Copper(ii)-catalyzed stereoselective 1,2-addition: Vs. Ferrier glycosylation of "armed" and "disarmed" glycal donors

Article abstract of DOI:10.1039/d0ob01042a

Selective activation of "armed' and "disarmed"glycal donors enabling the stereo-controlled glycosylations by employing Cu(ii)-catalyst as the promoter has been realized. The distinctive stereochemical outcome in the process is mainly influenced by the presence of diverse protecting groups on the donor and the solvent system employed. The protocol is compatible with a variety of aglycones including carbohydrates, amino acids, and natural products to access deoxy-glycosides and glycoconjugates with high α-anomeric selectivity. Notably, the synthetic practicality of the method is amply verified for the stereoselective assembling of trisaccharides comprising 2-deoxy components. Mechanistic studies involving deuterated experiments validate the syn-diastereoselective 1,2-addition of acceptors on the double bond of armed donors.

Full text of DOI:10.1039/d0ob01042a

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DOI: 10.1039/D0OB01042A
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ARTICLE
Copper(II)-Catalyzed Stereoselective 1,2-Addition vs Ferrier
Glycosylation of “Armed” and “Disarmed” Glycal Donors†
Manoj Kumar,a Thurpu Raghavender Reddy,a Aakanksha Gurawaa and Sudhir Kashyap*a
Received 00th January 20xx,
Accepted 00th January 20xx
Selective activation of “armed’ and ‘’disarmed’’ glycal donor enabling the stereo-controlled
glycosylations by employing Cu(II)-catalyst as the promoter has been realized. The distinctive
stereochemical outcome in the process is mainly influenced by the presence of diverse protecting
groups on the donor and the solvent system employed. The protocol is compatible with a variety
of aglycones including carbohydrates, amino-acids, and natural-products to access the deoxy-
glycosides and glycoconjugates in high -anomeric selectivity. Notably, the synthetic practicality
of the method is amply verified for the stereoselective assembling of trisaccharides comprising 2-
deoxy components. Mechanistic studies involving deuterated experiments validate the syn-
diastereoselective 1,2-addition of acceptor on the double bond of armed donor.
DOI: 10.1039/x0xx00000x
www.rsc.org/
position led to direct 1,2-addition or a Ferrier glycosylation
involving an allylic coupling of acceptor to enol-ether
functionality.[15] The stereochemical outcome in two
Introduction
2-Deoxyglycosides constitute
a
prominent class of
competing pathways are generally governed by the reactivity
of donor and the judicious influence of C-3 electron-
donating/withdrawing functional group.[16] The activation of
1,2-double bond in glycals is generally proceeds via
oxocarbenium ion or allyloxycarbenium intermediates
producing kinetically controlled 1,2 addition product and
thermodynamically favoured 2,3-unsaturated glycoside
respectively. Essentially, the glycosides comprising 2,3-
olefinic moiety, also known as “pseudo-glycals” offer further
synthetic potential as chiral precursors in numerous
complexity-generating chemical transformations.[17]
carbohydrate chiral skeleton owing to the absence of C-2
hydroxyl substituents[1-3] In addition to the well appreciated
role as important structural motif in the synthesis of numerous
bioactive molecules, natural products and drug molecules,[2]
the 2-deoxysugars are frequently utilized as clinical agents in
pharmaceutical studies as well.[3] However, stereo-controlled
preparation of 2-deoxyglycosides remains a challenging task
due to the absence of a stereo directing linkage or NGP at C-2
position[4] and susceptibility of 2-deoxyglycoside-linkage in
acidic conditions to result undesired elimination products.[5] To
overcome these obstacles, several indirect strategies involving
de novo synthesis,[6] pre-activation of glycosyl donor[7] or
installing temporary prosthetic group at the C-2 position have
been developed.[8] In parallel, many direct methods including
Umpolung approaches for the synthesis of 2-deoxysugar have
been evolved utilizing glycosyl halides,[9] glycosyl imidates,[10]
thioglycosides,[11]
glycosyl
phosphate/phosphoroamidite/phosphite/phosphorodithioate,
[12]
and (2-carboxyl)benzyl glycoside donor.[13]
Besides, suitably functionalized glycals have been widely
explored as stable glycosyl donor in nucleophilic addition of
aglycones on 1-2 double bond to obtain 2-deoxyglycosides
(Scheme 1).[14] However, the lack of C-2 auxiliary group and the
presence of stereoelectronically diverse substituent at C-3
Carbohydrate Chemistry Research Laboratory (CCRL), Department of Chemistry,
Malaviya National Institute of Technology (MNIT), Jaipur-302017, INDIA. E-mail:
skashyap.chy@mnit.ac.in, skr.kashyap@gmail.com.
Electronic Supplementary Information (ESI) available: [General procedures,
characterization data, spectral charts are provided]. See DOI: 10.1039/x0xx00000x
Scheme 1. Synthesis of 2-deoxyglycosides from glycals and Cu-catalyzed stereoselective
glycosylation of “Armed” and “Disarmed” glycal donor
This journal is © The Royal Society of Chemistry 20xx
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Indeed, these scaffolds constitute several biologically active Apparently, the thermodynamically-stable glycosVidieew A4rtbiclecOonulilnde
products, antibiotics, nucleosides, cardiac glycoconjugates, be obtained in 90% yields with high D-sOeIl:e1c0t.1iv0i3t9y/D(0>O9B90:110)4b2Ay
and sugar-based therapeutic targets.[18]
performing the reaction in acetonitrile after 2 h, however
Despite the synthetic difficulties associated with installing competitive kinetic product was not observed (entry 8). The
selective glycosidic-linkages, development of stereoselective predominant allylic rearrangement attributed by the nature of
methods for the synthesis of 2-deoxysugars continues to be an C-3 acetate as a better leaving group than the ether linkage. In
interesting and nontrivial goal for carbohydrate researchers. contrast, the substrate with disarmed benzoyl group 1c failed
During our endeavour,[19] we previously successfully applied to undergo 1,2-addition reaction in toluene even after
Cu(II)-triflate as a mild Lewis acid catalyst in stereoselective prolonged reaction time (entry 9). Whereas, employing
Ferrier glycosylation.[19j] We further demonstrated the acetonitrile as the solvent led to non-selective activation of 1c
versatility and efficiency of Cu-catalysis in regioselective furnishing 2-deoxy 3c (39%, ; >85:15) and rearranged 4c
iodoglycosylation of 1,2-glycals comprising both armed and (10%, ; >99:1) in 60:40 ratios (entry 10).
disarmed donors.[19d] Subsequent anomeric activation of 2-
iodo-glycosyl acetate employing Cu(II)-catalyst enabling the
Table 1. Optimization of selective glycosylation of glycal donors in various conditions.[a]
expeditious synthesis of 2-deoxy-2-iodo glycosides with high
anomeric selectivity (Scheme 1). Enamoured of the inherent
moisture/air stability and effectiveness in glycosylation,[20] we
aimed to investigate the potential of Cu-catalysis in direct
activation of armed and disarmed galactal donor. Inspired by
these precedents and continuing our research interest in
glycochemistry, herein we present the development of stereo-
3,4 Yields (%)[d]
Entry Donor,
Catalyst (mol%)
t (h), T (°C ),
Solvent
3:4 [c]
(-selectivity)[e]
Conv.(%)[b]
controlled glycosylation employing Cu(II)-triflate as an
effective promoter allowing the synthesis of 2-deoxy and 2,3-
dideoxyglycosides under additive/ligand-free conditions. The
complementary approach is amenable to access structurally
defined 2-deoxy-linked trisaccharide by judicious selection of
the glycosyl donor and the solvent system.
1[f]
2
1a, Cu(OTf)2 (5)
1a, Cu(OTf)2 (5)
1a, Cu(OTf)2 (5)
1a, Cu(OTf)2 (5)
1a, Cu(OTf)2 (5)
1b, Cu(OTf)2 (5)
1b, Cu(OTf)2 (5)
1b, Cu(OTf)2 (5)
1c, Cu(OTf)2 (5)
1c, Cu(OTf)2 (5)
ACN
ACN
DCE
THF
24, rt, <10
NA
NA
NA
NA
24, 50, <20 NA
3
24, 50, <5
24, 50, 60
NA
4
100:0 45 (>95)
Results and discussion
To begin our studies, we first examined the activation of
per-O-benzylated galactal 1a as an armed donor with menthol
5
toluene 0.5, 50, 100 100:0 92 (>95)
toluene 8, 50, 100 78:22 53 (>80), 19 (>99)
6
(2a) as a model acceptor promoted by a catalytic amount of
7
DCM
ACN
3, 50, 100
2, 50, 100
70:30 45 (>95), 17 (>99)
0:100 90 (>99)
Cu(II)-triflate (5 mol%). As summarized in Table 1, the reaction
provided a very poor conversion in acetonitrile at room
temperature (entry 1); however a slight improvement was
observed when the reaction was performed at 50 °C for 24 h
(entry 2). Further changing the solvent to dichloroethane
significantly diminished the reaction rate allowing the
complete recovery of donor 1a (entry 3). Subsequently, the
use of THF as the solvent gave better conversion to obtain the
corresponding 2-deoxy glycoside 3a in 45% yields (entry 4). To
our delight, switching the solvent to toluene resulted selective
activation of armed donor 1a providing 1,2-addition product
3a in 92% yields without formation of Ferrier rearranged
glycoside (entry 5).[21] We further anticipated that the polarity
of the solvent and stereo-electronic diverse nature of
substituents impart crucial role in the stereochemical outcome
and the reactivity of donor substrate. Thus, the glycosylation
coupling of readily accessible disarmed donor 1b with 2a
under aforementioned reaction conditions afforded a mixture
of the kinetic 2-deoxy galactoside 3b (53%, ; >80:20) and
thermodynamically-controlled 2,3-unsaturated glycoside 4b
8
9
toluene 24, 50, 0
ACN 3, 50, 100
toluene 12, 50, 100 55:45 34 (>85), 9 (>99)
NR
NR
10
60:40 39 (>85), 10 (>99)
11[g] 1d, Cu(OTf)2 (5)
12
1e, Cu(OTf)2 (5)
ACN
1, 50, 100
0:100 88 (>90)
13[h] 1a, TMSOTf (10) toluene 24, 0-rt, 50
NA
NA
14[h,i] 1a, TfOH (10)
toluene 0.5, 0-rt, 100 NA
NA complex
NA
15[h] 1a, BF3∙OEt2 (10) toluene 24, 0-rt, 50
NA
16[h]
1b, TMSOTf (10) ACN
24, 0-rt, 50
0:100 30 (>99)
17[h]
1b, TfOH (10)
ACN
0.5, 0-rt,100 58:42 44 (>82), 16 (>99)
[a]Reaction conditions: Glycal donor 1a-1e (1.0 equiv.), menthol 2a (1.2
equiv.), and catalyst (5-10 mol%) in solvent (2 mL), stirred at 50 °C under
inert atmosphere (N2) unless otherwise noted. [b]As observed by thin-layer
chromatography. [c]Examined by 1H NMR spectroscopy of crude reaction
mixture. [d]The isolated and unoptimized yields. [e]The
/β ratios were
(19%, ; >99:1) in 78:22 ratio (entry 6). Though, similar determined by 1H NMR analysis. [f]Reaction at rt. [g]Mixture of Ferrier and 2-
results were obtained when the reaction was performed in
DCM solvent producing a mixture of 1,2-addition and Ferrier
product 3b:4b albeit with a different ratios; 70:30 (entry 7).
deoxy benzyl-glucosides, observed by 1H NMR spectrum. [h]Reactions
conducted at 0 °C to rt. [i]Inseparable complex mixture of undesired
products as a result of decomposition.
2 | J. Name., 2012, 00, 1-3
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To further probe the selective activation of 1,2-double bond in deoxydisaccharides 17-23 in satisfactory yields. NVoietwewArtoicrlethOynl,inae
armed and disarmed glycal donor, benzylated and acetylated uridine derived un-protected nucleoside
DOI: 10.1b03a9s/eD0O2Br010w42aAs
glucals (1d and 1e) were subjected to optimal glycosylation incorporated successfully with excellent selectivity to access
reactions. Activation of armed glucal donor 1d with menthol the venerable 2-deoxyglycoconjugates 24 and 25 in good
2a in toluene found to be unsatisfactory providing the yields without formation of thermodynamically favored Ferrier
inconsistent ratios of the corresponding direct 1,2-addition 3d product. These findings further highlight the potential of the
and Ferrier product 4d through competitive pathways (entry protocol in the stereoselective synthesis of 2-
11). In addition, we also observed a considerable amount of deoxyglycoconjugates.
benzyl-glucosides (2-deoxy/Ferrier), resulting from the facile
Enthusiastically, we demonstrated the extension of our
elimination of C-3 benzyl group and subsequent reacting as method in two-step sequential synthesis of oligosaccharide
competitive nucleophile. Presumably, the disarmed donor 1e (Scheme 2). Thus, the disaccharide 19 readily synthesized by
reacted in complete selectivity producing thermodynamically- glycosylation coupling of glycal donor 1f with 2n and following
stable glucoside 4e (88%, ; 90:10)[19j] as the sole product sequential deprotection of 6-O-ester with NaOMe in MeOH
(entry 12). Meanwhile, 1,2-addition reaction of 1a in the afforded the disaccharide acceptor 26 in 85% yields.[21]
presence of various catalysts such as TMSOTf, TfOH, or Subsequently, 1,2-direct addition of 26 with 1f employing
BF3∙OEt2 under optimal conditions found to be sluggish (either Cu(II)-catalyzed glycosylation furnished the desired
very slow or fast) resulting a poor conversion or undesired trisaccharide 27 in 68% yields with
-selectivity. The
complex reaction mixture (entries 13-15). Besides, the deacetylation reaction was repeated to obtain the
coupling between 1b and acceptor 2a employing TMSOTf as an corresponding 28 (70%) comprising a free OH group.
activator favors the selective Ferrier glycosylation albeit with
Table 2. Scope for the kinetically-controlled glycosylation of armed donor with
decreased rate (entry 16). Notably, the use of strong acid TfOH
,[b]
various aglycones.[a]
failed to produce selective activation attributing two
competitive Ferrier rearrangement and 1,2-addition pathways
(entry 17).
Having orthogonal activation model for armed and
disarmed glycal donor, we next systematically evaluated the
scope of the optimized glycosylation reactions using a range of
acceptors. As summarized in Table 2, the kinetic-controlled
1,2-addition of primary and secondary alcohols comprising
various
functionalities,
and
diversely
protected
monosaccharide and amino-acids proceeded smoothly
furnishing the corresponding 2-deoxyglycosides 5-25 in good
yields (72-94%) with high -selectivity (up to 100). The Cu(II)-
catalyzed 1,2-addition of 1a with allyl alcohol (2b), 2-
ethoxyethanol (2c), benzyl alcohol (2d) performed well to
afford 2-deoxyglycosides 5-7 in good yields. Subsequently, the
acceptors comprising alicyclic ring system
underwent stereoselective glycosylation to provide the
corresponding glycosides (80%) and (72%), respectively.
Furthermore, N-hydroxyphthalimide 2g),
(2e and 2f)
8
9
(
9-
fluorenemethanol (2h) and highly functionalized steroid such
as cholesterol (2i) were reacted smoothly to obtain the
kinetically-favored 2-deoxy--glycosides 10-13 in good yields
(78-86%). Notably, the N-hydroxyl amine derived glycosides
constitute a masked O-aminoxy-glycosyl, synthetically useful
aminoxy functionality at anomeric carbon to access the
valuable
neoglycoconjugates.[22]
Encouragingly,
the
glycosylation of Cbz-Ser-OMe (2j), Fmoc-Thr-OMe (2k), and N-
Fmoc-protected 4-hydroxy-L-proline (2l) were subjected under
present conditions to efficiently generate the corresponding
amino-acid-conjugated deoxysugars 14-16 in good yields and
high
-selectivity. Next, we evaluated the glycosylation of
sugar-derived acceptors to access the 2-deoxy-linked
disaccharides. Thus, the selective glycosylation of differently
protected galactal donors (1a, 1f and 1g) employing glucosyl
[a]Reaction conditions: Glycal Donor 1a, 1f or 1g (1.0 equiv.), acceptor (1.2 equiv.),
and Cu(OTf)2 (5 mol%) in toluene (2 mL), stirred at 50 °C under N2 atmosphere.
[b]Isolated yields after column chromatography as a mixture of , based on
relative integration of anomeric protons in 1H NMR spectrum.
(2m-2o), mannosyl (2p), and galactosyl (2q) derived acceptors
enabling the stereoselective formation of -(1-6, 1-4)-linked 2-

