Synthesis of the tetrasaccharide glycoside moiety of Solaradixine and rapid NMR-based structure verification using the program CASPER

Tetrahedron 72 (2016) 912e927

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Tetrahedron

journal homepage: w ww.elsevier.com/locate/tet

Synthesis of the tetrasaccharide glycoside moiety of Solaradixine

and rapid NMR-based structure veriﬁcation using the program

CASPER

*

€

Thibault Angles d’Ortoli, Goran Widmalm

Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden

a r t i c l e i n f o

a b s t r a c t

Article history:

The major glycoalkaloid in the roots of Solanum laciniatum is Solaradixine having the branched tetra-

Received 9 September 2015

Received in revised form 9 December 2015

Accepted 21 December 2015

Available online 23 December 2015

saccharide b-D-Glcp-(1/2)-b-D-Glcp-(1/3)[a-L-Rhap-(1/2)]-b-D-Galp linked to O3 of the steroidal al-

kaloid Solasodine. We herein describe the synthesis of the methyl glycoside of the tetrasaccharide using

a super-armed disaccharide as a donor molecule. A 2-(naphthyl)methyl protecting group was used in the

synthesis of the donor since it was tolerant to a wide range of reaction conditions. The 6-O-benzylated-

hexa-O-tert-butyldimethylsilyl-protected

formation, was successfully glycosylated at O3 of a galactoside acceptor molecule. However, subsequent

glycosylation at O2 by a rhamnosyl donor was unsuccessful and instead a suitably protected -Rhap-

(1/2)- -Galp-OMe disaccharide was used as the acceptor molecule together with a super-armed

Glcp-(1/2)- -Glcp-SEt donor in the glycosylation reaction, to give a tetrasaccharide in a yield of 55%,

b-D-Glcp-(1/2)-b-D-Glcp-SEt donor, which avoided 1,6-anydro

Keywords:

Glycosylation

Oligosaccharide

Saponin

a-L

b

-D

b-D-

b-D

CASPER

which after deprotection resulted in the target molecule, the structure of which was veriﬁed by the NMR

chemical shift prediction program CASPER.

Chemical shift prediction

1. Introduction

Solanum laciniatum produces glycoalkaloids that exert various

biological activities. Several different glycoalkaloids are found in

Saponins are glycosides with one or more sugars in their

structure and the aglycone is either a triterpene, a steroid or a ste-

roidal alkaloid.^1e5The oligosaccharide portion is typically made

the leaves, berries and roots of this species. Besides trisaccharide-

containing saponins, larger glycoalkaloids are present in the

roots, having Solasodine (Fig. 1) as the sapogenin, viz., Sola-

from a limited number of different monosaccharides, viz.,

D

-glu-

shabanine having a tetrasaccharide with a terminal

linked glucosyl residue, Solaradixine (1b) containing a tetra-

saccharide but instead with a terminal -(1/2)-linked glucosyl

residue (Fig. 1) and Solaridine comprising a pentasaccharide with

a terminal -(1/6)-linked glucosyl residue attached to the

(1/2)-linked glucosyl residue of Solaradixine.¹⁷

b-(1/6)-

cose, -galactose, -glucuronic acid, -xylose, -arabinose or L-

D

L

rhamnose, and linked to O3 of the aglycone (sapogenin);⁶the

number of oligosaccharides possible to form is still very large. These

amphiphilic compounds are secondary metabolites widely spread

in the plant kingdom and several have been found in marine ani-

mals.^7,8Saponins are biologically active compounds that can be

used in pharmacological applications owing to their cytotoxic ef-

fects as well as their immunostimulatory, anti-inﬂammatory, an-

tiviral and hypoglycemic activities among others.^9e15

b

b-

Synthesis of saponins and oligosaccharide glycosides^18e20

thereof facilitates corroboration of their structures, chemical

modiﬁcation of functional groups to study their impact and effects

in biological environments as well as enabling sufﬁcient amounts of

material for in vitro as well as in vivo studies.^21e27Herein we de-

scribe, to the best of our knowledge, for the ﬁrst time, the synthesis

Members of the plant family Solanaceae include, inter alia,

eggplant, tomato and potato.¹⁶Glycoalkaloids, as well as oligosac-

charides and saponins, from these plants have anticarcinogenic

properties inhibiting cell growth both in culture and in vivo.

of the branched tetrasaccharide

b-D-Glcp-(1/2)-b-D-Glcp-(1/3)

[a

-L

-Rhap-(1/2)]- -Galp-OMe (1) corresponding to the glyco-

b-D

side moiety of the glycoalkaloid Solaradixine from S. laciniatum and

its rapid structure veriﬁcation based on unassigned ¹H and ¹³C NMR

spectra as implemented in the computer program CASPER.

* Corresponding author. E-mail address: goran.widmalm@su.se (G. Widmalm).

http://dx.doi.org/10.1016/j.tet.2015.12.042

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

913

Scheme 1. Formation of thioglycoside acceptor 8. Reagents and conditions: (a) NAPBr,

NaH, DMF, 3 h, 90%; (b) 2 M HCl, EtOH, 80 ^ꢀC, 4 h, 80%; (c) Ac₂O, pyridine, 90%; (d)

BF₃$Et₂O, EtSH, CHCl₃, 3 h, 68%; (e) 1 M NaOMe, MeOH, 16 h, 88%; (f) PhCH(OMe)₂,

CSA, CH₃CN, 2 h, 55 ^ꢀC, 82%.

Fig. 1. Schematic of methyl

-D-glucopyranosyl-(1/3)]-

(1b) and Solasodine.

a

-L-rhamnopyranosyl-(1/2)[

b-D-glucopyranosyl-(1/2)-

b

b-D-galactopyranoside (1), the glycoalkaloid Solaradixine

Formation of the b-(1/2)-linkage between the two orthogo-

nally protected glucosyl donors³³employed a glycosylation strat-

egy in which a trimethylsilyl triﬂate-promoted coupling²⁸of the

known trichloroacetimidate donor 9³⁴with acceptor 8 gave di-

saccharide 10 in 75% yield (Scheme 2).

2. Results and discussion

2.1. Tetrasaccharide synthesis

It has been noted by Boons and co-workers that thioethyl mi-

gration from an acceptor to a donor molecule can occur.³⁵Herein

we were able to suppress this side-reaction by increasing the po-

larity of the solvent used, i.e., by employing a mixture of DCM and

toluene in equal proportions. The 4,6-O-benzylidene group was

regioselectively opened in a good yield (68%) using BH₃$NMe₃and

AlCl₃in THF³⁶to give 11 with a 6-O-benzyl group, suitably posi-

tioned to suppress 1,6-anhydro formation in the subsequent gly-

cosylation reaction (vide infra). Deprotection of 11 using DDQ

cleaved selectively the NAP group³⁷and furnished diol 12 in 85%

yield, followed by O-deacetylation using sodium methoxide in

methanol to give compound 13 in 91% yield. The super-armed di-

saccharide donor 14 was then obtained in 82% yield from 13, using

tert-butyldimethylsilyl triﬂate as the reagent for the O-silylation

reaction.^29,38The arming effect of the donor as a result of the steric

crowding due to the tert-butyldimethylsilyl (TBS) protecting

groups^39e42resulted in a conformational switch from standard ⁴C₁

chair conformation for the pyranose rings of the two glucosyl res-

idues to ³S₁skew-like conformations, based on, inter alia,

In the synthesis of the branched target tetrasaccharide 1 three

glycosidic linkages are to be formed. Realizing that

glucosyl-containing disaccharides have been utilized as donors in

glycosylation reactions with very high

-anomeric selectivity,²⁸we

b-(1/2)-linked

b

envisioned that this could be a suitable donor, especially since

super-armed monosaccharide donors had been used for glycosyl-

ation reactions at O4 of a protected glucosyl acceptor,²⁹i.e., at

a secondary carbon atom. If this strategy were to be chosen,

a suitably protected methyl galactopyranoside could be used as an

acceptor, followed by a second glycosylation reaction by a rham-

nosyl donor molecule or one could use a preformed disaccharide

acceptor, which had been made by glycosylation of a rhamnosyl

donor to O2 of the methyl galactopyranoside.

Formation of a suitably protected monosaccharide, which has

a thioethyl group to be used as the leaving group in the glycosyl-

ation reaction and that can be employed as the acceptor molecule

in order to form the b-(1/2)-linked donor disaccharide utilized

a 2-naphthylmethyl (NAP) protecting group at O3, which was in-

troduced to diisopropylidene glucose (2) using sodium hydride and

NAPBr (Scheme 1) to give compound 3.

The NAP protecting group was chosen since it can be selec-

tively removed in the presence of O-benzyl groups and that it is

stable to strong acids and bases.³⁰Subsequent removal of the

isopropylidene groups by hydrochloric acid treatment gave 4,

which was O-acetylated using pyridine and acetic anhydride to

give 5. The donor functionality was introduced by treatment

0

J_H1,H2¼5.1 Hz, J_{H1 ,H2}¼5.8 Hz, J_H2,H3<2 Hz and J_{H2 ,H3}<2 Hz, in good

agreement with NMR data for the corresponding hepta-TBDMS-

protected glucosyl-containing disaccharide donor,²⁸and a 3,4-di-

O-TBDPS-protected glucosyl donor.⁴⁰

With the disaccharide donor in hand the known mono-

saccharide methyl 4,6-O-benzylidene-a-D

-galactopyranoside 15⁴³

was regioselectively protected at O2 by an O-acetyl group using

acetic anhydride and pyridine to give compound 16, albeit in a low

yield (Scheme 3).

with BF₃$Et₂O and ethanethiol to give 6, which was O-deacety-

31

ꢀ

lated under Zemplen conditions resulting in 7, followed by

The b-(1/3)-linkage between the disaccharide donor 14 and

protection of O4 and O6 with a 4,6-O-benzylidnene group using

benzaldehyde dimethyl acetal and camphor sulfonic acid for its

installation, to give compound 8. The different transformations

from 2 to 8³²were carried out in good to excellent yields ranging

between 68% and 90% leading to a selectively protected mono-

saccharide having both donor and acceptor functionalities in

place.

the relatively unreactive acceptor 16 was facilitated by using Tf₂O-

DMDS⁴⁴as the promoter system. Several activators were tried in-

cluding NIS/TfOH, NIS/AgOTf, NIS/TMSOTf and MeOTf at different

temperatures, but only Tf₂O-DPS and Tf₂O-BSP gave similar results

to Tf₂O-DMDS, which was judged to be the best reagent, in the

presence of the sterically hindered base DTBMP. The reaction

resulted in the formation of a mixture of trisaccharides, viz., the

914

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

Scheme 2. Formation of armed donor 14. Reagents and conditions: (a) TMSOTf, CH₂Cl₂/Tol 1:1, ꢁ25 ^ꢀC / rt, 2 h, 75%; (b) BH₃$NMe₃, AlCl₃, THF, 6 h, 68%; (c) DDQ, CH₂Cl₂/MeOH 4:1,

4 h, 85%; (d) 1 M NaOMe, MeOH, 16 h, 91%; (e) TBDMSOTf, DMAP, pyridine, 80 ^ꢀC, 24 h, 82%.

Scheme 3. Formation of acceptors 16 and 19. Reagents and conditions: (a) Ac₂O, pyridine, rt, 16 h, 22%; (b) FmocCl, DMAP, pyridine-CH₃CN, 16 h, 68%; (c) NIS, AgOTf, CH₂Cl₂,

0

^ꢀC/rt, 1 h, NEt₃, 30 min, 82%.

anticipated compound 20a, but also by-products that were of lower

molecular mass as indicated by mass spectroscopy (Scheme 4).

¹H NMR spectroscopy revealed that the mixture contained three

compounds and NMR assignments of these in the mixture showed

that labile TBS ether groups, from two different ring positions, had

been cleaved off during the coupling, resulting in trisaccharides

20b and 20c. These by-products seemed to form no matter the

amount of base added or the promoter system used. It was decided

to continue to aim for the target tetrasaccharide by removing the O-

acetyl protective group in 20a using sodium methoxide in metha-

nol, thereby unveiling the alcohol function, to give 21 in 55% yield.

Glycosylation of acceptor 20a with rhamnosyl donor 17, even in

large excess, under NIS/AgOTf conditions remained, however, un-

successful and another route had to be chosen.

As noted above the alternative route would employ a preformed

disaccharide acceptor. Diol 15 was again used but this time

a regioselective protection of O3 was carried out by reacting Fmoc

chloride in a mixture of pyridine and acetonitrile (2:1) to give ac-

ceptor 18 in 68% yield (Scheme 3).⁴⁵Rhamnosyl donor 17 was

glycosylated with 18 using NIS/AgOTf as the activator, followed by

addition of trimethylamine to remove the Fmoc protecting group at

O3,²³which subsequently furnished disaccharide acceptor 19 in

82% yield. The correspondingly protected disaccharide methyl

D-galactopyranoside, in which only O-acetyl groups are utilized to

obtain the pertinent protection scheme, was recently synthesized

in order to facilitate phosphoglycerol functionalization at O-3 of the

galactosyl residue.⁴⁶The disaccharide donor for the synthesis of the

tetrasaccharide was in the second strategy chosen to have 6-O-

benzyl groups at both of the exocyclic positions, in order to sup-

press side-reactions such as 1,6-anhydro formation in the suc-

ceeding glycosylation reaction (Scheme 5).

Ethyl 1-thio-a/b-D-glucopyranoside (23) was selectively ben-

zylated at O6 using sodium hydride and benzyl bromide in DMF to

give 24 in 72% yield,⁴⁷followed by treatment with benzoyl chlo-

ride in pyridine to give 25 in 97% yield, which subsequently was

hydrolyzed to provide an a/b-anomeric mixture of the function-

alized hemiacetal 26 that was transformed into tri-

chloroacetimidate derivative 27 with an overall yield of 66% over

two steps. Disaccharide formation was carried out by glycosylation

of acceptor 8 with donor 27 using TMSOTf as promotor to give

compound 28 in 84% yield. The acetal functionality in 28 was

regioselectively opened, using the same conditions as for the

transformation of 10/11 described above, to form 6-O-benzyl-

derivatized disaccharide 29 in 79% yield. Notably, water was added

to the mixture since is known to increase the rate of the reaction

for electron-deﬁcient substrates and the procedure is fully com-

patible with thioglycoside-derivatized sugars.⁴⁸Using the same

2,3,4-tri-O-acetyl- -L-rhamnopyranosyl-(1/2)-4,6-di-O-acetyl-b-

a

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

915

Scheme 4. Synthesis of trisaccharide acceptor 21 and attempted formation of tetrasaccharide 22. Reagents and conditions: (a) Tf₂O-DMDS, DTBMP, CH₂Cl₂, ꢁ78 ^ꢀC, 15 min, 68%

(20ae20c); (b) 1 M NaOMe, MeOH, 16 h, 55%; (c) NIS, AgOTf, CH₂Cl₂, 0 ^ꢀC.

Scheme 5. Formation of armed donor 32. Reagents and conditions: (a) NaH, BnBr, DMF, 0 ^ꢀC/rt, 6e8 h, 72%; (b) BzCl, pyridine, 0 ^ꢀC/rt, 16 h, 97%; (c) NIS, H₂O, CH₂Cl₂-acetone,

8 h, 78%; (d) Cl₃CCN, K₂CO₃, CH₂Cl₂, 4 h, 85%; (e) TMSOTf, CH₂Cl₂-toluene, 16 h, ꢁ10 ^ꢀC/rt, 84%; (f) BH₃$NMe₃, AlCl₃, H₂O, THF, 16 h, 79%; (g) DDQ, CH₂Cl₂/MeOH 4:1, 4 h, 88%; (h)

1 M NaOMe, MeOH, 16 h, 93%; (i) TBDMSOTf, DMAP, pyridine, 80 ^ꢀC, 24 h, 86%.

series of deprotection and protection reactions as for the trans-

formations of 11/14 given above, compound 29 was transformed

by cleavage of the NAP group (30, 88%), O-debenzoylation (31, 93%)

and O-silylation to give disaccharide donor 32 in 86% yield. Like for

compound 14 the super-armed donor 32 also had the pyranose

rings of the two glucosyl residues in ³S₁skew-like conformations,

0

as deduced from inter alia, J_H1,H2¼6.0 Hz, J_{H1 ,H2}¼5.1 Hz,

0 0

_H2,H3<2 Hz and J_{H2 ,H3}<2 Hz.

J

916

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

Formation of the

b

-(1/3)-linkage was successful by coupling

structures.^52,53It relies on ¹H and ¹³C NMR chemical shift data of

mono-, di- and trisaccharides and given components (or some of

these, i.e., unknowns may be part of the input) and will investigate

all permutations possible based on the input data. In order to speed

donor 32 with acceptor 19 using BSP/Tf₂O as the promoter system

together with the hindered base TTBP⁴⁹to give a tetrasaccharide

product in 55% yield (Scheme 6).

Scheme 6. Formation of tetrasaccharide 1. Reagents and conditions: (a) BSP, Tf₂O, TTBP, CH₂Cl₂, ꢁ78/ꢁ10 ^ꢀC, 30 min, 55% (33a and 33b); (b) TBAF 1 M in THF, THF (c) Ac₂O, DMAP,

pyridine, 16 h, 80% over two steps; (d) NaOMe, MeOH, 16 h, 87%; (e) 10e20% Pd/C, 3 atm, MeOH/H₂O, 6 h, 89%.

The product was a mixture of the anticipated compound 33a

(50% yield) and 33b (5% yield), which had lost its TBS group at O3⁰

as deduced from 2D NMR experiments, inter alia, ¹H,¹H-TOCSY ex-

periments that revealed a ¹H resonance at 3.25 ppm from the HO3⁰

hydroxyl group; the loss of the TBS group is presumably due to

steric crowding during the reaction (cf. Scheme 4 above) or in the

tetrasaccharide product. For the next step, deprotection of the O-

silyl groups, the two tetrasaccharides were mixed and O-desilyla-

tion was carried out by treatment with a solution of TBAF in THF

followed by O-acetylation, to facilitate puriﬁcation by column

chromatography, using pyridine and acetic anhydride to give

compound 35 in 80% yield over two steps. Hydrogenolysis

employing Palladium on carbon (loading 10e20%) as catalyst fur-

nished the tetrasaccharide target compound 1 in 89%, the ¹H NMR

spectrum of which is shown in Fig. 2.

up the structural calculations due to the potentially very large

number of combinations possible, J_H1,H2and J_C1,H1data can be uti-

lized as part of the input in order to limit the number of structures

for which calculations are carried out. The ¹H and ¹³C chemical

shifts can also be predicted for a given structure. As input to CASPER

the sugar components used in the synthesis were given, i.e.,

D-Galp-

OMe, -Glcp (twice) and

D

L

-Rhap together with ¹H and ¹³C NMR data.

