Could diastereoselectivity in the presence of O-2 chiral nonparticipating groups be an indicator of glycopyranosyl oxacarbenium ions in glycosylation reactions?

Article

pubs.acs.org/joc

Could Diastereoselectivity in the Presence of O-2 Chiral

Nonparticipating Groups Be an Indicator of Glycopyranosyl

Oxacarbenium Ions in Glycosylation Reactions?

Rishi Kumar and Dennis M. Whitfield*

National Research Council, Institute for Biological Sciences, 100 Sussex Drive, Ottawa, Ontario, Canada K1A 0R6

S

* Supporting Information

ABSTRACT: Although long postulated, the existence of glycopyranosyl oxacarbenium ions as intermediates or transition states

(TS) in chemical glycosylation reactions has not been convincingly demonstrated experimentally. It is anticipated that

elucidation of such reactive species will greatly assist synthetic chemists to control the α/β stereoselectivity by rational means.

Previous density functional theory (DFT) calculations from our group found that the torsion potential about C-2−O-2 in

protected glycopyranosyl donors changed from a conventional 3-fold rotor to a 2-fold rotor with a strong syn (CH-2−C-2−O-2−

CPg) preference once the donor was ionized to its oxacarbenium ion. This suggested to us that if CPg of the protecting group

was a chiral carbon, then diastereoselectivity might be observed in glycosylation reactions that proceed through oxacarbenium

ions. The hypothesis to test is as follows: if a nonparticipating O-2 racemic chiral protecting group exhibits diastereoselectivity in

glycosylation reactions, then the reaction probably proceeds through an oxacarbenium ion intermediate or TS. We present data

for O-2 ether-protected ^D-glucopyranosyl donors where the racemic protecting group 1-methyl 1′-methylcyclopropylmethyl

(MCPM) provides the chirality. MCPM proves to be more activating than the O-2-benzyl ether, and in cases where the donor is

otherwise deactivated, several examples of moderate diastereoselectivity are found. These results can be interpreted to indicate

that a continuum of reactivity exists where some glycosyl donors form oxacarbenium ions in glycosylation reactions but more

reactive donors do not. The strongly activating properties of the cyclopropylmethyl ether functionality and the ability to induce

diastereoselectivity with chiral derivatives strongly suggest widespread applications.

suggested that most reactions follow a S_N1 mechanism with

only a few cases with very strong nucleophiles that any evidence

for the presence of competing S_N2 pathways was found.²⁹⁻³²

Most authors draw the S_N1 mechanism as involving an isolated

in the sense of not ion-paired or otherwise strongly associated

oxacarbenium ion. Such delocalized oxacarbenium ions have a

well-established position in organic chemistry.³³⁻³⁶A further

hypothesis is that stereoselectivity of glycosylation would be

governed by facially selective attack on oxacarbenium ions. This

hypothesis was first made on the basis of density functional

theory (DFT) calculations as the two conformer hypothesis.³⁷

Subsequently, it has been studied experimentally notably by

Woerpel’s group and in some cases is a satisfactory explanation

but for nucleophile: oxacarbenium ion pairs that react at or near

diffusion control such selectivity breaks down.³⁸⁻⁴⁵A second

1. INTRODUCTION

The assembly of carbohydrate building blocks into oligosac-

charides by glycosylation has become a mainstream endeavor in

organic synthesis.¹⁻⁴This is mainly due to the numerous applica-

tions of synthetic oligosaccharides in glycobiology and increasingly

as therapeutic agents such as antithrombotic drugs and pre-

ventative vaccines.⁵In recent years, the chemical yields of

glycosylation reaction have improved but the control of

stereospecificity still lags that of traditional organic chemistry.^6,7

This major shortcoming is at least in part due to the lack of

definitive knowledge of the transitions states or reactive inter-

mediates of glycosylation reactions.⁸⁻¹⁴Three significant types

of studies have led to some hypotheses for such species namely

kinetic isotope effects,¹⁵⁻¹⁹NMR studies of donor activation

conditions²⁰⁻²⁴and computational studies of hypothetical TSs

and intermediates.²⁵⁻²⁸

Classical kinetic studies of glycosylation reactions with rela-

tively poor leaving groups, often under solvolysis conditions,

Received: December 24, 2011

Published: March 19, 2012

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hypothesis that is being increasingly considered is based on the

classic model of Winstein and involves reaction through contact

ion pairs (CIP) or solvent separated ions pairs (SSIP).⁴⁶⁻⁵⁰

The original version of this hypothesis considered nucleophilic

attack on a CIP to resemble S_N2 and lead to inversion of the

stereochemistry of the CIP whereas SSIP would react to favor

the anomeric effect and any other steric or electronic factors

present in the system. Some recent variations of this

mechanism, which include solvent participation⁵¹and the

obligatory proton transfer^26,27from the nucleophilic hydroxyl,

suggest possible additional interactions of the nucleophile with

the leaving group.

The achievement of such knowledge for glycosylation reactions

is a primary goal of our research group. In this work we present

a novel method that works toward this goal. This method

derives from an unexpected DFT computational result on the

conformations of glycopyranosyl oxacarbenium ions. We found

that the dihedral angle CH-2−C-2−O-2−C(pg) where C(pg)

is the first C-atom of the O-2 protecting group of the donor

exhibit a unimodal syn conformation with the absolute value

typically <20°.⁷¹This effect was further shown to probably arise

from a unimodal hyperconjugative interaction of an O-2 lone

pair with the O-5−C-1 pseudo double bond of the cation.⁷²

Further studies supported that this conformation followed

ionization.⁵⁴Consideration of the conformational rigidification

after ionization suggested to us that it might be possible to test

for ionization by making C*(pg) a chiral carbon. The premise

is that the inherent 3-fold flexibility about C-2−O-2 in neutral

species and CIPs would lead to little or no diastereoselectivity

in a glycosylation reaction since low barrier C-2−O-2 rota-

tion could occur but in the ionized state the relatively rigid

C-2−O-2 conformation would allow the C*(pg) chirality to

affect the facial selectivity, see Figure 1. In the remainder of this

One early experimental example from Lemieux’s group which

succinctly summarizes these classical studies is the observation

that 3,4,6-tri-O-acetyl-α-^D-glucopyranosyl chloride under sol-

volysis conditions in aqueous acetic acid leads to 3,4,6-tri-O-

acetyl-β-^D-glucopyranosyl acetate and the isomeric β-chloride

gives the α-acetate. Both reactions were shown to be strictly

first order and hence S_N1 like.⁵²The facially selective oxa-

carbenium ion hypothesis above would require that α-anomers

ionize to oxacarbenium ions that show opposite facial selectivity

from those from β-anomers. Since ^D-glucopyranosyl oxacarbe-

nium ions can potentially exist in at least two different con-

4

5

formers namely H₃and S₁then this hypothesis of different

conformations hence different products is plausible.⁵³Compu-

tational ionization studies show that β-positioned leaving

groups ionize by a different conformational pathway then iso-

meric α-positioned leaving groups. This difference is because β-

anomers must proceed through antiperiplanar conformations.⁵⁴

However, the ultimate conformations from both anomers for

D-glucopyranosyl oxacarbenium ions are both ⁴H₃.⁵⁵In this case,

a mechanism involving CIPs is more appealing to reconcile

Lemieux’s observations.

However, like most of these early mechanistic studies the

reaction conditions do not reflect the current glycosylation

methodologies where highly reactive glycosyl donors are usually

activated, often preactivated,⁵⁶⁻⁶²with strong promoters at low

temperatures in relatively nonpolar solvents where the most

polar solvent commonly used is acetonitrile and the least polar

solvent is toluene. Dichloromethane and a few related chloro-

hydrocarbon solvents as well as simple dialkyl ethers are also

commonly used. The reagents and reactants thus favor ioniza-

tion but the solvents do not. In the cases where neighboring

group participation from O-2 is possible, typically with O-2

esters, then further stabilized dioxolenium ions can be formed.

In these cases Density Functional Theory (DFT) computation

shows such ions to be about 60 kJ mol⁻¹more stable then their

oxacarbenium ion isomers. In accord with this greater stability

is that their existence has been confirmed experimentally in the

solid state and in solution.^50,63,64As well, anomeric (thio)-

sulphonium ions and some closely related doubly stabilized

species can be studied experimentally.⁶⁵⁻⁶⁹However, to the

best of our knowledge, in the absence of such participation, the

existence of oxacarbenium ions in current glycosylation method-

ologies is still unresolved.

Figure 1. Computationally, ionization has been shown to rigidify the

C-2−O-2 dihedral angle such that the chirality at C(pg) may affect

facial selective attack in a S_N1 like process. Conformational mobility in

neutral S_N2 like species is expected to remove such diastereoselectivity.

Methanol is portrayed as the nucleophilic acceptor for simplicity. More

complex acceptors can be anticipated to show more pronounced

interactions with the chiral protecting group. The conformations drawn

are based on our initial premise that the O-2--Cpg torsion should be trans,

in which case the reactivity could be as shown on steric grounds. This

torsional preference is addressed by DFT calculations in this work.

manuscript diastereoselectivity refers to the C*(pg) chiral

protecting group. We also report α:β ratios but these are not

the focus of this work.

A number of people have studied the effect of O-2 nonpartici-

pating groups on glycosylation reactions. Most studies have focused

on the effects on reactivity where electron-donating groups are

considered activating and electron withdrawing groups deactivat-

ing.⁷³⁻⁷⁶More recent studies have found further subtleties relating

to substituents at other positions⁷⁷including effects on the regio-

selectivity and stereoselectivity of glycosylations.^78,79

In this work we synthesized a selection of D-glucopyranosyl

donors of differing reactivity with O-2 protected by the

1-methyl 1′-cyclopropylmethyl (MCPM) protecting group.⁸⁰

We introduced this group a number of years ago as a cleavable

protecting group for polymer-supported oligosaccharide synthesis

From a synthetic organic chemists viewpoint what is

desirable is a condition or set of conditions that allow high

stereoselective control proceeding through intermediates and

TSs whose structures are known. Such knowledge would allow

synthetic chemists to vary protecting groups, leaving groups,

promoters, solvents, additives, etc. in a systematic way. Many

reactions in traditional organic chemistry have been studied at

this level often leading to highly stereoselective processes.⁷⁰

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a

Scheme 1. Synthesis of 2-O-MCPM Glycosyl Donors

a

(a)RuCl₃, CeCl₃, NaIO₄, EtOAc, CH₃CN, H₂O, 1 h, rt; (b) Thexylsilyl Chloride, Imidazole, DMF, 16 h, 0 °C; (c) MCPMTCI, AgOTf, DCM,

22 h, −40 °C; (d) TBAF, AcOH, THF, 2 h, rt; (e) CCl₃CN, NaH, DCM, 1−2 h, 0 °C; (f) PhSH, BF₃.Et₂O, MS4, DCM; (g) N-phenyl-2,

2,2-triflouroacetimidoyl chloride, K₂CO₃−H₂O, Acetone, 20−24 h, rt; (h) α,α-DMT, pTSA, DMF, 3 h, 60 °C; (i) PvCl, Pyridine, DMAP, DCM,

26 h, −25 °C.

with examples of its successful use at O-3, O-4 and O-6. These

results are complemented by a recent study showing the utility

of MCPM as an anomeric protecting group.⁸¹It is readily

installed and cleaved, as well it is electron donating of moderate

size and hence an activating group. This work shows that the

MCPM group at O-2 is more activating then O-benzyl or as it is

commonly called arming.^82,83The anomeric selectivity is also

different from typical O-2 benzyl donors.⁸⁴⁻⁸⁷Further, we

show that in cases where the donor is otherwise disarmed^77,88−91

that the chirality at C*(pg) leads to diastereoselectivity. This

principle is not to be confused with chiral auxiliary mediated which

relies in most cases on the formation of 6-membered participating

rings.^92,93Some fundamental aspects of the conformational

preferences of O-2 MCPM substituted D-glucopyranosyl

donors are also studied by DFT calculations.⁹⁴⁻⁹⁸

resulting ethers are diastereomeric. Within experimental error

the two diastereomeric MCPM ethers were a 50:50 mixture.