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Prominently, amino-acid derived acceptors wereViaewusAprtiiccleioOunslinlye
coupled with donor 1b employing FeDrrOieI:r10g.1l0y3c9o/sDy0lOatBi0o1n042toA
access the corresponding glycoconjugates 38-39 in good yields.
Pleasingly, the selective activation of 1b with primary (6-OH)
and secondary (4-OH) glucosyl acceptors were performed
successfully to obtain the
-(1-6) 40 and -(1-4) 41
disaccharides in 82% and 79% yields respectively. Indeed,
nucleoside base as glycosyl acceptor favors the formation of
thermodynamically-controlled O-galactoside 42 as the sole
Scheme 2. Stereoselective synthesis of the trisaccharide comprising 2-deoxy product with 81% yields with exclusive
component in sequential steps. Reaction conditions: (a) 1,2-Addition; glycal 1f (1.0
equiv.), 2n (1.2 equiv.), Cu(OTf)2 (5 mol%), toluene (2 mL), 50 °C, 15 h, (b)
Deprotection; 19 or 27 (1.0 equiv.), NaOMe (0.1 equiv.), MeOH, rt, 4 h, (c) 1,2-Addition;
glycal 1f (1.0 equiv.), 26 (1.2 equiv.), Cu(OTf)2 (5 mol%), toluene (2 mL), 50 °C, 6 h.
-anomer. More
importantly, the activation of disarmed donor achieved in
complete stereoselective manner allowing the expeditious
preparation of “pseudo-galactals” derivatives. It is pertinent to
mention that the selective glycosylation of 1b is particularly
challenging due to the high reactivity of per-O-acetylated
galactal towards competing allylic rearrangement and direct
1,2-addition pathways.[16c]
We next investigated the selective glycosylation of disarmed
donor 1b under optimum thermodynamically-controlled
conditions. Pleasingly, all the reactions worked well affording
the corresponding 2,3-unsaturated galactosides 29-42 in good
To gain insights into selective glycosylation, we performed
1,2-addition reactions of 1a with CH3OH, CD3OH and CD3OD as
the nucleophilic acceptors, respectively (Scheme 3). The 1H
NMR spectroscopy analyses confirm the formation of
corresponding 2-deoxy--glycosides 43-45 involving least
steric encumbrance pathways. Notably, the glycosylation
to excellent yields (70-94%) with -selectivity (>99:1), results
are summarized in Table 3. We accomplished the glycosylation
of disarmed donor 1b with allyl, propargyl, 2-ethoxyethanol,
benzyl alcohol, cyclopropyl- and cyclohexylmethanol to obtain
the desired products 29-34 in moderate-to-good yields. The
Ferrier-type rearrangement of acceptors comprising hydroxyl-
amine, fluorenylmethyl and steroidal moieties were performed
smoothly affording their corresponding galactosides 35-37 in
good yields with excellent selectivites (up to 100).
coupling between 1a and CD3OD presumably proceeding
through analogous intermediates;
the syn-diastereoselective addition on C1-C2 double bond to
give D3-methyl-2D-
-galactoside 45 [14j]
A B
-[4H5] and -[4H3] ensured

.
Though a detail mechanism awaits further studies, a
plausible rationalization for the kinetic and thermodynamic
controlled glycosylation may be proposed (Scheme 4). Initially,
the Cu(II)-triflate coordinates with C1-C-2 double bond of the
Table 3. Scope for the thermodynamically-controlled glycosylation of disarmed
donor with various aglycones.[a],[b]
favoured conformation A
-[4H5] in armed glycal 1a and oxygen
of the acceptor leading to the polarization of the double bond.
Subsequent activation of the enol-ether functionality will
facilitate the formation of a half-chair oxocarbenium ion
preferred [4H3] configuration. Finally, the nucleophilic
addition of activated-acceptor (RO-) from the less-hindered
B with
a
axial side of depicted
kinetically favoured
B

-[4H3] will unambiguously produce the
-glycoside 3a. The predominant
-
selectivity certainly attributed to the vinylogous anomeric
effect (VAE) and the stereochemistry and stability of the half-
chair transient states.[14] Additional experiments were
conducted to further substantiate the correlation between
rationalized transitions states and distinctive stereochemical
outcome.
[a]Reaction conditions: Glycal Donor 1b (1.0 equiv.), acceptor (1.2 equiv.), and
Cu(OTf)2 (5 mol%) in acetonitrile (2 mL), stirred at 50 °C under inert atmosphere.
[b]The isolated yields as a mixture of  anomers, determined by 1H NMR
spectrum.
Scheme 3. Glycosylation with acceptors including deuterated methanol to probe the
mechanistic hypothesis for syn-1,2-addition.
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In addition, the one-pot sequential Ferrier glycosVyielawtAiortincleoOfnl1inbe
DOI: 10.1039/D0OB01042A
following selective anomeric activation of resultant O-allyl
donor 29 with acceptors 2a and 2n by using NBS, facilitating
the release of bromonium ion
G producing unequivocally 2,3-
unsaturated glycosides 4a (68%) and 40 (70%) with equivalent
stereoselectivity.[21] These observations infidelity established
the role of penultimate transient species and directing
influence of the catalyst.
Conclusions
In summary, we have successfully developed a flexible and
practical approach for the stereoselective activation of 1,2-
double bond in galactal donor employing Cu(II)-catalyst as the
promoter to obtain the 2-deoxy and 2,3-unsaturated
glycoconjugates. The protocol is highly advantageous and
ensured the divergent and stereoselective glycosylation
affording kinetic (2-deoxy) or thermodynamic (2,3-dideoxy)
Scheme 4. Mechanistic rationalization for the cu-catalyzed stereoselective
glycosylation of “Armed” glycal donor and one-pot sequential anomeric activation.
Accordingly, the coupling of 1a with 2b under standard 1,2-
addition conditions following one-pot anomeric activation of
product with
-selectivity. The intrinsic reactivity of “armed’
and “disarmed” donor with subtle electronic nature of
protecting groups led to orthogonal glycosylation processes
and largely controlled by the choice of suitable solvent system.
The scope of the selective activation methods were
substantiated for a wide range of acceptors and tolerated
various sensitive functionalities in amino-acids and
carbohydrates. Synthetic application of this method is further
highlighted in the stereoselective synthesis of 2-deoxy linked
oligosaccharides by readily functional group manipulation.
Further mechanistic investigations into solvent-dependent
glycosylation of armed/disarmed glycosyl donor and potential
application to the synthesis of oligosaccharides are in progress.
allyl glycosyl donor
formation of bromonium ion C [7d]
epibromohydrin following glycosidic linkage with 2a resulted
5
with acceptor 2a using NBS facilitate the
.
Subsequent elimination of
D
3a with same selectivity albeit with a different yields (62% over
2-steps). Similar results were obtained in the glycosylation
coupling of monosaccharide aglycone 2n affording the
corresponding disaccharide 18 in 65% yields. The
stereochemical outcome reveals the formation of an identical
putative pseudo-chair oxocarbenium ion B.
The alternative mechanism of allylic rearrangement in
disarmed donor could be postulated on the basis of our
experimental results and analogy to prior reports.[15] As
illustrated in Scheme 5, alongside coordinating with double-
Experimental
bond from sterically favourable

-face in distorted [4H5]
General Synthesis Information: Moisture and air-sensitive
reactions were performed in flame-dried round bottom flasks,
fitted with rubber septa or glass gas adapters, under a positive
pressure of nitrogen. Moisture and air-sensitive liquids or
solutions were transferred via nitrogen-flushed syringe.
Experiments were monitored by thin layer chromatography
(TLC). Melting points were obtained in open capillary tubes
using a micro melting point apparatus and were uncorrected.
Unless otherwise noted, materials were obtained from
commercial suppliers and used without purification. Removal
of solvent under reduced pressure refers to distillation with a
Büchi rotary evaporator attached to a vacuum pump (~3
mmHg). Products obtained as solids or high boiling oils were
dried under vacuum (~1 mmHg). Analytical TLC was performed
using Whatman 250-micron aluminum backed UV F254 pre-
coated silica gel flexible plates. Subsequent to elution,
ultraviolet illumination at 254 nm allowed for visualization of
UV active materials. Staining with p-anisaldehyde, basic
potassium permanganate solution, or Molisch's reagents
allowed for further visualization. Proton and Carbon nuclear
magnetic resonance spectra (1H, 13C NMR) were recorded on
Avance 300, 400 or 500 MHz and ECS 400 MHz (JEOL) NMR
spectrometers. The proton resonances are annotated as:
conformation of 1b and ROH, Cu-catalyst also interacts with
pseudo-axial oriented OAc at C-3 position. This significantly
induced bond lengthening of C(3)-OAc in Cu-complex E
-[4H5]
and likely to activate the 3-OAc as leaving group to generate a
more-stable allyloxycarbenium ion intermediate F-[5H4]. The
delocalization involving ring oxygen and endocyclic double-
bond and stereochemical factor (anchimeric assistance of the
6-OAc) associated with the transient state thus directing the
approach of acceptor from the
thermodynamically-controlled 4a
-face to give the
.
Scheme 5. Proposed hypothesis for the activation of “Disarmed” glycal donor under
thermodynamic conditions and one-pot anomeric activation.
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chemical shift (δ) relative to tetramethylsilane (δ 0.0) using the compound 4b as a pale yellow solid (121 mg, 0.33V0iemw Amrtioclle,O9n0lin%e
o
1
DOI: 10.1039/D0OB01042A
residual solvent signal as an internal standard or yield;
-only). Mp: 72-74 C; Rf (50% EtOAc/Hexane) 0.5; H
tetramethylsilane itself: chloroform-d (δ 7.26, singlet), NMR (400 MHz, CDCl3) δ 6.11 (dd, J = 10.0, 5.0 Hz, 1H), 6.05
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, (dd, J = 10.0, 2.8 Hz, 1H), 5.15 (d, J = 2.5 Hz, 1H), 5.02 (dd, J =
multiplet; br, broad), coupling constant (J, Hz), and number of 5.1, 2.5 Hz, 1H), 4.42 (ddd, J = 7.4, 4.7, 2.6 Hz, 1H), 4.27-4.17
protons for a given resonance is indicated by nH. The chemical (m, 2H), 3.45 (td, J = 10.6, 4.4 Hz, 1H), 2.09 (s, 3H), 2.08 (s, 3H),
shifts of 13C NMR are reported in ppm relative to the central 1.71-1.59 (m, 3H), 1.52-1.38 (m, 1H), 1.02 (dt, J = 13.6, 7.5 Hz,
line of the triplet at δ 77.00 ppm for CDCl3. IR spectra were 3H), 0.93 (d, J = 3.7 Hz, 3H), 0.91 (d, J = 4.2 Hz, 3H), 0.89-0.81
recorded on a PerkinElmer FT-IR spectrometer and wave (m, 2H), 0.79 (d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
numbers of maximum absorption peaks are presented in cm-1. 170.7, 170.4, 130.7, 124.7, 95.6, 80.7, 66.6, 63.2, 63.0, 48.9,
Mass analyses (ESI-MS) and HRMS were performed on Xevo 43.2, 34.2, 31.7, 25.6, 23.1, 22.4, 21.1, 20.8, 16.1; HRMS (ESI)
G2-S QTTOF (Waters, USA) Spectrometer.
General experimental procedure for the synthesis of 2- 391.2090.
m/z [M + Na]+ calculated for [C20H32O6Na]+: 391.2091; found
deoxyglycosides:
Prop-2-enyl-3,4,6-tri-O-benzyl-2-deoxy-
-D-lyxo-
Menthyl-3,4,6-tri-O-benzyl-2-deoxy--D-lyxo-
hexapyranoside (5): Glycosylation of 3,4,6-tri-O-benzyl-D-
hexapyranoside (3a): A preformed solution of 3,4,6-tri-O- galactal (100 mg, 0.240 mmol, 1.0 equiv.) with Allyl alcohol (19
o
benzyl-D-galactal (100 mg, 0.240 mmol, 1.0 equiv.) and L- µL, 17 mg, 0.288 mmol, 1.2 equiv.) at 50 C for 4 h, purified by
Menthol (45 mg, 0.288 mmol, 1.2 equiv.) in toluene (2 mL) was silica gel column chromatography to obtain glycoside
added 5 mol% Cu(OTf)2 and the resulting mixture was stirred light yellow solid (98 mg, 0.206 mmol, 86% yield,97:03).
5 as a
1
at 50
C temperature under N2 atmosphere until the Rf (20% EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ 7.36-
completion of starting material, typically for 30 min. (adjudged 7.23 (m, 15H), 5.89 (ddd, J = 22.4, 10.8, 5.6 Hz, 1H), 5.24 (ddd,
by TLC). The reaction mixture was diluted with EtOAc (10 mL), J = 17.2, 3.3, 1.6 Hz, 1H), 5.17-5.12 (m, 1H), 5.02 (d, J = 2.8 Hz,
quenched with saturated NaHCO3 (5 mL) and extracted with 1H), 4.93 (d, J = 11.6 Hz, 1H), 4.69-4.56 (m, 3H), 4.46 (dt, J =
EtOAc (3 × 30 mL). The combined organic layers were washed 14.6, 11.8 Hz, 3H), 4.13 (ddt, J = 13.0, 5.1, 1.4 Hz, 1H), 3.98 -
with brine solution, dried over anhydrous Na2SO4, 3.90 (m, 3H), 3.64-3.53 (m, 2H), 2.24 (td, J = 12.3, 3.7 Hz, 1H),
concentrated in vacuo and purified by silica gel column 2.02 (dd, J = 12.6, 4.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
chromatography using hexane-EtOAc as eluent to afford the 138.8, 138.5, 138.0, 134.2, 128.3, 128.1, 127.7, 127.6, 127.4,
compound 3a as a colorless syrup (126 mg, 0.220 mmol, 92% 127.2, 116.9, 97.0, 74.7, 74.2, 73.4, 72.9, 70.4, 69.9, 69.5, 67.8,
1
yield, ; 95:05). Rf (15% EtOAc/Hexane) 0.5; H NMR (400 31.1; the overall spectroscopic data are in complete
MHz, CDCl3) δ 7.36-7.31 (m, 7H), 7.31-7.23 (m, 8H), 5.03 (d, J = agreement with assigned structures and consistent with
2.9 Hz, 1H), 4.94 (d, J = 11.7 Hz, 1H), 4.67-4.55 (m, 4H), 4.55- literature.[16b]
4.38 (m, 2H), 4.06 (t, J = 6.4 Hz, 1H), 3.93 (m, 1H), 3.64-3.52
Ethoxyethyl-3,4,6-tri-O-benzyl-2-deoxy--D-lyxo-
(m, 2H), 3.30 (td, J = 10.5, 4.2 Hz, 1H), 2.19 (td, J = 12.3, 3.4 Hz, hexapyranoside (6): Glycosylation of 3,4,6-tri-O-benzyl-D-
1H), 2.03 (ddd, J = 16.7, 14.8, 7.8 Hz, 4H), 1.65-1.54 (m, 3H), galactal (100 mg, 0.240 mmol, 1.0 equiv.) with Ethoxy ethanol
1.22-1.11 (m, 1H), 1.00-0.92 (m, 1H), 0.90 (d, J = 6.9 Hz, 3H), (28 µL, 26 mg, 0.288 mmol, 1.2 equiv.) at 50 oC for 3 h, purified
0.88-0.84 (m, 1H), 0.81 (d, J = 6.5 Hz, 3H), 0.75 (d, J = 6.9 Hz, by silica gel column chromatography to obtain glycoside
6
as a
3H); 13C NMR (101 MHz, CDCl3) δ 139.0, 138.6, 138.2, 128.4, yellow oil (93 mg, 0.183 mmol, 76% yield, 