Using only 1D NMR data in the form of ¹H and ¹³C chemical shifts in

combination with J_H1,H2and J_C1,H1data it was not possible to deduce

the structure of 1 as given by the synthesis pathway. NMR data

from 2D NMR experiments were needed, namely, correlations

(unassigned) observed in ¹H,¹H-TOCSY, ¹H,¹³C-HSQC and ¹H,¹³C-

HMBC spectra. The ﬁve top-ranked structural suggestions are given

in Fig 3, where the structure of the target tetrasaccharide 1 is the

top-ranked one.

That this procedure works and that we have synthesized

compound 1 was conﬁrmed by assignment of the ¹H and ¹³C

chemical shifts (Table 1) using the NMR experiments described

above. In addition, there was agreement between calculated and

experimental high resolution mass spectrometry data for the

pseudomolecular ion from an ESI-MS spectrum, i.e., [MþNa]^þm/z

calcd for C₂₅H₄₄O₂₀Na 687.2324, found 687.2326, as well as sim-

ulation of the ¹H NMR spectrum by reﬁnement of proton chemical

shifts and scalar coupling constants by an iterative total line-shape

2.2. Structure veriﬁcation

For structural characterization and veriﬁcation of tetra-

saccharide 1 an NMR-based methodology was tested to investigate

if this could be carried out rapidly using unassigned ¹H and ¹³C NMR

chemical shift data. The computer program CASPER^50,51was ini-

tially developed to elucidate the primary structure of poly-

saccharides, but it is also possible to investigate oligosaccharide

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

917

1

Fig. 2. H NMR spectrum at 600 MHz of tetrasaccharide 1 at 5 ^ꢀC (a) and the corresponding spectrum simulated by total-lineshape analysis using the PERCH NMR software (b). The

HDO resonance in the experimental spectrum (d_H5.02) was removed prior to the lineshape ﬁtting procedure.

analysis employing NMR spin simulation⁵⁴using the PERCH

software.

extraction of highly accurate ¹H chemical shifts in conjunction with

scalar coupling constants (Table 1). The excellent agreement be-

tween experimental ¹H and ¹³C NMR chemical shifts and those

predicted by CASPER for tetrasaccharide 1 is illustrated in Fig. 4,

underscoring the potential of CASPER to be used as a part of the

structural veriﬁcation process in chemical or chemoenzymatic

synthesis of oligosaccharides.

Being able to simulate the ¹H spectrum, which is in excellent

agreement with the experimental one (Fig. 2), then facilitates

3. Conclusions

The strategy for synthesis of the oligosaccharide component of

the glycoalkaloid Solaradixine from S. laciniatum was such that al-

ternative schemes were possible prior to its execution. The order of

glycosylations was of paramount importance in the synthesis of

methyl lycoteraoside, a tetrasaccharide constituent of a-tomatine,

where steric hindrance was the culprit in the unsuccessful pathway

but could be circumvented by an alternative scheme, both of which

employed a monosaccharide as the donor and a trisaccharide as an

acceptor.²²Herein, the pertinently functionalized monosaccharide

building blocks facilitated glycosylation to give a disaccharide do-

nor that subsequently was super-armed by substitution with sev-

eral TBS-groups enforcing sterical crowding and conformational

changes of the constituent sugar residues. The successful glyco-

sylation, with very high

b-selectivity, of the hydroxyl group at

a secondary carbon utilized a disaccharide acceptor molecule that

facilitated formation of a tetrasaccharide, which after protection

gave the branched target molecule. Furthermore, rapid structure

veriﬁcation of the synthesized tetrasaccharide was carried out by

using unassigned ¹H and ¹³C NMR data as input to the program

CASPER, which is available to the scientiﬁc community at http://

www.casper.organ.su.se/casper/.⁵⁵

4. Experimental section

4.1. General

Dry solvents, including toluene (Tol), dichloromethane (DCM),

tetrahydrofuran (THF), diethyl ether (Et₂O) and acetonitrile (ACN)

were obtained from a VAC solvent puriﬁer system (Hawthorne, CA,

USA). Dry N,N-dimethylformamide (DMF) was purchased from

Acros Organics (Morris Plains, NJ, USA) and used as received. Pyr-

idine (Pyr) was distilled over CaH₂and dried over molecular sieves

Fig. 3. CASPER output of the ﬁve top-ranked structural suggestions for the synthesized

tetrasaccharide presented in CFG format (blue and yellow ﬁlled circles represent ^D-

glucopyranose and ^D-galactopyranose residues, respectively, and a green ﬁlled triangle

represents ^L-rhamnopyranose). The relative deviations for structures 1e5 are 1.00, 1.01,

1.03, 1.03 and 1.09, respectively.

ꢁ

(4 A). Methanol (MeOH) and chloroform (CHCl₃) were dried over

ꢁ

molecular sieves (4 A). All reagents were used as received. A ni-

trogen ﬂow was used for reactions requiring inert atmosphere.

918

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

Table 1

¹H and ¹³C NMR chemical shifts (ppm) and J_HH(Hz) data from experiments at 5 ^ꢀC and d_H

/d_Cpredicted by the CASPER program

Residue

-Glcp-(1/

1

2

3

4

5

6

b

-D

¹H

Expt

³J_HH

4.874

3.472

9.64

3.35

74.05

74.79

3.661

9.24

3.504

9.05

3.54

76.38

76.40

3.724

9.21

3.413

9.82

3.40

70.41

70.50

3.455

9.44

3.434

6.37^a

3.51

76.93

77.28

3.454

4.23^a

3.47

76.49

76.53

3.926

6.27

3.743^a

ꢁ12.31

3.931^b

3.91

7.99 (163)^d

4.78

1.97^b

0.96^b

calcd

Expt

calcd

Expt

³J_HH

calcd

Expt

calcd

Expt

³J_HH

calcd

Expt

calcd

Expt

³J_HH

calcd

Expt

calcd

3.73

61.77

61.79

3.744^a

ꢁ11.97

3.73

¹³C

¹H

103.67

104.22

4.764

/2)-

b

-D

-Glcp-(1/3)

3.892^b

3.90

7.93 (164)^d

4.73

3.65

3.70

3.48

¹³C

¹H

102.74

103.42

5.184

80.33

82.51

4.035

3.25

77.31

76.62

3.751

9.66

70.16

70.26

3.468

9.93

61.08

61.54

1.275

a-L-Rhap-(1/2)

1.74 (176)^d

4.94

4.05

3.78

3.46

3.73

1.31

17.11

17.56

3.753^b

ꢁ11.73

3.78

¹³C

¹H

101.85

103.46

4.437

71.18

70.93

3.655

9.61

3.74

78.56

79.16

71.23

71.09

4.012

3.40

3.82

81.26

84.19

72.76

72.83

4.113

0.84

4.20

69.94

69.27

69.50

69.87

3.706

8.04^a

3.70

/2,3)-

b-

D

-Galp-OMe^c

3.793^a

3.79

7.87 (163)^d

4.41

4.14^b

¹³C

103.44

103.59

75.37

75.46

61.69

61.48

a

H6_pro-R

.

b

c

H6_pro-S

.

CH₃(OMe) Expt: 3.586, 57.80; calcd: 3.59, 57.49.

d

¹J_H1,C1at 45 ^ꢀC.

ꢁ

Powdered molecular sieves (4 A) were activated by heating under

high vacuum. Column chromatography was performed on a Biotage

Isolera ﬂash chromatographysystem (Uppsala, Sweden) usingKP-Sil

or HP-Sil snap silica gel cartridges and puriﬁcation on t-C18 Sep-

pak^Òcartridges. TLC was carried out on silica gel 60 F₂₅₄plates

(20ꢂ20 cm, 0.2 mm thickness) and monitored with UV light

254e360 nm or by a staining solution prepared from Ceric Ammo-

nium Sulfate (2 g) in ethanol (40 mL) and 2 M sulfuric acid (40 mL).

Puriﬁcation of the target compound (1) by gel permeation

A 1D ¹H NMR spectrum of compound 1 recorded at 600 MHz

and processed with an applied Gaussian function for resolution

enhancement was utilized as input for the NMR spin simulation

n

software PERCH. Accurate ¹H NMR chemical shifts and J_HH

coupling constants were determined by iterative ﬁtting thereby

handling strong overlaps and higher order effects. The simulated

and the experimental spectra appeared highly similar according to

visual inspection and the total root-mean-square value was less

than 0.1%.

€

chromatography was performed on an AKTAÔ system equipped

with a SuperdexÔ column (GE Healthcare, Uppsala, Sweden). The

4.1.1. 1,2:5,6-Di-O-isopropylidene-3-O-(2-naphthyl)methyl-

a-D-glu-

eluent system was H₂O with 1% BuOH at a ﬂowrate of 1 mL min^ꢁ1

.

copyranose (3). 1,2:5,6-Di-O-isopropylidene- -glucofuranose 2

a-D

UV and RI detection were used to monitor elution.

(10 g, 38 mmol) and 2-methylnaphtyl bromide (9.25 g, 1.1 equiv)

was introduced in a round-bottomed ﬂask. Dry dimethylformamide

(35 mL) was poured into the mixture and sodium hydride 60% in oil

dispersion (1.54 g, 1.2 equiv) was slowly added at 0 ^ꢀC. Then, the

mixture was allowed to reach room temperature. After 6 h of stir-

ring, excess NaH was neutralized with methanol. The product was

precipitated by adding 300 mL of crushed ice. The upper layer was

transferred to a separation funnel, diluted with dichloromethane

and washed with water. The organic layer was dried over MgSO₄

and concentrated to dryness to give after puriﬁcation by column

chromatography (Toluene/EtOAc 10:1, R_f¼0.4) 13.8 g of yellow oil

NMR spectra for characterization of isolated compounds were

recorded at 25 ^ꢀC, except where otherwise stated, on Bruker spec-

trometers operating at ¹H frequencies of 400, 500 or 600 MHz. The

NMR chemical shifts (d) are reported in ppm and referenced to TMS

or sodium 3-trimethylsilyl-(2,2,3,3-²H₄)-propanoate (TSP) as in-

ternal standards, d_H¼0.0, or to the residual solvent peaks for CDCl₃,

d_H¼7.26, or MeOH-d₄d_H¼3.31. ¹³C chemical shifts were referenced

to external 1,4-dioxane in D₂O, d_C¼67.40, or internally to the CDCl₃

residual solvent peak, d_C¼77.16, or to the MeOH-d₄residual solvent

peak, d_C¼49.00. J coupling constants are reported in Hertz (Hz). All

new compounds synthesized were fully characterized using 1D ¹H,

1D ¹H-decoupled ¹³C, 2D ¹H,¹H-DQF-COSY, 2D ¹H,¹³C-multiplicity-

edited-HSQC proton coupled or decoupled and 2D ¹H,¹³C-HMBC

NMR experiments. If required, 1D ¹H,¹H-TOCSY, 2D ¹H,¹H-TOCSY, 2D

¹H,¹³C-H2BC, 2D ¹³C,¹H-HETCOR or 2D ¹H,¹³C-HSQC-TOCSY experi-

ments were acquired. Abbreviations for ¹H NMR multiplicity of

signals: s (singlet), d (doublet), t (triplet), dd (doublet of doublet), q

(quadruplet), dt (doublet of triplet), dq (doublet of quadruplet), ddd

(doublet of doublet of doublet), m (multiplet), br (broad resonance),

nr (not resolved). Of the two protons constituting the hydroxy-

methyl group, the one resonating at higher ﬁeld is denoted H-6a,

and the one at lower ﬁeld is denoted H-6b. The terminal glucosyl

residue is denoted by G⁰, the internal one by G, galactose by Gal and

rhamnose by R. High-resolution mass spectra were recorded on

Bruker Daltonics micrOTOF or micrOTOFQ spectrometers (Billerica,

MA, USA) using electrospray ionization (ESI) in positive mode.

Samples of 1 mg mL^ꢁ1were prepared using a solution of 1:1 ACN/

H₂O containing 0.1% formic acid.

(90%). ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d 7.85e7.80 (m, 4H, HeAr),

7.49e7.45 (m, 3H, HeAr), 5.93 (d, J_H1,H23.74, 1H, H-1), 4.85 (d, J_gem

12.03, 1H, NapCH₂), 4.80 (d, J_gem12.03, 1H, NapCH₂), 4.63 (d, J_H1,H2

3.74, 1H, H-2), 4.42 (ddd, J_H4,H57.80, J_H5,H6a5.86, J_H5,H6b6.13, 1H, H-

5), 4.16 (dd, J_H3,H43.10, J_H4,H57.80, 1H, H-4), 4.14 (dd, J_H5,H6b6.13,

J_gem8.75, 1H, H-6b), 4.08 (d, J_H3,H43.10, 1H, H-3), 4.03 (dd, J_H5,H6a

5.86, J_gem8.75, 1H, H-6a), 1.49, 1.43, 1.40, 1.31, (4 s, 12H, CH₃). ¹³

C

NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d

135.2, 133.4, 133.2 (3ꢂC-ipso),

128.4, 128.0, 127.9, 126.6, 126.3, 126.1, 125.8 (7 CeAr), 112.0, 109.2

(23ꢂ(CH₃)₂CH), 105.48 (C-1), 82.9 (C-2), 81.8 (C-3), 81.5 (C-4), 72.7

(C-5), 72.6 (NapCH₂), 67.6 (C-6), 27.0, 26.4, 25.6 (4 CH₃). ESI-HRMS:

[MþNa]^þm/z calcd for C₂₃H₂₈O₆Na 423.1784, found 423.1788.

4.1.2. 3-O-(2-Naphthyl)methyl- -glucopyranose (4). Compound 3

D

(13.8 g, 34.5 mmol) was dissolved in EtOH (65 mL) and 2M HCl

(33 mL) was added in a 250 mL round-bottomed ﬂask. The mixture

was heated to 80 ^ꢀC and the reaction was followed by TLC (TLC:

R_f¼0.2 DCM/MeOH 9:1). At completion, the mixture was

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

919

(30 mL) and acetic anhydride (7.66 mL, 75 mmol) was added at 0 ^ꢀC.

The mixture was left to attain room temperature and was stirred

overnight. At completion, the reaction was quenched with MeOH at

0

^ꢀC. Solvents were evaporated and co-evaporation with toluene

was performed. The brown oil obtained was taken up into EtOAc

and washed successively with brine, 1 M HCl, brine, satd NaHCO₃

and brine. The solution was dried over MgSO₄and solvents were

evaporated to afford the desired product. The

a-anomeric form

could be isolated by recrystallization from cold EtOH while the

residual crude was puriﬁed by chromatography (R_f¼0.6 Toluene/

EtOAc 2:1) to give 4.1 g of 5 as a slightly yellow oil with an overall

yield of 91%. ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz)

b

-anomeric form:

d

7.85e7.32 (4 m, 7H, HeAr), 5.66 (d, J_H1,H28.17, 1H, H-1), 5.20 (dd,

J_H1,H28.17, J_H2,H39.39, 1H, H-2), 5.19 (dd, J_H3,H49.25, J_H4,H59.94, 1H,

H-4), 4.78 (s, 2H, NapCH₂), 4.23 (dd, J_H5,H6b4.95, J_gem12.53, 1H, H-

6b), 4.10 (dd, J_H5,H6a2.33, J_gem12.53, 1H, H-6a), 3.81 (dd, J_H2,H39.39,

J_H3,H49.25, 1H, H-3), 3.73 (ddd, J_H4,H59.94, J_H5,H6a2.33, J_H5,H6b4.95,

1H, H-5), 2.10, 2.08 1.94, 1.93 (4 s, 12H, CH₃). ¹³C NMR (CDCl₃, 25 ^ꢀC,

100 MHz) b-anomeric form: d 170.9, 169.4, 169.4, 169.2 (4 C]O),

135.1, 133.3, 133.1 (3ꢂC-ipso), 128.4, 128.0, 127.8, 126.7, 126.4, 126.3,

125.8 (7 CeAr), 92.2 (C-1), 80.1 (C-3), 74.4 (NapCH₂), 73.2 (C-5), 71.8

(C-2), 69.2 (C-4), 61.9 (C-6), 21.0, 20.9, 20.9, 20.8 (4 CH₃). ESI-HRMS:

[MþNa]^þm/z calcd for C₂₅H₂₈O₁₀Na 511.1580, found 511.1583.

4.1.4. Ethyl 2,4,6-tri-O-acetyl-3-O-(2-naphthyl)methyl-1-thio-

glucopyranoside (6). 1,2,4,6-Tetra-O-acetyl-3-O-(2-naphthyl)

methyl- -glucopyranose 5 (2.1 g, 4.3 mmol) previously obtained

b-D-

D

was dissolved in dry CHCl₃(10 mL). The reaction mixture was

cooled to 0 ^ꢀC and ethanethiol (0.24 mL, 1.1 equiv) and borontri-

ﬂuoride etherate (0.59 mL, 1.1 equiv) were successively added

dropwise. The addition of reagents was carried out during 5 min

and the mixture was stirred for 2 h at this temperature. Then, the

mixture was washed twice with a satd solution of NaHCO₃(20 mL)

and with water (10 mL). The organic layer was dried over Na₂SO₄

and concentrated to dryness. The residue was puriﬁed by column

chromatography (Toluene/EtOAc 4:1) to give 1.37 g of white

needles in 68% yield. ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d 7.84e7.32

(4 m, 7H, HeAr), 5.17e5.14 (m, 2H, H-2, H-4), 4.78 (m, 2H, NapCH₂),

4.40 (d, J_H1,H210.02, 1H, H-1), 4.19 (dd, J_H5,H6b5.18, J_gem12.33, 1H,

H-6b), 4.12 (dd, J_H5,H6a2.47, J_gem12.33, 1H, H-6a), 3.76 (dd, J 9.29, J

9.20, 1H, H-3), 3.63 (ddd, J_H4,H510.02, J_H5,H6a2.47, J_H5,H6b5.18, 1H, H-

5), 2.70 (dq, 2H, SCH₂CH₃), 2.07, 1.98, 1.92 (3 s, 9H, CH₃), 1.26 (t, 3H,

SCH₂CH₃). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d 170.9, 169.5, 169.45,

(3 C]O), 135.4, 133.4, 133.1 (3ꢂC-ipso), 128.4, 128.0, 127.8, 126.6,

126.4, 126.2, 125.8 (7 CeAr), 83.8 (C-1), 81.7 (C-3), 76.4 (C-5), 74.4

(NapCH₂), 71.4 (C-4), 69.9 (C-2), 62.6 (C-6), 24.1 (SCH₂CH₃), 21.1,

20.9, 20.9 (3 CH₃), 14.9 (SCH₂CH₃). ESI-HRMS: [MþNa]^þm/z calcd

for C₂₅H₃₀O₈SNa 513.1559, found 513.1556.