The anomeric silyl group was readily removed to give the

hemiacetals 4a and 4b.

These were subsequently converted to their trichloroaceti-

midates 5a and 5b or their N-phenyl trifluoroacetimidates^101,102

6a or 6b.

Trichloroacetimidates, especially the tri-O-benzyl 5b, were

particularly unstable to standard silica gel chromatography even

in the presence of triethylamine or diisopropylethylamine

(DIEPA) in the chromatography solvents. Thus, a slightly

modified version of the original Schmidt NaH procedure was

used and the donors 5b were used without chromatographic

purification.^103,104The N-phenyl trifluoroacetimidates were

more stable and could be chromatographed before use. Using

these protocols the diastereomeric ratios at the MCPM chiral

center were very close to 50:50 in all of the donors. After pre-

liminary experiments with 5a, 5b, 6a and 6b a more deactivated

donor was sought. Starting from ^D-glucose the 4,6-O-

benzylidene-3-O-pivaloyl donor 6c was synthesized by standard

protecting group manipulations.^105,106Similarly donor 5a was con-

verted to its phenylthio-glycoside 7a by treatment with 0.05 mol

equiv of BF₃·OEt₂in the presence of thiophenol (Scheme 2).

When the reaction was done at ice bath temperature an

approximately 20% yield of the α-thioglycoside was found. In

this product the diastereomeric ratio at the MCPM C was close

to 1:1. When the reaction was repeated at −40 °C the yield

2. RESULTS AND DISCUSSION

2.1. Synthesis of Donors. Since we wished to investigate

the effect of the MCPM group at O-2 we started our syntheses

(see Scheme 1) from the readily available tri-O-acetyl-^D-glucal

(for 1a) or tri-O-benzyl-D-glucal (for 1b) using an oxidative 1,2-

diol formation reaction introduced by Misra.⁹⁹The anomeric

position could then be selectively protected as its β-D-thexylsilyl

derivatives 2a and 2b.¹⁰⁰The free 2-OH could then be MCPM

etherified under Lewis acid catalysis⁸⁰in the presence of excess

MCPM-trichloroacetimidate to give 3a and 3b. Since MCPM is

synthesized from racemic 1-methyl 1′-cyclopropylmethanol the

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To directly compare the reactivity of the 2-O-MCPM group,

the reactivity was compared by competition with the well-known

2,3,4,6-tetra-O-benzyl-^D-glucopyranosyl donor 16. The results

shown in Scheme 4 demonstrate that the 2-O-MCPM group is

more activating then the 2-O-benzyl group, at least in this

example.

Scheme 2. Synthesis of Anomeric Phenylthioglycosides 7

Reactive donors 5b and 6b showed no R-, S-MCPM

diastereoselectivity under any glycosylation conditions. This

result suggests that reactive donors do not require oxacarbe-

nium ion formation to permit reactivity. With the less reactive

donors 5a, 5b and 6c a small diastereoselectivity was observed

especially with the secondary acceptor 9. For α-glycosides, this

ranged from no selectivity to a high of 1.6:1 (R:S). For β-

glycosides, when formed, selectivity was as high as 1:4.66 (R:S).

These observations are consistent with oxacarbenium ion

formation according to our hypothesis.

To compare with previously reported conditions the α-

thiophenyl donor 7 was preactivated under conditions that

should lead to the α-triflate and then reacted with acceptor 8 at

−70 °C. The disaccharide 10a was obtained as an α:β mixture

1:1.7 and the diastereomeric ratio were α 1.17:1 and β 1.56:1

(Scheme 5). The greater diastereoselectivity for β-glycosides

fits the observed result with the β-thiophenyl glycoside β-7 and

above for deactivated donor and acceptor combinations above.

This is consistent with the model of Figure 1 where the MCPM

protecting group should be located on the β-face in the

glycopyranosyl oxacarbenium ion.

2.3. Deprotection. The 2-O-MCPM group was cleaved

from disaccharides 10b and 11b by treatment with 10%

trifluoroacetic acid (TFA) in dichloromethane for 1.5 h in an

ice bath. The acid labile isopropylidene group was also

cleaved under these conditions such that for disaccharides

11b the triols 15 were isolated and for disaccharides 10b the

alcohols 14 were isolated in good yields. Elimination of the

MCPM group simplified the NMR spectra and so the α:β

ratios could be more reliably determined. In all cases the

MCPM protecting group was completely cleaved and the

products isolated in good yields without complications

(Scheme 6).

improved to close to 80% and the α:β ratio was 1:1.86.

Interestingly the diastereomeric ratio of the MCPM C in the

α-thioglycoside was still 1:1 but for the β-thioglycoside

1:2.33, R:S.

2.2. Glycosylation. As test acceptors a primary alcohol of a

6-OH ^D-mannose derivative (8)^107,108and a secondary alcohol

4-OH ^L-rhamnose derivative (9)¹⁰⁹were used. The results of

glycosylations are shown in Scheme 3. Reactions with un-

stable 5b were performed at −60 °C in a dichloromethane/

cyclohexane mixture whereas the slightly more stable donors 5a

were reacted in the same solvent mixture, but at −40 °C.

Reactions with purified 6b were done at −75 °C in dichloro-

methane and with 6a at −60 °C. For partially deactivated donor

6c reaction with primary alcohol 8 proceeded at −75 °C but

the secondary alcohol 9 required slight warming to −50 °C to

complete the reaction. In all cases, small amounts of

trimethylsilyltrifluoromethanesulfonate (TMSOTf) promoted

the reaction. The relatively low temperatures for reaction sug-

gested that the 2-O-MCPM was an activating protecting group.

Note that 3,4,6-tri-O-acyl-2-O-benzyl-^D-glucopyranosyl donors

are considered to be superdisarmed.¹¹⁰In all cases the disac-

charides were the major products with little or no donor left

and little or no unreacted acceptors were left too. The only

discernible byproducts were small amounts of the hemiacetals 4a,

4b or 4c.

The NMR spectra of the diastereomeric α/β-glycosides were

often quite complicated. Assignments were made by standard

1

2.4.1. Conformational Analysis by DFT Computa-

tion. CH-2−C-2−O-2−C(MCPM) Torsion. Previous studies

from our group have established that the CH-2−C-2−O-2−

C(Pg) torsion angle in glycopyranosyl oxacarbenium ions, like

the ones expected to form from the donors used in this study,

have a bimodal distribution with anti and syn conformations. In

all cases studied to date the syn conformation is more stable

than anti, typically by about 10 kJ mol⁻¹. This preference

strongly suggests that in equilibrated glycopyranosyl oxacarbe-

nium ions this will be the only conformation significantly

populated. This preference was attributed to a unimodal

hyperconjugative interaction between a lone pair on O-2 and

the O-5−C-5 pseudo double bond. A π-type orbital associated

with this bond is often the LUMO of glycopyranosyl

oxacarbenium ions making this association probable. That the

2D NMR methods such as H−¹H-COSY, H−¹H-TOCSY

and ¹³C−¹H-HSQC. In several cases 1D ¹H-nuclear Overhauser

effect (NOE) spectra were run in order to establish proton−

proton proximity that aided in the assignment of diastereomers

and anomers. Representative examples are given in the

Supporting Information. Diastereomeric ratios as well as α/β

ratios were estimated by integration of relevant single peaks in

the assigned ¹H spectra. Note the absolute configuration at the

MCPM C is not known with certainty in any cases and the R:S

ratios (labels) could be reversed in all cases.

The 3,4,6-tri-O-benzyl 2-O-MCPM donors 5b and 6b gave a

marked preference for β-glycosides. This is quite different from

the usual α-preference for 2-O-benzyl donors.^84−86,111The

more deactivated 3,4,6-tri-O-acetyl 2-O-MCPM donors 5a and

6a showed a marked α-preference. DFT calculations of the

2,3,4,6-tetra-O-methyl-^D-glucopyranosyl oxacarbenium ion sug-

4

MCPM group at O-2 in the H₃or the closely related in

conformational space E₃conformations as well as the ⁵S₁

conformation of the glucopyranosyl oxacarbenium ion also

showed this preference was readily established by DFT

calculations. For calculation details see the Experimental

section and ref 71. For the R-MCPM isomer, the syn to anti

energy differences were found to be −8.0 and −13.6 kJ mol⁻¹

and for the S-MCPM −37.3 and −14.6 kJ mol⁻¹. Note that all

degrees of freedom were not optimized in each conformer as

4

5

gested that both the H₃and S₁conformers should be β-

selective if hydrogen bonding between the nucleophile and the

oxacarbenium ion could occur.¹¹²Otherwise the ⁴H₃conformer

5

is α-selective and the S₁conformer β-selective on stereo-

electronic grounds.⁵³These results strongly suggest that the

2-O-MCPM group activates the anomeric position differently

than 2-O-benzyl (Table 1).

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Scheme 3. Glycosylation

only the C-2−O-2 torsion was varied. These differences clearly

show the “normal” syn to anti, syn preference, see Table 2. This

question was not studied further and all other conformers studied

were optimized starting from syn C-2−O-2 conformations.

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cases the C-5−C-6 exocyclic conformation was optimized. Only

the lowest energy conformations are shown. The rotameric

profiles show the standard gt ≈ gg > tg preferences. Table 3

shows the energy differences and some selected geometric

features of 17. For example, the ring torsion τ₅is nearly 0 (i.e.,

planar) in all cases. As well, the O-5−C-1 bond lengths are all

about 1.26 0.02 Å and the O-5−C-1−C-2 bond angles are

about 125 2° which is consistent with an oxacarbenium ion

structure. The ring conformations are described as descriptors

where a value of 1.0 would be a perfect match and 0.0 a perfect

mismatch, see Table 2 and Figure 3. This system of classi-

fication divides the 6-membered ring conformational space into

38 regions, which occupy the same volume of a 3-dimensional

Table 1. Total Yields, α:β Ratios, and MCPM

Diastereoselectivity for Glycosylation Reactions

a

b

donor acceptor

R¹

Ac

R²

Ac

R³α(R:S) β(R:S)

yield

5a

5b

5a

5b

6a

6b

6c

6a

6b

6c

8

9

8

9

Ac

Bn

Ac

Bn

Ac

Bn

Pv

Ac

Bn

Pv

1:1

50%

Bn

1:1 69%; 1:2(α:β)

2.7:1 44%; 3:2(α:β)

1:1 65%; 1:3(α:β)

55%

Ac

1.6:1

1:1

Bn

Ac

1:1

Bn

1:1

1:1 77%; 1:2(α:β)

55%

CHPh

Ac

CHPh

Ac

1.27:1

1.25:1

1:1

4.66:1 55%; 4:1(α:β)

1:1 70%; 1:3(α:β)

Bn

CHPh

1.13:1

67%

1

sphere without user bias.¹¹⁴All H₃conformations of 17 have

4

a

Diastereoselective ratios (R:S) were obtained from H NMR inte-

coefficients close to 1.0 and hence are nearly perfect half chairs

b

gration and are reproducible to 5%. Stereoselective ratios were

obtained from H NMR integration and are reproducible to 5%.

with all substituents pseudoequatorial. For 16 the closely

1

5

related in conformational space E₃is also populated. The S₁

conformations show more variability and are displaced from the

pseudorotational equator of the conformational sphere toward

the C₄pole.