97:03). Rf (20%
1
128.3, 128.1, 127.6, 127.6, 127.4, 127.4, 127.3, 99.8, 79.9, EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ 7.36-7.26 (m,
74.9, 74.2, 73.4, 73.2, 70.4, 69.8, 69.7, 48.9, 42.9, 34.3, 31.6, 15H), 5.08 (d, J = 3.1 Hz, 1H), 4.94 (d, J = 11.6 Hz, 1H), 4.63
25.7, 23.2, 22.2, 21.1,16.3; the overall spectroscopic data are (ddd, J = 29.0, 14.6, 8.9 Hz, 6H), 4.53-4.40 (m, 4H), 4.02-3.92
in complete agreement with assigned structures and (m, 3H), 3.69-3.50 (m, 3H), 2.25 (td, J = 12.4, 3.7 Hz, 1H), 2.04
consistent with literature.[16d]
(dd, J = 12.6, 4.5 Hz, 1H), 0.91-0.83 (m, 3H); 13C NMR (101
General experimental procedure for the synthesis of 2,3- MHz, CDCl3) δ 138.9, 138.5, 138.1, 137.8, 128.4, 128.2, 128.2,
unsaturated glycosides:
127.9, 127.8, 127.7, 127.6, 127.5, 127.3, 97.1, 74.8, 74.3, 73.5,
72.9, 70.5, 70.0, 69.5, 68.9, 31.9, 31.1, 22.7, 14.1; HRMS (ESI)
Menthyl-4,6-di-O-acetyl-2,3-dideoxy--D-threo-hex-2-
enopyranoside (4a): A preformed solution of 3,4,6-tri-O- m/z [M + Na]+ calculated for [C31H38O6Na]+: 529.2561; found
acetyl-D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) and L- 529.2560.
Menthol (68 mg, 0.440 mmol, 1.2 equiv.) in acetonitrile (2 mL)
was added 5 mol% Cu(OTf)2 and the resulting mixture was hexapyranoside (7)
stirred at 50 C temperature under N2 atmosphere until the galactal (100 mg, 0.240 mmol, 1.0 equiv.) with Benzyl alcohol
completion of starting material, typically for 3 h (adjudged by (30 µL, 31 mg, 0.288 mmol, 1.2 equiv.) at 50 oC for 4 h, purified
TLC). The reaction mixture was diluted with EtOAc (10 mL), by silica gel column chromatography to obtain glycoside as a
Benzyl-3,4,6-tri-O-benzyl-2-deoxy-
-D-lyxo-
:
Glycosylation of 3,4,6-tri-O-benzyl-D-

7
quenched with saturated NaHCO3 (5 mL) and extracted with pale yellow semi solid (106 mg, 0.202 mmol, 84% yield,
1
EtOAc (3 × 30 mL). The combined organic layers were washed 95:05). Rf (50% EtOAc/Hexane) 0.5; H NMR (400 MHz,
with brine solution, dried over anhydrous Na2SO4, CDCl3) δ 7.36-7.24 (m, 20H), 5.08 (d, J = 3.2 Hz, 1H), 4.93 (d, J =
concentrated in vacuo and purified by silica gel column 11.6 Hz, 1H), 4.70-4.55 (m, 5H), 4.46 (dt, J = 14.2, 11.8 Hz, 3H),
chromatography using hexane-EtOAc as eluent to afford the 4.01-3.92 (m, 2H), 3.66-3.52 (m, 2H), 2.25 (td, J = 12.4, 3.7 Hz,
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 16
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
1H), 2.04 (dd, J = 12.7, 4.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 73.6, 73.2, 72.6, 71.7, 70.5, 68.7, 28.8; HRMS (EVSiIe)wmArt/iczle[OMnlin+e
+
+
DOI: 10.1039/D0OB01042A
138.8, 138.4, 138.0, 137.8, 128.3, 128.2, 128.2, 127.9, 127.7, NH4] calculated for [C35H37O7N2] : 597.2595; found 597.2594.
127.6, 127.6, 127.5, 127.3, 97.0, 74.8, 74.2, 73.4, 72.9, 70.4,
70.0, 69.5, 68.8, 31.1; the overall spectroscopic data are in
Pthalimido-3,4-di-O-benzyl-6-O-triisopropylsilyl-2-deoxy-
-D-lyxo-hexapyranoside (11): Glycosylation of 6-OTIPS-2,3-

complete agreement with assigned structures and consistent di-O-acetyl-D-galactal (100 mg, 0.207 mmol, 1.0 equiv.) with N-
o
with literature.[14k]
Hydroxyphthalimide (40 mg, 0.248 mmol, 1.2 equiv.) at 50 C
for 10 min., purified by silica gel column chromatography to
Cyclopropylmethyl-3,4,6-tri-O-benzyl-2-deoxy--D-lyxo-
hexapyranoside (8): Glycosylation of 3,4,6-tri-O-benzyl-D- obtain glycoside 11 as a white semi solid (112 mg, 0.173 mmol,
1
galactal (100 mg, 0.240 mmol, 1.0 equiv.) with 84% yield, -only). Rf (10% EtOAc/Hexane) 0.5; H NMR (400
cyclopropylmethanol (23 µL 21 mg, 0.288 mmol, 1.2 equiv.) at MHz, CDCl3) δ 7.80 (dt, J = 7.6, 3.9 Hz, 2H), 7.75-7.70 (m, 2H),
o
50 C for 3 h, purified by silica gel column chromatography to 7.37 (dd, J = 9.0, 6.2 Hz, 6H), 7.34-7.22 (m, 4H), 5.60 (s, 1H),
obtain glycoside
8 as a colorless semi solid (93 mg, 0.192 4.96 (d, J = 11.3 Hz, 1H), 4.71 (d, J = 11.3 Hz, 1H), 4.69-4.61 (m,
1
mmol, 80% yield, ; 93:07). Rf (50% EtOAc/Hexane) 0.5; H 2H), 4.60-4.55 (m, 1H), 4.18-4.09 (m, 2H), 3.81 (t, J = 8.8 Hz,
NMR (400 MHz, CDCl3) δ 7.30 (ddd, J = 25.3, 14.3, 9.1 Hz, 15H), 1H), 3.72 (dd, J = 9.3, 5.8 Hz, 1H), 2.40 (dd, J = 9.7, 3.1 Hz, 2H),
5.05 (d, J = 2.9 Hz, 1H), 4.93 (d, J = 11.6 Hz, 1H), 4.68-4.52 (m, 1.15-1.01 (m, 21H); 13C NMR (101 MHz, CDCl3) δ 163.4, 139.0,
4H), 4.51-4.39 (m, 2H), 3.95 (dt, J = 16.4, 4.4 Hz, 2H), 3.64-3.51 138.3, 134.3, 129.0, 128.4, 128.2, 128.1, 127.6, 127.4, 127.3,
(m, 2H), 3.40 (dd, J = 10.7, 7.0 Hz, 1H), 3.27 (dd, J = 10.6, 7.0 123.4, 103.7, 74.7, 73.8, 73.6, 72.6, 70.5, 61.6, 28.8, 18.0, 17.9,
Hz, 1H), 2.24 (td, J = 12.3, 3.7 Hz, 1H), 2.03 (dd, J = 12.6, 4.1 Hz, 11.9, 1.0; HRMS (ESI) m/z [M
1H), 1.09-0.98 (m, 1H), 0.55-0.44 (m, 2H), 0.18 (ddd, J = 13.2, [C37H48NO7Si]+: 646.3195; found 646.3194.
9.8, 5.1 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 138.8, 138.5,
9-Fluorenylmethyl-3,4,6-tri-O-benzyl-2-deoxy-
+
H]+ calculated for

-D-lyxo-
138.0, 128.3, 128.3, 128.2, 128.1, 127.7, 127.6, 127.4, 127.2, hexapyranoside (12): Glycosylation of 3,4,6-tri-O-benzyl-D-
97.2, 74.9, 74.2, 73.4, 72.8, 71.9, 70.4, 69.7, 69.6, 31.2, 10.3, galactal (100 mg, 0.240 mmol, 1.0 equiv.) with 9-
3.3, 2.7; HRMS (ESI) m/z [M
[C31H36O5Na]+: 511.2455; found 511.2453.
Cyclohexylmethyl-3,4,6-tri-O-benzyl-2-deoxy-
+
Na]+ calculated for Flourenemethanol (9-FM) (56 mg, 0.288 mmol, 1.2 equiv.) at

50 C for 7 h, purified by silica gel column chromatography to

-D-lyxo-
obtain glycoside 12 as a pale yellow semi solid (114 mg, 0.187
1
hexapyranoside (9): Glycosylation of 3,4,6-tri-O-benzyl-D- mmol, 78% yield,; 96:04). Rf (20% EtOAc/Hexane) 0.5; H
galactal (100 mg, 0.240 mmol, 1.0 equiv.) with NMR (400 MHz, CDCl3) δ 7.30-7.13 (m, 23H), 5.00 (d, J = 3.0 Hz,
cyclohexylmethanol (35 µL, 33 mg, 0.288 mmol, 1.2 equiv.) at 1H), 4.86 (d, J = 11.6 Hz, 1H), 4.54 (ddd, J = 19.2, 15.4, 6.9 Hz,
o
50 C for 9 h, purified by silica gel column chromatography to 4H), 4.39 (ddd, J = 23.3, 12.9, 7.2 Hz, 4H), 3.94-3.85 (m, 3H),
obtain glycoside
9 as a pale yellow oil (93 mg, 0.175 mmol, 3.56-3.46 (m, 2H), 2.18 (td, J = 12.4, 3.7 Hz, 1H), 1.97 (dd, J =
1
72% yield, ; 96:04). Rf (10% EtOAc/Hexane) 0.5; H NMR 12.6, 4.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 138.8, 138.4,
(400 MHz, CDCl3) δ 7.36-7.24 (m, 15H), 4.95-4.90 (m, 2H), 4.66- 138.0, 137.8, 128.3, 128.2, 128.2, 127.9, 127.7, 127.6, 127.6,
4.55 (m, 4H), 4.54-4.40 (m, 2H), 3.96-3.87 (m, 2H), 3.58 (qd, J = 127.5, 127.3, 97.0, 74.8, 74.2, 73.4, 72.9, 70.4, 70.0, 69.5, 68.9,
9.4, 4.9 Hz, 2H), 3.41 (dd, J = 9.4, 7.2 Hz, 1H), 3.16 (dd, J = 9.4, 31.1; HRMS (ESI) m/z [M + H]+ calculated for [C41H41O5]+:
6.1 Hz, 1H), 2.26-2.17 (m, 1H), 1.99 (dd, J = 13.3, 3.5 Hz, 1H), 613.2949; found 613.2942.
1.77-1.62 (m, 4H), 1.60-1.50 (m, 1H), 1.17 (dd, J = 22.9, 13.3
Cholesteryl-3,4,6-tri-O-benzyl-2-deoxy--D-lyxo-
Hz, 3H), 0.89 (tdd, J = 13.4, 11.2, 5.8 Hz, 3H); 13C NMR (101 hexapyranoside (13): Glycosylation of 3,4,6-tri-O-benzyl-D-
MHz, CDCl3) δ 138.9, 138.5, 138.1, 128.3, 128.3, 128.2, 128.2, galactal (100 mg, 0.240 mmol, 1.0 equiv.) with Cholesterol