Fig. 4. Comparison between experimental and CASPER-predicted ¹H and ¹³C NMR

chemical shifts (top and bottom, respectively) of tetrasaccharide 1.

neutralized with Amberlite OH^ꢁ. The resin was ﬁltered off and

washed with methanol. The crude product was concentrated and

co-evaporated with toluene to dryness. The white precipitate ob-

tained was ﬁltered and washed with cold ethyl acetate to give 8.8 g

(80%) of compound 4 as a colorless oil. ¹H NMR (CD₃OD, 25 ^ꢀC,

4.1.5. Ethyl 4,6-O-benzylidene-3-O-(2-naphthyl)methyl-1-thio-b-D-

glucopyranoside (8). Compound 6 (4.0 g, 8.2 mmol) was dissolved

in methanol (50 mL), NaOMe in MeOH was added (general pro-

cedure: 2 equiv per acyl group using a 1M solution) and the mixture

was stirred at room temperature overnight. TLC (R_f¼0.2, DCM/

MeOH 9:1) analysis indicated completion of the reaction and the

solution was neutralized with Dowex-H^þ. The resin was ﬁltered,

washed with methanol and solvents were evaporated. The product

400 MHz) b-anomeric form: d 7.92e7.41 (4 m, 7H, HeAr), 5.06 (m,

2H, NapCH₂), 4.57 (d, J_H1,H27.77, 1H, H-1), 3.87 (dd, J_H5,H6b2.40, J_gem

12.00, 1H, H-6b), 3.68 (dd, J_H5,H6a5.88, J_gem12.00, 1H, H-6a), 3.49

(dd, J_H3,H49.54, J_H4,H58.78,1H, H-4), 3.43 (dd, J_H2,H38.88, J_H3,H49.54,

1H, H-3), 3.34 (ddd, J_H4,H58.78, J_H5,H6a5.88, J_H5,H6b2.40, 1H, H-5),

ethyl 3-O-(2-naphthyl)methyl-1-thio-

obtained in 88% yield (2.6 g) as a colorless syrup. ¹H NMR (CDCl₃,

25 ^ꢀC, 400 MHz):

7.88e7.44 (2 m, 7H, HeAr), 5.18 (d, J_gem11.08,

b-D-glucopyranoside 7 was

3.33 (m, 1H, H-2). ¹³C NMR (CD₃OD, 25 ^ꢀC, 100 MHz)

b-anomeric

form:

d

138.0, 134.8, 134.4 (3ꢂC-ipso), 128.9, 128.8, 128.6, 127.5,

d

127.3, 126.9, 126.8 (7 CeAr), 98.3 (C-1), 86.4 (C-3), 78.0 (C-5), 76.5

(C-2), 76.0 (NapCH₂), 71.6 (C-4), 62.8 (C-6). ESI-HRMS: [MþNa]^þm/z

calcd for C₁₇H₂₀O₆Na 343.0260, found 343.0263.

1H, NapCH₂), 4.94 (d, J_gem11.08, 1H, NapCH₂), 4.37 (d, J_H1,H29.54,

1H, H-1), 3.88 (dd, J_H5,H6b3.53, J_gem11.85,1H, H-6b), 3.75 (dd, J_H5,H6a

5.10, J_gem11.85, 1H, H-6a), 3.62 (dd, J_H3,H49.25, J_H4,H59.14, 1H, H-4),

3.54 (dd, J_H1,H29.54, J_H2,H38.73, 1H, H-2), 3.47 (dd, J_H2,H38.73, J_H3,H4

9.25, 1H, H-3), 3.39 (ddd, J_H4,H59.14, J_H5,H6a5.10, J_H5,H6b3.53, 1H, H-

5), 2.73 (dq, 2H, SCH₂CH₃), 2.50, 2.10, 1.60 (3 br, 3H, OH), 1.32 (t, 3H,

4.1.3. 1,2,4,6-Tetra-O-acetyl-3-O-(2-naphthyl)methyl-

D-glucopyr-

anose (5). Compound 4 (3 g, 9.4 mmol) was dissolved in pyridine

920

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

SCH₂CH₃). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d

135.9, 133.5, 133.2

after 4 h (R_f¼0.7 Pentane/EtOAc 1:1) the reaction was stopped by

addition of 1 mL of satd NaHCO₃. The reaction mixture was diluted

with diethyl ether and washed twice with a solution of satd

NaHCO₃and dried over Na₂SO₄. The residue was puriﬁed by ﬂash

chromatography to yield 0.205 g (68%) of compound 11 as a color-

(3ꢂC-ipso), 128.7, 128.1, 127.9, 127.1, 126.4, 126.2, 126.0 (7 CeAr),

86.8 (C-1), 85.1 (C-3), 79.6 (C-5), 75.0 (NapCH₂), 73.4 (C-2), 70.3 (C-

4), 62.9 (C-6), 24.8 (SCH₂CH₃), 15.5 (SCH₂CH₃). ESI-HRMS: [MþNa]^þ

m/z calcd for C₁₉H₂₄O₅SNa 387.1442, found 387.1446.

Ethyl 3-O-(2-naphthyl)methyl-1-thio-

b-D

-glucopyranoside

7

less oil. ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d 7.95e7.27 (5 m, 12H,

(2.6 g, 7.2 mmol) was dissolved in acetonitrile (20 mL) and benz-

aldehyde dimethyl acetal (1.45 mL, 1.5 equiv) and anhydrous

camphor sulfonic acid (300 mg, 0.2 equiv) were successively added

to the mixture. The reaction mixture was stirred for 2 h at 55 ^ꢀC

(TLC: R_f¼0.4 Toluene/EtOAc 4:1); it was then cooled and quenched

with NEt₃(0.175 mL). The residue obtained was concentrated to

dryness and recrystallized from cold methanol. The product was

ﬁltered and dried to afford 2.7 g (82% yield) of ethyl 4,6-O-benzy-

HeAr G), 5.23e5.10 (m, 4H, H-1, H-2, H-3, H-4 G⁰), 5.04 (d, J_gem

10.51, 1H, NapCH₂G) 4.94 (d, J_gem10.51, 1H, NapCH₂G), 4.57 (2 d,

J_gem11.92, 2H, PhCH₂G), 4.42 (d, J_H1,H29.69, 1H, H-1 G), 4.20 (dd,

J_H5,H6b5.14, J_gem12.33,1H, H-6b G⁰), 4.09 (dd, J_H5,H6a2.63, J_gem12.33,

1H, H-6a G⁰), 3.78 (dd, J_H5,H6b4.94, J_gem10.04, 1H, H-6b G), 3.74 (dd,

J_H1,H29.69, J_H2,H38.74, 1H, H-2 G), 3.73 (ddd, J_H3,H48.77, J_H4,H510.06,

J_H4,OH-42.30, 1H, H-4 G), 3.69 (dd, J_H5,H6a5.67, J_gem10.04, 1H, H-6a

G), 3.59 (ddd, J_H4,H59.70, J_H5,H6a2.63, J_H5,H6b5.14, 1H, H-5 G⁰), 3.58

(dd, J_H2,H38.73, J_H3,H48.77, 1H, H-3 G), 3.46 (ddd, J_H4,H510.06, J_H5,H6a

5.67, J_H5,H6b4.94, 1H, H-5 G), 2.89 (d, J_H4,OH-42.30, 1H, OH-4 G), 2.68

(dq, 2H, SCH₂CH₃G), 2.07, 2.05, 2.02, 2.00 (4s, 12H, CH₃G⁰), 1.25 (t,

lidene-3-O-(2-naphthyl)methyl-1-thio-

b

-

D

-glucopyranoside

8 as

a white powder. ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d

7.85e7.35 (5 m,

12H, HeAr), 5.59 (s, 1H, CHPh), 5.12 (d, J_gem11.85, 1H, NapCH₂), 4.99

(d, J_gem11.85, 1H, NapCH₂), 4.46 (d, J_H1,H29.70, 1H, H-1), 4.36 (dd,

J_H5,H6b4.93, J_gem10.50, 1H, H-6b), 3.78 (dd, J_H5,H6a10.23, J_gem10.50,

1H, H-6a), 3.77e3.69 (m, 2H, H-4, H-3), 3.61 (m, 1H, H-2), 3.50 (ddd,

J_H4,H59.05, J_H5,H6a10.50, J_H5,H6b4.93, 1H, H-5), 2.75 (dq, 2H,

SCH₂CH₃), 2.54 (d, 1H, OH-2), 1.31 (t, 3H, SCH₂CH₃). ¹³C NMR (CDCl₃,

3H, SCH₂CH₃G). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d 170.8, 170.4,

169.5, 169.3 (4 C]O G⁰), 137.6, 135.7, 133.6, 133.3 (4ꢂC-ipso G),

128.8, 2ꢂ128.7, 128.2, 128.1, 3ꢂ127.9, 127.4, 2ꢂ126.4, 126.3,

(12 CeAr G), 100.1 (C-1 G⁰), 86.7 (C-3 G), 83.7 (C-1 G), 77.1 (C-5 G),

76.5 (C-2 G), 75.9 (NapCH₂G), 74.0 (PhCH₂G), 74.0 (C-4 G), 73.4 (C-

3 G⁰), 72.1 (C-2 G⁰), 71.9 (C-5 G⁰), 71.1 (C-6 G), 68.6 (C-4 G⁰), 62.3 (C-6

G⁰), 24.0 (SCH₂CH₃G), 21.0, 20.9, 20.8, 20.7 (4 CH₃G⁰), 14.8

(SCH₂CH₃G). ESI-HRMS: [MþNa]^þm/z calcd for C₄₀H₄₈O₁₄SNa

807.2662, found 807.2660.

25 ^ꢀC, 100 MHz):

d

137.4, 135.9, 133.4, 133.2 (4ꢂC-ipso), 129.2,

3ꢂ128.4, 128.1, 127.8, 127.0, 3ꢂ126.2, 126.1, 126.0 (12 CeAr), 101.5

(CHPh), 86.8 (C-1), 81.5 (C-3), 81.4 (C-4), 74.8 (NapCH₂), 73.3 (C-2),

71.0 (C-5), 68.8 (C-6), 24.7 (SCH₂CH₃), 15.4 (SCH₂CH₃). ESI-HRMS:

[MþNa]^þm/z calcd for C₂₆H₂₈O₅SNa 475.1555, found 475.1553.

4.1.8. Ethyl 2,3,4,6-tetra-O-acetyl-

b-D-glucopyranosyl-(1/2)-6-O-

4.1.6. Ethyl 2,3,4,6-tetra-O-acetyl-

b-

D-glucopyranosyl-(1/2)-4,6-O-

benzyl-1-thio- -glucopyranoside (12). Compound 11 (120 mg,

b-D

benzylidene-3-O-(2-naphthyl)methyl-1-thio-

(10). A solution of trichloroacetimidate 9 (720 mg, 1.41 mmol,

1.6 equiv) and acceptor 8 (400 mg, 0.88 mmol) in dry CH₂Cl₂/Tol-

b

-

D

-glucopyranoside

0.15 mmol) was dissolved in a mixture of CH₂Cl₂/MeOH 4/1 and 2,3-

dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 87 mg, 2.5 equiv)

was added and the reaction was stirred until completion, moni-

tored by TLC. Once complete (R_f¼0.37 Pentane/EtOAc 1:4), the re-

action mixture was diluted with CH₂Cl₂and 1 mL of satd NaHCO₃

was added. The two phases were separated and the organic phase

was washed twice more with the solution of satd NaHCO₃and

subsequently dried over Na₂SO₄. The residue was puriﬁed by ﬂash

chromatography to yield the desired product 12, 84 mg (85% yield)

uene (1:1, 14 mL) was stirred for 20 min in the presence of mo-

ꢁ

lecular sieves (4 A, 0.4 g). TMSOTf (8

mL, 0.05 equiv) was then added

at ꢁ25 ^ꢀC. The reaction was monitored by TLC (pentane/EtOAc 2:1)

and allowed to warm up to room temperature. NEt₃was added to

quench the reaction and the mixture was ﬁltered through Celite. It

was then diluted with CH₂Cl₂and washed successively with solu-

tions of satd NaHCO₃, brine and dried over Na₂SO₄. The solvent was

removed in vacuo, and the residue obtained was puriﬁed by ﬂash

chromatography (TLC: R_f¼0.45 Pentane/EtOAc 2:1) to yield 10 in

75% yield (0.52 g) as a white powder. ¹H NMR (CDCl₃, 25 ^ꢀC,

as a colorless oil. ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d 7.37e7.27 (m,

5H, HeAr G), 5.22 (dd, J_H2,H39.40, J_H3,H49.33, 1H, H-3 G⁰), 5.09 (dd,

J_H3,H49.33, J_H4,H510.00, 1H, H-4 G⁰), 5.02 (dd, J_H1,H28.02, J_H2,H39.40,

1H, H-2 G⁰), 4.94 (d, J_H1,H28.02, 1H, H-1 G⁰), 4.57 (2 d, J_gem12.01, 2H,

PhCH₂G), 4.44 (d, J_H1,H29.37, 1H, H-1 G), 4.23 (dd, J_H5,H6b5.22, J_gem

12.18, 1H, H-6b G⁰), 4.16 (dd, J_H5,H6a2.54, J_gem12.18, 1H, H-6a G⁰),

3.73 (m, 2H, H-6b, H-6a G), 3.72 (ddd, J_H4,H510.00, J_H5,H6a2.54,

J_H5,H6b5.22, 1H, H-5 G⁰), 3.63e3.51 (m, 3H, H-4, H-3, H-2 G), 3.44

(ddd, 1H, H-5 G), 3.14 (nr, 1H, OH G), 3.06 (nr, 1H, OH G), 2.70 (dq,

2H, SCH₂CH₃G), 2.08, 2.06, 2.02, 2.00 (4s, 12H, CH₃G⁰), 1.27 (t, 3H,

400 MHz):

d 7.91e7.35 (5 m, 12H, HeAr G), 5.60 (s, 1H, CHPh G),

5.24e5.13 (m, 4H, H-2, H-1, H-3, H-4 G⁰), 5.08 (d, J_gem10.32, 1H,

NapCH₂G), 4.87 (d, J_gem10.32, 1H, NapCH₂G), 4.51 (d, J_H1,H29.14,

1H, H-1 G), 4.40 (dd, J_H5,H6b5.06, J_gem10.52, 1H, H-6b G), 4.20 (dd,

J_H5,H6b5.26, J_gem12.25,1H, H-6b G⁰), 4.10 (dd, J_H5,H6a2.59, J_gem12.25,

1H, H-6a G⁰), 3.88e3.80 (m, 2H, H-2, H-3 G), 3.80e3.72 (m, 2H, H-4,

H-6a G), 3.56 (ddd, J_H4,H59.95, J_H5,H6a2.59, J_H5,H6b5.26, 1H, H-5 G⁰),

3.50 (m, J_H5,H6b5.06, 1H, H-5 G), 2.72 (dq, 2H, SCH₂CH₃G), 2.07,

2.06, 2.03, 2.00 (4 s, 12H, CH₃G⁰), 1.27 (t, 3H, SCH₂CH₃G). ¹³C NMR

SCH₂CH₃G). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d 170.9, 170.4, 169.8,

169.5 (4 C]O G⁰), 137.7 (C-ipso G), 2ꢂ128.6, 128.0, 2ꢂ127.9 (5 CeAr

G), 100.0 (C-1 G⁰), 83.0 (C-1 G), 79.8 (C-2 G), 77.7 (C-4 G), 77.6 (C-5

G), 73.8 (PhCH₂G), 73.0 (C-3 G⁰), 72.0 (C-3 G), 72.1 (C-5 G⁰), 71.9 (C-2

G⁰), 70.6 (C-6 G), 68.5 (C-4 G⁰), 62.1 (C-6 G⁰), 24.3 (SCH₂CH₃G), 21.0,

20.9, 2ꢂ20.7 (4 CH₃G⁰), 14.9 (SCH₂CH₃G). ESI-HRMS: [MþNa]^þm/z

calcd for C₂₉H₄₀O₁₄SNa 667.2036, found 667.2034.

(CDCl₃, 25 ^ꢀC, 100 MHz):

d

170.7, 170.4, 169.5, 169.3 (4 C]O G⁰),

137.3, 135.3, 133.5, 133.3 (4ꢂC-ipso G), 129.2, 128.7, 3ꢂ128.5, 128.3,

128.2, 127.9, 127.6, 126.6, 126.4, 3ꢂ126.1 (12 CeAr G), 101.4 (CHPh

G), 100.2 (C-1 G⁰), 84.4 (C-1 G), 83.7 (C-2 G), 81.8 (C-4 G), 77.1 (C-3

G), 75.7 (NapCH₂G), 73.3 (C-3 G⁰), 72.0 (C-2 G⁰), 71.9 (C-5 G⁰), 70.2

(C-5 G), 68.8 (C-6 G), 68.6 (C-4 G⁰), 62.3 (C-6 G⁰), 24.0 (SCH₂CH₃G),

21.0, 20.8, 20.6, 20.6 (4 CH₃G⁰), 14.7 (SCH₂CH₃G). ESI-HRMS:

[MþNa]^þm/z calcd for C₄₀H₄₆O₁₄SNa 805.2506, found 805.2510.