2.4.2. Glucose Ring Conformations. Our previous DFT

studies have shown that besides the H₃conformation a ring

1

4

inverted ⁵S₁is a distinct minimum on the conformational

potential energy surface of a variety of substituted ^D-

glucopyranosyl oxacarbenium ions.⁵²Similar ions have been

found for the per-O-methyl xylo and galacto configured

pyranosyl ions.²⁷In all these conformations, O-2−C-2 lie

nearly in the C-5−O-5−C-1−C-2 plane. The corresponding

C-5−O-5−C-1−C-2 torsion angle (τ₅in our nomenclature) is

expected to be planar in a fully ionized oxacarbenium ion.

For the 2,3,4,6-tetra-O-methyl-^D-glucopyranosyl ion a pathway

2.4.3. Effect of MCPM Chirality. The simplistic model (see

Figure 1), which prompted this study, was partly based on the

idea that the remaining degrees of freedom of the MCPM

group would be identical and hence the chirality would exhibit

itself by reversing the relative positions of the two smallest

groups, namely the methyl and the hydrogen. A previous study

of chiral at the aglycone carbon of mannosides found this to be

true with both isomers having the largest group anti.¹¹⁵

However, our recent study of the neutral mannosides with

MCPM at the anomeric center found that the Ψ(C-1−O-1−

C(MCPM)−C(Cp) torsion angle had different minima.⁸⁰The

S-isomer was found in the 180° conformation postulated above

but the R-isomer in the unexpected 60° conformer. In the

present study the postulated oxacarbenium ions are not ob-

servable by NMR. Thus, only DFT calculations can be per-

formed. The remaining degree of freedom is the χ₂= O-2−

CH(CH₃)−CHcp−CcpH₂torsion angle that can be estimated

from the ground state NMR from the J_CH−CHcpcoupling

constant. In all cases to date this has a value >8 Hz suggesting a

predominant but not exclusive preference for the 180° con-

formation. No attempt was made to determine the conforma-

tional preference of this torsion but in all calculations this

torsion was not restrained. Thus it was necessary to attempt to

optimize the χ1 = C-2−O-2−CH(CH₃)−CHcp torsion angle.

This proved challenging as simple incremental rotations about

O-2−C(Cp) led to discontinuities unless the increment size

was small. These discontinuities included ring conformational

4

connecting the H₃to ⁵S₁conformations involving ring flatten-

1

ing through a S₃transition state and then pseudorotation, has

been found by ab initio molecular dynamics (AIMD)

calculations.¹¹³Several local minima are found on this pathway

but all are connected by low energy barriers, that is, pseudo-

rotation, and are therefore not predicted to be distinctly popu-

lated for glucose derivatives with noninteracting protecting

groups. In the donors studied here this is likely the case with a

small possibility of some conformations having benzyl-to-

benzyl interactions that could be favorable or unfavorable. For

modeling studies we have not considered this computationally

difficult problem and have used only methyl or acetyl groups on

O-3, O-4 and O-6.

For both R, S-pairs of isomers of 3,4,6-tri-O-acetyl (17) or

tri-O-methyl-2-O-MCPM-^D-glucopyranosyl ions (16) both the

5

⁴H₃and S₁conformations were found as minima, that is, no

negative frequencies in second derivative calculations. In all

Scheme 4. Direct Competitive Comparison of 2-O-Benzyl and 2-O-MCPM Donors

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Scheme 5. Preactivation of Thiophenyl Donor α-7

Scheme 6. Deprotection of MCPM Ethers

Table 2. Comparison Showing C-2−O-2 syn−anti Energy Difference and Some Geometric Parameters for R-MCPM or

S-MCPM 3,4,6-tri-O-Methyl-2-O-MCPM-^D-glucopyranosyl Ions, 16

a

chair

skew

descriptor

boat

descriptor

CH-2−C-2−O-2−C

(MCPM)°

C-2−O-2 −C(MCPM)−

C(Cp)°

CH-5−C-5−C-6−O-

6°

ΔE kJ

compound

descriptor

mol⁻¹

R-syn

R-anti

S-syn

E₃0.886

⁴H₃0.883

E₃0.886

⁴H₃0.755

¹C₄0.308

¹C₄0.234

¹C₄0.196

¹C₄0.431

¹S₅0.039

⁴C₁0.053

¹S₅0.092

⁴C₁0.220

⁵S₁0.747

⁵S₁0.829

⁵S₁0.952

⁵S₁0.522

B_O,30.055

²E 0.114

−38.4

−162.2

−24.6

164.8

80.9

125.2

−45.3

−41.8

−44.8

−41.5

−156.3

−159.2

−157

−8.0

b

0.0

−37.3

0.0

B_O,30.041

^2,5B 0.013

^O,3B 0.086

^O,3B 0.006

^O,3B 0.077

^O,3B 0.085

−165.6

75.6

b

S-anti

R-syn

R-anti

S-syn

33.1

−55.7

−90.1

−64.9

−110.7

−13.6

0.0

175.1

−30.8

−164.9

−14.6

0.0

S-anti

−155.8

a

Where the conformation is an intermediate conformation (half chair or envelope) the descriptors are permutated to give the conformation in terms

b

of the intermediate conformation and the next two best descriptors. Energy of the anti conformer set to 0.0 kJmol⁻¹.

Table 3. Comparison Showing Some Geometric Parameters for R-MCPM or S-MCPM 3,4,6-tri-O-Acetyl-2-O-MCPM-D-

a

glucopyranosyl Ions, 17

O-5−C-1− C-5−O-5−C-1−C-

CH-5−C-5−C-6−

O-6°

ΔE

compound C-1−O-5 Å

C-2°

2, τ₅°

CH-2−C-2−O2−C(MCPM)° C-2−O-2−C(MCPM)−C(Cp)°

kJ mol⁻¹

4

R-syn H₃

1.258

1.259

1.263

1.268

125.7

125.8

124.5

124.6

11.1

12.8

3.7

−10.9

−17.6

−9.5

31.3

−55.1

−160.8

54.7

37.7

40

31.2

35.4

4

S-syn H₃

b

5

R-syn S₁

−62.2

74.1

0.0

5

S-syn S₁

−5.7

−55.4

11.5

a

b

For ring descriptors see Figure 3. Lowest energy conformer set to 0.0 kJ mol⁻¹.

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5

Figure 2. Rotational energy profiles for rotation about O-2−C(Cp), χ₁, for the S₁conformations of 17.

4

5

switches between H₃or S₁and jumps in nonrotated bonds

like C-2−O-2 and C-3−O-3 to avoid steric clashes. A

representative pair of profiles is shown in Figure 2. Each

point in Figure 2 is a full DFT optimization except that the

O-2−C(Cp) torsion angle is fixed. The results show that like our

results with Ψ variation for anomeric MCPM χ₁has different

minimum for each of R and S. The large C-2−O-2 syn−anti

difference for S-syn 16 is likely the result of S-anti 16 having a

different O-2−C(Cp) minimum, which was not optimized.

These results compromise our simplistic interpretation but

still suggest that the steric and electronic environment about

C-1 differ due to the chirality at the MCPM carbon which is in

turn partly due to the rigidification of the C-2−O-2 torsion.

Thus, if an equilibrated oxacarbenium ion is formed it is

probable that the two faces will have differential reactivity. The

experimental results above suggest that the differences are more

pronounced for the β-face than the α-face. Figure 3 shows the

lowest energy conformations of the oxacarbenium ions (17)

corresponding to the deactivated donors 5a, 6a and 7. The two

Figure 3. Ball and stick representations of the lowest energy

conformations of 17. Ring descriptors are displayed above the

corresponding structures.

5

⁴H₃ions are quite flat whereas the S₁isomers are very bent.

4

2.4.4. Possible R,S-Assignments of the β-SPh Glycosides 7.

The disaccharides synthesized in this work are currently too

large for DFT calculations but the thiophenyl compound 7 is

amenable to DFT. Thus we optimized the R- and S-isomers of

For the H₃conformers the R-isomer has the α-face the most

5

shielded whereas for the S₁isomers it is the S-isomer which

most shields the β-face. Thus, in fully equilibrated systems the

5

R-isomer of the S₁should be the most reactive on the β-face.

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Figure 4. Trajectories of computational ionization leading to 17 in 3D conformational space. (a) α-Triflate(R) and (b) α-triflate(S). (c) β-Triflate(R) and

(b) β-triflate(S). Each point is a full DFT optimization including solvation except that the C-1--O_Tfis fixed and incremented at each subsequent data point.

The lines in (c) and (d) are drawn to connect before and after the conformational jump.

the β-anomer of 7. We also did some NMR studies of 7b which

clearly showed a marked difference between the NOE’s result-

ing for irradiating CH-2 of the two isomers, see Supporting

Information. On the basis of this analysis, the predominant

isomer is tentatively assigned as S.

2.4.5. Kinetic Questions. A further question that can be

addressed by computation is the kinetic pathway to the

oxacarbenium ion. We have previously developed a protocol to

assess this by slowly lengthening the C-1−X bond where X is a

suitable leaving group.^55,116To avoid discontinuities caused by

the accumulating negative charge on the leaving group, a Li⁺

ion is placed in a fixed position relative to the leaving group.

The trifluoromethanesulfonate(triflate) leaving group was

chosen, as there is considerable evidence that in some cases

comparable to our experimental an anomeric triflate is formed

before O-glycosylation. Typically the α-triflate accumulates but

this does not guarantee that the less stable and hence more

reactive β-triflates are not the active species.⁵⁵We studied 4

cases for this work namely R- or S-MCPM and α- or β-triflate

for the 3,4,6-tri-O-acetyl ^D-glucopyranosyl donors. The results

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The C-2−O-2 dihedral was set to syn or anti conformations. The syn

conformation then had its ω_Hconformation searched by rotational

variation. Then the χ₁side chain was optimized by rotational variation.

Experimentation revealed that 120 × 3° increments were used to

minimize discontinuities. The procedure was then repeated for the

3,4,6-tri-O-acetyl analogue 17. Similarly, the conformations of the

neutral R- or S- at MCPM C, phenyl 3,4,6-tri-O-acetyl-2-O-(1-methyl-1′-

methylcyclopropylmethyl)-1-thio-β-^D-glucopyranoside 7 were optimized.

In this case, the phi (CH-1−C-1−S−Cip) torsion was optimized too.

are shown in Figure 4a−d where each point represents a point

in the 3D-conformational space of 6-membered ring and is a

separate fully optimized DFT calculation. At each point the

C-1−O-triflate bond length is constant and at each step this bond

length is increased. In all cases the final conformation is close to

5

4

⁴H₃and not S₁. This kinetic formation of the H₃conformers

is likely a result of the stabilization by the counterion. The path-

4

way to H₃is different for each diastereomer. In the α-cases

(a and b) both paths are incremental but follow slightly different

arcs in conformational space. For the β-cases (c and d) after a

short lengthening the ring undergoes an abrupt conformational

change to a conformer that is consistent with the antiperiplanar

hypothesis. Such conformers are near the pseudorotational

equator on the 3D representation. This is entirely consistent

with previous results for a variety of protecting groups, leaving

groups and pyranosyl configurations. Subsequently the con-

4

formers slowly convert to near H₃again with slightly different

5

arcs for R- and S-MCPM. To arrive at the more stable S₁

conformation the ions must equilibrate. The AIMD results suggest

the barrier is low but what triggers such a change and the role of

counterions is still obscure. The current results suggest reaction

through ⁴H₃conformations for the deactivated donors whereas the

more reactive donors likely react before becoming ionized. In this

case, the counterion likely plays an important role in reactivity and

the influence of the conformation about C-2−O-2, which is turn

influenced by the configuration at the Cpg−O-2 carbon, plays only

a minor role.