127.7, 127.6, 127.5, 127.3, 97.8, 74.9, 74.2, 73.4, 73.0, 70.4, (111 mg, 0.288 mmol, 1.2 equiv.) at 50 C for 5 min., purified
69.7, 69.6, 37.8, 31.2, 30.1, 29.9, 26.6, 25.8, 25.7; the overall by silica gel column chromatography to obtain glycoside 13 as
spectroscopic data are in complete agreement with assigned a white solid (158 mg, 0.196 mmol, 82% yield, ; 94:06). Rf
1
structures and consistent with literature.[16b]
(10% EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ 7.36-
7.25 (m, 15H), 5.26 (d, J = 4.4 Hz, 1H), 5.14 (d, J = 3.1 Hz, 1H),
Pthalimido-3,4,6-tri-O-benzyl-2-deoxy-
hexapyranoside (10)
-D-lyxo-
:
Glycosylation of 3,4,6-tri-O-benzyl-D- 4.93 (d, J = 11.6 Hz, 1H), 4.67-4.55 (m, 3H), 4.47 (dd, J = 30.7,
galactal (100 mg, 0.240 mmol, 1.0 equiv.) with N- 11.7 Hz, 2H), 4.02-3.96 (m, 1H), 3.94 (d, J = 2.4 Hz, 1H), 3.65-
o
Hydroxyphthalimide (47 mg, 0.288 mmol, 1.2 equiv.) at 50 C 3.54 (m, 2H), 3.50-3.40 (m, 1H), 2.28 (d, J = 8.0 Hz, 2H), 2.22
for 12 h, purified by silica gel column chromatography to (dd, J = 11.6, 3.6 Hz, 1H), 2.05-1.78 (m, 6H), 1.60 (s, 3H), 1.55-
obtain glycoside 10 as a pale yellow semi solid (120 mg, 0.207 1.29 (m, 14H), 1.10 (ddd, J = 23.4, 16.6, 6.4 Hz, 5H), 0.99 (s,
1
mmol, 86% yield, ; 94:06). Rf (20% EtOAc/Hexane) 0.5; H 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.86 (dd, J = 6.6, 1.8 Hz, 6H), 0.67
NMR (400 MHz, CDCl3) δ 7.78 (d, J = 3.2 Hz, 2H), 7.71 (d, J = 2.8 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 140.9, 138.9, 138.6, 138.1,
Hz, 2H), 7.38-7.25 (m, 15H), 5.59 (s, 1H), 4.94 (d, J = 11.4 Hz, 128.4, 128.4, 128.2, 127.7, 127.6, 127.5, 127.3, 121.6, 95.6,
1H), 4.80 (t, J = 6.4 Hz, 1H), 4.64 (d, J = 5.7 Hz, 4H), 4.51 (dd, J = 76.1, 75.0, 74.3, 73.4, 73.1, 70.5, 69.8, 69.6, 56.7, 56.1, 50.1,
26.5, 11.9 Hz, 2H), 4.10 (d, J = 8.6 Hz, 1H), 3.69-3.60 (m, 1H), 42.3, 40.0, 39.7, 39.5, 37.1, 36.7, 36.2, 35.8, 31.9, 31.8, 31.7,
3.59-3.50 (m, 1H), 2.41 (d, J = 6.6 Hz, 2H); 13C NMR (101 MHz, 28.2, 28.0, 27.8, 24.3, 23.8, 22.8, 22.6, 21.0, 19.4, 18.7, 11.8;
CDCl3) δ 163.5, 138.7, 138.3, 138.2, 134.3, 129.0, 128.4, 128.3, the overall spectroscopic data are in complete agreement with
128.2, 128.1, 127.6, 127.5, 127.4, 127.3, 123.5, 103.9, 74.5, assigned structures and consistent with literature.[14k]
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 16
ARTICLE
O-(3,4,6-tri-O-benzyl-2-deoxy-
(benzyloxycarbonyl)-L-serinemethyl ester (14): Glycosylation 73.4, 73.3, 72.8, 72.8, 70.5, 70.4, 70.3, 69.7, 69.6, 67.5, 67.3,
of 3,4,6-tri-O-benzyl-D-galactal (100 mg, 0.240 mmol, 1.0 58.1, 57.7, 52.3, 52.2, 51.8, 51.3, 47.1, 47.0, 37.5, 36.4, 31.1,
equiv.) with Cbz-Ser-OMe (63 mg, 0.288 mmol, 1.2 equiv.) at 30.9; HRMS (ESI) m/z [M + Na]+ calculated for [C48H49NO9Na]+:
50 oC for 15 min., purified by silica gel column chromatography 806.3300; found 806.3302.
Journal Name

-D-lyxo-hexapyranosyl)-N- 124.7, 119.9, 119.8, 97.2, 97.1, 74.5, 74.4, 74.2, 74.1, 73.6,
View Article Online
DOI: 10.1039/D0OB01042A
to obtain glycoside 14 as a pale yellow semi solid (134 mg,
0.201 mmol, 84% yield,
-only). Rf (30% EtOAc/Hexane) 0.5; 1H deoxy-
NMR (400 MHz, CDCl3) δ 7.35-7.24 (m, 20H), 5.84 (d, J = 8.8 Hz, Glycosylation of 3,4,6-tri-O-benzyl-D-galactal (100 mg, 0.240
1H), 5.14-5.04 (m, 2H), 4.91 (dd, J = 10.8, 7.4 Hz, 2H), 4.58 (dd, mmol, 1.0 equiv.) with 6-Hydroxy-2,3,4-tri-O-benzoyl-
Methyl
2,3,4-tri-O-benzoyl-6-O-(3,4,6-tri-O-benzyl-2-


-D-lyxo-hexapyranosyl)-

-D-glucopyranoside (17):
-
J = 11.3, 3.5 Hz, 3H), 4.52 (dd, J = 9.2, 4.1 Hz, 1H), 4.42 (dd, J = methoxy glucopyranoside (146 mg, 0.288 mmol, 1.2 equiv.) at
40.8, 12.0 Hz, 2H), 3.96 (dd, J = 10.7, 3.5 Hz, 1H), 3.90-3.79 (m, 50 oC for 15 min., purified by silica gel column chromatography
4H), 3.73 (s, 3H), 3.58-3.48 (m, 2H), 2.19 (td, J = 12.4, 3.7 Hz, to obtain glycoside 17 as a white solid (190 mg, 0.206 mmol,
1
1H), 1.92 (dd, J = 12.7, 4.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 86% yield, 91:09). Rf (50% EtOAc/Hexane) 0.5; H NMR
170.7, 170.4, 170.3, 155.9, 136.1, 129.8, 128.5, 128.2, 128.1, (400 MHz, ) δ 7.99 (d, J = 7.1 Hz, 2H), 7.92 (d, J = 7.1 Hz, 2H),
125.4, 94.6, 69.2, 67.2, 67.1, 62.7, 62.5, 54.4, 52.6, 20.8, 20.6; 7.87 (d, J = 7.1 Hz, 2H), 7.54-7.16 (m, 24H), 6.12 (t, J = 9.9 Hz,
the overall spectroscopic data are in complete agreement with 1H), 5.64 (t, J = 9.9 Hz, 1H), 5.28 (dd, J = 10.2, 3.6 Hz, 1H), 5.20
assigned structures and consistent with literature.[7c]
O-(3,4,6-tri-O-benzyl-2-deoxy-
(d, J = 3.6 Hz, 1H), 5.00 (d, J = 3.0 Hz, 1H), 4.89 (d, J = 11.6 Hz,
-D-lyxo-hexapyranosyl)-N- 1H), 4.57 (d, J = 12.3 Hz, 4H), 4.27 (dd, J = 32.7, 12.0 Hz, 2H),

(Fluorenylmethyloxycarbonyl)-L-threoninemethyl ester (15): 4.21-4.16 (m, 1H), 3.95 (ddd, J = 12.0, 4.4, 2.3 Hz, 1H), 3.87 (s,
Glycosylation of 3,4,6-tri-O-benzyl-D-galactal (100 mg, 0.240 1H), 3.83 (dd, J = 10.8, 5.5 Hz, 2H), 3.58 (dd, J = 11.1, 3.0 Hz,
mmol, 1.0 equiv.) with Fmoc-Thr-OMe(106 mg, 0.288 mmol, 1H), 3.50-3.42 (m, 1H), 3.39 (s, 3H), 2.18 (td, J = 12.4, 3.6 Hz,
1.2 equiv.) at 50 oC for 3 h, purified by silica gel column 1H), 1.98 (dd, J = 12.7, 4.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
chromatography to obtain glycoside 15 as a colorless viscous 165.8, 165.3, 138.9, 138.6, 138.2, 133.3, 133.2, 133.0, 129.9,
oil (142mg, 0.184 mmol, 77% yield, ; 92.08). Rf (20% 129.8, 129.7, 129.3, 129.1, 129.0, 128.4, 128.3, 128.3, 128.2,
EtOAc/Hexane) 0.5; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.4 128.1, 128.1, 127.5, 127.5, 127.4, 98.1, 96.9, 74.4, 74.2, 73.1,
Hz, 2H), 7.63 (dd, J = 6.8, 5.0 Hz, 2H), 7.40 (t, J = 7.5 Hz, 3H), 72.9, 72.0, 70.7, 70.4, 69.8, 69.4, 69.3, 68.1, 65.7, 55.4, 30.9;
7.36-7.29 (m, 16H), 5.43 (d, J = 9.7 Hz, 1H), 4.93 (dd, J = 7.4, 4.1 the overall spectroscopic data are in complete agreement with
Hz, 2H), 4.65-4.58 (m, 4H), 4.50 (d, J = 11.7 Hz, 1H), 4.45-4.40 assigned structures and consistent with literature.[7c]
(m, 3H), 4.38-4.34 (m, 1H), 4.27 (t, J = 7.0 Hz, 1H), 3.94 (d, J =
6.7 Hz, 2H), 3.86 (ddd, J = 12.2, 4.3, 2.1 Hz, 1H), 3.73 (s, 3H),
Methyl 2,3,4-tri-O-benzyl-6-O-(3,4,6-tri-O-benzyl-2-deoxy-
-D-lyxo-hexapyranosyl)- -D-glucopyranoside (18):


3.56 (dd, J = 6.3, 4.0 Hz, 2H), 2.22-2.12 (m, 1H), 1.86 (dd, J = Glycosylation of 3,4,6-tri-O-benzyl-D-galactal (100 mg, 0.240
12.6, 4.4 Hz, 1H), 1.25 (s, 3H); 13C NMR (101 MHz, CDCl3) δ mmol, 1.0 equiv.) with 6-Hydroxy-2,3,4-tri-O-benzyl-
-
171.2, 156.1, 143.8, 143.7, 141.3, 138.7, 138.2, 137.9, 128.4, methoxy glucopyranoside (133 mg, 0.288 mmol, 1.2 equiv.) at
128.3, 128.2, 128.2, 127.7, 127.6, 127.6, 127.5, 127.4, 127.0, 50 oC for 20 min., purified by silica gel column chromatography
125.0, 120.0, 99.3, 75.1, 74.2, 73.5, 72.7, 70.3, 69.4, 67.1, 58.7, to obtain glycoside 18 as a colorless oil (165mg, 0.187 mmol,
1
52.4, 47.1, 31.2, 24.6, 18.5;HRMS (ESI) m/z [M + H]+ calculated 78% yield, 96:04). Rf (50% EtOAc/Hexane) 0.5; H NMR
for [C47H50NO9]+: 772.3480; found 772.3482.
(400 MHz, CDCl3) δ 7.38-7.21 (m, 30H), 5.02 (d, J = 2.8 Hz, 1H),
-D-lyxo-hexapyranosyl)-N- 4.98 (d, J = 10.7 Hz, 1H), 4.91 (d, J = 11.6 Hz, 1H), 4.84 (d, J =
O-(3,4,6-tri-O-benzyl-2-deoxy-
(Fluorenylmethyloxycarbonyl)-L-Proline methyl ester (16): 10.9 Hz, 1H), 4.79 (dd, J = 11.6, 2.9 Hz, 2H), 4.68 (d, J = 12.2 Hz,
Glycosylation of 3,4,6-tri-O-benzyl-D-galactal (100 mg, 0.240 1H), 4.59 (dd, J = 7.6, 4.0 Hz, 2H), 4.57-4.54 (m, 2H), 4.52 (d, J =
mmol, 1.0 equiv.) with Fmoc-Hyp-OMe (105 mg, 0.288 mmol, 10.9 Hz, 1H), 4.37 (dd, J = 29.9, 11.8 Hz, 2H), 3.98 (t, J = 9.2 Hz,
o
1.2 equiv.) at 50 C for 15 min., purified by silica gel column 1H), 3.88 (d, J = 6.2 Hz, 3H), 3.81 (dd, J = 11.4, 4.6 Hz, 1H), 3.71
chromatography to obtain glycoside 16 as a white semi solid (dd, J = 9.4, 3.8 Hz, 1H), 3.59 (dd, J = 15.4, 9.1 Hz, 1H), 3.54-
(135 mg, 0.172 mmol, 72% yield, 90:10). Rf (40% 3.43 (m, 4H), 3.31 (s, 3H), 2.20 (td, J = 12.5, 3.5 Hz, 1H), 2.01
EtOAc/Hexane) 0.5; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.5 (dd, J = 12.6, 4.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 138.8,
Hz, 2H), 7.61-7.51 (m, 2H), 7.38 (t, J = 7.5 Hz, 3H), 7.35-7.27 138.7, 138.3, 138.2, 138.1, 138.0, 128.5, 128.4, 128.3, 128.2,
(m, 16H), 5.04 (dd, J = 11.8, 3.1 Hz, 1H), 4.93 (dd, J = 11.6, 3.3 128.1, 128.0, 127.9, 127.7, 127.6, 127.5, 127.4, 98.3, 97.8,
Hz, 1H), 4.63-4.56 (m, 3H), 4.52-4.44 (m, 2H), 4.44-4.38 (m, 82.1, 79.9, 77.8, 75.8, 75.0, 74.3, 74.2, 73.3, 72.8, 70.2, 70.0,
3H), 4.38-4.29 (m, 2H), 4.26 (t, J = 7.0 Hz, 1H), 3.90 (s, 1H), 69.8, 69.3, 66.0, 55.0, 31.0 the overall spectroscopic data are
3.88-3.85 (m, 1H), 3.70 (s, 1H), 3.69-3.62 (m, 2H), 3.60 (s, 1H), in complete agreement with assigned structures and
3.55 (dt, J = 12.2, 5.9 Hz, 3H), 2.45-2.34 (m, 1H), 2.31-2.21 (m, consistent with literature.[7c,14k]
1H), 2.12 (ddd, J = 13.0, 9.5, 6.2 Hz, 1H), 1.96 (dd, J = 10.9, 6.2
Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 172.8, 172.8, 154.7, 2-deoxy-
154.4, 144.0, 143.8, 143.7, 143.5, 141.2, 141.1, 141.0, 138.6, Glycosylation of 6-OAc-3,4-di-O-benzyl-D-galactal (100 mg,
138.5, 138.3, 138.2, 137.9, 137.8, 128.3, 128.3, 128.3, 128.1, 0.271 mmol, 1.0 equiv.) 6-Hydroxy-2,3,4-tri-O-benzyl-
Methyl 2,3,4-tri-O-benzyl-6-O-(6-O-Acetyl-3,4-di-O-benzyl-