4.1.9. Ethyl

b-D-glucopyranosyl-(1/2)-6-O-benzyl-1-thio-b-D-glu-

copyranoside (13). For general acyl group deprotection conditions

see the above reaction conditions for compound 7. Starting from

ethyl 2,3,4,6-tetra-O-acetyl-

zyl-1-thio- -glucopyranoside (80 mg) 12 O-deacylation yielded

compound 13 as a colorless oil (R_f¼0.35 DCM/MeOH 9:1) in 91%

b-D-glucopyranosyl-(1/2)-6-O-ben-

4.1.7. Ethyl 2,3,4,6-tetra-O-acetyl-

benzyl-3-O-(2-naphthyl)methyl-1-thio-

b

-

D

-glucopyranosyl-(1/2)-6-O-

-glucopyranoside

b-D

(11). Disaccharide 10 (0.3 g, 0.38 mmol) was dissolved in dry THF

(5 mL) at room temperature. BH₃$NMe₃complex (336 mg,12 equiv)

was added to the mixture that was let to stir for 5 min under N₂

atmosphere. Anhydrous AlCl₃(307 mg, 6 equiv) was added and

yield (57 mg). ¹H NMR (CD₃OD, 25 ^ꢀC, 400 MHz):

d 7.38e7.24 (m,

5H, HeAr G), 4.70 (d, J_H1,H27.74, 1H, H-1 G⁰), 4.58 (s, 2H, PhCH₂G),

4.49 (d, J_H1,H29.40, 1H, H-1 G), 3.86 (dd, J_H5,H6b2.39, J_gem11.88, 1H,

H-6b G⁰), 3.82 (dd, J_H5,H6b1.89, J_gem11.12, 1H, H-6b G), 3.70 (dd,

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

921

J_H5,H6a5.20, J_gem11.88, 1H, H-6a G⁰), 3.64 (dd, J_H5,H6a5.85, J_gem11.12,

1H, H-6a G), 3.61 (dd, J_H2,H38.72, J_H3,H48.57, 1H, H-3 G), 3.54 (dd,

J_H1,H29.40, J_H2,H38.72, 1H, H-2 G), 3.44 (ddd, J_H4,H59.94, J_H5,H6a5.85,

J_H5,H6b1.89, 1H, H-5 G), 3.38 (dd, J_H3,H48.57, J_H4,H59.94, 1H, H-4 G),

3.35e3.34 (m, 2H, H-3, H-4 G⁰), 3.29 (m, J_H5,H6a5.20, J_H5,H6b2.39,1H,

H-5 G⁰), 3.25 (dd, J_H1,H27.74, J_H2,H39.25, 1H, H-2 G⁰), 2.74 (dq, 2H,

SCH₂CH₃G), 1.27 (t, 3H, SCH₂CH₃G). ¹³C NMR (CD₃OD, 25 ^ꢀC,

25 ^ꢀC, 100 MHz):

(5 CeAr), 101.7 (C-1), 101.7 (CHPh), 75.7 (C-4), 72.2 (C-2), 71.9 (C-3),

69.1 (C-6), 66.7 (C-5), 56.2 (OMe), 21.2 (CH₃). ESI-HRMS: [MþNa]^þ

m/z calcd for C₁₆H₂₀O₇Na 347.1107, found 347.1111.

d

170.7 (C]O), 137.4 (C-ipso), 129.5, 128.4, 126.6

4.1.12. Ethyl 2,3,4-tri-O-acetyl-1-thio-a/b-L-rhamnopyranose (17). L-

Rhamnopyranose (1.03 g, 6.3 mmol, 1 equiv) was dissolved in

pyridine (30 mL) and acetic anhydride (4.74 mL, 50.4 mmol) was

added at 0 ^ꢀC. The mixture was left to attain room temperature

and was stirred overnight. At completion (R_f¼0.66 Pentane/EtOAc

1:1), the reaction was quenched with MeOH at 0 ^ꢀC. Solvents

were evaporated and co-evaporation with toluene was per-

formed. The brown oil obtained was dissolved in EtOAc, washed

successively with brine, 1 M HCl, brine, saturated NaHCO₃and

brine. The solution was dried over MgSO₄and solvents were

evaporated to afford the desired product. The residual anomeric

100 MHz): G

d

139.7 (C-ipso G), 2ꢂ129.3, 2ꢂ128.8, 128.6 (5 CeAr G),

104.8 (C-1 G⁰), 84.4 (C-1 G), 81.6 (C-2 G), 80.9 (C-5 G), 79.6 (C-3 G),

78.1 (C-5 G⁰), 78.0 (C-3 G⁰), 75.8 (C-2 G⁰), 74.4 (PhCH₂G), 71.4 (C-4

G⁰), 71.4 (C-4 G), 70.9 (C-6 G), 62.7 (C-6 G⁰), 24.8 (SCH₂CH₃G), 15.3

(SCH₂CH₃G). ESI-HRMS: [MþNa]^þm/z calcd for C₂₁H₃₂O₁₀SNa

499.1614, found 499.1617.

4.1.10. Ethyl

anosyl-(1/2)-3,4-di-O-tert-butyldimethylsilyl-6-O-benzyl-1-thio-

-glucopyranoside (14). Ethyl 6-O-benzyl-2-O-( -glucopyr-

anosyl)-1-thio- -glucopyranoside (13, 0.24 g, 0.5 mmol) was

2,3,4,6-tetra-O-tert-butyldimethylsilyl-b-D-glucopyr-

b

-

D

b

-D

mixture (

lowish oil was isolated (1.85 g, 89%). ¹H NMR (CDCl₃, 25 ^ꢀC,

400 MHz): -anomer: 6.02 (d, 1H, J_H1,H21.93, H-1), 5.30 (dd, J_H2,H3

a/b: 92/8) was puriﬁed by chromatography and a yel-

b-D

dissolved in dry pyridine (7.5 mL) and DMAP (12 mg, 0.2 equiv) was

added to the mixture. TBDMSOTf (1.46 mL, 12.6 equiv) was sub-

sequently added dropwise at 0 ^ꢀC, and the reaction mixture was

heated to 80 ^ꢀC and was left to proceed overnight. The reaction

(R_f¼0.5 Pentane/DCM 1:1) was left to cool down and then

quenched by addition of MeOH. The mixture was extracted with

dichloromethane and successively washed with 1 M HCl, satd

aqueous NaHCO₃and brine. The solution was dried over anhydrous

Na₂SO₄and solvents were evaporated. The resulting residue was

puriﬁed by chromatography to afford 0.48 g (82% yield) of 14 as

a

3.52, J_H3,H410.08, 1H, H-3), 5.25 (dd, J_H1,H21.93, J_H2,H33.52, 1H, H-

2), 5.12 (dd, J_H3,H410.08, J_H4,H59.97, 1H, H-4), 3.94 (dq, J_H4,H59.97,

J_H5,H66.24, 1H, H-5), 2.17, 2.16, 2.06, 2.00 (4s, 12H, CH₃), 1.24 (d,

J_H5,H66.24, 3H, H-6). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

a-anomer:

d

170.2, 170.0, 169.9, 168.5 (4ꢂC]O), 90.8 (C-1), 70.6 (C-2), 68.9

(C-4), 68.9 (C-3), 68.8 (C-5), 21.0, 20.92, 20.89, 20.8 (4ꢂCH₃), 17.6

(C-6). ESI-HRMS: [MþNa]^þm/z calcd for C₁₄H₂₀O₉Na 355.1005,

found 355.1008.

2,3,4,6-Tetra-O-acetyl-L-rhamnopyranose (1.75 g, 5.3 mmol)

a colorless syrup. ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d

7.36e7.28 (m,

was dissolved in dry CHCl₃(15 mL), the reaction mixture was

cooled to 0 ^ꢀC and ethanethiol (0.76 mL, 2 equiv) and borontri-

ﬂuoride diethyl etherate (3.23 mL, 5 equiv) were successively

added dropwise. The addition was carried out during 5 min and

the mixture was stirred for 2 h at this temperature followed by

2 h more at room temperature. The mixture was then washed

twice with 20 mL of a 5% NaOH solution and with 10 mL of

water. The organic layer was dried over MgSO₄and concentrated

to dryness. Puriﬁcation by column chromatography (R_f¼0.72

Pentane/EtOAc 1:1) gave 1.51 g (86%) of 17 as colorless oil

5H, HeAr G), 5.14 (d, J_H1,H25.82,1H, H-1 G), 4.95 (d, J_H1,H25.78,1H, H-

1 G⁰), 4.60 (d, J_gem12.17, 1H, PhCH₂G), 4.53 (d, J_gem12.17, 1H, PhCH₂

G), 3.96 (dd, J_H2,H3<2,1H, H-3 G), 3.90 (ddd,1H, H-5 G), 3.94 (dd,1H,

H-4 G⁰), 3.89 (dd, 1H, H-4 G), 3.83 (dd, J_H1,H25.82, J_H2,H3<2, 1H, H-2

G), 3.83 (dd, 1H, H-5 G⁰), 3.74 (dd, J_H2,H3<2, 1H, H-3 G⁰), 3.72 (dd,1H,

H-6b G⁰), 3.66 (dd, 1H, H-6a G⁰), 3.66 (dd, 1H, H-6b G), 3.60 (dd, 1H,

H-6a G), 3.59 (dd, J_H1,H25.78, J_H2,H3<2, 1H, H-2 G⁰), 2.70 (dq, 2H,

SCH₂CH₃G), 1.26 (t, 3H, SCH₂CH₃G), 3ꢂ0.89, 2ꢂ0.88, 0.85 (6 s, 54H,

C(CH₃)₃), 0.13, 3ꢂ0.089, 3ꢂ0.079, 0.069, 0.057, 2ꢂ0.042, 0.019 (12 s,

36H, SiCH₃). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d

138.7 (C-ipso G),

(

a

/

b

-anomeric ratio 85/15). ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

a-anomeric form: 5.34 (dd, J_H1,H21.56, J_H2,H33.39, 1H, H-2), 5.24

2ꢂ128.4, 2ꢂ127.8, 127.5 (5 CeAr G), 101.1 (C-1 G⁰), 82.3 (C-1 G), 81.2

(C-2 G), 81.0 (C-5 G⁰), 79.5 (C-3 G⁰), 79.4 (C-5 G), 77.7 (C-2 G⁰), 76.1

(C-3 G), 73.4 (PhCH₂G), 71.7 (C-4 G), 71.6 (C-6 G), 70.3 (C-4 G⁰), 64.3

(C-6 G⁰), 3ꢂ26.15, 3ꢂ26.05 (6 C(CH₃)₃), 25.3 (SCH₂CH₃G), 18.5,

4ꢂ18.1, 18.05 (6 C(CH₃)₃), 15.0 (SCH₂CH₃G), ꢁ3.4, ꢁ3.7, ꢁ3.8, ꢁ3.9,

ꢁ4.2, 2ꢂꢁ4.4, 3ꢂꢁ4.5, 2ꢂꢁ5.1 (12 SiCH₃). ESI-HRMS: [MþNa]^þm/z

calcd for C₅₇H₁₁₆O₁₀SSi₆Na 1183.6802, found 1183.6806.

(dd, J_H2,H33.39, J_H3,H410.04, 1H, H-3), 5.20 (d, J_H1,H21.56, 1H, H-1),

5.10 (dd, J_H3,H410.04, J_H4,H59.84, 1H, H-4), 4.24 (dq, J_H4,H59.84,

J_H5,H66.26 1H, H-5), 2.64 (dq, 2H, SCH₂CH₃), 2.16, 2.06, 1.99 (3 s,

9H, CH₃), 1.30 (t, 3H, SCH₂CH₃), 1.24 (d, J_H5,H66.26, 3H, H-6). ¹³C

NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

a-anomeric form: d 170.2, 170.1,

170.0 (3 C]O), 82.1 (C-1), 71.7 (C-2), 71.5 (C-4), 69.6 (C-3), 67.1

(C-5), 25.6 (SCH₂CH₃), 21.1, 20.9, 20.8 (3 CH₃), 17.5 (C-6), 14.9

(SCH2CH3). ESI-HRMS: [MþNa]^þm/z calcd for C₁₄H₂₂O₇NaS

357.0984, found 357.0980.

4.1.11. Methyl 4,6-O-benzylidene-2-O-acetyl-b-D-galactopyranoside

(16). Compound 15 (0.56 g, 1.99 mmol) was dissolved in dry pyri-

dine (10 mL) and acetic anhydride (0.375 mL, 3.99 mmol) was

added at room temperature and the mixture was stirred overnight.

At completion, the reaction was quenched with MeOH at 0 ^ꢀC.

Solvents were evaporated and co-evaporation with toluene was

performed. The brown oil obtained was taken up into EtOAc and

washed successively with brine, 1M HCl, brine, satd NaHCO₃and

brine. The organic phase was dried over MgSO₄and solvents were

evaporated. The residual mixture was puriﬁed by column chro-

matography (R_f¼0.28 Pentane/EtOAc 1:4) to obtain compound 15

as a white powder (142 mg, 22%). ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

4.1.13. Methyl 4,6-O-benzylidene-3-O-ﬂuorenylmethyloxycarbonyl-

b-D-galactopyranoside (18). Compound 15 (300 mg, 1.1 mmol) and

DMAP (13 mg, 0.1 equiv) were dissolved in a 2/1 mixture of pyri-

dine/acetonitrile (5 mL). FMOCCl (303 mg, 1.1 equiv) was added

portionwise at ꢁ10 ^ꢀC. The mixture was left to attain room tem-

perature and was stirred overnight. At completion (TLC: R_f¼0.6

Pentane/EtOAc 1:9), the reaction was quenched with MeOH at 0 ^ꢀC.

It was then diluted with EtOAc and washed successively with brine,

1 M HCl, brine, saturated NaHCO₃and brine. The solution was dried

over Na₂SO₄. Solvents were evaporated and co-evaporation with

toluene was performed. The residue obtained was puriﬁed by

chromatography to give 365 mg (68% yield) of pure 18. ¹H NMR

d

7.55e7.48 (m, 2H, HeAr), 7.42e7.35 (m, 3H, HeAr), 5.56 (s, 1H,

CHPh), 5.10 (dd, J_H1,H28.00, J_H2,H39.98, 1H, H-2), 4.38 (d, J_H1,H28.00,

1H, H-1), 4.37 (dd, J_H5,H6b1.57, J_gem12.47, 1H, H-6b), 4.22 (dd, J_H3,H4

3.89, J_H4,H51.23, 1H, H-4), 4.10 (dd, J_H5,H6a1.97, J_gem12.47, 1H, H-6a),

3.74 (ddd, J_H2,H39.98, J_H3,H43.89, J_H3,OH-311.24, 1H, H-3), 3.53 (s, 3H,

OMe), 3.50 (ddd, J_H4,H51.23, J_H5,H6a1.97, J_H5,H6b1.57, 1H, H-5), 2.44

(dd, J_H3,OH-311.24, 1H, OH-3), 2.13 (s, 3H, CH₃). ¹³C NMR (CDCl₃,

(CDCl₃, 25 ^ꢀC, 400 MHz):

CHPh), 4.73 (dd, J_H2,H310.12, J_H3,H43.65, 1H, H-3), 4.47 (d, J_H,CH7.84,

J_gem10.37, 1H, ArCHCH₂OCO), 4.42 (d, J_H,CH5.19, J_gem10.37, 1H,

ArCHCH₂OCO), 4.42 (dd, J_H3,H43.65, J_H4,H51.01, 1H, H-4), 4.36 (dd,

d 7.76e7.19 (m, 13H, HeAr), 5.52 (s, 1H,

922

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

J_H5,H6b1.61, J_gem12.42, 1H, H-6b), 4.30 (d, J_H1,H27.80, 1H, H-1), 4.29

(dd, J_H,CH2a7.84, J_H,CH2b5.19, 1H, ArCHCH₂OCO), 4.10 (dd, J_H1,H27.80,

J_H2,H310.12, 1H, H-2), 4.08 (dd, J_H5,H6a1.83, J_gem12.42, 1H, H-6a),

3.60 (s, 3H, OMe), 3.51 (ddd, J_H4,H51.01, J_H5,H6a1.83, J_H5,H6b1.61, 1H,

white solids 20a, 20b and 20c in 18, 25 and 25% yield, respectively.

20a: ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

7.47e7.26 (m, 10H, HeAr),

d

5.21 (d, J_H1,H22.80, 1H, G), 5.19 (s, 1H, CHPh), 5.19 (dd, J_H1,H28.04,

J_H2,H310.02, 1H, H-2 Gal), 4.92 (d, J_H1,H26.08, 1H, H-1 G⁰), 4.61 (d,

J_gem12.04, 1H, PhCH₂G), 4.48 (d, J_gem12.04, 1H, PhCH₂G), 4.43 (dd,

J_H3,H43.32, J_H4,H50.79, 1H, H-4 Gal), 4.31 (d, J_H1,H28.04, 1H, H-1 Gal),

4.12 (dd, J_H3,H45.41, J_H4,H510.71, 1H, H-4 G), 4.00 (dd, J_H5,H6b1.39,

J_gem12.16, 1H, H-6b Gal), 3.99 (dd, 1H, H-4 G⁰), 3.87 (ddd, J_H4,H5

10.61, J_H5,H6a2.54, J_H5,H6b4.02, 1H, H-5 G), 3.81 (dd, 1H, H-2 G), 3.79

(dd, 1H, H-3 G), 3.78 (ddd, 1H, H-5 G⁰), 3.77 (dd, 1H, H-3 Gal), 3.76

(dd, 1H, H-6b G⁰), 3.75 (dd, 1H, H-3 G⁰), 3.66 (dd, J_H5,H6b4.02, 1H, H-

6b G), 3.63 (dd, 1H, H-6a G⁰), 3.62 (dd, J_H5,H6a2.54, 1H, H-6a G), 3.58

(dd, 1H, H-2 G⁰), 3.46 (s, 3H, OMe Gal), 3.29 (dd, J_H5,H6a1.75, J_gem

12.16, 1H, H-6a Gal), 3.12 (ddd, J_H4,H50.79, J_H5,H6a1.75, J_H5,H6b1.39,

1H, H-5 Gal), 2.05 (s, 3H, CH₃), 0.90, 0.89, 0.88, 0.87, 0.80, 0.75 (6 s,

54H, C(CH₃)₃), 0.11, 0.10e0.05, ꢁ0.012, ꢁ0.13, ꢁ0.14 (12 s, 36H,

H-5), 2.44 (nr, 1H, OH-2). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d 154.8

(ArCHCH₂OC]O), 143.5, 143.2, 2ꢂ141.4, 137.6, (5 C-ipso), 129.1,

2ꢂ128.3, 2ꢂ128.0, 127.3, 127.3, 2ꢂ126.4, 2ꢂ125.4, 2ꢂ120.2

(13 CeAr), 104.0 (C-1), 101.0 (CHPh), 77.4 (C-3), 73.3 (C-4), 70.3

(ArCHCH₂OCO), 69.1 (C-6), 68.7 (C-2), 66.5 (C5), 57.4 (OMe), 46.8

(ArCHCH₂OCO). ESI-HRMS: [MþNa]^þm/z calcd for C₂₉H₂₈O₈Na

527.1682, found 527.1679.