The DFT calculations were carried out with the Amsterdam Density

Functional (ADF) program system, ADF2005. The atomic orbitals

were described as an uncontracted triple-ζ function basis set with a

single-π polarization function on all atoms, which were taken from the

ADF library (TPZ).^118−122A set of s, p, d, f, and g Slater functions

centered on all nuclei were used to fit the electron density, and to

evaluate the Coulomb and exchange potentials accurately in each SCF

cycle. The local part of the V_xcpotential (LDA) was described using

the VWN parametrization,¹²³in combination with the gradient

corrected (CGA) Becke’s functional for the exchange and Perdew’s

function for correlation (BP86). The CGA approach was applied self-

consistently in geometry optimizations. Second derivatives were evaluated

numerically by a two point formula. The solvation parameters (CH₂Cl₂)

within the COSMO procedure were dielectric constant ε = 9.03, ball

radius = 2.4 Å, ball radius = 1.3 Å; with atomic radii of C = 1.989 Å,

O = 1.7784 Å and H = 1.3 Å. Initial geometries all started with

3. CONCLUSION

The electron donating ability of cyclopropylmethyl ethers, the

parents of the MCPM protecting group, has been known for

some time.¹¹⁷However, to the best of our knowledge this pro-

perty has never been directly compared to O-2 nonparticipating

benzyl ethers. The experimental observation that O-2-MCPM

is more activating then O-2 benzyl provides another tool in the

carbohydrate chemist’s toolbox. We chose the method of using

50:50 R:S at the chiral protecting group and looking for prod-

ucts with enriched R or S as this was experimentally accessible

although the NMR analyses are tedious. The preferred method

of separately using optically pure chiral protecting groups

requires a highly accurate absolute kinetic method. The devel-

opment of such a kinetic method is a desirable objective.

Further, the observation of modest but real diastereoselectivty

in certain glycosylation reactions provide a possible sensor for

glycosylation conditions that proceed through oxacarbenium

ion species. Our results also suggest that the converse is true

and that highly reactive glycosyl donors do not react through

oxacarbenium ions but through something closer to CIPs. The

TSs of such glycosylation reactions is an active area of research

for us. Overall these results should help guide the experi-

mentalist to find a combination of protecting groups, solvent,

promoters etc. to enable stereoselective high yielding glycosylation

reactions.

4

protected ^D-glucopyranosyl MCPM glycosides in C₁conformations

with all side chains (methyl or acetyl protecting groups) in minimum

energy conformations. All calculations used internal coordinates. For

torsion angle variation starting from a minimized conformation the

torsion angle was set as a variable and varied in 3° increments, that is,

120 increments for a full circle. For some torsion variations 6°

increments were used. All other internal coordinates were allowed to

relax during optimization. All minima were characterized as true

minima by frequency calculations.

4.2. General Experimental Details. NMR spectra were recorded

on a 400 MHz (¹H) and 100 MHz (¹³C) spectrometer with tetra-

methylsilane or the residual signal of the solvent as the internal

standard. Chemical shifts are quoted in ppm and J values in Hz. Mass

spectra were recorded on a Quadrupole time-of-flight mass spectro-

meter using electrospray ionization (ESI) or time-of- flight mass spectro-

meter using matrix-assisted laser desorption/ionization (MALDI).

Analytical thin-layer chromatography was performed on precoated plates

of silica gel and visualized with H₂SO₄−H₂O (1:20 v/v) followed by

heating. Flash column chromatography was performed using silica gel

(230−400 mesh). All solvents and reagents were purified and dried

according to standard procedures.

4.3. General Procedure for the Synthesis of 3. A solution

of compound 2b (10 g, 16.867 mmol) and silver triflate (4.76 g,

18.6 mmol) in dichloromethane (50 mL) was flushed with argon gas

and cooled to −40 °C. To this well stirred cooled reaction solution

was added 1-methyl 1′-cyclopropylmethyl trichloroacetimidate

(MCPMTCI) (5.9 mL, 33.7 mmol) slowly over 30 min. The reaction

was then allowed to stir for 22 h and was monitored by TLC (10:1 v/v

hexane/EtOAc, run ×2). The reaction was quenched by adding excess

of ammonium bicarbonate and allowing the solution to stir for a while.

The solution was filtered through Celite to remove the solid; the

filtrate obtained was concentrated to give the crude product. The

crude product was purified by silica gel chromatography using 15:1 v/v

4. EXPERIMENTAL SECTION

4.1. Computational Details. Preliminary conformational anal-

ysis was done using the AM1 Hamiltonian as implemented in the

Hyperchem-version 10 PC based molecular modeling program. The

4

models were built by appropriate modifications of the idealized H₃

5

and S₁conformations of R- or S-3,4,6-tri-O-methyl-2-O-(1-methyl-1′-

methylcyclopropylmethyl)-^D-glucopyranosyl cation, 16. The resulting

structures were reoptimized with DFT with a total charge of +1. The

conformations of the various side chains were optimized as follows.

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hexane/EtOAc solvent mixture as eluant to afford pure compound 3b

as syrup (8.4 g, 75%).

ESI-HRMS: Calcd. for C₃₁H₅₄NO₇Si [M + NH₄]⁺m/z 580.3670.

Obsd. m/z 580.3666.

4.4. General Procedure for the Synthesis of 4. Dried

compound 3b (8.1 g, 12.254 mmol) was taken in a R.B. flask and

was dissolved in THF (40 mL) under argon atmosphere. To the well-

stirred solution was added 1 M tetrabutylammonium fluoride in

THF (24.5 mL, 24.5 mmol), followed by glacial acetic acid (0.7 mL,

12.3 mmol). The reaction was stirred at room temperature for 2 h.

The reaction after completion was evaporated under vacuum followed

by coevaporation with toluene. The crude was purified over silica gel

using 5:1 v/v hexane/ethyl acetate solvent mixture as eluant to afford

compound 4b as a syrup (5.1 g, 81%).

4.5. General Procedure for the Synthesis of Trichloroaceti-

midate Donor 5. The solution of compound 4 in dichloromethane

was stirred under argon atmosphere and cooled to 0 °C. To the cooled

solution was added trichloroacetonitrile (3 equiv) by syringe and the

solution was allowed to stir. After 15 min was added NaH (95% in oil,

1 equiv) slowly and the reaction was allowed to stir for 2 h on an ice-

bath. The reaction was worked up by initially adding few drops of

water and then adding more water. The solution was transferred to a

separating funnel and the organic layer extracted with DCM, dried

with anhyd. sodium sulfate and concentrated to afford crude 5b. In the

case of acetyl protected donor 5a, the crude was purified by silica

gel chromatography using 6:1 v/v hexane/EtOAc solvent mixture as

eluant.

Thexylsilyl 3,4,6-tri-O-Acetyl-2-O-(R,S-1-methyl 1′-Cyclopropyl-

methyl)-β-^D-glucopyranoside (3a). Colorless syrup, yield 76%, ¹H

NMR 400 MHz, CDCl₃, δ 5.08 (at, J = 9.4 Hz and 9.6 Hz, H-3 S);

5.07 (at, J = 9.4 Hz, 1H, H-3 R); 4.95 (at, J = 9.8 Hz and 9.6 Hz, 1H,

H-4 S); 4.90 (at, J = 9.8 Hz, 1H, H-4 R), 4.65 (d, J = 7.4 Hz, 1H, H-1

R); 4.60 (d, J = 7.4 Hz, 1H, H-1 S); 4.18−4.07 (m, 4H, H-6_abR, H-6_ab

S); 3.66−3.61 (m, 2H, H-5 R, H-5 S); 3.52 (dd, J = 9.4 Hz and 7.6 Hz,

1H, H-2 S); 3.40 (dd, J = 9.3 Hz and 7.3 Hz, 1H, H-2 R); 3.37−3.30

(m, 1H, CH-mcpm-R); 3.26−3.20 (m, 1H, CH-mcpm-S); 2.06; 2.02

(2s, 24H, CH₃CO × 6); 1.67−1.60 (m, 2H, CHCMe₂); 1.17 (d, J =

6.2 Hz, 3H, CH₃-mcpm-R); 1.10 (d, J = 6.1 Hz, 3H, CH₃-mcpm R);

0.87; 0.85 (2bs, 24H, CH₃× 8); 0.70−0.55 (m, 2H, CH); 0.51−0.32

(m, 4H, CH₂); 0.17−0.10 (m, 14H, SiMe₂× 4, CH₂× 2); 0.01−0.04

(m, 1H, CH₂-cp-ring). ¹³C NMR 100 MHz, CDCl₃, δ 170.64, 170.15,

169.99, 169.88 (CO × 6); 98.24 (C-1 S); 98.08 (C-1 R); 80.15 (CH-

ring-R); 78.88 (CH-ring-S); 77.56 (C-2 S); 77.54 (C-2 R); 74.33 (2C,

C-3 R, S); 71.49 (C-5); 71.39 (C-5); 69.36 (C-4); 69.29 (C-4); 62.73

(C-6); 62.68 (C-6); 33.79 (CH-thexyl); 33.76 (CH-thexyl); 24.81;

24.78 (C-thexyl); 21.07 (CH₃-mcpm-S); 20.83, 20.80, 20.70 (CH₃CO

× 6); 20.07, 20.00, 19.83, 19.73 (CH₃× 4); 19.32 (CH₃-mcpm-R);

18.53, 18.52, 18.35 (CH₃× 4); 16.86; 16.34 (CH-mcpm); 5.16, 3.43,

1.34, 0.22 (CH₂-mcpm × 4); −2.18; −2.26; −2.76; −3.11 (SiMe × 4).

ESI-HRMS: Calcd. for C₂₅H₄₈NO₉Si [M + NH₄]⁺m/z 534.3098.

Obsd. m/z 534.3079.

Thexylsilyl 3,4,6-tri-O-Benzyl-2-O-(R,S-1-methyl 1′-Cyclopropyl-

methyl)-β-^D-glucopyranoside (3b). Colorless syrup, yield 75%, ¹H

NMR 400 MHz, CDCl₃, δ 7.36−7.16 (m, 30H, Ar−H); 5.06 (d, J =

11.1 Hz, 1H, CH₂Ph); 4.96 (d, J = 11.1 Hz, 1H, CH₂Ph); 4.83−4.76

(m, 4H, CH₂Ph); 4.61−4.50 (m, 8H, H-1 R, H-1 S, CH₂Ph × 6); 3.72

(t, J = 8.5 Hz and 7.9 Hz, 1H, H-2); 3.70 (m, 4H, H-6_abR, H-6_abS);

3.62−3.52 (m, 5H, H-5 R, H-3 R, H-4 R, H-2 S, CH-mcpm R); 3.47−

3.41 (m, 4H, H-3 S, H-4 S, H-5 S, CH-mcpm S); 1.69−1.65 (m, 2H,

CH-thexyl); 1.23 (d, J = 8.2 Hz, 3H, CH₃-ring); 1.19 (d, J = 8.2 Hz,

3H, CH₃-ring); 0.94−0.81 (m, 25H, 8 × Me, CH-ring); 0.63−0.33 (m,

8H, CH₂-ring × 8); 0.19; 0.16 (2bs, 12H, SiMe₂× 2); 0.00−0.04 (m,

1H, CH-ring). ¹³C NMR 100 MHz, CDCl₃, δ 139.1, 138.9, 138.3

(ipso-C × 3); 128.3−127.3 (Ar−C); 98.6 (C-1); 98.4 (C-1); 85.0 (2C,

C-4 × 2); 79.6 (C-2); 79.5 (C-2); 79.4 (CH-mcpm); 78.5 (CH-

mcpm); 78.1 (2C, C-3 × 2); 75.8; 75.6; 74.9; 74.7 (C-5); 74.6 (C-5);

69.2 (2C, C-6 × 2); 33.7 (2C, CHMe₂× 2); 24.7 (2C, CMe₂× 2);

20.2; 20.1; 19.8; 19.8; 19.1; 18.6; 18.4; 17.2; 16.3; 5.6; 3.7; 1.3;

0.3; −1.9; −2.0; −2.8; −3.0 (SiMe₂× 4). ESI-HRMS: Calcd. for

C₄₀H₆₀NO₆Si [M + NH₄]⁺m/z 678.4190. Obsd. m/z 678.4196.