-D-lyxo-hexapyranosyl)- -D-glucopyranoside (19):

-
128.0, 127.6, 127.6, 127.5, 127.4, 127.4, 127.4, 127.4, 127.4, methoxy glucopyranoside (151 mg, 0.326 mmol, 1.2 equiv.) at
127.2, 127.1, 127.0, 126.9, 126.9, 126.8, 124.9, 124.9, 124.8, 50 oC for 15 h, purified by silica gel column chromatography to
8 | J. Name., 2012, 00, 1-3
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obtain glycoside 19 as a white solid (212 mg, 0.254 mmol, 94% 128.2, 127.6, 127.5, 127.2, 98.5, 97.8, 74.8, 73.9, 72.5, 70.4,
View Article Online
o
1
DOI: 10.1039/D0OB01042A
yield,
-only). Mp: 86-87 C; Rf (30% EtOAc/Hexane) 0.5; H 70.4, 70.2, 69.2, 68.9, 67.1, 65.7, 64.3, 55.3, 30.7, 20.4; HRMS
NMR (400 MHz, CDCl3) δ 7.40 - 7.19 (m, 25H), 5.03 (d, J = 2.5 (ESI) m/z [M + NH4]+ calculated for [C50H54NO14]+: 892.3539;
Hz, 1H), 4.96 (dd, J = 21.4, 11.2 Hz, 2H), 4.87 (d, J = 11.0 Hz, found 892.3540.
1H), 4.79 (d, J = 11.3 Hz, 2H), 4.69 (d, J = 12.2 Hz, 1H), 4.64 (d, J
= 4.6 Hz, 1H), 4.62-4.55 (m, 3H), 4.48 (d, J = 11.1 Hz, 1H), 4.08 di-O-benzyl-2-deoxy-
Methyl 2,3,4-tri-O-benzoyl-6-O-(6-O-triisopropylsilyl-3,4-
-D-lyxo-hexapyranosyl)- -D-


(dd, J = 11.2, 7.2 Hz, 1H), 4.04-3.96 (m, 2H), 3.88-3.81 (m, 1H), mannopyranoside (22): Glycosylation of 6-OTIPS-3, 4-di-O-
3.80-3.70 (m, 4H), 3.60 (d, J = 10.4 Hz, 1H), 3.51 (dd, J = 9.6, 3.5 benzyl-D-galatal (100 mg, 0.207 mmol, 1.0 equiv.) with 6-
Hz, 1H), 3.43 (t, J = 9.3 Hz, 1H), 3.31 (s, 3H), 2.20 (td, J = 12.4, hydroxy-2,3,4-tri-O-benzoyl-
-methoxy
mannopyranoside
o
3.4 Hz, 1H), 2.10-1.95 (m, 1H), 1.84 (s, 3H); 13C NMR (101 MHz, (126 mg, 0.248 mmol, 1.2 equiv.) at 50 C for 2 h, purified by
CDCl3) δ 170.4, 138.6, 138.3, 138.1, 138.0, 128.4, 128.4, 128.3, silica gel column chromatography to obtain glycoside 22 as a
128.2, 128.0, 127.9, 127.6, 127.4, 127.3, 98.0, 97.7, 82.0, 79.9, white semi solid (182 mg, 0.184 mmol, 89% yield, -only). Rf
77.9, 75.8, 74.9, 74.1, 73.9, 73.2, 72.4, 70.2, 69.6, 69.0, 65.9, (10% EtOAc/Hexane) 0.5; 1H NMR (400 MHz,CDCl3 ) δ 8.09 (d, J
64.0, 54.9, 30.6, 20.7; HRMS (ESI) m/z [M + H]+ calculated for = 7.3 Hz, 2H), 7.96 (d, J = 7.4 Hz, 2H), 7.82 (d, J = 7.4 Hz, 2H),
[C50H57O11]+: 833.3895; found 833.3894.
7.55 (d, J = 7.2 Hz, 1H), 7.52-7.41 (m, 3H), 7.40-7.24 (m, 15H),
Methyl 2,3,6-tri-O-benzyl-4-O-(3,4,6-tri-O-benzyl-2-deoxy- 5.87 (dd, J = 13.2, 6.4 Hz, 2H), 5.67-5.62 (m, 1H), 5.02 (d, J = 2.8
-D-lyxo-hexapyranosyl)- -D-glucopyranoside (20): Hz, 1H), 4.91 (dd, J = 6.4, 5.1 Hz, 2H), 4.65 (d, J = 11.5 Hz, 1H),
Glycosylation of 3,4,6-tri-O-benzyl-D-galactal (100 mg, 0.240 4.46 (s, 2H), 4.23-4.11 (m, 1H), 3.94-3.83 (m, 3H), 3.71 (dd, J =
mmol, 1.0 equiv.) with 4-Hydroxy-2,3,6-tri-O-benzyl- 13.2, 5.2 Hz, 3H), 3.64 (d, J = 3.2 Hz, 1H), 3.43 (s, 3H), 2.22-2.13


-
methoxy glucopyranoside (133 mg, 0.288 mmol, 1.2 equiv.) at (m, 1H), 1.93 (d, J = 4.3 Hz, 1H), 1.60 (s, 3H), 0.96 (d, J = 3.5 Hz,
50 oC for 15 min., purified by silica gel column chromatography 18H); 13C NMR (101 MHz,CDCl3 ) δ 165.4, 165.4, 165.4, 138.9,
to obtain glycoside 20 as a colorless oil (175 mg, 0.199 mmol, 138.5, 133.4, 133.2, 133.0, 129.8, 129.7, 129.6, 129.3, 129.2,
1
83% yield,

-only). Rf (50% EtOAc/Hexane) 0.5; H NMR (400 129.1, 128.5, 128.3, 128.3, 128.2, 128.1, 127.4, 127.3, 127.2,
MHz, CDCl3) δ 7.29-7.13 (m, 30H), 5.40 (d, J = 3.2 Hz, 1H), 4.92 98.3, 97.7, 74.5, 74.3, 72.8, 71.7, 70.4, 70.1, 70.1, 69.3, 67.6,
(d, J = 10.9 Hz, 1H), 4.80 (d, J = 11.7 Hz, 1H), 4.66 (d, J = 12.1 66.2, 62.5, 55.1, 30.9, 17.9, 17.9, 11.7; HRMS (ESI) m/z [M +
Hz, 1H), 4.60-4.53 (m, 2H), 4.51 (dd, J = 7.8, 3.9 Hz, 3H), 4.45 NH4]+ calculated for [C57H72NO13Si]+: 1006.4767; found
(dd, J = 11.6, 9.7 Hz, 3H), 4.34-4.20 (m, 3H), 3.80 (ddd, J = 20.0, 1006.4766.
19.0, 9.3 Hz, 4H), 3.66-3.50 (m, 3H), 3.41 (ddd, J = 10.5, 7.8, 3.7
1,2,3,4-di-O-isopropylidene-6-O-(3,4,6-tri-O-benzyl-2-
Hz, 3H), 3.31 (s, 3H), 2.06 (td, J = 12.5, 3.9 Hz, 1H), 1.80 (dd, J = deoxy--D-lyxo-hexapyranosyl)--D-galactopyranoside (23):
12.4, 4.2 Hz, 1H);13C NMR (101 MHz, CDCl3) δ 138.8, 138.7, Glycosylation of 3,4,6-tri-O-benzyl-D-galactal (100 mg, 0.240
138.4, 138.3, 138.0, 137.9, 128.4, 128.4, 128.3, 128.2, 128.1, mmol, 1.0 equiv.) with 6-hydroxy-1,2,3,4-di-O-isopropylidene-
128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.5, 127.3, 99.6,
-D-galactopyranoside (75 mg, 0.288 mmol, 1.2 equiv.) at 50
97.7, 93.3, 82.0, 79.9, 75.8, 75.5, 74.4, 74.3, 74.2, 73.5, 73.4, oC for 15 min., purified by silica gel column chromatography to
73.2, 73.0, 72.9, 72.6, 70.6, 70.4, 70.3, 70.3, 69.8, 69.5, 69.2, obtain glycoside 23 as a white solid (138 mg, 0.240 mmol, 85%
1
55.2, 31.9, 31.6, 30.8; the overall spectroscopic data are in yield, 96:04). Rf (50% EtOAc/Hexane) 0.5; H NMR (400
complete agreement with assigned structures and consistent MHz, CDCl3) δ 7.36-7.22 (m, 15H), 5.52 (d, J = 5.0 Hz, 1H), 5.03
with literature.[7c]
(d, J = 2.9 Hz, 1H), 4.92 (d, J = 11.6 Hz, 1H), 4.65-4.54 (m, 4H),
Methyl
2,3,4-tri-O-benzoyl-6-O-(3,4,6-tri-O-benzyl-2- 4.45 (dd, J = 28.0, 11.8 Hz, 2H), 4.30 (dd, J = 5.0, 2.4 Hz, 1H),
deoxy--D-lyxo-hexapyranosyl)--D-mannopyranoside (21): 4.21 (dd, J = 7.9, 1.5 Hz, 1H), 3.95 (d, J = 6.5 Hz, 4H), 3.75 (dd, J
Glycosylation of 6-OAc-3,4-di-O-benzyl-D-galactal (100 mg, = 10.7, 6.8 Hz, 1H), 3.70-3.57 (m, 2H), 3.54 (dd, J = 9.1, 5.7 Hz,
0.271 mmol, 1.0 equiv.) with 6-hydroxy-2,3,4-tri-O-benzoyl-

-
1H), 2.22 (td, J = 12.3, 3.3 Hz, 1H), 2.03 (dd, J = 12.6, 4.2 Hz,
methoxy mannopyranoside (165 mg, 0.326 mmol, 1.2 equiv.) 1H), 1.51 (s, 3H), 1.42 (s, 3H), 1.32 (s, 6H); 13C NMR (101 MHz,
o
at 50 C for 7 h, purified by silica gel column chromatography CDCl3) δ 138.8, 138.5, 138.0, 128.3, 128.2, 128.1, 127.8, 127.6,
to obtain glycoside 21 as a white solid (213 mg, 0.243 mmol, 127.4, 127.3, 109.2, 108.5, 97.5, 96.3, 74.6, 74.3, 73.3, 72.8,
90% yield; -only). Mp: 59-61 °C; Rf (30% EtOAc/Hexane) 0.5; 71.0, 70.6, 70.5, 70.3, 69.7, 69.1, 65.8, 65.5, 31.0, 26.1, 25.9,
1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.1 Hz, 2H), 7.94 (d, J = 24.9, 24.5; the overall spectroscopic data are in complete
7.3 Hz, 2H), 7.83 (d, J = 7.3 Hz, 2H), 7.51 (t, J = 7.4 Hz, 2H), 7.43 agreement with assigned structures and consistent with
(t, J = 8.0 Hz, 3H), 7.40-7.34 (m, 6H), 7.34-7.23 (m, 8H), 6.01 (t, literature.[7c,14k]
J = 10.0 Hz, 1H), 5.85 (dd, J = 10.1, 3.2 Hz, 1H), 5.66 (dd, J = 3.0,
5-O-(3,4,6-tri-O-benzyl-2-deoxy--D-lyxo-
1.8 Hz, 1H), 5.07 (d, J = 2.8 Hz, 1H), 4.98-4.89 (m, 2H), 4.61 (d, J hexapyranosyl)(1→5’)-2’-3’-O-isopropylidene uridine (24):
= 11.6 Hz, 1H), 4.59-4.51 (m, 2H), 4.22 (d, J = 9.9 Hz, 1H), 4.02 Glycosylation of 3,4,6-tri-O-benzyl-D-galactal (100 mg, 0.240
(dt, J = 13.7, 6.9 Hz, 2H), 3.93 (dd, J = 11.2, 4.6 Hz, 1H), 3.86 mmol, 1.0 equiv.) with 2,3-O-isopropylidene uridine (82 mg,
o
(dt, J = 12.2, 6.0 Hz, 2H), 3.80 (s, 1H), 3.64 (dd, J = 11.0, 2.6 Hz, 0.288 mmol, 1.2 equiv.) at 50 C for 3 h, purified by silica gel
1H), 3.47 (s, 3H), 2.23 (td, J = 12.4, 3.5 Hz, 1H), 2.05 (dd, J = column chromatography to obtain glycoside 24 as a colorless
12.5, 4.4 Hz, 1H), 1.69 (s, 3H); 13C NMR (101 MHz,CDCl3) δ semi solid (133 mg, 0.189 mmol, 79% yield, 90:10). Rf
1
170.4, 165.5, 165.4, 165.3, 138.3, 138.3, 133.5, 133.4, 133.1, (50% EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ 9.48 (s,
129.7, 129.6, 129.6, 129.3, 129.1, 129.1, 128.5, 128.4, 128.3, 1H), 7.39-7.25 (m, 15H), 5.81 (d, J = 2.6 Hz, 1H), 5.65 (dd, J =
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Journal Name
8.1, 1.9 Hz, 1H), 4.99 (d, J = 3.1 Hz, 1H), 4.92 (d, J = 11.6 Hz, 127.6, 127.4, 127.3, 98.1, 97.8, 82.0, 79.9, 77.8, 75.7, 74.7,
View Article Online
DOI: 10.1039/D0OB01042A
1H), 4.64-4.59 (m, 2H), 4.58-4.52 (m, 3H), 4.52-4.39 (m, 3H), 74.2, 73.9, 73.2, 73.1, 70.8, 70.2, 69.6, 65.9, 62.8, 55.0, 30.6;
4.37 (dd, J = 6.6, 3.2 Hz, 1H), 3.91 (s, 1H,), 3.83-3.76 (m, 3H), the overall spectroscopic data are in complete agreement with
3.61 (dd, J = 11.2, 3.0 Hz, 1H), 3.56 (dd, J = 6.3, 1.8 Hz, 2H), assigned structures and consistent with literature.[14m]
2.26 (td, J = 12.6, 3.6 Hz, 1H), 1.83 (dd, J = 12.8, 4.4 Hz, 1H),
Methyl 2,3,4-tri-O-benzyl (6-O-acetyl-3,4-di-O-benzyl-2-
1.57 (s, 3H), 1.33 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 163.3, deoxy-
149.9, 140.7, 138.5, 137.9, 137.7, 128.4, 128.3, 128.2, 128.2, deoxy-


-D-lyxo-hexapyranosyl)-(1→6)-(3,4-di-O-benzyl-2-
-D-lyxo-hexapyranosyl)-(1→6)- -D-glucopyranoside