4.1.14. Methyl 2,3,4-tri-O-acetyl-

a

-L-rhamnopyranosyl-(1/2)-4,6-

O-benzylidene- -galactopyranoside (19). A solution of thioglyco-

b-D

side 17 (100 mg, 0.3 mmol, 1.5 equiv) and acceptor 18 (100 mg,

0.2 mmol) in dry CH₂CL₂was stirred for 20 min in the presence of

molecular sieves (4 A, 0.4 g) under N₂atmosphere. NIS (2 equiv)

SiCH₃). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d 169.1 (C]O Gal), 138.6,

ꢁ

and AgOTf (0.5 equiv) were added at 0 ^ꢀC. The reaction was mon-

itored by TLC and left to stir at room temperature for one hour. Once

the acceptor was consumed, TEA (25 equiv) was added to quench

the reaction and to cleave the FMOC protecting group. After 30 min

(R_f¼0.56 Pentane/EtOAc 1:2), the mixture was ﬁltered through

Celite. It was then diluted with CH₂Cl₂and washed successively

with solutions of satd Na₂S₂O₃, brine and dried over Na₂SO₄. The

solvent was removed in vacuo and the residue thus obtained was

puriﬁed by ﬂash chromatography to yield 90 mg of 19 as a white

138.1 (2 C-ipso), 2ꢂ128.7, 2ꢂ128.3, 4ꢂ128.1, 2ꢂ126.7 (10 CeAr),

102.0 (C-1 Gal), 101.9 (C-1 G⁰), 101.6 (C-1 G), 100.8 (CHPh Gal), 81.8

(C-5 G⁰), 79.9 (C-2 G), 79.7 (C-3 G⁰), 78.8 (C-3 G), 77.7 (C-2 G⁰), 77.1

(C-3 Gal), 75.7 (C-4 Gal), 73.5 (PhCH₂G), 72.9 (C-5 G), 72.5 (C-4 G),

70.4 (C-2 Gal), 70.2 (C-6 G), 70.2 (C-4 G⁰), 68.7 (C-6 Gal), 66.9 (C-5

Gal), 64.1 (C-6 G⁰), 55.8 (OMe Gal), 26.15, 26.1e26.0 (6 C(CH₃)₃), 21.1

(CH₃), 18.4e18.1 (6 C(CH₃)₃), ꢁ2.8 to ꢁ5.2 (12 SiCH₃). 20b and 20c:

¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d 7.51e7.29 (m, 10H, HeAr), 5.56

(s, 1H, CHPh Gal 20c), 5.33 (dd, J_H1,H28.07, J_H2,H39.93, 1H, H-2 Gal

20c), 5.30 (s, 1H, CHPh Gal 20b), 5.25 (dd, J_H1,H28.00, J_H2,H310.20,

1H, H-2 Gal 20b), 5.04 (d, J_H1,H26.38, 1H, H-1 G⁰20b), 5.02 (d, J_H1,H2

3.49, 1H, H-1 G 20c), 4.89 (d, J_H1,H25.30, 1H, H-1 G⁰20c), 4.83 (d,

J_H1,H25.03, 1H, H-1 G 20b), 4.58e4.52 (2 d, J_gem12.19, 2H, PhCH₂G,

20b), 4.54e4.49 (2 d, J_gem11.68, 2H, PhCH₂G, 20c), 4.40 (dd, J_H3,H4

3.35, J_H4,H50.51, 1H, H-4 Gal, 20c), 4.37 (dd, J_H3,H43.53, J_H4,H50.51,

1H, H-4 Gal, 20b), 4.325 (d, J_H1,H28.00, 1H, H-1 Gal, 20b), 4.32 (dd,

J_H5,H6b1.51, J_gem12.38, 1H, H-6b Gal, 20c), 4.30 (d, J_H1,H28.07, 1H, H-

1 Gal, 20c), 4.08 (dd, J_H5,H6b1.52, J_gem12.30, 1H, H-6b Gal, 20b), 4.03

(dd, J_H5,H6a1.76, J_gem12.38, 1H, H-6a Gal, 20c), 3.96 (m, 1H, H-4 G⁰,

20b), 3.91 (dd, J_H2,H38.81, J_H3,H48.32,1H, H-3 G, 20c), 3.84 (dd, J_H2,H3

9.93, J_H3,H43.35, 1H, H-3 Gal, 20c), 3.81 (ddd, 1H, H-5 G, 20c), 3.80

(dd, J_H2,H310.20, J_H3,H43.53, 1H, H-3 Gal, 20b), 3.77 (dd, 1H, H-3 G⁰,

20b), 3.75 (ddd, 1H, H-5 G, 20b), 3.74 (dd, 1H, H-4 G⁰, 20c), 3.74 (dd,

1H, H-3 G⁰, 20c), 3.73 (m, 2H, H-6b G⁰20c, H-6b G 20b), 3.71 (ddd,

1H, H-5 G⁰, 20b), 3.71 (dd, 1H, H-4 G, 20b), 3.70 (m, 2H, H-6a, H-6b

G⁰, 20b), 3.69 (ddd, 1H, H-5 G⁰, 20c), 3.67 (dd, 1H, H-6b G, 20c), 3.62

(m, 2H, H-2 G 20c, H-2 G 20b), 3.62 (dd, 1H, H-6a G⁰, 20c), 3.61 (dd,

1H, H-6a G, 20b), 3.59 (dd, 1H, H-2 G⁰, 20c), 3.58 (dd, 1H, H-2 G⁰,

20b), 3.55 (dd, 1H, H-4 G, 20c), 3.54 (dd, 1H, H-3 G, 20b), 3.53 (dd,

1H, H-6a G, 20c), 3.48 (s, 3H, OMe Gal, 20b), 3.48 (s, 3H, OMe Gal,

20c), 3.46 (dd, J_H5,H6a1.83, J_gem12.30, 1H, H-6a Gal, 20b), 3.36 (ddd,

J_H4,H50.51, J_H5,H6a1.76, J_H5,H6b1.51,1H, H-5 Gal, 20c), 3.11 (ddd, J_H4,H5

0.51, J_H5,H6a1.83, J_H5,H6b1.52, 1H, H-5 Gal, 20b), 2.99 (nr, 1H, OH-3,

20b), 2.22 (nr, 1H, OH-4 20c), 2.06 (s, 3H, CH₃, 20b), 2.02 (s, 3H, CH₃,

20c), 0.91e0.83 (10 s, 90H, C(CH₃)₃), 0.14, 0.12e0.05, ꢁ0.05 (20s,

powder (82% yield). ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d 7.51e7.35

(m, 5H, HeAr Gal), 5.54 (s, 1H, CHPh Gal), 5.36 (dd, J_H1,H21.73, J_H2,H3

3.44, 1H, H-2 R), 5.28 (dd, J_H2,H33.44, J_H3,H410.09, 1H, H-3 R), 5.22

(d, J_H1,H21.73, 1H, H-1 R), 5.01 (dd, J_H3,H410.09, J_H4,H510.02, 1H, H-4

R), 4.35 (dd, J_H5,H6b1.39, J_gem12.45, 1H, H-6b Gal), 4.28 (d, J_H1,H2

7.49, 1H, H-1 Gal), 4.23 (dq, J_H4,H510.02, J_H5,H66.29, 1H, H-5 R), 4.17

(dd, J_H3,H43.61, J_H4,H50.93, 1H, H-4 Gal), 4.08 (dd, J_H5,H6a1.81, J_gem

12.45, 1H, H-6a Gal), 3.82 (ddd, J_H2,H39.20, J_H3,H43.61, J_H3,OH-310.03,

1H, H-3 Gal), 3.77 (dd, J_H1,H27.49, J_H2,H39.20, 1H, H-2 Gal), 3.56 (s,

3H, OMe Gal), 3.48 (ddd, J_H4,H50.93, J_H5,H6a1.81, J_H5,H6b1.39, 1H, H-5

Gal), 2.50 (nr, 1H, OH-3 Gal). 2.12, 2.06, 1.98 (3 s, 9H, CH₃R), 1.20 (d,

J_H5,H66.29, 3H, H-6 R). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d 170.4,

2ꢂ170.2 (3C]O R), 137.4 (C-ipso Gal), 129.4, 2ꢂ128.4, 2ꢂ126.5

(5 CeAr Gal), 102.4 (C-1 Gal), 101.6 (CHPh Gal), 98.1 (C-1 R), 76.1 (C-

2 Gal), 75.8 (C-4 Gal), 73.8 (C-3 Gal), 71.2 (C-4 R), 69.9 (C-2 R), 69.5

(C-3 R), 69.2 (C-6 Gal), 66.6 (C-5 R), 66.6 (C-5 Gal), 56.9 (OMe Gal),

21.1, 21.0, 20.9 (CH₃R), 17.2 (C-6 R), ESI-HRMS: [MþNa]^þm/z calcd

for C₂₆H₃₄O₁₃Na 577.1897, found 577.1901.

4.1.15. Methyl 2,3,4,6-tetra-O-tert-butyldimethylsilyl-

anosyl-(1/2)-3,4-di-O-tert-butyldimethylsilyl-6-O-benzyl-

copyranosyl-(1/3)-4,6-O-benzylidene-2-O-acetyl- -galactopyr-

anoside (20a). Methyl 2,3,4,6-tetra-O-tert-butyldimethylsilyl-

glucopyranosyl-(1/2)-4-O-tert-butyldimethylsilyl-6-O-benzyl-

glucopyranosyl-(1/3)-4,6-O-benzylidene-2-O-acetyl-

actopyranoside (20b). Methyl 2,3,4,6-tetra-O-tert-butyldimethylsilyl-

b-

D-glucopyr-

b-D

-glu-

b-D

b

-

D

-

b

-

b-D-gal-

b

-

D

-glucopyranosyl-(1/2)-3-O-tert-butyldimethylsilyl-6-O-benzyl-

-glucopyranosyl-(1/3)-4,6-O-benzylidene-2-O-acetyl- -gal-

60H, SiCH₃). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d 169.9 (C]O Gal,

b

D

b

-

D

20c), 169.5 (C]O Gal, 20b), 138.5, 138.2, 138.0, 137.9 (4 C-ipso),

129.0, 128.9, 2ꢂ128.7, 2ꢂ128.6, 8ꢂ128.2, 128.1, 2ꢂ128.0, 127.9,

2ꢂ126.6, 2ꢂ126.5 (20 CeAr), 103.2 (C-1 G⁰, 20c), 102.05 (C-1 G⁰,

20b), 102.0 (C-1 G, 20b), 102.0 (C-1 Gal, 20c), 101.9 (C-1 Gal, 20b),

101.8 (C-1 G, 20c), 101.1 (CHPh Gal, 20b), 100.9 (CHPh Gal, 20c), 82.2

(C-4 G⁰, 20c), 81.5 (C-5 G⁰, 20c), 80.3 (C-2 G, 20b), 79.8 (C-3 Gal,

20c), 79.6 (C-4 G⁰, 20b), 79.3 (C-3 G⁰, 20c), 79.0 (C-2 G, 20c), 78.9 (C-

2 G⁰, 20c), 77.9 (C-3 Gal, 20b), 77.8 (C-2 G⁰, 20b), 77.4 (C-3 G, 20b),

75.6 (C-4 Gal, 20b), 75.3 (C-4 Gal, 20c), 74.5 (C-3 G, 20c), 74.4 (C-5

G⁰, 20b), 73.7 (PhCH₂G, 20c), 73.6 (PhCH₂G, 20b), 72.6 (2 C-4 G,

20b, 20c), 71.6 (C-5 G, 20b), 70.4 (C-5 G, 20c), 70.4 (C-2 Gal, 20c),

70.3 (C-6 G, 20b), 69.9 (C-3 G⁰, 20b), 69.6 (C-2 Gal, 20b), 69.5 (C-6 G,

20c), 69.0 (C-6 Gal, 20c), 68.8 (C-6 Gal, 20b), 67.0 (C-5 Gal, 20c),

actopyranoside (20c). A 1 M solution of the promoter system

Tf₂O-DMDS (1.1 equiv) in dry CH₂Cl₂was added to the mixture

containing the armed-donor 14 (40 mg, 0.035 mmol), the acceptor

ꢁ

16 (1.2 equiv), 2,6-DTBMP (2 equiv) and activated 4 A molecular

sieves (100 mg) in dry CH₂Cl₂(0.5 mL) at ꢁ78 ^ꢀC under N₂atmo-

sphere. The reaction mixture was stirred for 15 min and was

allowed to reach ꢁ40 ^ꢀC (20a R_f¼0.65, 20b, 20c R_f¼0.45 Pentane/

EtOAc 4:1). It was then quenched with NEt₃(3 equiv), diluted with

CH₂Cl₂, ﬁltered through Celite and washed with a 2 M HCl solution,

aqueous NaHCO₃and brine. The organic phase was dried over

Na₂SO₄and concentrated under vacuum. After evaporation, the

resulting material was puriﬁed by chromatography to afford as

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

923

66.7 (C-5 Gal, 20b), 64.6 (C-6 G⁰, 20c), 63.8 (C-6 G⁰, 20b), 56.0 (OMe

Gal, 20b), 55.9 (OMe Gal, 20c), 26.5, 26.2e25.9 (10 C(CH₃)₃), 21.5

(CH₃, 20b), 21.4 (CH₃, 20c), 18.7e17.9 (10 C(CH₃)₃), ꢁ2.9 to ꢁ5.2 (10

SiCH₃). ESI-HRMS: [MþNa]^þm/z calcd for 20a: C₇₁H₁₃₀O₁₇Si₆Na

1445.7821, found 1445.7823, for 20b and 20c: C₆₅H₁₁₆O₁₇Si₅Na

1331.6957, found 1331.6954.

form: d 7.35e7.28 (m, 5H, HeAr), 5.35 (d, J_H1,H25.41, 1H, H-1), 4.85

(br, 1H, OH-3), 4.56 (2d, J_gem12.11, 2H, PhCH₂), 4.13 (br, 1H, OH-4),

4.11 (ddd, J_H4,H59.84, J_H5,H6a3.10, J_H5,H6b4.64, 1H, H-5), 3.96 (br,

1H, OH-2), 3.82 (m, 1H, H-2), 3.74 (dd, J_H5,H6b4.64, J_gem10.88, 1H,

H-6b), 3.69 (dd, J_H5,H6a3.10, J_gem10.88, 1H, H-6a), 3.63 (dd, J_H2,H3

9.28, J_H3,H49.45, 1H, H-3), 3.55 (dd, J_H3,H49.45, J_H4,H59.84, 1H, H-4),

2.59 (m, 2H, SCH₂CH₃), 1.26 (t, 3H, SCH₂CH₃). ¹³C NMR (CDCl₃,

4.1.16. Methyl 2,3,4,6-tetra-O-tert-butyldimethylsilyl-

anosyl-(1/2)-3,4-di-O-tert-butyldimethylsilyl-6-O-benzyl-

copyranosyl-(1/3)-4,6-O-benzylidene- -galactopyranoside

b

-D-glucopyr-

25 ^ꢀC, 100 MHz):

a-anomeric form:

d

138.1 (C-ipso), 2ꢂ128.5,

b

-

D

-glu-

3ꢂ127.7 (5 CeAr), 86.1 (C-1), 75.2 (C-3), 73.6 (PhCH₂), 71.6 (C-2),

71.2 (C-5), 70.9 (C-4), 69.7 (C-6), 25.2 (SCH₂CH₃), 15.1 (SCH₂CH₃).

ESI-HRMS: [MþNa]^þm/z calcd for C₁₅H₂₂O₅SNa 337.1086, found

337.1082.

b-D

(21). For general acyl group deprotection conditions see the above

reaction conditions for compound 7. Starting from 20 mg of com-

pound 20a (TLC: R_f¼0.45 Pentane/EtOAc 4:1) O-deacylation yielded

compound 21 in 55% yield as a colorless oil. ¹H NMR (CDCl₃, 25 ^ꢀC,

4.1.19. Ethyl 2,3,4-tri-O-benzoyl-6-O-benzyl-1-thio-a/b-D-glucopyr-

400 MHz):

d

7.47e7.26 (m, 10H, HeAr), 5.21 (d, J_H1,H24.71, 1H, H-1

anoside (25). Compound 24 (500 mg, 1.6 mmol) was dissolved in

dry pyridine (30 mL). Benzoyl chloride (0.74 mL, 6.4 mmol, 4 equiv)

was added slowly at 0 ^ꢀC. The mixture was left to attain room

temperature and was stirred overnight. At completion (TLC: R_f¼0.72

Pentane/EtOAc 3:1), the reaction was quenched with MeOH at 0 ^ꢀC.