Thexylsilyl 4,6-O-Benzylidene-2-O-(R,S-1-methyl 1′-Cyclopropyl-

methyl)-3-O-pivaloyl-β-^D-glucopyranoside (3c). Colorless syrup,

yield 72%, ¹H NMR 400 MHz, C₆D₆, δ 7.61−7.59 (m, Ar−H);

7.19−7.16 (m, Ar−H); 7.10−7.07 (m, Ar−H); 5.54 (t, J = 9.4 Hz, 1H,

H-3 S); 5.50 (at, J = 9.2 and 9.5 Hz, 1H, H-3 R); 5.21 (s, 1H, PhCH);

5.20 (s, 1H, PhCH); 4.51 (d, J = 7.0 Hz, 1H, H-1 R); 4.47 (d, J = 7.2

Hz, 1H, H-1 S); 4.06−4.03 (m, 2H, H-6_aR, H-6_aS); 3.81−3.77 (dd,

J = 7.2 Hz and 9.0 Hz, 1H, H-2 S); 3.64−3.59 (m, 2H, H-2 R, CH-

mcpm R); 3.53−3.46 (m, 1H, CH-mcpm S); 3.44−3.39 (m, 2H, H-6_b

R, H-6_bS); 3.36−3.31 (m, 2H, H-4 R, H-4 S); 3.08−3.02 (m, 2H, H-5

R, H-5 S); 1.75−1.65 (m, 2H, CHMe₂); 1.36 (d, J = 6.2 Hz, 3H, Me-

mcpm S); 1.26−1.24 (m, 21H, Pv × 2, Me-mcpm R); 0.98−0.91 (m,

24H, 8 × Me); 0.89−0.79 (m, 2H, cp-ring); 0.64−0.51 (m, 4H, cp-

ring); 0.41−0.22 (m, 4H, cp-ring); 0.19−0.08 (m, 14H, SiMe₂× 2,

2 × cp-ring). ¹³C NMR 100 MHz, C₆D₆, δ 176.7 (2C, 2 × CO);

128.9−126.4 (Ar−C); 101.2 (2 × PhCH); 99.0 (C-1 R); 98.9 (C-1 S);

79.7 (C-4 R); 79.6 (C-4 S); 78.9 (OCH-mcpm R); 78.2 (OCH-mcpm

S); 78.0 (C-2 S); 77.8 (C-2 R); 73.7 (C-3 R); 73.6 (C-3 S); 68.8 (2C,

C-6 R, C-6 S); 65.9 (C-5 R); 65.8 (C-5 S); 34.2 (CHMe₂); 27.4 (2C,

CMe₃of Pv × 2); 25.0 (CMe₂); 21.2 (CH₃-mcpm); 20.3 (CH₃-

mcpm); 20.3 (3C), 20.0 (3C) (CMe₃× 6); 18.8 (2C), 18.6 (2C), 17.3

(2C), 17.0 (2C) (Me × 8); 5.0 (CH₂-mcpm); 3.8 (CH₂-mcpm); 1.3,

0.8 (CH₂-mcpm); −2.0, −2.2, −2.6, −2.8 (SiMe₂× 4). ESI-MS:

Calcd. for C₃₁H₅₀NaO₇Si [M + Na]⁺m/z = 585.79 obsd. m/z 585.65.

4.6. General Procedure for the Synthesis of N-Phenyl

Trifluoroacetimidate Donor 6. To the solution of compound 4

and N-phenyl trifluoroacetimidoyl chloride (2 equiv) in acetone was

added few drops of water and K₂CO₃(2 equiv) and the reaction was

allowed to stir for 4 h at rt. After the completion of reaction more

acetone was added and the solution was passed through a Celite bed.

The filtrate obtained was concentrated and purified by silica gel

chromatography using 6:1 v/v hexane/EtOAc solvent mixture as

eluant to afford pure donor 5 as colorless oil.

4.7. General Procedure for Glycosylation. The acceptor

solution in DCM (1 equiv) along with MS4 Å was stirred under argon

atmosphere and cooled to the required temperature. The donor

solution (1.2 equiv) in either in cyclohexane (5) or DCM (6) was

injected by syringe/canulation and the reaction solution was stirred for

20 min. To this well stirred and cooled solution was added TMSOTf

(equivalent according to Scheme 3). The reaction was allowed to stir

at the temperature and time period mentioned in Scheme 3. The

reaction was quenched by adding triethylamine. The reaction medium

was washed with sat. sodium bicarbonate solution and extracted with

DCM. The organic layer was dried, concentrated and then purified by

silica gel chromatography to give the pure glycosylated product.

Methyl (3,4,6-tri-O-Acetyl-2-O-(R,S-1-methyl 1′-Cyclopropyl-

methyl)-α-^D-glucopyranosyl)-(1→6)-2,3,4-tri-O-benzyl-α-D-manno-

pyranoside (10a). White amorphous solid, yield 50%, ¹H NMR, C₆D₆,

400 MHz, δ 7.38−7.32 (m, Ar−H); 7.29−7.27 (m, Ar−H); 7.22−7.06

(m, Ar−H); 5.83 (at, J = 9.6 Hz, 1H, gH-3 S); 5.81 (at, J = 9.8 Hz, 1H,

gH-3 R); 5.38−5.33 (m, 2H, gH-4 R, gH-4 S); 5.12 (d, J = 3.5 Hz, 1H,

gH-1 R); 5.10 (d, J = 3.5 Hz, 1H, gH-1 S); 5.07−5.02 (m, 2H,

OCH₂Ph × 2); 4.74 (d, J = 1.2 Hz, 1H, mH-1 R); 4.72 (d, J = 1.4 Hz,

1H, mH-1 S); 4.71−4.46 (m, 6H, OCH₂Ph × 6); 4.43−4.41 (m, 4H,

OCH₂Ph × 4); 4.38−4.28 (m, 6H, gH-5 R, gH-5 S, gH-6_aR, gH-6_bR,

gH-6_aS, gH-6_bS); 4.13−3.87 (m, 10H, mH-3 R, mH-3 S, mH-4 R,

mH-4 S, mH-5 R, mH-5 S, mH-6_aR, mH-6_bR, mH-6_aS, mH-6_bS);

3.76 (m, 2H, mH-2 R, mH-2 S); 3.60 (dd, J = 10.0 Hz and 3.3 Hz, 1H,

gH-2 S); 3.49 (dd, J = 10.0 Hz and 3.5 Hz, 1H, gH-2 R); 3.24 (s, 3H,

OCH₃R); 3.20 (s, 3H, OCH₃S); 2.84−2.77 (m, 1H, CH-mcpm R);

2.62−2.56 (m, 1H, CH-mcpm S); 1.82 (s, 3H, Ac × 1); 1.81; 1.80;

1.79 (3s, 9H, Ac × 3); 1.74 (bs, 6H, Ac × 2); 1.10−1.08 (m, 6H,

CH₃-mcpm × 2); 0.78−0.60 (m, 2H, CH-mcpm R, CH-mcpm S);

0.34−0.27 (m, 2H, CH₂-mcpm R, CH₂-mcpm S); 0.25−0.14 (m, 4H,

CH₂-mcpm R, CH₂-mcpm S); −0.03−0.11 (m, 2H, CH₂-mcpm R,

CH₂-mcpm S); ¹³C NMR, C₆D₆, 100 MHz, δ 170.11 (2C, CO);

169.63 (2C, CO); 169.53 (CO); 169.46 (CO); 139.61 (2C), 139.52,

139.22, 139.16, 139.02 (6 × ipso C); 128.54−127.53 (Ar−C); 99.42

(mC-1 R); 99.32 (mC-1 S); 97.96 (gC-1 R); 97.46 (gC-1 S); 81.09

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(mC-3 R); 81.00 (mC-3 S); 80.93 (CH-mcpm S); 79.17 (CH-mcpm R);

76.92 (gC-2 R); 75.91 (mC-2 R); 75.88 (mC-2 S); 75.79 (2C, mC-4 R,

mC-4 S); 75.65 (OCH₂Ph); 75.13 (OCH₂Ph); 75.07 (OCH₂Ph); 73.25

(OCH₂Ph × 2); 72.53 (gC-3 R); 72.48 (gC-3 S); 72.27 (OCH₂Ph);

72.14 (2C, mC-5 R, mC-5 S); 69.52 (gC-4 R); 69.46 (gC-4 S); 68.04

(gC-5 R); 67.99 (gC-5 S); 67.89 (mC-6 R); 67.11 (mC-6 S); 62.38

(gC-6 R); 62.34 (gC-6 S); 54.60 (OCH₃); 54.56 (OCH₃); 21.11

(CH₃-mcpm R); 20.87 (CH₃-mcpm S); 20.64, 20.55, 20.43, 20.41,

20.33 (2C, 6 × OAc); 17.36 (CH-mcpm R); 16.91 (CH-mcpm S); 4.46,

3.90, 1.57, 1.26 (4 × CH₂-mcpm). ESI-HRMS: Calcd. for C₄₅H₆₀NO₁₄

[M + NH₄]⁺m/z 838.4008. Obsd. m/z 838.3996

gH-4S), 5.29−5.25 (m, 2H, CH₂× 2); 5.10 (d, J = 3.5 Hz, 1H, gH-

1R); 5.02−5.00 (m, 2H, CH₂ × 2); 4.90 (d, J = 3.5 Hz, 1H, gH-1S);

4.72 (dd, J = 4.4 and 12.3 Hz, 1H, gH-6_aR), 4.71 (dd, J = 4.8 Hz and

12.1 Hz, 1H, gH-6_aS); 4.51−4.39 (m, 6H, gH-5R, gH-5S, gH-6_bR, gH-

6_bS, rH-1R, rH-1S); 4.27 (dd, J = 13.2 Hz and 4.5 Hz, 2H, OCH₂-

CHCH₂× 2), 3.93−3.88 (m, 4H, rH-2R, OCH₂-CHCH₂× 2,

rH-2S); 3.80−3.69 (m, 4H, rH-3R, rH-3S, rH-4R, rH-4S), 3.54 (at, J =

10.2 Hz, 1H, gH-2R); 3.51 (at, J = 10.3 Hz, 1H, gH-2S); 3.28−3.14

(m, 2H, rH-5R, rH-5S); 2.83−277 (m, 1H, OCH-Me-cp R); 2.62−

2.55 (m, 1H, OCH-Me-cp S); 1.83 (bs, 12H, CH₃CO × 4); 1.77 (bs,

6H, CH₃CO × 2); 1.56 (bs, 6H, iso-CH₃× 2); 1.48 (d, J = 6.0 Hz, 3H,

rCH₃R); 1.41 (d, J = 6.2 Hz, 3H, rCH₃S); 1.20 (bs, 6H, iso-CH₃× 2);