127.8, 127.7, 127.7, 127.7, 127.5, 127.5, 127.4, 114.2, 101.9, (27): Glycosylation of 6-OAc-3,4-di-O-benzyl-D-galactal (100
97.9, 92.9, 85.2, 84.9, 80.8, 74.2, 73.6, 73.5, 72.2, 70.4, 70.1, mg, 0.271 mmol, 1.0 equiv.) was treated with Methyl-2,3,4-tri-
69.4, 67.1, 30.8, 29.6, 29.6, 27.1, 25.2; HRMS (ESI) m/z [M + O-benzyl-6-O-(3,4-di-O-benzyl-2-deoxy--D-lyxo-
Na]+ calculated for [C39H44N2O10Na]+: 723.2888; found hexapyranosyl)-
-D-glucopyranoside 26 (271 mg, 0.326 mmol,
723.2887.
5-O-(6-O-triisopropylsilyl-3,4-di-O-benzyl-2-deoxy-
lyxo-hexapyranosyl)(1→5’)-2’-3’-O-isopropylidene
1.2 equiv.) at 50 oC for 6 h, purified by silica gel column
chromatography to obtain glycoside 27 as a white semi solid

-D-
uridine (213 mg, 0.184 mmol, 68% yield,
-only). Rf (30%
1
(25): Glycosylation of 6-OTIPS-3, 4-di-O-benzyl-D-galatal(100 EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ7.33 (dt, J =
mg, 0.207 mmol, 1.0 equiv.) with 2,3-O-isopropylidene uridine 9.1, 5.0 Hz, 35H), 5.00 (d, J = 2.7 Hz, 1H), 4.98 (d, J = 10.8 Hz,
o
(70 mg, 0.248 mmol, 1.2 equiv.) at 50 C for 4 h, purified by 1H), 4.93 (d, J = 4.1 Hz, 1H), 4.90 (d, J = 4.1 Hz, 1H), 4.83 (d, J =
silica gel column chromatography to obtain glycoside 25 as a 11.0 Hz, 1H), 4.79 (d, J = 6.7 Hz, 1H), 4.77 (d, J = 5.3 Hz, 1H),
white semi solid (119 mg, 0.155 mmol, 75% yield, -only). Rf 4.67 (dd, J = 7.2, 4.9 Hz, 2H), 4.60 (dt, J = 6.4, 3.0 Hz, 6H), 4.48
(40% EtOAc/Hexane) 0.5; 1H NMR (400 MHz, CDCl3) δ 9.23 (d, J (s, 2H), 4.06 (dd, J = 6.2, 3.5 Hz, 1H), 3.97 (t, J = 9.3 Hz, 1H),
= 23.0 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.31 (ddd, J = 20.7, 11.6, 3.86 (d, J = 9.4 Hz, 1H), 3.76-3.66 (m, 7H), 3.55-3.49 (m, 3H),
8.1 Hz, 10H), 5.86 (d, J = 2.6 Hz, 1H), 5.68 (d, J = 8.1 Hz, 1H), 3.32 (d, J = 5.5 Hz, 3H), 2.15 (dd, J = 12.3, 3.5 Hz, 1H), 2.06 (dd,
4.98 (d, J = 3.0 Hz, 1H), 4.94 (d, J = 11.6 Hz, 1H), 4.68 (d, J = J = 20.8, 8.5 Hz, 4H), 1.93 (t, J = 3.3 Hz, 1H), 1.90 (d, J = 2.9 Hz,
11.6 Hz, 1H), 4.61 (dd, J = 6.1, 2.7 Hz, 1H), 4.55 (d, J = 6.3 Hz, 3H), 1.77 (d, J = 3.9 Hz, 1H); 13C NMR (101 MHz,CDCl3) δ 170.6,
3H), 4.38 (d, J = 2.7 Hz, 1H), 3.94 (s, 1H), 3.76 (ddd, J = 20.1, 138.6, 138.6, 138.4, 138.4, 138.3, 138.3, 138.1, 113.9, 98.2,
10.8, 4.2 Hz, 3H), 3.60 (dd, J = 7.4, 4.2 Hz, 2H), 2.27 (td, J = 97.9, 97.3, 82.0, 79.9, 77.7, 75.8, 74.8, 74.7, 74.4, 74.0, 73.9,
12.6, 3.6 Hz, 1H), 1.83 (dd, J = 12.1, 4.0 Hz, 2H), 1.58 (s, 3H), 73.3, 72.7, 72.4, 70.4, 70.3, 69.8, 69.7, 68.7, 66.4, 65.8, 63.9,
1.33 (s, 3H), 1.05 (dd, J = 10.1, 4.6 Hz, 21H); 13C NMR (101 55.1, 30.8, 30.7, 20.7;HRMS (ESI) m/z [M + H]+ calculated for
MHz, CDCl3) δ 163.1, 149.9, 140.4, 138.6, 137.9, 128.5, 128.2, [C70H79O15]+: 1159.5413; found 1159.5413.
127.7, 127.5, 127.5, 114.1, 101.9, 97.8, 92.8, 85.1, 80.9, 74.2,
73.7, 72.7, 72.1, 70.1, 66.8, 62.9, 30.9, 27.2, 25.3, 17.9, 11.8; lyxo-hexapyranosyl)-(1→6)-(3,4-di-O-benzyl-2-deoxy-
HRMS (ESI) m/z [M + H]+ calculated for [C41H59N2O10Si]+: lyxo-hexapyranosyl)-(1→6)-
-D-glucopyranoside (28):
Methyl 2,3,4-tri-O-benzyl (3,4-di-O-benzyl-2-deoxy-

-D-

-D-

A
767.3933; found 767.3932.
preformed solution of Methyl (6-O-acetyl-3,4-di-O-benzyl-
2deoxy- -D-lyxo-hexapyranosyl)-(1→6)-(3,4-di-O-benzyl-2-
deoxy- -D-lyxo-hexapyranosyl)-(1→6)-2,3,4-tri-O-benzyl- -D-
preformed solution of Methyl 2,3,4-tri-O-benzyl-6-O-(6-O- glucopyranoside 27 (100 mg, 0.086 mmol, 1.0 equiv.) in MeOH
acetyl-2-deoxy-3,4-di-O-benzyl- -D-lyxohexapyranosyl)- -D- (5 mL) was treated with NaOMe (5 mg, 0.103 mmol, 0.1 equiv.)
Methyl 2,3,4-tri-O-benzyl-6-O-(3,4-di-O-benzyl-2-deoxy-

-

D-lyxo-hexapyranosyl)-

-D-glucopyranoside
(26):
A




glucopyranoside 19 (100 mg, 0.120 mmol, 1.0 equiv.) in MeOH at room temperature under nitrogen atmosphere for 4 h,
(5 mL) was treated with NaOMe (8 mg, 0.144 mmol, 0.1 equiv.) purified by silica gel column chromatography to obtain
at room temperature under nitrogen atmosphere. The glycoside 28 as a white solid (67 mg, 0.060 mmol, 70% yield).
1
reaction was stirred until the completion of starting material, Rf (40% EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ 7.38-
typically for 4 h (adjudged by TLC). The reaction mixture was 7.29 (m, 35H), 5.00 (d, J = 2.5 Hz, 1H), 4.97 (d, J = 10.7 Hz, 1H),
diluted with DCM (10 mL), quenched with saturated NaHCO3 (5 4.93 (d, J = 2.4 Hz, 1H), 4.91 (d, J = 2.2 Hz, 1H), 4.83 (d, J = 11.0
mL) and extracted with DCM (3 × 30 mL). The combined Hz, 1H), 4.79 (d, J = 8.7 Hz, 1H), 4.76 (d, J = 7.2 Hz, 1H), 4.69-
organic layers were washed with brine solution, dried over 4.63 (m, 3H), 4.63-4.57 (m, 6H), 4.52 (d, J = 12.4 Hz, 2H), 3.97
anhydrous Na2SO4, concentrated in vacuo and purified by silica (t, J= 9.2 Hz, 1H), 3.86 (d, J = 9.7 Hz, 1H), 3.72 (dd, J = 18.8, 7.6
gel column chromatography using hexane and EtOAc as eluent Hz, 6H), 3.58-3.49 (m, 5H), 3.43 (dd, J = 11.4, 7.0 Hz, 2H), 3.38-
to afford the compound 26 as colorless oil (80 mg, 0.102 3.34 (m, 1H), 3.31 (s, 3H), 2.22-2.15 (m, 1H), 2.08 (dd, J = 12.6,
1
mmol, 85% yield). Rf (50% EtOAc/Hexane) 0.5; H NMR (400 3.6 Hz, 1H), 2.02 (dd, J = 12.2, 3.9 Hz, 1H), 1.76 (dd, J = 12.6,
MHz, CDCl3) δ 7.37-7.22 (m, 25H), 5.05 (d, J = 2.8 Hz, 1H), 5.03- 4.1 Hz, 1H); 13C NMR (101 MHz,CDCl3) δ 138.7, 138.4, 138.2,
4.95 (m, 2), 4.94-4.86 (m, 2H), 4.80 (d, J = 11.3 Hz, 2H), 4.69 (d, 128.6, 128.5, 128.5, 128.4, 128.1, 128.0, 128.0, 127.8, 127.7,
J = 12.1 Hz, 1H), 4.67-4.55 (m, 4H), 4.47 (d, J = 11.3 Hz, 1H), 127.6, 127.5, 127.3, 98.5, 98.0, 82.2, 80.0, 78.0, 75.9, 74.9,
3.99 (t, J = 9.2 Hz, 1H), 3.88-3.81 (m, 1H), 3.80-3.71 (m, 3H), 74.5, 74.1, 74.0, 73.4, 73.1, 72.5, 71.0, 70.5, 70.4, 69.8, 69.6,
3.63 (dd, J = 11.1, 6.2 Hz, 1H), 3.60-3.50 (m, 3H), 3.43 (dt, J = 66.6, 66.3, 63.1, 55.2, 31.0; the overall spectroscopic data are
14.0, 7.0 Hz, 2H), 3.32 (s, 3H), 2.20 (td, J = 12.4, 3.5 Hz, 1H), in complete agreement with assigned structures and
2.04 (dd, J = 12.6, 4.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ consistent with literature.[14m]
138.6, 138.3, 138.2, 138.0, 128.4, 128.4, 127.9, 127.8, 127.8,
10 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
Prop-2-enyl-4,6-di-O-acetyl-2,3-dideoxy-
enopyranoside (29): Ferrier glycosylation of 3,4,6-tri-O-acetyl- 2H), 2.09 (s, 3H), 2.08 (s, 3H); C NMR (101 MHz, CDCl3) δ
D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) with Allyl alcohol 170.6, 170.4, 137.3, 130.5, 128.5, 128.2, 127.9, 125.3, 92.8,
(30 µL, 25 mg, 0.440 mmol, 1.2 equiv.) at 50 oC for 3 h, purified 69.8, 66.9, 62.8, 20.8, 20.8; the overall spectroscopic data are
by silica gel column chromatography to obtain glycoside 29 as in complete agreement with assigned structures and
ARTICLE

-D-threo-hex-2-
11.5 Hz, 1H), 4.43 (ddd, J = 7.6, 5.3, 2.5 Hz, 1H), 4.30 - 4.18 (m,
View Article Online
13
DOI: 10.1039/D0OB01042A
a pale yellow semi solid (67 mg, 0.249 mmol, 78% yield,


;
consistent with literature.[14k,16b,16f]
1
98:02). Rf (20% EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3)
Cyclopropylmethyl-4,6-di-O-acetyl-2,3-dideoxy--D-threo-
δ 6.13 (dd, J = 10.0, 5.3 Hz, 1H), 6.05 (dd, J = 10.0, 2.9 Hz, 1H), hex-2-enopyranoside (33): Ferrier glycosylation of 3,4,6-tri-O-
5.95 (ddd, J = 22.5, 11.0, 5.7 Hz, 1H), 5.31 (d, J = 17.1 Hz, 1H), acetyl-D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) with
5.22 (d, J = 10.2 Hz, 1H), 5.13 (d, J = 2.7 Hz, 1H), 5.03 (dd, J = cyclopropylmethanol (35 µL, 31 mg, 0.440 mmol, 1.2 equiv.) at
o
5.3, 2.4 Hz, 1H), 4.40-4.35 (m, 1H), 4.30-4.22 (m, 3H), 4.09 (dd, 50 C for 4 h, purified by silica gel column chromatography to
J = 12.7, 6.4 Hz, 1H), 2.09 (s, 6H); 13C NMR (101 MHz, CDCl3) δ obtain glycoside 33 as a pale yellow oil (77 mg, 0.271 mmol,
1
170.6, 170.3, 133.9, 130.5, 125.3, 117.7, 93.0, 68.9, 66.7, 62.8, 74% yield, ; 93:07). Rf (20% EtOAc/Hexane) 0.5; H NMR
20.8, 20.7; the overall spectroscopic data are in complete (400 MHz, CDCl3) δ 6.12 (dd, J = 10.3, 5.1 Hz, 1H), 6.06 (dd, J =
agreement with assigned structures and consistent with 10.0, 2.8 Hz, 1H), 5.13 (d, J = 2.8 Hz, 1H), 5.03 (dd, J = 5.2, 2.5
literature.[16b,16f]
Hz, 1H), 4.40 (td, J = 6.3, 2.5 Hz, 1H), 4.27-4.16 (m, 2H), 3.53
2'-Propyn-1'-yl-4,6-di-O-acetyl-2,3-dideoxy-