Solvents were evaporated and co-evaporation with toluene was

performed. The brown oil obtained was dissolved in EtOAc and

washed successively with brine, 1M HCl, brine, satd NaHCO₃and

brine. The solution was dried over Na₂SO₄and solvents were

evaporated. The residue was puriﬁed by column chromatography

and 968 mg (97% yield) of white solid 25 was isolated. ¹H NMR

G), 5.29 (s, 1H, CHPh Gal), 4.93 (d, J_H1,H25.97, 1H, H-1 G⁰), 4.56 (d,

J_gem12.09, 1H, PhCH₂G), 4.50 (d, J_gem12.09, 1H, PhCH₂G), 4.33 (dd,

J_H3,H43.39, J_H4,H50.71, 1H, H-4 Gal), 4.23 (d, J_H1,H27.74, 1H, H-1 Gal),

4.16 (d, J_H5,H6b1.51, J_gem12.17, 1H, H-6b Gal), 3.96 (m, 1H, H-4 G⁰),

3.94 (ddd, 1H, H-5 G), 3.92 (dd, 1H, H-4 G), 3.89 (m, 2H, H-2 G, H-3

G), 3.87 (dd, 1H, H-2 Gal), 3.77 (ddd, 1H, H-5 G⁰), 3.76 (dd, 1H, H-3

G⁰), 3.72 (m, 2H, H-6a, H-6b G⁰), 3.71 (dd, 1H, H-6a Gal), 3.64 (dd,

1H, H-6b G), 3.59 (dd, 1H, H-2 G⁰), 3.55 (dd, 1H, H-6a G), 3.54 (dd,

1H, H-3 Gal), 3.54 (s, 3H, OMe Gal), 3.26 (ddd, 1H, H-5 Gal), 2.88 (nr,

1H, OH-2 Gal); 0.90, 0.885, 2ꢂ0.88, 0.84, 0.82, (6 s, 54H, C(CH₃)₃),

0.12, 0.10e0.05, ꢁ0.05, ꢁ0.13, (12 s, 36H, SiCH₃). ¹³C NMR (CDCl₃,

(CDCl₃, 25 ^ꢀC, 400 MHz):

a-anomeric form: d 8.00e7.13 (m, 20H,

25 ^ꢀC, 100 MHz):

d

138.6, 138.3 (2 C-ipso), 128.7, 2ꢂ128.6, 2ꢂ128.1,

HeAr), 6.04 (dd, J_H2,H39.86, J_H3,H49.95, 1H, H-3), 5.97 (d, J_H1,H25.83,

1H, H-1), 5.68 (dd, J_H3,H49.95, J_H4,H59.72, 1H, H-4), 5.50 (dd, J_H1,H2

5.83, J_H2,H39.86, 1H, H-2), 4.70 (ddd, J_H4,H59.72, J_H5,H6a3.73, J_H5,H6b

3.73, 1H, H-5), 4.55 (2d, J_gem12.03, 2H, PhCH₂), 3.69 (m, 2H, H-6a, H-

6b), 2.63 (m, 2H, SCH₂CH₃), 1.27 (t, 3H, SCH₂CH₃). ¹³C NMR (CDCl₃,

2ꢂ128.0, 127.8, 2ꢂ126.7 (10 CeAr), 104.2 (C-1 Gal), 102.2 (C-1 G),

102.0 (C-1 G⁰), 101.0 (CHPh Gal), 82.0 (C-5 G⁰), 81.6 (C-3 Gal), 80.3

(C-2 G), 79.3 (C-3 G⁰), 78.0 (C-3 G), 77.8 (C-2 G⁰), 75.8 (C-5 G), 75.75

(C-4 Gal), 73.5 (PhCH₂G), 72.5 (C-4 G), 71.2 (C-6 G), 70.3 (C-4 G⁰),

69.5 (C-2 Gal), 69.2 (C-6 Gal), 66.9 (C-5 Gal), 64.0 (C-6 G⁰), 56.9

(OMe Gal), 26.2, 26.1e26.0 (5C(CH3)3), 18.5e18.1 (5 C(CH₃)₃), ꢁ3.3

to ꢁ5.1 (5 SiCH₃). ESI-HRMS: [MþNa]^þm/z calcd for

25 ^ꢀC, 100 MHz):

a-anomeric form: d 165.8, 165.5, 165.3 (3C]O),

137.7,133.5,133.4,133.2 (4 C-ipso), 2ꢂ130.1, 2ꢂ129.9, 2ꢂ129.8,129.3,

129.2, 129.1, 2ꢂ128.5, 2ꢂ128.4, 4ꢂ128.3, 2ꢂ127.8, 127.7 (20 CeAr),

82.1 (C-1), 73.7 (PhCH₂), 71.9 (C-2), 71.3 (C-4), 69.6 (C-3), 69.4 (C-5),

68.5 (C-6), 24.3 (SCH₂CH₃),14.7 (SCH₂CH₃). ESI-HRMS: [MþNa]^þm/z

calcd for C₃₆H₃₄O₈SNa 649.1872, found 649.1874.

C

₆₉H₁₂₈O₁₆Si₆Na 1403.7716 found 1403.7720.

4.1.17. Ethyl 1-thio- -glucopyranoside (23). For general acyl

a/b-D

group deprotection conditions see the above reaction conditions

for compound 7. Starting from ethyl 2,3,4,6-tetra-O-acetyl-1-thio-

4.1.20. 2,3,4-Tri-O-benzoyl-6-O-benzyl-a/b-D-glucopyranose

a

/

b

-

D

-glucopyranoside⁵⁶(3 g, 13 mmol, 90/10

a

/

b

, TLC: R_f¼0.15

DCM/MeOH 9:1) O-deacylation yielded 1.58 g of compound 23 as

a colorless oil (92%). ¹H NMR (CD₃OD, 25 ^ꢀC, 400 MHz):

-anomeric

form: 5.37 (d, J_H1,H25.48, 1H, H-1), 3.99 (ddd, J_H4,H59.82, J_H5,H6a

(26). Compound 26 (1 g, 1.6 mmol) was dissolved in a 4:1 DCM/

Acetone mixture (30 ml), NIS (719 mg, 2 equiv) was added pro-

gressively at 0 ^ꢀC. After 30 min, 5 equiv of water were added

dropwise at room temperature. At completion (TLC: R_f¼0.45 Pen-

tane/EtOAc 3:1), the reaction was quenched with a 10% aq solution

of Na₂S₂O₃. The mixture was diluted with DCM and washed three

times with Na₂S₂O₃solution (20 mL). The DCM solution was dried

over Na₂SO₄, ﬁltered and concentrated to dryness. Puriﬁcation by

column chromatography gave 726 mg (78% yield) of white solid 26.

¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz): d a-anomeric form: 8.00e7.15 (m,

20H, HeAr), 6.20 (dd, J_H2,H39.94, J_H3,H49.88, 1H, H-3), 5.75 (dd,

J_H1,H23.71, J_H1,OH-13.52, 1H, H-1), 5.58 (dd, J_H3,H49.64, J_H4,H510.10,

1H, H-4), 5.29 (dd, J_H1,H23.71, J_H2,H39.94, 1H, H-2), 4.54 (2d, J_gem

12.00, 2H, PhCH₂), 4.53 (m,1H, H-5), 3.68e3.66 (m, 2H, H-6a, H-6b),

a

d

5.45, J_H5,H6b2.35, 1H, H-5), 3.83 (dd, J_H5,H6b2.35, J_gem11.90, 1H, H-

6b), 3.74 (dd, J_H5,H6b5.45, J_gem11.90, 1H, H-6a), 3.71 (dd, J_H1,H25.48,

J_H2,H39.77, 1H, H-2), 3.55 (dd, J_H2,H39.77, J_H3,H48.98, 1H, H-3), 3.35

(dd, J_H3,H48.98, J_H4,H59.82, 1H, H-4), 2.64 (m, 2H, SCH₂CH₃), 1.32 (t,

3H, SCH₂CH₃). ¹³C NMR (CD₃OD, 25 ^ꢀC, 400 MHz):

a-anomeric

form:

d 86.8 (C-1), 75.6 (C-3), 73.9 (C-5), 73.1 (C-2), 71.8 (C-4), 62.5

(C-6), 24.9 (SCH₂CH₃), 15.2 (SCH₂CH₃). ESI-HRMS: [MþNa]^þm/z

calcd for C₈H₁₆O₅SNa 247.0616, found 247.0619.

4.1.18. Ethyl

6-O-benzyl-1-thio-

a/

b

-D-glucopyranoside

(24). In

a 50 mL round-bottomed ﬂask, ethyl 1-thio-

a

/b

-D

-glucopyranoside

3.56 (d, J_H1,OH-13.52, 1H, OH-1). b-anomeric form: d 5.89 (dd, J_H2,H3

(500 mg, 2.2 mmol) was dissolved in DMF (10 mL) and 60% so-

dium hydride in oil dispersion (300 mg, 8.9 mmol, 4 equiv) was

progressively added at room temperature; 30 min later, benzyl

bromide (0.4 ml, 3.3 mmol, 1.5 equiv) was added dropwise at 0 ^ꢀC.

The reaction mixture was slowly left to attain room temperature.

After disappearance of the starting material (7 h), the reaction was

quenched with methanol at 0 ^ꢀC. The mixture was washed with

NaHCO₃and brine, dried over Na₂SO₄, ﬁltered and concentrated to

dryness. The residue obtained was puriﬁed by column chroma-

tography (TLC: R_f¼0.75 Acetone/Pentane 3:1) to yield 505 mg of

9.95, J_H3,H49.65, 1H, H-3), 5.62 (dd, J_H3,H49.65, J_H4,H59.77, 1H, H-4),

5.33 (dd, J_H1,H28.02, J_H2,H39.95, 1H, H-2), 4.99 (dd, J_H1,H28.02,

J_H1,OH-18.52, 1H, H-1), 4.54 (2d, J_gem11.95, 2H, PhCH₂), 4.04 (d,

J_H1,OH-18.52,1H, OH-1), 3.99 (ddd,1H, H-5), 3.68e3.66 (m, 2H, H-6a,

H-6b). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d

166.9, 2ꢂ166.0, 165.9,

165.5, 165.3 (6 C]O), 137.6, 137.5, 133.7, 2ꢂ133.5, 133.4, 133.4, 133.2

(8 C-ipso) 2ꢂ130.1, 2ꢂ130.0, 6ꢂ129.9, 2ꢂ129.8, 129.4, 2ꢂ129.2,

129.1, 129.0, 128.9, 4ꢂ128.6, 10ꢂ128.5, 2ꢂ128.4, 2ꢂ128.1, 2ꢂ128.0,

2ꢂ127.8 (40 CeAr);

a

-anomeric form:

d

90.5 (C-1), 73.8 (PhCH₂),

-anomeric

d 96.1 (C-1), 74.4 (C-2), 74.0 (C-5), 73.9 (PhCH₂),72.7 (C-3),

72.4 (C-2), 70.4 (C-3), 69.8 (C-4), 69.0 (C-5), 68.9 (C-6).

form:

b

24 (72%) as an oil. ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

a

-anomeric

924

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

69.7 (C-4), 68.8 (C-6). ESI-HRMS: [MþNa]^þm/z calcd for

let to stir for 5 min under N₂atmosphere. Anhydrous AlCl₃(327 mg,

2.34 mmol, 6 equiv) was added and once it was fully dissolved,

2 equiv of water was added dropwise; after 16 h (R_f¼0.6 Pentane/

EtOAc 2:1) the reaction was stopped by addition of 5 mL of water.

The reaction mixture was dissolved in EtOAc and washed with

a solution of 1 M HCl, followed by brine and subsequently dried

over Na₂SO₄. The mixture was ﬁltered and concentrated to dryness.

Puriﬁcation by column chromatography yielded 317 mg (79% yield)

C

₃₄H₃₀O₉Na 605.1788, found 605.1792.

4.1.21. 2,3,4-Tri-O-benzoyl-6-O-benzyl-

a/

b

-D-glucopyranosyl

tri-

chloroacetimidate (27). To a solution of compound 26 (1.2 g,

2.06 mmol) and Cl₃CCN (2.06 mL, 20.6 mmol, 10 equiv) in dry

CH₂Cl₂(40 mL) was added freshly dried and powdered K₂CO₃

(1.14 g, 8.24 mmol, 4 equiv) at room temperature with intensive

stirring. After 4 h (TLC: R_f¼0.65 Pentane/EtOAc 3:1), the mixture

was diluted with CH₂Cl₂and ﬁltered through a Celite pad. Solvents

were evaporated and the brown residue was immediately puriﬁed

by ﬂash chromatography to yield 1.27 g (85% yield) of 27 as a foam.

of 29 as a colorless oil. ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d 7.96e7.14

(m, 32H, HeAr), 5.85 (dd, J_H2,H39.63, J_H3,H49.55, 1H, H-3 G⁰), 5.65

(dd, J_H3,H49.55, J_H4,H58.45, 1H, H-4 G⁰), 5.63 (dd, J_H1,H27.96, J_H2,H3

9.63, 1H, H-2 G⁰), 5.43 (d, J_H1,H27.96, 1H, H-1 G⁰), 4.85 (d, J_gem11.50,

1H, NapCH₂G), 4.75 (d, J_gem11.50, 1H, NapCH₂G), 4.60 (d, J_gem

12.12, 1H, PhCH₂G⁰), 4.56 (d, J_gem11.92, 1H, PhCH₂G), 4.55 (d, J_gem

12.12, 1H, PhCH₂G⁰), 4.52 (d, J_gem11.92, 1H, PhCH₂G), 4.47 (d, J_H1,H2

9.75, 1H, H-1 G), 3.91 (ddd, 1H, H-5 G⁰), 3.89 (dd, J_H1,H29.75, J_H2,H3

8.72, 1H, H-2 G), 3.74e3.62 (m, 3H, H-6a, H-6b, H-4 G), 3.72 (m, 2H,

H-6a, H-6b G⁰), 3.47 (dd, J_H2,H38.72, J_H3,H48.77, 1H, H-3 G), 3.38

(ddd, 1H, H-5 G), 2.73 (dq, 2H, SCH₂CH₃G), 2.56 (nr, 1H, OH-4 G),

¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

a-anomeric form: d 8.62 (s, 1H,

NH), 7.98e7.12 (m, 20H, HeAr), 6.86 (d, J_H1,H23.65, 1H, H-1), 6.25

(dd, J_H2,H310.02, J_H3,H49.98, 1H, H-3), 5.85 (dd, J_H3,H49.98, J_H4,H5

10.06, 1H, H-4), 5.60 (dd, J_H1,H23.65, J_H2,H310.02, 1H, H-2), 4.54 (2 d,

J_gem11.96, 2H, PhCH₂), 4.48 (ddd, J_H4,H510.06, J_H5,H6a4.16, J_H5,H6b

2.72, 1H, H-5), 3.74 (dd, J_H5,H6b2.72, J_gem11.20, 1H, H-6b), 3.68 (dd,

J_H5,H6a4.16, J_gem11.20, 1H, H-6a). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

a

-anomeric form:

d

165.8, 165.4, 165.2 (3 C]O), 160.6 (C]NH),

1.28 (t, 3H, SCH₂CH₃G). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d 165.9,

137.5, 133.5, 133.4, 133.3 (4 C-ipso), 2ꢂ130.0, 2ꢂ129.9, 2ꢂ129.8,

129.1, 129.0, 128.7, 2ꢂ128.5, 2ꢂ128.4, 2ꢂ128.35, 2ꢂ128.3, 2ꢂ127.9,

127.7 (20 CeAr), 93.5 (C-1), 90.9 (CCl₃), 73.7 (PhCH₂), 72.1 (C-5),

70.9 (C-2), 70.5 (C-3), 68.8 (C-4), 68.1 (C-6). ESI-HRMS: [MþNa]^þ

m/z calcd for C₃₆H₃₀Cl₃NO₉Na 748.0884, found 748.0880.

165.3, 165.2 (3 C]O G⁰), 138.1, 137.8, 135.9, 133.5, 133.4, 2ꢂ133.3,

133.2 (8 C-ipso), 6ꢂ129.9, 129.4, 129.3, 129.1, 2ꢂ128.7, 3ꢂ128.6,

4ꢂ128.5, 4ꢂ128.4, 2ꢂ128.2, 2ꢂ128.0, 2ꢂ127.9, 3ꢂ127.8, 3ꢂ127.7,

2ꢂ127.6, 126.6, 126.4, 126.15, 125.8 (40 CeAr), 100.5 (C-1 G⁰), 86.9

(C-2 G), 83.9 (C-1 G), 77.4 (C-5 G), 77.0 (C-3 G), 75.5 (NapCH₂G),

74.2 (C-2), 74.1 (C-5 G⁰), 74.0 (PhCH₂G⁰), 73.8 (PhCH₂), 73.6 (C-3 G⁰),

73.1 (C-4), 72.6 (C-2 G⁰), 70.9 (C-6), 70.1 (C-4 G⁰), 69.4 (C-6 G⁰), 24.4

(SCH₂CH₃), 14.9 (SCH₂CH₃). ESI-HRMS: [MþNa]^þm/z calcd for

4.1.22. Ethyl

2,3,4-tri-O-benzoyl-6-O-benzyl-

b-

D-glucopyranosyl-

(1/2)-4,6-O-benzylidene-3-O-(2-naphthyl)methyl-1-thio-

b-D

-glu-

copyranoside (28). A solution of the trichloroacetimidate-

containing compound 27 (1.27 g, 1.76 mmol, 2 equiv) and accep-

tor 8 (400 mg, 0.88 mmol) in a mixture of dry CH₂CL₂and dry

C₆₀H₅₈O₁₃SNa 1041.3496, found 1041.3498.

4.1.24. Ethyl

2,3,4-tri-O-benzoyl-6-O-benzyl-

b-D-glucopyranosyl-

toluene 1/1 (25 mL) was stirred for 20 min in the presence of

(1/2)-6-O-benzyl-1-thio-b-D

-glucopyranoside (30). Compound 29

ꢁ

molecular sieves (4 A, 0.6 g). TMSOTf (12.8

mL, 0.08 equiv) was

(150 mg, 0.15 mmol) was dissolved in a mixture of CH₂Cl₂/MeOH 4/

1 and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 85 mg,

0.38 mmol, 2.5 equiv) was added whereafter the reaction mixture

was stirred until completion, monitored by TLC (R_f¼0.45 Pentane/

EtOAc 1:1). Once complete, the reaction mixture was diluted with

CH₂Cl₂and 1 mL of satd NaHCO₃was added. The two phases were

separated and the organic phase was washed twice more with the

solution of satd NaHCO₃and then dried over Na₂SO₄. The residue

was puriﬁed by ﬂash chromatography to yield compound 30 as

a white powder in 88% yield (114 mg). ¹H NMR (CDCl₃, 25 ^ꢀC,

added dropwise at ꢁ10 ^ꢀC. The reaction was monitored by TLC

(pentane/EtOAc 3:1) and left to stir overnight. NEt₃was added to

quench the reaction and the mixture was ﬁltered through Celite. It

was then diluted with CH₂Cl₂and washed successively with solu-

tions of satd NaHCO₃, brine and dried over Na₂SO₄. The solvent was

removed in vacuo and the residue thus obtained was puriﬁed by

ﬂash chromatography to yield 895 mg of 28 (84%) as a white solid.

¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d 7.98e7.15 (m, 32H, HeAr), 5.86

(dd, J_H2,H39.59, J_H3,H49.53, 1H, H-3 G⁰), 5.63 (dd, J_H1,H27.95, J_H2,H3

9.59,1H, H-2 G⁰), 5.61 (dd, J_H3,H49.53, J_H4,H58.61,1H, H-4 G⁰), 5.53 (s,

1H, CHPh G), 5.52 (d, J_H1,H27.95, 1H, H-1 G⁰), 4.88 (d, J_gem10.78, 1H,

NapCH₂G), 4.69 (d, J_gem10.78, 1H, NAPCH₂G), 4.59 (d, J_gem11.95,

1H, PhCH₂G⁰), 4.56 (d, J_H1,H29.48, 1H, H-1 G), 4.54 (d, J_gem11.95, 1H,

PhCH₂G⁰), 4.35 (dd, J_H5,H6b5.09, J_gem10.51, 1H, H-6b G), 3.96 (dd,

J_H1,H29.48, J_H2,H38.14, 1H, H-2 G), 3.87 (ddd, 1H, H-5 G⁰), 3.77e3.67

(m, 3H, H-6a, H-4, H-3 G), 3.70 (m, 2H, H-6a, H-6b G⁰), 3.43 (ddd,

400 MHz):

d 7.99e7.14 (m, 25H, HeAr), 5.89 (dd, J_H2,H39.55, J_H3,H4

9.49, 1H, H-3 G⁰), 5.58 (dd, J_H3,H49.49, J_H4,H59.78, 1H, H-4 G⁰), 5.53

(dd, J_H1,H27.82, J_H2,H39.55, 1H, H-2 G⁰), 5.29 (d, J_H1,H27.82, 1H, H-1

G⁰), 4.55 (2 d, J_gem12.00, 2H, PhCH₂G), 4.55 (2 d, J_gem11.74, 2H,

PhCH₂G⁰), 4.45 (d, J_H1,H29.65, 1H, H-1 G), 4.02 (ddd, 1H, H-5 G⁰),

3.73 (m, 2H, H-6a, H-6b G⁰), 3.70 (m, 2H, H-6a, H-6b G), 3.65 (dd,

J_H1,H29.65, J_H2,H38.81, 1H, H-2 G), 3.54 (ddd, J_H2,H38.81, J_H3,H48.74,

J_H3,OH-32.98, 1H, H-3 G), 3.47 (ddd, J_H3,H48.74, J_H4,H59.27, J_H4,OH-4

1.81, 1H, H-4 G), 3.39 (ddd, 1H, H-5 G), 3.25 (d, J_H3,OH-32.98, 1H, OH-

3 G), 2.84 (d, J_H4,OH-41.81, 1H, OH-4 G), 2.58 (dq, 2H, SCH₂CH₃G),

1H, H-5 G), 2.77 (dq, 2H, SCH₂CH₃G), 1.29 (t, 3H, SCH₂CH₃G). ¹³

NMR (CDCl₃, 25 ^ꢀC, 100 MHz): 165.9, 165.4, 165.3 (3C]O G⁰),

C

d

138.0, 137.2, 135.7, 133.5, 133.4, 133.3, 2ꢂ133.2 (8 C-ipso), 2ꢂ130.0,

6ꢂ129.9, 129.5, 129.2, 2ꢂ129.1, 4ꢂ128.6, 4ꢂ128.5, 4ꢂ128.4,

4ꢂ128.3, 128.2, 127.9, 3ꢂ127.8, 127.6, 126.8, 126.3, 126.2, 3ꢂ126.1

(40 CeAr) 101.4 (CHPh G), 100.6 (C-1 G⁰), 84.6 (C-1 G), 83.6 (C-3 G),

81.8 (C-4 G), 76.9 (C-2 G), 75.3 (NapCH₂G), 74.2 (C-5 G⁰), 74.0

(PhCH₂G⁰), 73.6 (C-3 G⁰), 72.6 (C-2 G⁰), 70.2 (C-5 G), 70.1 (C-4 G⁰),

69.3 (C-6 G⁰), 68.8 (C-6 G), 24.5 (SCH₂CH₃G), 14.9 (SCH₂CH₃G). ESI-

HRMS: [MþNa]^þm/z calcd for C₆₀H₅₆O₁₃SNa 1039.3339, found

1039.3335.

1.26 (t, 3H, SCH₂CH₃G). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d 165.9,

165.5, 165.4 (3 C]O G⁰), 137.9, 137.7, 133.5, 133.3, 133.3 (5 C-ipso),

6ꢂ129.9, 129.6, 129.1, 129.0, 4ꢂ128.6, 4ꢂ128.5, 6ꢂ128.4, 2ꢂ128.0,

127.9, 4ꢂ127.8 (30 CeAr), 99.8 (C-1 G⁰), 83.1 (C-1 G), 79.2 (C-2 G),

77.7 (C-5 G), 77.6 (C-3 G), 74.0 (PhCH₂G⁰), 74.0 (PhCH₂G), 73.7 (C-5

G⁰), 73.3 (C-3 G⁰), 72.4 (C-2 G⁰), 71.9 (C-4 G), 70.6 (C-6 G), 70.0 (C-4

G⁰), 69.3 (C-6 G⁰), 24.4 (SCH₂CH₃G), 14.7 (SCH₂CH₃G). ESI-HRMS:

[MþNa]^þm/z calcd for C₄₉H₅₀O₁₃SNa 901.2870, found 901.2873.

4.1.23. Ethyl

2,3,4-tri-O-benzoyl-6-O-benzyl-

b

-

D

-glucopyranosyl-

4.1.25. Ethyl 6-O-benzyl-

thio- -glucopyranoside (31). For general acyl group depro-

tection conditions see the above reaction conditions for compound

b-D-glucopyranosyl-(1/2)-6-O-benzyl-1-

(1/2)-6-O-benzyl-3-O-(2-naphthyl)methyl-1-thio-

b

-

D

-glucopyr-

b-D

anoside (29). Disaccharide 28 (400 mg, 0.39 mmol) was dissolved

in dry THF (8 mL) at room temperature. BH₃$NMe₃complex

(114 mg, 1.56 mmol, 4 equiv) was added to the mixture, which was

7. Starting from ethyl 2,3,4-tri-O-benzoyl-6-O-benzyl-

b

-D-gluco-

pyranosyl-(1/2)-6-O-benzyl-1-thio- -glucopyranoside

b

-

D

(30,

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

925

200 mg, 0.23 mmol, TLC: R_f¼0.45 DCM/MeOH 9:1) O-deacylation

yielded compound 31 as a colorless oil in 93% yield. ¹H NMR

molecular sieves were also present) dissolved in dry dichloro-

methane. The mixture was left to stir and allow to reach ꢁ10 ^ꢀC and

was then quenched by addition of NEt₃(0.015 mL, 0.11 mmol,

2.5 equiv). The mixture was diluted with dichloromethane and

ﬁltered through a pad of Celite. The ﬁltrate was successively

washed with water, brine and dried over Na₂SO₄. After evaporation

of the solvent, the resulting material was puriﬁed by chromatog-

raphy to afford a total yield of 55% of 33a (50%) and 33b (5%).

(R_f¼0.6 33a, 0.3 33b, Pentane/EtOAc 3:1). 33a: ¹H NMR (CDCl₃,

(CD₃OD, 25 ^ꢀC, 400 MHz):

d 7.39e7.21 (m, 10H, HeAr), 4.71 (d, J_H1,H2

7.76, 1H, H-1 G⁰), 4.64 (s, 2H, PhCH₂G⁰), 4.58 (s, 2H, PhCH₂G), 4.47

(d, J_H1,H29.28, 1H, H-1 G), 3.87e3.79 (2 dd, 2H, H-6b G, H-6b G⁰),

3.72e3.62 (2 dd, 2H, H-6a G, H-6a G⁰), 3.58 (dd, J_H2,H38.70, J_H3,H4

8.43, 1H, H-3 G), 3.55 (dd, J_H1,H29.28 J_H2,H38.70, 1H, H-2 G), 3.44

(ddd, 1H, H-5 G), 3.42 (ddd, 1H, H-5 G⁰), 3.38 (dd, 1H, H-4 G⁰), 3.36

(dd, 1H, H-4 G), 3.35 (dd, 1H, H-3 G⁰), 3.27 (dd, J_H1,H27.76 J_H2,H39.26,

1H, H-2 G⁰), 2.70 (dq, 2H, SCH₂CH₃G), 1.21 (t, 3H, SCH₂CH₃G). ¹³

NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

C

25 ^ꢀC, 400 MHz):

d 7.48e7.19 (m, 15H, HeAr), 5.54 (d, J_H1,H21.30, 1H,

d

139.8, 139.7 (2 C-ipso), 4ꢂ129.3,

H-1 G), 5.34 (dd, J_H2,H33.22, J_H3,H49.89, 1H, H-3 R), 5.32 (s, 1H, CHPh

Gal), 5.22 (dd, J_H1,H21.70, J_H2,H33.22, 1H, H-2 R), 5.10 (d, J_H1,H24.48,

1H, H-1 G⁰), 5.05 (dd, J_H3,H49.89, J_H4,H510.00, 1H, H-4 R), 4.90 (d,

J_H1,H21.70, 1H, H-1 R), 4.60 (d, J_gem12.05, 1H, PhCH₂G), 4.59 (s, 2H,

PhCH₂G⁰), 4.52 (dd, J_H3,H43.22, 1H, H-4 Gal), 4.49 (d, J_gem12.05, 1H,

PhCH₂G), 4.22 (dq, J_H4,H510.00, J_H5,H66.12, 1H, H-5 R), 4.10 (dd, 1H,

H-3 G⁰), 4.02 (dd, 1H, H-4 G), 4.01 (dd, 1H, H-4 G⁰), 3.96 (d, J_H1,H2

7.73, 1H, H-1 Gal), 3.94 (ddd, 1H, H-5 G), 3.91 (dd, 1H, H-6b Gal),

3.88 (dd, 1H, H-2 G), 3.80 (dd, J_H1,H27.73, J_H2,H39.97, 1H, H-2 Gal),

3.74 (dd, 1H, H-3 G), 3.72 (ddd, 1H, H-5 G⁰), 3.71 (dd, 1H, H-2 G⁰),

3.65 (dd,1H, H-6b G), 3.62 (m, 2H, H-6a, H-6b G⁰), 3.54 (dd,1H, H-6a

G), 3.48 (dd, J_H2,H39.97, J_H3,H43.22, 1H, H-3 Gal), 3.42 (s, 3H, OMe

Gal), 3.18 (dd, 1H, H-6a Gal), 2.84 (ddd, 1H, H-5 Gal), 2.08, 2.04, 1.83

(3s, 9H, CH₃R), 1.13 (s, 3H, H-6 R), 0.89, 0.88, 0.85, 0.84, 0.76 (5s,

45H, C(CH₃)₃), 0.13, 0.12, 0.10, 0.09, 2ꢂ0.07, 0.01, ꢁ0.01, ꢁ0.27,

4ꢂ128.8,128.6,128.5 (10 CeAr),104.8 (C-1 G⁰), 84.6 (C-1 G), 81.3 (C-

2 G), 80.9 (C-5 G), 79.8 (C-3 G), 78.1 (C-3 G⁰), 77.5 (C-5 G⁰), 75.8 (C-2

G⁰), 74.7 (PhCH₂G⁰), 74.4 (PhCH₂G), 71.6 (C-4 G), 71.4 (C-4 G⁰), 70.9

(C-6 G), 70.8 (C-6 G⁰), 24.8 (SCH₂CH₃G), 15.4 (SCH₂CH₃G). ESI-

HRMS: [MþNa]^þm/z calcd for C₂₈H₃₈O₁₀SNa 589.2083, found

589.2080.

4.1.26. Ethyl 2,3,4-tri-O-tert-butyldimethylsilyl-6-O-benzyl-

copyranosyl-(1/2)-3,4-di-O-tert-butyldimethylsilyl-6-O-benzyl-1-

thio- -glucopyranoside (32). Ethyl 6-O-benzyl-2-O-(6-O-benzyl-

-glucopyranosyl)-1-thio- -glucopyranoside (31, 0.120 g,

0.21 mmol) was dissolved in dry pyridine (5 mL) and DMAP (cat)

was added to the mixture. TBDMSOTf (725 L, 3.15 mmol, 15 equiv)

b-D-glu-

b-D

b

-D

b-D

m

was added dropwise at 0 ^ꢀC, the mixture was heated to 80 ^ꢀC and

the reaction was left to proceed overnight. The reaction mixture

(R_f¼0.5 Pentane/DCM 1:1) was left to cool down and then

quenched by addition of MeOH. The mixture was extracted with

dichloromethane and successively washed with 1 M HCl, satd

aqueous NaHCO₃and brine. The solution was dried over anhydrous

Na₂SO₄and solvents were evaporated. The resulting residue was

puriﬁed by chromatography to afford compound 32 as a colorless

syrup in 86% yield (139 mg). ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

ꢁ0.30 (10 s, 30H, SiCH₃). ¹³C NMR (CDCl₃, 25 ^ꢀC, 100 MHz):

d 170.4,

170.1, 169.2 (3 C]O), 139.6, 138.4, 138.3 (3 C-ipso), 2ꢂ128.7,

2ꢂ128.6, 128.4, 3ꢂ128.1, 2ꢂ128.0, 2ꢂ127.1, 126.9, 2ꢂ126.4

(15 CeAr), 102.5 (C-1 Gal), 102.4 (C-1 G⁰), 102.2 (C-1 G), 99.9 (CHPh

Gal), 98.3 (C-1 R), 81.6 (C-2 G), 80.2 (C-3 G), 80.0 (C-5 G⁰), 79.8 (C-3

Gal), 76.8 (C-4 G⁰), 76.8 (C-2 G⁰), 75.7 (C-4 Gal), 75.4 (C-2 Gal), 73.6

(PhCH₂G), 72.9 (C-5 G), 72.6 (PhCH₂G⁰), 72.1 (C-4 G), 72.1 (C-4 R),

71.1 (C-3 G⁰), 70.9 (C-6 G⁰), 70.7 (C-2 R), 70.4 (C-6 G), 69.3 (C-3 R),

68.7 (C-6 Gal), 66.4 (C-5 Gal), 66.3 (C-5 R), 56.1 (OMe Gal) 2ꢂ26.3,

26.2, 26.1, 26.0 (5 C(CH₃)₃), 2ꢂ21.1, 20.7 (3 CH₃R), 18.2, 2ꢂ18.1, 17.9,

17.8 (5 C(CH₃)₃), 17.0 (C-6 R), ꢁ3.3, ꢁ3.4, 2ꢂꢁ3.8, 2ꢂꢁ4.0, 2ꢂꢁ4.4,

ꢁ4.5, ꢁ4.6 (10 SiCH₃). 33b: ¹H NMR (CDCl₃, 25 ^ꢀC, 400 MHz):

d

7.36e7.22 (m, 10H, HeAr), 5.11 (d, J_H1,H25.96, 1H, H-1 G), 4.94 (d,

J_H1,H25.13, 1H, H-1 G⁰), 4.60 (d, J_gem12.16, 1H, PhCH₂G⁰), 4.54 (s, 2H,

PhCH₂G), 4.53 (d, J_gem12.16, 1H, PhCH₂G⁰), 3.99 (ddd, 1H, H-5 G⁰),

3.96 (dd, J_H2,H3<2, 1H, H-3 G), 3.91 (ddd, 1H, H-5 G), 3.90 (dd, 1H, H-

4 G), 3.89 (dd, 1H, H-4 G⁰), 3.87 (dd, J_H2,H3<2, 1H, H-2 G), 3.72 (dd,

d

7.68e7.65 (m, 2H, BSP)⁵⁷7.52e7.45 (m, 3H, BSP), 7.44e7.22 (m,

J

_H2,H3<2, 1H, H-3 G⁰), 3.65 (dd, 1H, H-6b G), 3.65 (dd, 1H, H-6b G⁰),

15H, HeAr), 5.30 (dd, J_H2,H33.42, J_H3,H410.04, 1H, H-3 R), 5.30 (s, 1H,

CHPh Gal), 5.22 (dd, J_H1,H21.54, J_H2,H33.42, 1H, H-2 R), 5.11 (d, J_H1,H2

1.54, 1H, H-1 R), 5.05 (d, J_H1,H21.23,1H, H-1 G), 5.00 (dd, J_H3,H410.04,

J_H4,H59.95, 1H, H-4 R), 5.00 (d, J_H1,H24.59, 1H, H-1 G⁰), 4.58 (d, J_gem

11.78, 1H, PhCH₂G), 4.53 (s, 2H, PhCH₂G⁰), 4.52 (d, J_gem11.78, 1H,

PhCH₂G), 4.30 (dd, J_H3,H43.31, 1H, H-4 Gal), 4.21 (dq, J_H4,H59.95,

J_H5,H66.21, 1H, H-5 R), 4.11 (d, J_H1,H27.70, 1H, H-1 Gal), 4.05 (dd,

J_H5,H6b1.01, J_gem12.18, 1H, H-6b Gal), 3.94 (dd, 1H, H-2 G), 3.92 (dd,

1H, H-2 Gal), 3.915 (dd, 1H, H-3 G⁰), 3.84 (ddd, 1H, H-5 G⁰), 3.76 (dd,

1H, H-4 G), 3.73 (dd,1H, H-6b G), 3.72 (ddd,1H, H-5 G), 3.70 (dd,1H,

H-4 G⁰), 3.695 (dd, 1H, H-2 G⁰), 3.63 (dd, 1H, H-3 Gal), 3.63 (dd, 1H,

H-6a G), 3.60 (m, 2H, H-6a, H-6b G⁰), 3.51 (dd, 1H, H-3 G), 3.48 (s,

3H, OMe Gal), 3.48 (dd, J_gem12.18, 1H, H-6a Gal), 3.25 (nr, 1H, OH-

3⁰), 3.15e3.10 (m, 2H, BSP), 3.05 (ddd, 1H, H-5 Gal), 2.99e2.93 (m,

2H, BSP), 2.06, 2.04, 1.93 (3 s, 9H, CH₃R), 1.67e1.51 (m, 6H, BSP),

1.14 (s, 3H, H-6 R), 0.87, 0.85, 0.83, 0.82 (4s, 36H, C(CH₃)₃), 0.08,

0.06, 0.04, 0.02, 0.01, ꢁ0.01, ꢁ0.02, ꢁ0.13 (8s, 24H, SiCH₃). ¹³C NMR

3.63 (dd, J_H2,H3<2, 1H, H-2 G⁰), 3.60 (dd, 1H, H-6a G), 3.59 (dd, 1H,

H-6a G⁰), 2.67 (dq, 2H, SCH₂CH₃G), 1.21 (t, 3H, SCH₂CH₃G), 2ꢂ0.89,

0.88, 0.87, 0.85 (5 s, 45H, C(CH₃)₃), 0.13, 2ꢂ0.095, 0.09, 0.089, 0.078,

0.056, 0.054, 0.050, 0.044, 0.019 (10 s, 30H, SiCH₃). ¹³C NMR (CDCl₃,

25 ^ꢀC, 100 MHz):

d

138.9, 138.75 (2 C-ipso), 2ꢂ128.4, 2ꢂ128.3,

2ꢂ127.8, 2ꢂ127.6,127.5,127.4 (10 CeAr),101.4 (C-1 G⁰), 82.2 (C-1 G),

81.0 (C-2 G), 79.5 (C-5 G), 79.0 (C-3 G⁰), 78.8 (C-5 G⁰), 77.4 (C-2 G⁰),

76.1 (C-3 G), 73.4 (PhCH₂G⁰), 73.3 (PhCH₂G), 71.7 (C-4 G), 71.7 (C-6

G), 71.6 (C-6 G⁰), 71.2 (C-4 G⁰), 4ꢂ26.1, 26.0 (5C(CH₃)₃), 25.3

(SCH₂CH₃G), 5ꢂ18.1 (5 C(CH₃)₃), 14.9 (SCH₂CH₃G), ꢁ3.5, ꢁ3.8,

ꢁ4.0, 2ꢂꢁ4.1, 2ꢂꢁ4.4, ꢁ4.5, 2ꢂꢁ4.6 (10 SiCH₃). ESI-HRMS:

[MþNa]^þm/z calcd for C₅₈H₁₀₈O₁₀SSi₅Na 1159.6407, found

1159.6404.