1.10 (d, J = 6.1 Hz, 3H, CH₃-mcpm R); 0.95 (d, J = 6.1 Hz, 3H, CH₃-

mcpm S); 0.65−0.57 (m, 2H, CH-cp × 2); 0.33−0.14 (m, 5H, CH₂-

ring × 5); 0.10- −0.10 (m, 2H, CH₂-ring × 2); −0.16−0.22 (m,

1H, CH₂-ring). ¹³C NMR 100 MHz, C₆D₆, δ 170.22, 169.66, 169.60

(CO × 6); 134.75 (2C, CHCH₂× 2); 116.55, 116.52 (CH₂× 2);

110.30 (2C, iso-C × 2); 99.87 (gC-1R); 99.54 (gC-1S); 97.57 (2C,

rC-1R, rC-1S); 82.38, 82.35 (rC-4R, rC-4S); 82.28 (OCH-Me-cp S);

79.86 (OCH-Me-cp R); 78.55, 78.49 (rC-3R, rC-3S); 77.52, 75.67

(gC-2R, gC-2S); 74.89 (2C, rC-2 × 2); 72.97, 72.82 (gC-3R, gC-3S);

70.36, 70.29 (rC-5R, rC-5S); 69.34, 69.24 (OCH₂× 2); 68.18, 68.14

(gC-5R, gC-5S); 61.95, 61.91 (gC-6R, gC-6S); 27.73 (2C), 26.20 (2C)-

(isopropylidine CH₃× 4); 21.14 (CH₃−CH-cp R); 20.63 (CH₃CO);

20.54 (CH₃−CH-cp S); 20.41, 20.34 (CH₃CO);19.01 (rCH₃R); 18.80

(rCH₃S): 17.46, 17.01 (CH-ring × 2); 4.54, 3.84, 1.32, 1.25 (CH₂ring × 4).

ESI-HRMS: Calcd. for C₂₉H₄₈NO₁₃[M + NH₄]⁺m/z 618.3120. Obsd. m/z

618.3147.

Allyl (3,4,6-tri-O-Acetyl-2-O-(R,S-1-methyl 1′-Cyclopropylmethyl)-

β-^D-glucopyranosyl)-(1→4)-2,3-O-isopropylidene-α-L-rhamnopyra-

noside (11a-β). Colorless oil, ¹H NMR 400 MHz, C₆D₆, δ 5.88−5.78

(m, 2H, CH₂CH-CH₂O × 2); 5.38 (at, J = 9.2 Hz and 9.4 Hz, 1H,

H-3S); 5.31 (at, J = 9.2 Hz and 9.4 Hz, 1H, H-3R); 5.32−5.20 (m, 4H,

CH₂CH−CH₂O × 2, gH-4R, gH-4S); 5.05−5.02 (m, 2H, CH₂

CH−CH₂O × 2); 4.97 (d, J = 7.8 Hz, 1H, gH-1R); 4.92 (d, J = 7.8 Hz,

1H, gH-1S); 4.59 (d, J = 2.7 Hz, 1H, rH-1R); 4.56 (d, J = 2.7 Hz, 1H,

rH-1S); 4.32−4.13 (m, 8H, OCH₂-CHCH₂× 2, rH-3R, rH-3S, rH-

4R, rH-4S, gH-6_aR, gH-6_aS); 4.04−3.90 (m, 6H, OCH₂-CHCH₂× 2,

rH-2R, rH-2S, gH-6_bR, gH-6_bS); 3.67 (at, J = 9.4 Hz and 7.8 Hz, 1H,

gH-2S); 3.43−3.28 (m, 5H, gH-2R, rH-5R, rH-5S, CH-mcpm-R, CH-

mcpm-S); 3.21−3.17 (m, 2H, gH-5R, gH-5S); 1.81 (s, 3H, CMe₂S);

1.74 (s, 3H, CMe₂R); 1.70 (s, 3H, CMe₂S); 1.68 (s, 3H, CMe₂R);

1.49 (d, J = 6.2 Hz, 3H, rCH₃S); 1.48 (d, J = 6.2 Hz, 3H, rCH₃R);

1.30 (d, J = 6.0 Hz, 3H, CH₃-mcpm S); 1.11 (d, J = 6.0 Hz, 3H, CH₃-

mcpm R); 0.92−0.81 (m, 2H, CH-ring × 2); 0.58−0.52 (m, 2H, CH₂-

ring × 2); 0.47−0.38 (m, 1H, CH₂-ring × 1); 0.37−0.22 (m, 2H, CH₂-

ring × 2); 0.04−0.02 (m, 1H, CH₂-ring × 1). ¹³C NMR 100 MHz,

C₆D₆, δ 169.87 (2C), 169.43 (2C), 169.36 (2C)(6 × CO); 134.79

(2C, CH₂CH × 2); 116.46 (2C, CH₂CH × 2); 110.68 (2C,

OCOMe₂× 2); 101.63 (2C, gC-1R, gC-1S); 97.51, 97.42 (rC-1R, rC-

2S); 80.29 (CH₃-mcpm-S); 79.43, 79.25 (rC-3R, rC-3S); 79.00 (CH₃-

mcpm-R); 78.61 (2C, rC-4R, rC-4S); 77.50, 77.23 (gC-2R, gC-2S);

74.91, 74.62 (rC-2R, rC-2S); 71.83 (2C, gC-5R, gC-5S); 70.70 (2C,

rC-5R, rC-5S); 69.24 (2C, gC-6RS); 69.10 (2C, gC-4R, gC-4S); 61.89

(2C, CH₂−CHCH₂× 2); 21.48 (CH₃-mcpm R); 20.45 (2C), 20.24

(2C)(CMe₂× 4); 19.99 (CH₃-mcpm S); 19.53 (2C, rCH₃R, rCH₃S);

17.58, 16.96 (CH-ring × 2); 4.66, 3.41, 1.84, 0.68 (CH₂-ring × 4).

ESI-HRMS: Calcd. for C₂₉H₄₈NO₁₃[M + NH₄]⁺m/z 618.3120. Obsd.

m/z 618.3035.

Methyl (3,4,6-tri-O-Benzyl-2-O-(R,S-1-methyl 1′-Cyclopropyl-

methyl)-α-^D-glucopyranosyl)−(1→6)-2,3,4-tri-O-benzyl-α-D-manno-

1

pyranoside (10b-α). Colorless amorphous solid, H NMR 400Mz,

CDCl₃, δ 7.32−7.21 (m, Ar−H); 7.07−7.06 (m, Ar−H); 5.04 (d, 1H,

gH-1 R); 5.00−4.97 (m, 2H, gH-1 S, 1 × CH₂Ph); 4.92−4.88 (m, 3H,

3 × CH₂Ph); 4.80−4.54 (m, 16H, mH-1 R, mH-1 S, 14 × CH₂Ph);

4.43−4.38 (m, 4H, 4 × CH₂Ph); 3.89−3.52 (m, 24H, gH-2 R, gH-2 S,

gH-3 R, gH-3S, gH-4 R, gH-4 S, gH-5 R, gH-5 S, gH-6_abR, gH-6_abS,

mH-2 R, mH-2 S, mH-3 R, mH-3 S, mH-4 R, mH-4 S, mH-5 R, mH-5

S, mH-6_abR, mH-6_abS); 3.27 (s, 3H, OCH₃R); 3.26 (s, 3H, OCH₃S);

3.15−3.04 (m, 1H, CH-mcpm R); 2.98−2.92 (m, 1H, CH-mcpm S);

1.22−1.19 (m, 6H, CH₃-mcpm R, CH₃-mcpm S); 0.89−0.81 (m, 2H,

2 × CH₂); 0.52−0.42 (m, 2H, CH); 0.37−0.27 (m, 4H, CH); 0.07−

0.02 (m, 2H, CH). ¹³C NMR 100 MHz, CDCl₃, δ 138.18, 138.03,

137.73, 137.57, 137.39, 137.15 (ipso-C × 12), 127.34−126.31 (Ar−C);

97.95 (2C, mC-1R, mC-1S); 97.13 (gC-1R); 96.37 (gC-1S); 80.77,

80.63 (gC-3R, gC-3S); 79.54, 79.45, 79.39 (mC-3R, mC-3S, CH-

mcpm R); 77.79 (2C, gC-2R, CH-mcpm S); 76.84, 76.77 (gC-2S, mC-

4R, mC-4S); 74.46, 74.39, 74.32, 74.19, 74.02, 73.93, 73.87, 73.80,

73.75, 72.42, 71.73, 71.10, 70.58, 70.47 (12 × CH₂Ph, gC-4R, gC-4S,

mC-2R, mC-2S); 69.08 (mC-5R, mC-5S); 67.66 (mC-6R, mC-6S);

66.40, 65.72 (gC-6R, gC-6S); 53.81, 53.77 (OCH₃); 20.06, 19.83

(CH₃-mcpm); 16.23, 15.68 (CH); 3.88, 3.72 (CH₂); 0.37, 0.00 (CH₂).

MALDI-HRMS: Calcd. for C₆₀H₆₈NaO₁₁[M + Na]⁺m/z 987.4654.

Obsd. m/z 987.4689

Methyl (3,4,6-tri-O-benzyl-2-O-(R,S-1-methyl 1′-cyclopropyl-

methyl)-β-^D-glucopyranosyl)-(1→6)-2,3,4-tri-O-benzyl-α-D-manno-

1

pyranoside (10b-β). Colorless amorphous solid, H NMR 400 MHz,

CDCl₃, δ 7.36−7.26 (m, 56H, Ar−H); 7.16−7.14 (m, 4H, Ar−H);

5.08 (d, 1H, J = 11.1 Hz, 1 × CH₂Ph); 5.01 (d, 1H, J = 11.4 Hz, 1 ×

CH₂Ph); 4.93−4.91 (m, 2H, 2 × CH₂Ph); 4.82−4.73 (m, 4H, 4 ×

CH₂Ph); 4.72−4.70 (m, 7H, mH-1 R, mH-1 S, 5 × CH₂Ph); 4.62−

4.49 (m, 11H, 11 × CH₂Ph); 4.37 (d, 1H, J = 7.6 Hz, gH-1 R); 4.33

(d, 1H, J = 7.6 Hz, gH-1 S); 4.22−4.19 (m, 2H, mH-6_aR, mH-6_aS);

3.89−3.75 (m, 9H, gH-2 S, gH-4 R, gH-4 S, mH-3 R, mH-3 S, mH-2

R, mH-2 S, mH-5 R, mH-5 S); 3.71−3.67 (m, 6H, mH-6_bR, mH-6_bS,

gH-6_aR, gH-6_aS, gH-6_bR, gH-6_bS); 3.59−3.57 (m, 4H, gH-3 R, gH-3

S, mH-4 R, mH-4 S); 3.50−3.41 (m, 5H, gH-2 R, gH-5 R, gH-5 S, CH-

mcpm R, CH-mcpm S); 3.30, 3.29 (2s, 6H, 2 × OCH₃); 1.24 (d, 3H,

J = 6.4 Hz, CH₃-mcpm R); 1.18 (d, 3H, J = 6.2 Hz, 3H, CH₃-mcpm S);

1.01−0.79 (m, 2H, 2 × CH-mcpm); 0.56−0.27 (m, 6H, 6 × CH₂-

mcpm); 0.09−0.02 (m, 1H, 1 × CH₂-mcpm); −0.05- −0.12 (m, 1H,

1 × CH₂-mcpm). ¹³C NMR 100 MHz, CDCl₃, δ 138.94, 138.72,

138.52 (4C), 138.35 (2C), 138.26 (2C), 138.24 (2C) (12 × ipso-C);

128.30−127.36 (60 × Ar−C); 104.34, 104.26 (2 × gC-1); 98.92, 98.73

(2 × mC-1); 84.93, 84.81 (2 × gC-3); 80.21, 80.15 (2 × mC-3); 79.79,

79.65 (2 × CH-mcpm); 78.21 (gC-2 S); 78.14 (gC-2 R); 77.98 (2C,

2 × mC-4); 75.86 (2C), 75.66 (2C), 75.16 (2C, 6 × CH₂Ph); 74.98,

74.93 (2 × gC-4); 74.83 (2 × CH₂Ph); 74.78, 74.71 (2 × gC-5); 74.64

(2 × CH₂Ph); 73.47, 72.73 (2 × mC-2); 72.00 (2 × CH₂Ph); 71.45,

71.33 (2 × mC-5); 69.76 (2C, 2 × mC-6); 69.13, 69.08 (2 × gC-6);

54.75, 54.69 (2 × OCH₃); 21.34, 19.35 (2 × CH₃-mcpm); 17.36,

16.34 (2 × CH-mcpm); 5.53, 3.95, 1.70, 0.42 (4 × CH₂-mcpm).