-D-threo-hex- (dd, J = 10.3, 7.4 Hz, 1H), 3.44 (dd, J = 10.4, 6.9 Hz, 1H), 2.09 (s,
2-enopyranoside (3): Ferrier glycosylation of 3,4,6-tri-O-acetyl- 3H), 2.07 (s, 3H), 1.15-1.07 (m, 1H), 0.63-0.53 (m, 2H), 0.29 -
D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) with Propargyl 0.21 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 170.5, 170.3, 130.7,
o
alcohol (25 µL, 24 mg, 0.440 mmol, 1.2 equiv.) at 50 C for 1 h, 125.1, 93.2, 73.0, 66.6, 62.9, 62.8, 20.8, 20.7, 10.4, 3.3, 2.9;
purified by silica gel column chromatography to obtain HRMS (ESI) m/z [M + Na]+ calculated for [C14H20O6Na]+:
glycoside 30 as a yellow oil (75 mg, 0.278 mmol, 76% yield, 307.1152; found 307.1154.
1
; 96:04). Rf (20% EtOAc/Hexane) 0.5; H NMR (400 MHz,
Cyclohexylmethyl-4,6-di-O-acetyl-2,3-dideoxy--D-threo-
CDCl3) δ 6.16 (dd, J = 10.0, 5.5 Hz, 1H), 6.05 (dd, J = 10.0, 2.9 hex-2-enopyranoside (34): Ferrier glycosylation of 3,4,6-tri-O-
Hz, 1H), 5.30 (d, J = 2.5 Hz, 1H), 5.04 (dd, J = 5.3, 2.2 Hz, 1H), acetyl-D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) with
4.33 (t, J = 5.6 Hz, 3H), 4.24 (d, J = 6.1 Hz, 2H), 2.48 (d, J = 2.2 cyclohexylmethanol (54 µL, 50 mg, 0.440 mmol, 1.2 equiv.) at
o
Hz, 1H), 2.09 (s, 3H), 2.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 50 C for 1 h, purified by silica gel column chromatography to
170.5, 170.3, 130.0, 125.7, 92.0, 78.8, 74.8, 67.0, 62.6, 62.5, obtain glycoside 34 as a light yellow solid (84 mg, 0.256 mmol,
1
54.5, 20.7, 20.7; the overall spectroscopic data are in complete 70% yield, ; 95:05). Rf (20% EtOAc/Hexane) 0.5; H NMR
agreement with assigned structures and consistent with (400 MHz, CDCl3) δ 6.11 (dd, J = 10.1, 5.2 Hz, 1H), 6.04 (dd, J =
literature.[14k,16f]
10.0, 2.9 Hz, 1H), 5.05-4.99 (m, 2H), 4.35 (ddd, J = 7.5, 5.1, 2.5
Hz, 1H), 4.28-4.18 (m, 2H), 3.60 (dd, J = 9.2, 7.0 Hz, 1H), 3.31
Ethoxyethyl-4,6-di-O-acetyl-2,3-dideoxy--D-threo-hex-2-
enopyranoside (31): Ferrier glycosylation of 3,4,6-tri-O-acetyl- (dd, J = 9.2, 6.2 Hz, 1H), 2.09 (s, 6H), 1.81-1.65 (m, 5H), 1.60
D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) with Ethoxy (ddd, J = 14.4, 7.5, 3.7 Hz, 1H), 1.32-1.13 (m, 3H), 0.95 (dd, J =
ethanol (42 µL, 39 mg, 0.440 mmol, 1.2 equiv.) at 50 oC for 3 h, 23.8, 12.0 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 170.6, 170.4,
purified by silica gel column chromatography to obtain 130.7, 125.0, 93.8, 74.1, 66.7, 62.9, 62.9, 37.9, 30.2, 30.0, 26.5,
glycoside 31 as a light yellow semi solid (76 mg, 0.264 mmol, 25.8, 25.7, 20.8, 20.8; the overall spectroscopic data are in
72% yield, 94:06). Rf (50% EtOAc/Hexane) 0.5; 1H NMR complete agreement with assigned structures and consistent
(400 MHz, CDCl3) δ 6.04 (dd, J = 10.1, 4.9 Hz, 1H), 6.00 (dd, J = with literature.[16b]
10.0, 2.7 Hz, 1H), 5.06 (d, J = 2.6 Hz, 1H), 4.96 (dd, J = 4.9, 2.5
Pthalimido-4,6-di-O-acetyl-2,3-dideoxy--D-threo-hex-2-
Hz, 1H), 4.34-4.28 (m, 1H), 4.20-4.10 (m, 2H), 3.83 (dt, J = 10.7, enopyranoside (35): Ferrier glycosylation of 3,4,6-tri-O-acetyl-
4.3 Hz, 1H), 3.64 (dt, J = 10.7, 5.2 Hz, 1H), 3.57-3.53 (m, 1H), D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) with N-Hydroxy
o
3.46 (dd, J = 7.0 Hz, 1H), 2.01 (s, 3H), 2.00 (s, 3H), 1.14 (t, J = phthalimide (71 mg, 0.440 mmol, 1.2 equiv.) at 50 C for 20
7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.5, 170.3, 130.5, min., purified by silica gel column chromatography to obtain
125.1, 94.0, 69.6, 67.4, 66.6, 66.5, 62.7, 62.7, 20.7, 20.7, 15.1; glycoside 35 as a white solid (104 mg, 0.278 mmol, 75% yield,
o
1
HRMS (ESI) m/z [M + H]+ calculated for [C14H23O6]+: 303.1438;
found 303.1437.
-only). Mp: 147-149 C; Rf (20% EtOAc/Hexane) 0.5; H NMR
(400 MHz, CDCl3) δ 7.78 (dd, J = 5.5, 3.1 Hz, 2H), 7.70 (dd, J =
5.5, 3.1 Hz, 2H), 6.33 (dd, J = 10.0, 4.9 Hz, 1H), 6.22 (dd, J =
Benzyl-4,6-di-O-acetyl-2,3-dideoxy--D-threo-hex-2-
enopyranoside (32): Ferrier glycosylation of 3,4,6-tri-O-acetyl- 10.1, 3.0 Hz, 1H), 5.64 (d, J = 2.9 Hz, 1H), 5.12 (dd, J = 5.5, 2.7
D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) with Benzyl Hz, 1H), 4.87 (td, J = 6.4, 2.7 Hz, 1H), 4.28 (dd, J = 11.3, 6.1 Hz,
o
alcohol (45 µL, 47 mg, 0.440 mmol, 1.2 equiv.) at 50 C for 1 h, 1H), 4.05 (dd, J = 11.3, 6.7 Hz, 1H), 2.02 (s, 3H), 2.01 (s, 3H); 13C
purified by silica gel column chromatography to obtain NMR (101 MHz, CDCl3) δ 170.6, 170.2, 163.5, 134.5, 128.9,
glycoside 32 as a light yellow viscous oil (101 mg, 0.315 mmol, 128.8, 126.1, 123.5, 98.4, 68.2, 61.9, 61.9, 20.8, 20.7; HRMS
1
86% yield, ; 96:04). Rf (20% EtOAc/Hexane) 0.5; H NMR (ESI) m/z [M + Na]+ calculated for [C18H17NO8Na]+: 398.0846;
(400 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 6.13 (dd, J = 10.1, 5.1 Hz, found 398.0845.
1H), 6.05 (dd, J = 10.0, 2.9 Hz, 1H), 5.17 (d, J = 2.8 Hz, 1H), 5.04
9-Fluorenylmethyl-4,6-di-O-acetyl-2,3-dideoxy--D-threo-
(dd, J = 5.4, 2.5 Hz, 1H), 4.82 (d, J = 11.5 Hz, 1H), 4.59 (d, J = hex-2-enopyranoside (36): Ferrier glycosylation of 3,4,6-tri-O-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
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Organic & Biomolecular Chemistry
Page 12 of 16
ARTICLE
Journal Name
acetyl-D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) with 9- galactal (100 mg, 0.367 mmol, 1.0 equiv.) with Fmoc-Hyp-OMe
View Article Online
o
Fluorenemethanol(9-FM) (86 mg, 0.440 mmol, 1.2 equiv.) at 50 (161 mg, 0.440 mmol, 1.2 equiv.) at 50 DCOIf:o10r.1503m9/iDn0.,OpBu0r1i0f4ie2dA
oC for 25 min., purified by silica gel column chromatography to by silica gel column chromatography to obtain glycoside 39 as
obtain glycoside 36 as a light yellow solid (141 mg, 0.344 a light yellow semi solid (174 mg, 0.300 mmol, 82% yield,
-
1
mmol, 94% yield, 96:04). Mp: 57-58 oC; Rf (30% only). Rf (60% EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ
1
EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ7.79-7.74 (m, 7.76 (dd, J = 7.5, 3.8 Hz, 2H), 7.62-7.52 (m, 2H), 7.40 (t, J = 7.4
2H), 7.61 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.32 (q, J = Hz, 2H), 7.30 (dd, J = 9.8, 4.9 Hz, 2H), 6.15 (td, J = 9.5, 5.6 Hz,
7.8 Hz, 2H), 6.18 (dd, J = 10.1, 5.2 Hz, 1H), 6.12 (dd, J = 10.0, 1H), 5.99 (dt, J = 10.1, 2.7 Hz, 1H), 5.15 (d, J = 2.8 Hz, 1H), 5.03
2.7 Hz, 1H), 5.15 (d, J = 2.6 Hz, 1H), 5.06 (dd, J = 5.2, 2.4 Hz, (dd, J = 5.5, 2.4 Hz, 1H), 4.54-4.43 (m, 3H), 4.43-4.37 (m, 1H),
1H), 4.41-4.35 (m, 1H), 4.25-4.18 (m, 1H), 4.17-4.08 (m, 2H), 4.34 (ddd, J = 7.4, 6.0, 2.3 Hz, 2H), 4.23 (d, J = 6.1 Hz, 2H), 3.79
4.06 (t, J = 5.5 Hz, 1H), 3.76 (dd, J = 9.0, 7.7 Hz, 1H), 2.08 (s, (dd, J = 11.5, 5.2 Hz, 1H), 3.76 (s, 2H), 3.72 (t, J = 3.4 Hz, 1H),
3H), 1.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.6, 170.4, 3.65 (s, 1H), 2.55 (qd, J = 8.0, 3.9 Hz, 1H), 2.28-2.20 (m, 1H),
144.7, 144.5, 144.3, 141.5, 141.2, 141.1, 130.5, 127.6, 127.5, 2.10 (s, 3H), 2.09 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 172.8,
127.1, 127.0, 126.9, 125.3, 125.1, 125.1, 124.7, 120.1, 119.9, 172.8, 170.6, 170.5, 170.2, 154.7, 154.4, 144.0, 143.9, 143.7,
94.3, 71.1, 67.1, 65.1, 62.9, 50.3, 47.8, 20.8, 20.5; HRMS (ESI) 143.5, 141.2, 130.1, 130.0, 127.6, 127.0, 125.4, 125.3, 125.0,
m/z [M + Na]+ calculated for [C24H24O6Na]+: 431.1465; found 125.0, 124.9, 124.8, 119.9, 94.0, 93.7, 76.6, 75.2, 67.6, 67.5,
431.1464.
67.2, 67.1, 63.1, 63.0, 62.6, 62.6, 58.0, 57.6, 52.4, 52.3, 52.2,
51.8, 47.2, 47.1, 37.8, 36.7, 20.8, 20.6, 20.6; HRMS (ESI) m/z
Cholesteryl-4,6-di-O-acetyl-2,3-dideoxy--D-threo-hex-2-
enopyranoside (37): Ferrier glycosylation of 3,4,6-tri-O-acetyl- [M + H]+ calculated for [C31H34NO10]+: 580.2177; found
D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) with Cholesterol 580.2178.
o
(170 mg, 0.440 mmol, 1.2 equiv.) at 50 C for 2 h, purified by
Methyl
-D-threo-hex-2-enopyranosyl)--D-
-only). Mp: 109- glucopyranoside (4): Ferrier glycosylation of 3,4,6-tri-O-acetyl-
111 C; Rf (20% EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) D-galactal (100 mg, 0.367 mmol, 1.0 equiv.) with 6-Hydroxy-
δ 6.11 (dd, J = 10.0, 5.3 Hz, 1H), 6.02 (dd, J = 10.0, 3.0 Hz, 1H), 2,3,4-tri-O-Benzyl- -methoxy glucopyranoside (204 mg, 0.440
2,3,4-tri-O-benzyl-6-O-(4,6-di-O-acetyl-2,3-
silica gel column chromatography to obtain glycoside 37 as a dideoxy-
white solid (163 mg, 0.286 mmol, 78% yield,


o
1

o
5.36 (d, J = 5.1 Hz, 1H), 5.22 (d, J = 2.8 Hz, 1H), 5.02 (dd, J = 5.3, mmol, 1.2 equiv.) at 50 C for 10 min., purified by silica gel
2.5 Hz, 1H), 4.46-4.38 (m, 1H), 4.28-4.16 (m, 2H), 3.58 (ddd, J = column chromatography to obtain glycoside 40 as a pale
15.8, 11.2, 4.6 Hz, 1H), 2.42 (dd, J = 12.5, 4.2 Hz, 1H), 2.33 (t, J yellow semi solid (203 mg, 0.300 mmol, 82% yield, -only). Rf
1
= 11.2 Hz, 1H), 2.08 (s, 3H), 2.07 (s, 3H), 1.93-1.77 (m, 3H), (50% EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ 7.38-
1.70-1.37 (m, 10H), 1.40-1.28 (m, 4H), 1.22-1.02 (m, 9H), 1.00 7.27 (m, 15H), 6.10 (dd, J = 10.1, 5.1 Hz, 1H), 6.04 (dd, J = 10.0,
(s, 3H), 0.91 (t, J = 6.3 Hz, 3H), 0.86 (dd, J = 6.6, 1.7 Hz, 6H), 2.8 Hz, 1H), 5.15 (d, J = 2.7 Hz, 1H), 4.99 (dd, J = 5.2, 2.5 Hz,
0.68 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.7, 170.4, 140.8, 1H), 4.99-4.89 (m, 2H), 4.83-4.77 (m, 2H), 4.70-4.58 (m, 3H),
131.1, 125.0, 121.8, 92.4, 77.9, 66.7, 63.0, 56.7, 56.1, 50.1, 4.32-4.26 (m, 1H), 4.19 (dd, J = 11.3, 5.6 Hz, 1H), 4.11 (dd, J =
42.3, 40.3, 39.7, 39.5, 37.1, 36.6, 36.2, 35.7, 31.9, 31.8, 28.2, 11.3, 7.3 Hz, 1H), 3.98 (dt, J = 10.9, 6.8 Hz, 2H), 3.80-3.70 (m,
28.0, 24.2, 23.8, 22.8, 22.5, 21.0, 20.8, 19.3, 18.7, 11.8; the 2H), 3.59-3.49 (m, 2H), 3.37 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H);
overall spectroscopic data are in complete agreement with 13C NMR (101 MHz, CDCl3) δ 170.5, 170.4, 138.6, 138.2, 138.1,
assigned structures and consistent with literature.[14k]
O-(4,6-di-O-acetyl-2,3-dideoxy- -D-threo-hex-2-
130.5, 128.4, 128.4, 128.1, 127.9, 127.9, 127.7, 127.6, 127.5,
124.9, 98.0, 94.2, 82.0, 79.9, 77.7, 75.8, 74.9, 73.3, 69.9, 66.8,

enopyranosyl)-N-(benzyloxycarbonyl)-L-serine methyl ester 66.7, 62.6, 62.6, 55.2, 20.8, 20.6; the overall spectroscopic
(38): Ferrier glycosylation of 3,4,6-tri-O-acetyl-D-galactal (100 data are in complete agreement with assigned structures and
mg, 0.367 mmol, 1.0 equiv.) with Cbz-Ser-OMe (96 mg, 0.440 consistent with literature.[14k,16f]
o
mmol, 1.2 equiv.) at 50 C for 15 min., purified by silica gel
Methyl
2,3,6-tri-O-benzyl-4-O-(4,6-di-O-acetyl-2,3-
-D-glucopyranoside
column chromatography to obtain glycoside 38 as a light dideoxy-

