-(benzyloxymethyl)-
3,4-dihydro-2H-pyran-5-yl)-6,6'-bis(benzyloxymethyl)octahydro-2H,2'H-2,3'-bipyran
(28):
Glycal 24 was dried over vacuum for 1 h prior to use. Glycal 24 (2.0 g, 6.4 mmol) was dissolved
in freshly distilled dry dichloromethane (100 mL). To this solution, powdered 4 Å molecular
sieves (1.0 g) was added and stirred for 1 h at room temperature. The solution was cooled to ꢀ78
oC and stirred for 15 min at the same temperature. Freshly distilled TMSOTf (0.35 mL, 1.92
o
mmol) was added at ꢀ78 C and stirred until completion (1 h). Triethylamine (0.27 mL, 1.92
o
mmol) was added at ꢀ78 C to quench the reaction and allowed to reach the room temperature.
Dichloromethane was evaporated under reduced pressure and the obtained crude was purified by
column chromatography over silica gel (hexanes/ethyl acetate) to obtain the pure compound
of disaccharide 25 (1.3 g, 65%) and trisaccharide 28 (0.3 g, 15%) as colourless liquids.
Data for trisaccharide 28,
Rf = 0.15 (20% EtOAc in Hexanes). 1H NMR (400 MHz, CDCl3): δ
= 7.40ꢀ7.27 (m, 30H, Ar(OBn)), 6.45 (s, 1H, Hꢀ1''), 4.69ꢀ4.65 (m, 4H, OCH2Ph), 4.63ꢀ4.59 (m,
4H, OCH2Ph), 4.50ꢀ4.44 (m, 4H, OCH2Ph), 4.12 (br. t J = 5.2 Hz, 1H, Hꢀ5), 4.04ꢀ4.00 (m, 1H,
Hꢀ5''), 3.80ꢀ3.79 (m, 3H, Hꢀ4'', 6a'', 6b''), 3.78 (d, J = 4.0 Hz, 1H, Hꢀ5'), 3.62 (dd, J = 5.6, 16.0
'
Hz, 3H, Hꢀ4, 6a, 6b ), 3.54ꢀ3.49 (m, 5H, 1, 1', 4', 6a', 6b ), 2.60ꢀ2.50 (m, 2H, Hꢀ2', 3a''), 2.33ꢀ2.27
(m, 1H, Hꢀ3b''), 2.04ꢀ1.96 (m, 1H, Hꢀ3b), 1.90ꢀ1.87 (m, 1H,Hꢀ2b), 1.74ꢀ1.68 (m, 1H, Hꢀ3a), 1.42ꢀ
1.32 (m, 2H, 3a', 3b'), 1.27 (dd, J = 2.4, 12.4 Hz, 1H, Hꢀ2a) ppm. 13C NMR (100 MHz, CDCl3): δ
= 141.57, 138.6, 138.5, 138.3, 138.0, 137.9, 128.3, 128,3, 128.3, 128.3, 128.3, 127.7, 127.6,
127.5, 127.5. 127.5, 127.4, 127.4, 127.3. 109.6, 80.7, 76.7, 74.6, 73.5, 73.4, 73.3, 73.1, 71.3,
70.6, 70.7, 70.5, 70.1, 69.9, 69.6, 68.9. 68.9, 68.7, 41.5, 29.7, 25.2, 23.8, 20.4 ppm. IR (neat): ν
͂
= 2929, 2860, 2359, 2331, 1669, 1495, 1451 cmꢀ1. HRMS (ESI): Calcd. for C60H70O9N[M +
NH4]+ 948.5051; found 948.5051.