MALDI-HRMS: Calcd. for C₆₀H₆₈NaO₁₁[M + Na]⁺m/z 987.4654.

Obsd. m/z 987.4693

Allyl (3,4,6-tri-O-Benzyl-2-O-(R,S-1-methyl 1′-Cyclopropylmeth-

yl)-β-^D-glucopyranosyl)-(1→4)-2,3-O-isopropylidene-α-L-rhamno-

1

pyranoside (11b-β). Colorless amorphous solid, H NMR 400 MHz,

C₆D₆, δ 7.42−7.37 (m, ArH); 7.31−7.29 (m, ArH); 7.20−7.05 (m,

ArH); 5.86−5.77 (m, 2H, OCH₂CHCH₂× 2); 5.30−5.26 (m, 2H,

OCH₂CHCH₂× 2); 5.19 (d, J = 11.5 Hz, 1H, CH₂Ph); 5.05−5.00

(m, 5H, gH-1 R, gH-1 S, CH₂Ph, OCH₂CHCH₂× 2); 4.88 (d, J =

11.5 Hz, 1H, CH₂Ph); 4.87 (d, J = 11.5 Hz, 1H, CH₂Ph); 4.84 (d, J =

11.5 Hz, 1H, CH₂Ph); 4.80 (d, J = 11.5 Hz, 1H, CH₂Ph); 4.60−4.57

(m, 4H, rH-1 R, rH-1 S, CH₂Ph × 2); 4.47−4.37 (m, 4H, CH₂Ph × 4);

4.36−4.26 (m, 5H, rH-3 R, rH-4 R, rH-4 S, OCH₂CHCH₂× 2);

Allyl (3,4,6-tri-O-Acetyl-2-O-(R,S-1-methyl 1′-Cyclopropylmethyl)-

α-^D-glucopyranosyl)-(1→4)-2,3-O-isopropylidene-α-L-rhamnopyra-

noside (11a-α). Colorless oil, ¹H NMR 400 MHz, C₆D₆, δ 5.85−5.76

(m, 4H, gH-3R, gH-3S, CH × 2), 5.55−5.48 (m, 2H, gH-4R,

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4.21 (at, J = 6.6 Hz and 6.4 Hz, 1H, rH-3 S); 4.06−4.01 (m, 2H, rH-2

R, rH-2 S); 3.97−3.90 (m, 3H, gH-6_aR, OCH₂CHCH₂× 2); 3.82−

3.73 (m, 2H, gH-3 R, gH-2 S); 3.67−3.55 (m, 9H, gH-4 S, gH-5 R,

gH-2 R, gH-3 S, gH-6_bR, gH-6_aS, gH-6_bS, CH-mcpm R, CH-mcpm

S); 3.45−3.37 (m, 4H, gH-4 R, gH-5 S, rH-5 R, rH-5 S); 1.58−1.55

(m, 12H, rCH₃R, rCH₃S, OCOMe₂× 2); 1.42 (d, J = 6.0 Hz, 3H,

CH₃-mcpm R); 1.31−1.28 (m, 9H, OCOMe₂× 2, CH₃-mcpm S);

1.01−0.87 (m, 2H, CH-ring × 2); 0.63−0.60 (m, 1H, CH₂-ring);

0.52−0.50 (m, 3H, CH₂-ring × 3); 0.41−0.35 (m, 2H, CH₂-ring × 2);

0.28−0.22 (m, 1H, CH₂-ring); 0.07−0.01 (m, 1H, CH₂-ring). ¹³C

NMR 100 MHz, C₆D₆, δ 139.92, 139.66, 139.35 (2C), 139.05

(2C)(ipso-C × 6); 134.84, 134.83 (OCH₂CHCH₂× 2); 128.53−

127.41 (Ar−C); 116.48, 116.41 (OCH₂CHCH₂× 2); 110.62,

110.61 (CMe₂× 2); 102.63 (gC-1 S); 102.14 (gC-1 R); 97.54 (rC-1

R); 97.47 (rC-1 S); 85.43, 85.18 (CH-mcpm × 2); 79.89 (gC-5 x1);

79.80, 79.72 (rC-3 × 2); 79.54 (gC-3 × 1); 79.23 (gC-5 × 1); 78.78,

78.40 (rC-4 × 2); 78.38 (2C, gC-2 × 2); 78.34 (2C, gC-3 × 1, gC-4 ×

1); 75.85 (CH₂Ph × 1); 75.71 (CH₂Ph × 1); 75.39 (gC-4 × 1); 74.98

(2C, rC-2 × 2); 74.77 (CH₂Ph × 1); 74.70 (CH₂Ph × 1); 73.50 (2C,

CH₂Ph × 2); 70.37 (2C, rC-5 × 2); 69.18 (2C), 69.14 (2C)(OCH₂×

2, gC-6 × 2); 27.54 (2C), 26.21, 26.17 (CMe₂× 4); 21.72 (CH₃-

mcpm); 19.91 (CH₃-mcpm); 19.68 (2C, rCH₃× 2); 17.87, 16.99

(CH-ring × 2); 5.45, 3.54, 1.82, 0.74 (CH₂-ring × 4). ESI-HRMS:

Calcd. for C₄₄H₆₀NO₁₀[M + NH₄]⁺m/z 762.4211. Obsd. m/z 762.4209.

Allyl (3,4,6-tri-O-Benzyl-2-O-(R,S-1-methyl 1′-Cyclopropylmeth-

yl)-α-^D-glucopyranosyl)-(1→4)-2,3-O-isopropylidene-α-L-rhamno-

4.65 (d, J = 12.8 Hz, 1H, PhCH₂); 4.55−4.54 (m, 2H, PhCH₂× 2);

4.52 (bs, 2H, PhCH₂× 2); 4.44−4.40 (m, 4H, PhCH₂× 4); 4.34−

4.17 (m, 4H, gH-6_aR, gH-6_aS, gH-5 R, gH-5 S); 4.14−4.06 (m, 2H,

mH-5 R, mH-5 S); 4.02−3.85 (m, 8H, mH-3 R, mH-3 S, mH-4 R,

mH-4 S, mH-6_abR, mH-6_abS); 3.81 (dd, J = 9.7 Hz and 3.5 Hz, 1H,

gH-2 S); 3.74 (bs, 2H, mH-2 R, mH-2 S); 3.66 (dd, J = 9.6 Hz and

3.5 Hz, 1H, gH-2R); 3.59−3.45 (m, 4H, gH-6_bR, gH-6_bS, gH-4 R,

gH-4 S); 3.17 (s, 3H, CH₃O R); 3.12−3.05 (m, 4H, CH₃O S, CH-

mcpm S); 2.84−2.78 (m, 1H, CH-mcpm R); 1.28−1.26 (m, 18H,

Me₃C × 6); 1.23−1.20 (m, 6H, CH₃-mcpm R, CH₃-mcpm S); 0.96−

0.74 (m, 2H, CH-ring × 2); 0.47−0.29 (m, 4H, CH₂-ring × 4); 0.27−

0.18 (m, 2H, CH₂-ring × 2); 0.09−0.03 (m, 1H, CH₂-ring × 1); 0.01−

0.05 (m, CH₂-ring × 1). ¹³C NMR 100 MHz, C₆D₆, δ 176.55 (2C,

CO × 2); 139.71, 139.63 (ipso-C-benzilidene × 2); 139.26 (2C), 139.23

(2C), 139.13, 138.32 (ipso-C- CH₂Ph × 6); 128.84−126.51 (Ar−C ×

40); 101.47 (2C, PhCH × 2); 99.50, 99.34 (mC-1 × 2); 99.03 (gC-1

R); 98.22 (gC-1 S); 81.08, 80.97 (mC-3 × 2); 80.71 (OCH-mcpm R);

80.69 (2C, gC-4 × 2); 78.07 (OCH-mcpm S); 77.39 (gC-2 R); 75.99,

75.96 (mC-2 × 2); 75.89 (gC-2 S); 75.73, 75.55 (mC-5 × 2); 75.17,

75.10 (OCH₂Ph × 2); 73.17, 73.12 (OCH₂Ph × 2); 72.50, 72.31

(mC-4 × 2); 72.20, 72.14 (OCH₂Ph × 2); 71.13, 71.08 (gC-3 × 2);

69.38, 69.33 (gC-6 × 2); 67.56, 66.52 (mC-6 × 2); 62.92, 62.87 (gC-5 ×

2); 54.65, 54.56 (OMe × 2); 38.98, 38.87 (CMe₃× 2); 27.46 (3C), 27.40

(3C)(CMe₃× 6); 21.06 (2C, CH₃-mcpm × 2); 17.35, 16.94 (CH-ring × 2);

4.86, 4.19, 1.37, 1.11 (CH₂-ring × 4). ESI-HRMS: Calcd. for C₅₁H₆₆NO₁₂

[M + NH₄]⁺m/z 884.4579. Obsd. m/z 884.4561.