-D-threo-hex-2-enopyranosyl)-
yellow semi solid (137 mg, 0.319 mmol, 87% yield, ; 95:05). (41): Ferrier glycosylation of 3,4,6-tri-O-acetyl-D-galactal (100
1
Rf (60% EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ 7.39- mg, 0.367 mmol, 1.0 equiv.) with 4-Hydroxy-2,3,6-tri-O-benzyl-
7.31 (m, 5H), 6.11 (dd, J = 10.0, 5.5 Hz, 1H), 5.94 (dd, J = 10.0,
-methoxy glucopyranoside (204 mg, 0.440 mmol, 1.2 equiv.)
3.0 Hz, 1H), 5.84 (d, J = 8.7 Hz, 1H), 5.17-5.09 (m, 2H), 5.02 (d, J at 50 oC for 20 min., purified by silica gel column
= 2.8 Hz, 1H), 4.99 (dd, J = 5.5, 2.3 Hz, 1H), 4.57 (dt, J = 8.5, 3.0 chromatography to obtain glycoside 41 as a light yellow semi
Hz, 1H), 4.30-4.25 (m, 1H), 4.24-4.15 (m, 2H), 4.03 (ddd, J = solid (196 mg, 0.289 mmol, 79% yield,
-only). Rf (50%
1
23.6, 10.5, 3.2 Hz, 2H), 3.77 (s, 3H), 2.08 (s, 3H), 2.03 (s, 3H); EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ 7.36-7.25 (m,
13C NMR (101 MHz, CDCl3) δ 170.7, 170.4, 170.3, 155.9, 136.1, 15H), 6.00 (dd, J = 10.0, 5.6 Hz, 1H), 5.69 (dd, J = 10.0, 3.0 Hz,
129.8, 128.5, 128.2, 128.1, 125.4, 94.6, 69.2, 67.2, 67.1, 62.7, 1H), 5.51-5.48 (m, 1H), 5.05 (d, J = 11.3 Hz, 1H), 4.90 (d, J = 5.6
62.5, 54.4, 52.6, 20.7, 20.6; HRMS (ESI) m/z [M + Na]+ Hz, 1H), 4.71 (dd, J = 20.0, 11.9 Hz, 3H), 4.63 (dd, J = 7.7, 4.2
calculated for [C22H27NO10Na]+: 488.1527; found 488.1526.
O-(4,6-di-O-acetyl-2,3-dideoxy- -D-threo-hex-2-
enopyranosyl)-N-(Fluorenylmethyloxycarbonyl)-L-Proline
Hz, 3H), 4.55 (d, J = 12.1 Hz, 1H), 4.08 (s, 2H), 3.95 (t, J = 9.2 Hz,
1H), 3.86-3.76 (m, 2H), 3.72-3.62 (m, 2H), 3.54 (dd, J = 9.6, 3.5
Hz, 1H), 3.41 (s, 3H), 2.04 (s, 3H), 1.92 (s, 3H); 13C NMR (101

methyl ester (39): Ferrier glycosylation of 3,4,6-tri-O-acetyl-D- MHz, CDCl3) δ 170.4, 170.3, 138.5, 138.2, 137.8, 130.5, 128.4,
12 | J. Name., 2012, 00, 1-3
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ARTICLE
128.2, 128.1, 127.9, 127.6, 127.5, 127.5, 127.4, 124.4, 97.6, unsaturated disaccharide 40 in 70% yield with VcieowmArpticleletOenline
-
DOI: 10.1039/D0OB01042A
95.1, 81.8, 80.1, 76.1, 75.5, 73.2, 72.9, 69.5, 69.4, 66.8, 62.6, selectivity.
62.3, 55.2, 31.8, 22.6, 20.7, 20.7; the overall spectroscopic Methyl-3,4,6-tri-O-benzyl-2-deoxy-

-D-lyxo-
data are in complete agreement with assigned structures and hexapyranoside (43): Glycosylation of 3,4,6-tri-O-benzyl-D-
consistent with literature.[16f]
galactal (100 mg, 0.240 mmol, 1.0 equiv.) with methanol (13
µL, 10 mg, 0.288 mmol, 1.2 equiv.) at 50 C for 3 h, purified by
o
5-O-(4,6-di-O-acetyl-2,3-dideoxy-

-D-threo-hex-2-
enopyranosyl)-2,3-O-isopropylidene uridine (42): Ferrier silica gel column chromatography to obtain glycoside 43 as an
glycosylation of 3,4,6-tri-O-acetyl-D-galactal (100 mg, 0.367 oil (98 mg, 0.218 mmol, 91% yield, ; 97:03). Rf (20%
1
mmol, 1.0 equiv.) with 2,3-O-isopropylidene uridine (124 mg, EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ 7.36-7.25 (m,
o
0.440 mmol, 1.2 equiv.) at 50 C for 3 h, purified by silica gel 15H), 4.94 (d, J = 11.6 Hz, 1H), 4.89 (d, J = 2.6 Hz, 1H), 4.63 (d, J
column chromatography to obtain glycoside 42 as a white semi = 11.7 Hz, 1H), 4.60 (s, 2H), 4.48 (dd, J = 36.0, 11.8 Hz, 2H),
solid (147 mg, 0.297mmol, 81% yield,
-only). Rf (60% 3.90 (dd, J = 13.2, 7.3 Hz, 3H), 3.60 (d, J = 6.3 Hz, 2H), 3.33 (s,
EtOAc/Hexane) 0.6; H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 3H), 2.24 (m, 1H), 2.01 (dd, J = 12.6, 3.6 Hz, 1H); 13C NMR (101
7.48 (d, J = 8.1 Hz, 1H), 6.16 (ddd, J = 10.0, 5.5, 0.9 Hz, 1H), MHz, CDCl3) δ 138.8, 138.5, 138.1, 128.4, 128.4, 128.3, 128.2,
5.97 (dd, J = 10.1, 3.0 Hz, 1H), 5.85 (d, J = 2.2 Hz, 1H), 5.69 (dd, 128.2, 127.7, 127.6, 127.5, 127.2, 98.9, 74.7, 74.2, 73.4, 72.9,
J = 8.1, 2.1 Hz, 1H), 5.12-5.09 (m, 1H), 5.03 (dd, J = 5.5, 2.2 Hz, 70.4, 69.7, 69.6, 54.8, 31.1; the overall spectroscopic data are
1H), 4.82 (qd, J = 6.3, 2.7 Hz, 2H), 4.41 (q, J = 3.4 Hz, 1H), 4.32- in complete agreement with assigned structures and
4.26 (m, 1H), 4.26-4.20 (m, 2H), 4.02 (dd, J = 10.8, 3.8 Hz, 1H,), consistent with literature.[14g]
1
3.80 (dd, J = 10.8, 3.3 Hz, 1H), 2.09 (s, 3H), 2.08 (s, 3H), 1.58 (s,
d3-Methyl-3,4,6-tri-O-benzyl-2-deoxy--D-lyxo-
3H), 1.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.8, 170.3, hexapyranoside (44): Glycosylation of 3,4,6-tri-O-benzyl-D-
163.1, 149.9, 141.3, 129.5, 126.0, 114.3, 102.0, 93.8, 93.3, galactal (100 mg, 0.240 mmol, 1.0 equiv.) with methanol d3 (11
o
85.6, 84.9, 80.9, 67.7, 67.1, 62.7, 62.4, 27.2, 25.3, 20.8, 20.7; µL, 10 mg, 0.288 mmol, 1.2 equiv.) at 50 C for 3 h, purified by
HRMS (ESI) m/z [M + H]+ calculated for [C22H29N2O11]+: silica gel column chromatography to obtain glycoside 44 as an
497.1766; found 497.1763.
oil (100 mg, 0.223 mmol, 93% yield, ; 91:09). Rf (20%
1
Direct 1,2-addition reaction of armed glycal 1a and anomeric EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ7.36-7.25 (m,
activation in One-pot: To a solution of glycal donor 1a (100 15H), 4.93 (d, J = 11.6 Hz, 1H), 4.87 (m, 1H), 4.66-4.55 (m, 4H),
mg, 0.240 mmol, 1.0 equiv.) and allyl alcohol 2b (19 µL, 17 mg, 4.51 (d, J = 11.8 Hz, 1H), 4.43 (s, 1H), 3.94-3.85 (m, 2H), 3.59
0.288 mmol, 1.2 equiv.) in Toluene (2 mL) was added 5 mol% (d, J = 6.1 Hz, 2H), 2.22 (m, 1H), 2.08-1.94 (m, 1H); 13C NMR
Cu(OTf)2 and the resulting mixture was stirred at 50

C
(101 MHz, CDCl3) δ 138.8, 138.5, 138.1, 129.0, 128.4, 128.3,
temperature under N2 atmosphere. After the completion of 128.2, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 127.2, 98.8,
the reaction the resulted allyl glycoside
5 was treated with L- 74.7, 74.6, 74.2, 73.4, 72.9, 70.4, 69.7, 69.6, 31.1; HRMS (ESI)
Menthol (45 mg, 0.288 mmol, 1.2 equiv.) and NBS (51 mg, m/z [M + H]+ calculated for [C28H30D3O5]+: 452.2511; found
0.288 mmol, 1.2 equiv.). The reaction mixture was stirred at 50 452.2510.

C under inert atmosphere for 3 h. The reaction mixture after
d3-Methyl-3,4,6-tri-O-benzyl-2-deoxy-2-dutero--D-lyxo-
extraction with ethyl acetate, usual workup, purified by silica hexapyranoside (45): Glycosylation of 3,4,6-tri-O-benzyl-D-
gel column chromatography to obtain pure compound 3a in galactal (100 mg, 0.240 mmol, 1.0 equiv.) with methanol d4 (11
o
62% yield over two-steps with ; 97:03.
µL, 10 mg, 0.288mmol, 1.2 equiv.) at 50 C for 3 h, purified by
Similarly, one-pot sequential glycosylation-anomeric activation silica gel column chromatography to obtain glycoside 45 as an
employing 2n as the acceptor in second step, purified by silica oil (98 mg, 0.223 mmol, 91% yield, ; 91:09). Rf (20%
1
gel column chromatography to obtain the glycoside 18 in 65% EtOAc/Hexane) 0.5; H NMR (400 MHz, CDCl3) δ 7.40-7.21(m,
yield with ; 96:04.
15H), 4.93 (d, J = 11.8 Hz, 1H), 4.87 (d, J = 11.8 Hz, 1H), 4.66-
Ferrier Glycosylation of disarmed glycal 1b and anomeric 4.55 (m, 3H), 4.52 (d, J = 11.8 Hz, 1H), 4.43 (d, J = 11.8 Hz, 1H),
activation in One-pot: To a solution of glycal donor 1b (100 3.87-3.76 (m, 2H), 3.52 (dd, J = 6.1, 1.6 Hz, 2H), 2.17 (m, 1H);
mg, 0.367 mmol, 1.0 equiv.) and allyl alcohol (30 µL, 25 mg, 13C NMR (101 MHz, CDCl3) δ 138.8, 138.5, 138.1, 129.0, 128.4,
0.440 mmol, 1.2 equiv.) in Acetonitrile (2 mL) was added 5 128.3, 128.2, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 127.2,
mol% Cu(OTf)2 and the resulting mixture was stirred at 50

C
97.8, 73.7, 73.6, 73.2, 72.4, 71.9, 69.4, 68.7, 68.6, 30.1; the
temperature under N2 atmosphere. After the completion of overall spectroscopic data are in complete agreement with
the reaction the resulted allyl glycoside 29 was treated with L- assigned structures and consistent with literature.[14g]
Menthol (68 mg, 0.440 mmol, 1.2 equiv.) and NBS (78 mg,
0.440 mmol, 1.2 equiv.). After the completion of starting
material, the reaction mixture was extracted with ethyl
acetate and purification through column chromatography on
Conflicts of interest
silica to afford glycoside 4a in 68% yield with ; 98:02.
Similarly, one-pot sequential Ferrier glycosylation-anomeric
activation employing 2n as the acceptor in second step,
purified by silica gel column chromatography to obtain the 2,3-
There are no conflicts to declare.
Acknowledgements
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 13
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Journal Name
10 H. Tanaka, A. Yoshizawa and T. Takahashi, Angew. Chem.,
SK gratefully acknowledges the Department of Science and
Technology, India for the Early Career Research Award and
Research Grant for Young Scientists (SERB-ECR/2017/001477).
The author thanks TEQIP-III for generous support and MRC
MNIT (Advanced Analytical and Characterization Centre) for
providing NMR spectroscopic and analytical data. The authors
are also grateful to the Director MNIT for providing necessary
infrastructure. AG acknowledges a UGC Fellowship.
View Article Online
Int. Ed., 2007, 46, 2505.
DOI: 10.1039/D0OB01042A
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Copper(II)-Catalyzed Stereoselective 1,2-Addition vs DFOeI: 1r0.r10i39e/Dr0OB01042A
Glycosylation of “Armed” and “Disarmed” Glycal Donors
Manoj Kumar, Thurpu Raghavender Reddy, Aakanksha Gurawa and
Dr. Sudhir Kashyap*
Carbohydrate Chemistry Research Laboratory (CCRL), Department of Chemistry,
Malaviya National Institute of Technology (MNIT), Jaipur-302017, INDIA.
Email: skashyap.chy@mnit.ac.in, skr.kashyap@gmail.com
Graphical Abstract for Table of Contents
ROH
Cu(OTf)2 (cat.)
(PO)n
ROH
Cu(OTf)2 (cat.)
(PO)n
OP
(PO)n
OP
O
O
O
BnO
BnO
O
O
BnO
BnO
MeCN, 50 
C
PhMe, 50 
C
O
OR
OR
O
O
O
2,3-unsaturated
glycoside
BnO
BnO
2-deoxyglycoside
BnO
"disarmed" donor
"armed" donor
1,2-addition
Kinetically-
controlled
BnO
O
O
BnO
Glycosylation-Deprotection-Glycosylation
Ferrier-Glycosylation
Thermodynamically
-controlled
OMe
Yields: 72-94%
-selective
BnO
BnO
Yields: 70-94%
-selective
BnO
OMe
Précising the selectivity: The thermodynamic-kinetic switch model enables the selective activation
of enol-ether moiety in “armed” and “disarmed” glycal donor leading to syn-diastereoselective direct
addition or an allylic rearrangement.