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(2R,3S,6S)-[5-2H]-3-acetoxy-6-ethoxy-3,6-dihydro-2H-pyran-2-yl)methyl acetate (30): 1,2ꢀ
Dideoxyꢀ[2ꢀ2H]ꢀ3,4,6ꢀtriꢀOꢀacetylꢀ ꢀarabinoꢀ1ꢀhexenopyranose18 29 (1.5 g, 5.48 mmol) was
D
dissolved in anhydrous benzene (25 mL). To this solution, at 0 oC, was added ethanol (0.50 mL,
8.61 mmol) and BF3.OEt2 (0.23 mL, 1.80 mmol) respectively. The solution was allowed slowly
to reach room temperature and stirred until completion (3 h). The reaction was quenched with
o
Et3N (0.3 mL, 2.22 mmol) at 0 C and concentrated under vacuo. The obtained crude was
purified by column chromatography over silica gel (hexanes/ethyl acetate) to obtain
colourless 2,3 unsaturated compound 30 (1.28 g, 90%) as the inseparable mixture of
anomers (
α
:β, 9:1) with α as the major isomer. Data for α anomer, Rf = 0.7 (30% EtOAc
1
in Hexanes). H NMR (400 MHz, CDCl3): δ = 5.84 (br. s, 1H), 5.27 (dd, J = 1.2, 9.6 Hz, 1H),
5.00 (s, 1H), 4.20 (d, J = 5.2 Hz, 1H), 4.14 (dd, J = 2.0, 12.0 Hz, 1H), 4.01ꢀ4.06 (m, 1H), 3.81ꢀ
13
3.77 (m, 1H), 3.57ꢀ3.50 (m, 1H), 2.05 (s, 3H), 2.04 (s, 3H), 1.21 (t, J = 6.8 Hz, 3H) ppm. C
NMR (100 MHz, CDCl3): δ = 170.7, 170.2, 128.8, 94.1, 65.7, 65.2, 64.2. 62.9, 20.8, 20.7, 15.2
ppm. IR (neat): ν͂
= 2986, 2895, 2366, 2311, 1733, 1444, 1365 cmꢀ1. HRMS (ESI): Calcd. for
C12H17DO6Na [M + Na]+ 282.1064; found 282.1062.
(2R,3S)-[5-2H]-3-(benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyran (31): To a solution of
β,γꢀunsaturated compound 30 (1.24 g, 4.78 mmol) in MeOH (20 mL) was added anhydrous solid
K2CO3 (66 mg, 0.47 mmol) and stirred until completion (2 h). MeOH was completely evaporated
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in vacuo and coꢀevaporated with toluene (2×10 mL). The crude compound was dried for 20 min
in vacuo and dissolved in anhydrous dioxane (15 mL) with stirring. Lithium aluminium hydride
(LAH) (0.19 g, 5.0 mmol) was added and heated to reflux until completion (12 h). The reaction
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was slowly quenched at 0 C with aq. NH4Cl (10 mL) and stirred for 30 min at room
temperature. The precipitated solid material was removed by filtration through celite. The crude
product was dissolved in EtOAc and washed with aq. NH4Cl, brine and concentrated in vacuo to
obtain the crude glycal, which was used in the next step without further purification.
The crude glycal was dried in vacuo for 30 min and dissolved in anhydrous THF (10 mL). NaH
(0.24 g, 10 mmol) was added slowly over portion wise in 10 min at 0 oC and stirred for 15 min at
o
the same temperature. BnBr (1.12 mL, 10 mmol) and TBAI (cat) were added at 0 C and stirred
until completion (12 h). The reaction was slowly quenched with aq. NH4Cl (2 mL). The mixture
was diluted with EtOAc and washed with aq. NH4Cl, brine and concentrated in vacuo. The
obtained crude was purified by column chromatography over silica gel (hexanes/ethyl acetate)
to obtain the pure deuterated glycal 31 (1.2 g, 70% over three steps) as colourless liquid.
Rf = 0.5 (10% EtOAc in Hexanes). 1H NMR (500 MHz, CDCl3): δ = 7.37ꢀ7.27 (m, 10H), 6.38 (s,
1H), 4.66ꢀ4.62 (m, 2H), 4.60ꢀ4.48 (m, 1H), 4.53 (d, J = 11.5 Hz, 1H), 3.94ꢀ3.90 (m, 1H), 3.82ꢀ
3.78 (m, 3H), 2.40 (ddd, J = 1.5, 6.0, 16.5 Hz, 1H), 2.10 (ddd, J = 2.5, 8.5, 16.5 Hz, 1H) ppm.
13C NMR (125MHz, CDCl3): δ = 143.1, 138.3, 138.2, 128.4, 128.3, 127.8, 127.7, 127.6, 127.6,
73.5, 71.1. 70.5, 69.1, 26.5 ppm. IR (neat): ν͂
= 3060, 3031, 2928, 2359, 2331, 1644, 1492 cmꢀ1.
HRMS (ESI): Calcd. for C20H21DO3Na [M + Na]+ 334.1529; found 334.1530.