4.1.27. Methyl 2,3,4-tri-O-acetyl-

tri-O-tert-butyldimethylsilyl-6-O-benzyl-

3,4-di-O-tert-butyldimethylsilyl-6-O-benzyl-

(1/3)]-4,6-O-benzylidene- -galactopyranoside (33a). Methyl

2,3,4-tri-O-acetyl- -rhamnopyranosyl-(1/2)[2,3,4-tri-O-tert-butyl-

dimethylsilyl-6-O-benzyl- -glucopyranosyl-(1/2)-4-O-tert-butyl-

dimethylsilyl-6-O-benzyl- -glucopyranosyl-(1/3)]-4,6-O-benzyli-

dene- -galactopyranoside (33b). Donor 32 (50 mg, 0.044 mmol),

a-

L

-rhamnopyranosyl-(1/2)[2,3,4-

-glucopyranosyl-(1/2)-

-glucopyranosyl-

b-D

b

-

D

(CDCl₃, 25 ^ꢀC, 100 MHz):

d

2ꢂ170.3, 169.6 (3 C]O), 138.9, 138.7,

b-

D

138.0 (3 C-ipso), 128.9, 2ꢂ128.6, 2ꢂ128.3, 2ꢂ128.2, 2ꢂ128.1, 128.0,

2ꢂ127.5, 127.3, 2ꢂ126.6 (15 CeAr), 103.6 (C-1 G⁰), 102.4 (C-1 Gal),

102.2 (C-1 G), 100.7 (CHPh Gal), 98.0 (C-1 R), 79.7 (C-2 G), 79.1 (C-4

G⁰), 78.9 (C-3 Gal), 78.1 (C-5 G⁰), 76.9 (C-3 G), 76.1 (C-4 Gal), 76.05

(C-2 G⁰), 74.4 (C-2 Gal), 74.2 (C-4 G), 73.6 (PhCH₂G), 73.1 (PhCH₂G⁰),

73.06 (C-5 G), 71.7 (C-4 R), 71.1 (C-3 G⁰), 70.8 (C-6 G⁰), 70.2 (C-2 R),

70.0 (C-6 G), 69.4 (C-3 R), 68.9 (C-6 Gal), 66.45 (C-5 Gal), 66.4 (C-5

R), 56.2 (OMe Gal) 26.2, 26.1, 2ꢂ26.0 (4C(CH₃)₃), 2ꢂ21.0, 20.9 (3 CH₃

R), 2ꢂ18.2, 18.1, 18.0 (4 C(CH₃)₃), 17.1 (C-6 R), 2ꢂꢁ3.9, 2ꢂꢁ4.0, ꢁ4.2,

ꢁ4.4, ꢁ4.8, ꢁ5.3 (8 SiCH₃). 33a: ESI-HRMS: [MþNa]^þm/z calcd for

a-L

b-D

BSP (9.4 mg, 0.045 mmol, 1.02 equiv) and TTBP (55 mg, 0.22 mmol,

ꢁ

5 equiv) were dissolved in dry CH₂Cl₂(2 mL) whereafter 4 A mo-

lecular sieves (100 mg) were added under N₂atmosphere and the

mixture was cooled down to ꢁ78 ^ꢀC; 1.2 equiv of Tf₂O was then

ꢁ

added dropwise, followed directly by acceptor 19 (2 equiv, 4 A

926

T. Angles d’Ortoli, G. Widmalm / Tetrahedron 72 (2016) 912e927

C₈₂H₁₃₆O₂₃Si₅Na 1651.8216, found 1651.8220. 33b: ESI-HRMS:

[MþNa]^þm/z calcd for C₇₆H₁₂₂O₂₃Si₄Na 1537.7352, found

1537.7352.

3.88 (dd, J_H1,H27.11, 1H, H-2 Gal), 3.87 (dd, J_H3,H43.26, 1H, H-3 Gal),

3.73 (dd, 1H, H-6b G), 3.72 (dd, 1H, H-6a G⁰), 3.66 (dd, J_H2,H33.26,

1H, H-3 R), 3.62 (dd, J_H1,H27.44,1H, H-2 G), 3.60 (dd,1H, H-3 G), 3.58

(dd, 1H, H-6a G), 3.56 (s, 3H, OMe Gal), 3.52 (ddd, 1H, H-5 G), 3.43

(dd, 1H, H-4 R), 3.41 (dd, 1H, H-4 G⁰), 3.41 (dd, J_H1,H27.94, 1H, H-2

G⁰), 3.40 (ddd, J_H5,H6b1.49, 1H, H-5 Gal), 3.33 (dd, 1H, H-4 G), 3.31

(dd, 1H, H-3 G⁰), 3.31 (ddd, 1H, H-5 G⁰), 1.24 (d, J_H5,H66.20, 3H, H-6

4.1.28. Methyl 2,3,4-tri-O-acetyl-

tri-O-acetyl-6-O-benzyl- -glucopyranosyl-(1/2)-3,4-di-O-acetyl-

6-O-benzyl- -glucopyranosyl-(1/3)]-4,6-O-benzylidene- -gal-

a-L-rhamnopyranosyl-(1/2)[2,3,4-

b-D

b

-

D

b-D

actopyranoside (35). Compounds 33a/33b (60 mg, 10:1 mixture)

were dissolved altogether in dry THF and 15 equiv of a 1M solution

of TBAF in THF was added dropwise at room temperature. At

completion, the mixture was taken into CH₂Cl₂and washed with

water. The organic phase was dried over Na₂SO₄, ﬁltered and con-

centrated to dryness. The compound obtained (34) was dissolved in

dry pyridine (3 mL). Acetic anhydride (10 equiv) and DMAP were

added and the reaction was left to stir overnight. The reaction was

stopped by adding a few drops of MeOH and the yellow oil was

washed with NaHCO₃, brine, 1M HCl and brine before being dried

over Na₂SO₄, ﬁltered and concentrated. Puriﬁcation by ﬂash chro-

matography (R_f¼0.55 EtOAc/Pentane 2:1) gave 38 mg of 35 as

a white powder (80% yield over two steps). ¹H NMR (CDCl₃, 25 ^ꢀC,

R). ¹³C NMR (CD₃OD, 25 ^ꢀC, 100 MHz):

d 139.8, 139.7, 139.6 (3 C-

ipso), 129.8, 2ꢂ129.5, 2ꢂ129.3, 2ꢂ129.2, 2ꢂ129.0, 2ꢂ128.9, 128.8,

128.5, 2ꢂ127.8 (15 CeAr), 105.0 (C-1 G⁰), 104.4 (C-1 G), 104.3 (C-1

Gal), 102.7 (C-1 R), 102.5 (CHPh Gal), 82.1 (C-2 G), 81.9 (C-3 Gal),

78.7 (C-3 G), 78.2 (C-5 G⁰), 78.1 (C-4 Gal), 77.5 (C-3 G⁰), 77.4 (C-2

Gal), 76.7 (C-5 G), 75.2 (C-2 G⁰), 74.7 (PhCH₂G⁰), 74.6 (PhCH₂G), 74.1

(C-4 R), 72.5 (C-3 R), 72.2 (C-2 R), 71.6 (C-4 G), 71.4 (C-6 G⁰), 71.3 (C-

4 G⁰), 70.1 (C-6 G), 70.0 (C-6 Gal), 69.8 (C-5 R), 67.7 (C-5 Gal), 56.9

(OMe Gal), 17.8 (C-6 R). ESI-HRMS: [MþNa]^þm/z calcd for

C₄₆H₆₀O₂₀Na 955.3576, found 955.3575.

4.1.30. Methyl

a-

L

-rhamnopyranosyl-(1/2)[b-D-glucopyranosyl-

(1/2)- -glucopyranosyl-(1/3)]-b-D

b

-

D

-galactopyranoside

400 MHz):

d

7.52e7.47 (m, 2H, HeAr), 7.37e7.20 (m, 13H, HeAr),

(1). Compound 36 (30 mg, 0.32 mmol) was dissolved in a 3/2 EtOH/

EtOAc mixture (2.5 mL) and 10e20% Pd/C catalyst (10 mg) was

added in a small pierced vial. This vial was left to stir overnight at

room temperature under 3 atm of H₂. Once TLC analysis indicated

full conversion (R_f¼0.5 EtOAc/MeOH/H₂O 7:2:1), the mixture was

ﬁltered through a Celite pad, washed with water and concentrated

5.48 (s, 1H, CHPh Gal), 5.34 (dd, J_H1,H21.62, J_H2,H33.51, 1H, H-2 R),

5.30 (d, J_H1,H21.62, 1H, H-1 R), 5.27 (dd, J_H2,H33.51, J_H3,H410.17, 1H,

H-3 R), 5.21 (dd, J_H2,H38.85, J_H3,H48.95, 1H, H-3 G), 5.12 (dd, J_H3,H4

9.55, J_H4,H59.61, 1H, H-4), 5.08 (dd, J_H3,H49.99, J_H4,H510.07, 1H, H-4

R), 5.04 (dd, J_H3,H49.08, J_H4,H510.03, 1H, H-4 G), 5.00 (dd, J_H2,H39.32,

J_H3,H49.48, 1H, H-3 G⁰), 4.86 (d, J_H1,H27.03, 1H, H-1 G), 4.79 (m, 2H,

H-1 G⁰, H-2 G⁰), 4.58 (d, J_gem12.00, 1H, PhCH₂G), 4.47 (d, J_gem12.12,

1H, PhCH₂G⁰), 4.43 (d, J_gem12.00, 1H, PhCH₂G), 4.32 (d, J_gem12.12,

1H, PhCH₂G⁰), 4.27 (dd, J_H3,H43.61, 1H, H-4 Gal), 4.27 (dd, J_H5,H6b

1.43, J_gem12.30, 1H, H-6b Gal), 4.24 (d, J_H1,H27.63, 1H, H-1 Gal), 4.19

(dq, J_H4,H510.07, J_H5,H66.22, 1H, H-5 R), 4.00 (dd, J_H1,H27.63, J_H2,H3

9.69, 1H, H-2 Gal), 3.91 (dd, J_H5,H6a1.62, J_gem12.30, 1H, H-6a Gal),

3.91 (dd, J_H2,H39.69, J_H3,H43.61, 1H, H-3 Gal), 3.73 (ddd, J_H4,H510.03,

J_H5,H6a4.99, J_H5,H6b2.70, 1H, H-5 G), 3.71 (dd, J_H1,H27.03, J_H2,H38.85,

1H, H-2 G), 3.59 (dd, 1H, H-6b G⁰), 3.56 (dd, 1H, H-6b G), 3.52 (s, 3H,

OMe Gal), 3.50 (dd, J_H5,H6b4.99, J_gem10.73,1H, H-6a G), 3.44 (dd,1H,

H-6a G⁰), 3.43 (ddd, J_H4,H59.61, 1H, H-5 G⁰), 3.30 (ddd, J_H5,H6a1.62,

J_H5,H6b1.43, 1H, H-5 Gal), 2.06, 2.05, 2.02, 1.99, 1.98, 1.96, 1.88, 1.84

(8 s, 24H, CH₃),1.13 (d, J_H5,H66.22, 3H, H-6 R). ¹³C NMR (CDCl₃, 25 ^ꢀC,

€

to dryness. The residue was puriﬁed on an AKTAÔ system equipped

with a SuperdexÔ column to give 19 mg of 1 as a white powder

(89%). ¹H and ¹³C NMR data: see Table 1. ESI-HRMS: [MþNa]^þm/z

calcd for C₂₅H₄₄O₂₀Na 687.2324, found 687.2326.

Acknowledgements

This work was supported by grants from the Swedish Research

Council and the Knut and Alice Wallenberg Foundation.

Supplementary data

Supplementary data associated with this article can be found in

the online version, at http://dx.doi.org/10.1016/j.tet.2015.12.042.

100 MHz):

d

170.6, 170.5, 170.4, 2ꢂ170.1, 169.9, 169.7, 169.4 (8C]O),

138.5, 138.0, 137.8 (3 C-ipso), 128.9, 2ꢂ128.6, 2ꢂ128.4, 2ꢂ128.2,

2ꢂ128.1, 128.0, 2ꢂ127.9, 127.5, 2ꢂ126.3 (15 CeAr), 102.9 (C-1 Gal),

101.4 (C-1 G), 100.8 (C-1 G⁰), 100.8 (CHPh Gal), 97.9 (C-1 R), 78.8 (C-

2 G), 78.1 (C-3 Gal), 76.3 (C-4 Gal), 75.2 (C-2 Gal), 73.8 (C-3 G⁰), 73.6

(PhCH₂G), 73.6 (C-3 G), 73.5 (C-5 G⁰), 73.4 (PhCH₂G⁰), 72.9 (C-2 G⁰),

72.5 (C-5 G), 71.2 (C-4 R), 69.7 (C-4 G), 69.7 (C-2 R), 69.5 (C-3 R),

69.1 (C-6 Gal), 68.9 (C-4 G⁰), 68.8 (C-6 G), 68.5 (C-6 G⁰), 66.9 (C-5 R),

66.5 (C-5 Gal), 56.8 (OMe Gal), 21.0, 3ꢂ20.9, 3ꢂ20.8, 20.7 (8 CH₃),

17.2 (C-6 R). ESI-HRMS: [MþNa]^þm/z calcd for C₆₂H₇₆O₂₈Na

1291.4421, found 1291.4419.

References and notes

1. Chen, Z.; Miller, A. R. In Horticultural Reviews ; Janick, J., Ed.; John Wiley & Sons:

New York, USA, 2001; Vol. 25, pp 171e196.

€

ꢂ

€

2. Guc¸ lu-Ustundag, O.; Mazza, G. Crit. Rev. Food Sci. Nutr. 2007 , 47 , 231e258.

3. Osbourn, A.; Goss, R. J. M.; Field, R. A. Nat. Prod. Rep. 2011 , 28 , 1261e1268.

4. Schwarz, S.; Xavier, N. M.; Csuk, R.; Rauter, A. M. Carbohydr. Chem. 2012 , 37 ,

326e373.

5. Munafo, J. P., Jr.; Gianfanga, T. J. Nat. Prod. Rep. 2015 , 32 , 454e477.

6. Francis, G.; Kerem, Z.; Makkar, H. P. S.; Becker, K. Br. J. Nutr. 2002 , 88 , 587e605.

7. Lorent, J. H.; Quetin-Leclercq, J.; Mingeot-Leclercq, M.-P. Org. Biomol. Chem.

2014 , 12 , 8803e8822.

8. Williams, J. R.; Gong, H. Lipids 200 7 , 42 , 77e86.

9. de Paula Barbosa, A. Afr. J. Pharm. Pharmcol. 2014 , 8 , 1049e1057.

10. Cham, B. E. Res. J. Biol. Sci. 200 7 , 2 , 503e514.

11. Punjabi, S.; Cook, L. J.; Kersey, P.; Marks, R.; Cerio, R. Int. J. Dermatol 2008 , 47 ,

78e82.

4.1.29. Methyl

pyranosyl-(1/2)-6-O-benzyl-

benzylidene- -galactopyranoside (36). For general acyl group

a

-

L

-rhamnopyranosyl-(1/2)[6-O-benzyl-

b-D-gluco-

b-D

-glucopyranosyl-(1/3)]-4,6-O-

b-D

deprotection conditions see the above reaction conditions for

compound 7. Compound 35 (55 mg, 0.43 mmol) was O-deacylated

(TLC: R_f¼0.25 DCM/MeOH 9:1) to give 35 mg of 36 (87% yield) as

12. Podolak, I.; Galanty, A.; Sobolewska, D. Phytochem. Rev. 2010 , 9 , 425e474.

13. Cham, B. E. Int. J. Clin. Med. 2011 , 2 , 473e477.

14. Cmoch, P.; Korda, A.; Rarova, L.; Oklestkova, J.; Strnad, M.; Luboradzki, R.;

ꢀ

ꢃ

ꢀ

Pakulski, Z. Tetrahedron 2014 , 70 , 2717e2730.

a colorless oil. ¹H NMR (CD₃OD, 25 ^ꢀC, 400 MHz):

d 7.47e7.17 (m,

ꢀ

ꢃ

ꢀ

15. Sidoryk, K.; Korda, A.; Rarova, L.; Oklestkova, J.; Strnad, M.; Cmoch, P.; Pakulski,

Z.; Gwardiak, K.; Karczewski, R.; Luboradzki, R. Tetrahedron 2015 , 71 ,

2004e2012.

15H, HeAr), 5.40 (s, 1H, CHPh Gal), 5.24 (d, J_H1,H21.69, 1H, H-1 R),

4.73 (d, J_H1,H27.94, 1H, H-1 G⁰), 4.65 (d, J_H1,H27.44, 1H, H-1 G), 4.68

(d, J_gem11.87, 1H, PhCH₂G⁰), 4.62 (d, J_gem11.87, 1H, PhCH₂G⁰), 4.47

(2 d, J_gem12.12, 2H, PhCH₂G), 4.38 (dd, J_H3,H43.26,1H, H-4 Gal), 4.35

(d, J_H1,H27.11, 1H, H-1 Gal), 4.12 (dd, J_H5,H6b1.49, J_gem12.29, 1H, H-6b

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Article Doi

Synthesis of the tetrasaccharide glycoside moiety of Solaradixine and rapid NMR-based structure verification using the program CASPER

DOI: 10.1016/j.tet.2015.12.042

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