Deuterated disaccharide (32) and trisaccharide (33): Glycal 31 was dried over vacuum for 1 h
prior to use. Glycal 31 (0.4 g, 1.2 mmol) was dissolved in freshly distilled dry dichloromethane
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The Journal of Organic Chemistry
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(20 mL). To this solution, powdered 4 Å molecular sieves (200 mg) was added and stirred for 1 h
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at room temperature. The solution was cooled to ꢀ78 C and stirred for 15 min at the same
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temperature. Freshly distilled TMSOTf (63.5 ꢀL, 0.36 mmol) was added at ꢀ78 C and stirred
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until completion (1 h). Triethylamine (48.5 ꢀL, 0.36 mmol) was added at ꢀ78 C to quench the
reaction and allowed to reach the room temperature. Dichloromethane was evaporated under
reduced pressure and the obtained crude was purified by column chromatography over silica
gel (hexanes/ethyl acetate) to obtain the pure compounds of disaccharide 32 (0.24 g,
60%) and trisaccharide 33 (0.12g, 30%) as colour less liquids. Data for disaccharide (32),
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Rf = 0.4 (20% EtOAc in Hexanes). H NMR (500 MHz, CDCl3): δ = 7.38ꢀ7.23 (m, 20 H), 6.44
(s, 1 H), 4.67 (d, J = 11.5 Hz, 1 H), 4.66 (d, J = 12.0 Hz, 1H), 4.61ꢀ4.57 (m, 4 H), 4.51 (d, J =
11.5 Hz, 1 H), 4.46 (d, J = 11.5 Hz, 1 H), 3.92ꢀ3.89 (m, 1 H), 3.83 (dd, J = 5.5, 8.0 Hz, 1 H),
3.80ꢀ3.77 (m, 3 H), 3.74ꢀ3.71 (m, 2 H), 3.50ꢀ3.47 (m, 1 H), 3.44ꢀ3.39 (m, 1 H), 2.52 (dd, J = 5.5,
16.5 Hz, 1 H), 2.30 (td, J = 4.5, 12.0 Hz, 1 H), 2.17ꢀ2.12 (m, 1 H), 1.53ꢀ1.48 (m, 1 H) ppm. 13C
NMR (125MHz, CDCl3): δ = 139.9, 138.7, 138.5, 138.3, 138.2, 128.4, 128.3, 128.3, 127.7,
127.7. 127.6, 127.6. 127.5, 127.4, 110.8, 80.9, 77.7, 73.5, 73.5, 73.3, 71.0, 70.9, 70.3, 70.0. 69.0,
29.4, 26.8 ppm. IR (neat): ν͂
= 3654, 3548, 2990, 2071, 2879, 2353, 1676, 1470, 1444 cmꢀ1.
HRMS (ESI): Calcd. for C40H43D2O6 [M+H]+ 623.3342; found 623.3340. Data for trisaccharide
(33), yield 30%, Rf = 0.6 (20% EtOAc in Hexanes). 1H NMR (500 MHz, CDCl3): δ = 7.36ꢀ7.27
(m, 30H), 6.45 (s, 1H), 4.66 (d, J = 11.5 Hz, 1H), 4.65ꢀ4.63 (m, 2H), 4.62ꢀ4.60 (m, 2H), 4.58ꢀ
4.57 (m, 2H), 4.56ꢀ4.55 (m, 1H), 4.46ꢀ4.42 (m, 4H), 4.07 (br. t, J = 5.0 Hz, 1H), 3.99ꢀ3.95 (m,
1H), 3.78ꢀ3.73 (m, 4H), 3.61ꢀ3.53 (m, 3H), 3.50ꢀ3.47 (m, 3H), 3.46ꢀ3.43 (m, 2H), 2.52 (dd, J =
4.0, 12.0 Hz, 1 H), 2.48 (dd, J = 5.0 Hz, 16.5 Hz, 1H), 2.27ꢀ2.22 (m, 1H), 1.93ꢀ1.90 (m, 1H),
13
1.35ꢀ1.28 (m, 2H) ppm. C NMR (125MHz, CDCl3): δ = 141.6, 138.7, 138.6, 138.4, 138.1,
138.0, 138.0, 128.3, 128.3, 128.3, 128.2, 127.7, 127.6, 127.6, 127.5, 127.5, 127.4, 127.3, 109.6.
80.7, 77.3, 76.7. 74.6, 73.5, 73.5, 73.4, 73.2, 71.3, 71.0, 70.6, 70.2, 70.0, 69.7, 69.0, 68.8, 29.7,
25.3, 23.7 ppm. IR (neat): ν͂
= 3658, 2977, 2885, 2366, 2334, 1663, 1467, 1448 cmꢀ1. HRMS
(ESI): Calcd. for C60H63D3O9K [M + K]+ 972.4532; found 972.4535.
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