1

pyranoside (11b-α). Colorless amorphous solid, H NMR 400 MHz,

Allyl (4,6-O-benzylidene-2-O-(R,S-1-methyl 1′-cyclopropylmeth-

yl)-3-O-pivaoyl-α-^D-glucopyranosyl)-(1→4)-2,3-O-isopropylidene-α-

L-rhamnopyranoside (13). Colorless oil, ¹H NMR 400 MHz, C₆D₆, δ

7.67−7.65 (m, 2H, ArH); 7.18−7.14 (m, 4H, ArH); 7.10−7.06 (m,

4H, ArH); 5.98 (at, J = 9.8 Hz and 9.6 Hz, 1H, gH-3 R); 5.97 (at, J =

9.6 Hz and 9.8 Hz, 1H, gH-3 S); 5.86−5.76 (m, 2H, OCH₂CHCH₂

× 2); 5.40 (s, 1H, PhCH); 5.38 (s, 1H, PhCH); 5.29 (d, J = 1.8 Hz,

1H, OCH₂CHCH₂); 5.24 (d, J = 1.7 Hz, 1H, OCH₂CHCH₂);

5.19 (d, J = 3.5 Hz, 1H, gH-1 R); 5.01 (bs, 1H, OCH₂CHCH₂);

4.99 (bs, 1H, OCH₂CHCH₂); 4.93 (d, J = 3.5 Hz, 1H, gH-1 S);

4.52 (d, J = 2.5 Hz, 1H, rH-1 R); 4.50 (d, J = 2.5 Hz, 1H, rH-1 S);

4.48−4.44 (m, 2H, gH-6_aR, gH-6_aS); 4.35−4.25 (m, 4H, gH-5 R, gH-

5 S, OCH₂CHCH₂× 2); 3.92−3.87 (m, 4H, OCH₂CHCH₂× 2,

rH-2 R, rH-2 S); 3.78 (dd, J = 10 Hz and 6.8 Hz, 1H, rH-4 R); 3.72−

3.58 (m, 7H, rH-4 S, gH-2 R, gH-2 S, gH-6_bR, gH-6_bS, rH-3 R, rH-3

S); 3.50 (at, J = 9.8 Hz, 1H, gH-4 R); 3.46 (at, J = 9.8 Hz, 1H, gH-4

S); 3.30−3.23 (m, 1H, rH-5 S); 3.22−3.10 (m, 2H, rH-5 R, OCH-

mcpm S); 2.89−2.82 (m, 1H, OCH-mcpm R); 1.53−1.52 (m, 3H,

rCH₃S); 1.43 (d, J = 6.2 Hz, 3H, rCH₃R); 1.27 (bs, 9H, CMe₃); 1.25

(bs, 9H, CMe₃); 1.21 (d, J = 6.2 Hz, 3H, CH₃-mcpm R); 1.06 (d, J =

6.1 Hz, 3H, CH₃-mcpm S); 0.75−0.61 (m, 2H, CH-ring × 2); 0.45−

0.16 (m, 7H, CH₂-ring × 7); −0.09−0.15 (m, 1H, CH₂-ring). ¹³C

NMR 100 MHz, C₆D₆, δ 176.76, 176.73 (2 × CO); 138.26, 138.22

(ipso-C₆H₅× 2); 134.84 (2C, OCH₂CHCH₂× 2); 128.89−127.48

(Ar−C); 116.45, 116.41 (OCH₂CHCH₂× 2); 110.13, 110.08

(CMe₂× 2); 101.59 (2C, PhCH × 2); 100.70 (gC-1 R); 100.10 (gC-1

S); 97.56, 97.55 (rC-1 R, rC-1 S); 82.58 (rC-4 R); 82.38 (rC-4 S);

82.02 (CH-mcpm R); 80.70 (2C, gC-4 R, gC-4 S); 78.46 (rC-3 R);

78.39 (CH-mcpm S); 77.96 (gC-2 R); gC-2 S); 76.00 (rC-3 S); 74.81

(2C, rC-2 R, rC-2 S); 71.52, 71.37 (gC-3 R, gC-3 S); 70.20, 70.13

(rC-5 R, rC-5 S); 69.53, 69.50 (gC-6 R, gC-6 S); 69.26, 69.24

(OCH₂CHCH₂× 2); 63.30, 63.20 (gC-5 R, gC-5 S); 38.96, 38.91

(CMe₃× 2); 27.69, 27.66 (OCOMe₂× 2); 27.43 (3C), 27.38

(3C)(CMe₃× 6); 26.19, 26.18 (OCOMe₂× 2); 21.33 (CH₃-mcpm

R); 20.45 (CH₃-mcpm S); 19.22, 18.93 (rCH₃R, rCH₃S); 17.37,

17.01 (CH-ring × 2); 4.86, 3.47, 1.25, 0.96 (CH₂-ring × 4). ESI-

HRMS: Calcd. for C₃₅H₅₄NO₁₁[M + NH₄]⁺m/z 664.3691. Obsd.

m/z 664.3666.

CDCl₃, δ 7.37−7.25 (m, 26H, Ar−H); 7.17−7.13 (m, 4H, Ar−H);

6.01−5.91 (m, 2H, OCH₂−CHCH₂× 2); 5.32 (d, J = 17.2 Hz, 1H,

OCH₂−CHCH₂× 1); 5.31 (d, J = 17.4 Hz, 1H, OCH₂−CHCH₂

× 1); 5.25 (d, J = 10.2 Hz, 1H, OCH₂−CHCH₂× 1); 5.24 (d, J =

10.3 Hz, 1H, OCH₂−CHCH₂× 1); 5.13 (d, J = 3.9 Hz, 1H, gH-1

R); 5.05 (d, J = 11.1 Hz, 2H, OCH₂Ph × 2); 5.00 (d, J = 3.7 Hz, 1H,

gH-1 S); 4.95 (d, J = 10.7 Hz, 1H, OCH₂Ph × 1); 4.87−4.80 (m, H,

OCH₂Ph × 6); 4.75−4.70 (m, 2H, rH-1 R, rH-1 S); 4.67−4.63 (m,

2H, OCH₂Ph × 2); 4.53−4.50 (m, H, OCH₂Ph × 1); 4.46−4.41 (m,

2H, OCH₂-CHCH₂× 2); 4.21−4.13 (m, 6H, OCH₂-CHCH₂×

2, rH-2 R, rH-2 S, rH-3 R, rH-3 S); 4.06−4.02 (m, 2H, gH-5 R, gH-5

S); 3.90−3.66 (m, 10H, gH-2 R, gH-2 S, g H-3 R, gH-3 S, gH-4 R, gH-

4 S, gH-6_aR, gH-6_aS, gH-6_bR, gH-6_bS); 3.57−3.45 (m, 4H, rH-4 R,

rH-4 S, rH-5 R, rH-5 S); 3.21−3.14 (m, 1H, CH-mcpm R); 3.12−3.06

(m, 1H, CH-mcpm S); 1.53, 1.52 (2bs, 6H, iso-CH₃× 2); 1.45 (d, J =

6.1 Hz, 3H, rCH₃R); 1.41 (d, J = 5.7 Hz, 3H, rCH₃S); 1.32, 1.31

(2bs, 6H, iso-CH₃× 2); 1.29−1.27 (m, 3H, CH₃-mcpm S); 1.23 (d,

3H, CH₃-mcpm R); 0.95−0.81 (m, 2H, CH-ring × 2); 0.62−0.52 (m,

2H, CH₂-ring × 2); 0.49−0.39 (m, 3H, CH₂-ring); 0.34−0.29 (m, 1H,

CH₂-ring × 1); 0.13−0.06 (m, 2H, CH₂-ring × 2). ¹³C NMR 100

MHz, CDCl₃, δ 139.06, 138.88 (2C), 138.36 (2C), 138.08 (ipso-C ×

6); 133.79 (2C, OCH₂-CHCH₂× 2); 128.35−127.32 (Ar−C);

118.24 (2C, OCH₂−CHCH₂× 2); 110.31 (2C, C(CH₃)₂× 2);

99.58 (gC-1 R); 99.02 (gC-1 S); 96.90 (2C, rC-1 R, rC-1 S); 82.04

(CH-mcpm); 80.85, 80.79 (rC-4 R, rC-4 S); 80.11 (CH-mcpm); 78.74

(2C, gC-2 R, gC-2 S); 78.45 (2C, rC-3 R, rC-3 S); 78.01 (2C, gC-3 R,

gC-3 S); 77.43 (2C, gC-4 R, gC-4 S); 75.53, 75.41, 75.08 (OCH₂Ph);

74.69 (2C, rC-2 R, rC-2 S); 73.56 (OCH₂Ph); 71.01, 70.92 (rC-5 R,

rC-5 S); 70.35 (2C, gC-5 R, gC-5 S); 70.16 (2C, OCH₂−CHCH₂×

2); 68.24, 68.14 (gC-6 R, gC-6 S); 27.95, 26.36 (C(CH₃)₂× 4); 21.19,

20.24 (2C, CH₃-mcpm R, CH₃-mcpm S); 18.24, 18.13 (rCH₃R, rCH₃

S); 17.17, 16.77 (CH-ring × 2); 5.14, 4.84, 1.02, 0.85 (CH₂-ring × 4).

ESI-HRMS: Calcd. for C₄₄H₆₀NO₁₀[M + NH₄]⁺m/z 762.4211.

Obsd. m/z 762.4209.

Methyl (4,6-O-Benzylidene-2-O-(R,S-1-methyl 1′-Cyclopropyl-

methyl)-3-O-pivaoyl-α-^D-glucopyranosyl)-(1→6)-2,3,4-tri-O-benzyl-

α-^D-mannopyranoside (12). colorless syrup, yield, 55%, ¹H NMR 400

MHz, C₆D₆, δ 7.63−7.61 (m,2H, Ar−H); 7.41−7.27 (m, 8H, Ar−H);

7.22−7.06 (m, 30H, Ar−H); 6.02−5.94 (m, 2H, gH-3R, gH-3S); 5.34

(s, 1H, PhCH₂R); 5.33 (s, 1H, PhCH₂S); 5.25 (d, J = 3.5 Hz, 1H,

gH-1R); 5.22 (d, J = 3.5 Hz, 1H, gH-1S); 5.08 (d, J = 11.7 Hz, 1H,

CH₂Ph); 5.04 (d, J = 11.9 Hz, 1H, CH₂Ph); 4.77 (d, J = 11.7 Hz, 1H,

CH₂Ph);4.69 (d, J=1.6 Hz, 1H, mH-1R); 4.68 (d, J = 1.7 Hz, 1H, mH-1S);

Phenyl 3,4,6-tri-O-acetyl-2-O-(R,S-1-methyl 1′-cyclopropylmeth-

yl)-1-thio-β-^D-glucopyranoside (7a-β). Colorless amorphous solid,

¹H NMR, CDCl₃, 400 MHz, δ 7.48 (m, 4H, ArH), 7.23 (m, 6H, ArH),

5.15 (m, 2H, H-3 R, H-3 S), 4.95 (m, 2H, H-4 R, H-4 S), 4.61 (d, J_1,2

=

9.8 Hz, 1H, H-1S), 4.55 (d, J_1,2=9.8 Hz, 1H, H-1 R), 4.27 - 4.02 (m,

4H, H-6_aR, H-6_aS, H-6_bR, H-6_bS), 3.79 (m, 1H, H-5 R), 3.69

3736

dx.doi.org/10.1021/jo202563f | J. Org. Chem. 2012, 77, 3724−3739

The Journal of Organic Chemistry

Article

(brt, J_2,3= 9.4 Hz, 1H, H-2 R), 3.61 (m, 1H, H-5 S), 3.48 (brt, J_2,3

=

OCH₂Ph × 4); 4.55−4.52 (m, 2H, OCH₂Ph × 2); 4.35 (d, J = 7.2 Hz,

gH-1); 4.21−4.19 (m, 1H, gH-6_a); 3.95−3.88 (m, 2H, gH-4, mH-3);

3.82−3.59 (m, 8H, mH-2, mH-4, mH-5, mH-6_a, mH-6_b, gH-2, gH-3,

gH-6_b); 3.49−3.46 (m, 1H, gH-5); 3.32 (s, 3H, OCH₃). ¹³C NMR,

CDCl₃, 100 MHz, δ 138.83, 138.40, 138.37, 138.20 (2C), 138.07

(ipso-C × 6); 128.36−127.52 (Ar−C); 103.48 (gC-1); 99.06 (mC-1);

84.41 (gC-2); 80.04 (mC-3); 77.32 (mC-4); 75.27 (gC-5); 75.09 (gC-

4); 75.02, 74.99 (OCH₂Ph × 7); 74.47 (mC-5); 74.41 (gC-3); 73.42

(2C), 72.85 (2C), 72.13 (OCH₂Ph × 5); 71.34 (mC-2); 68.90 (mC-

6); 68.23 (gC-6); 54.89 (OCH₃) ESI-HRMS: Calcd. for C₅₅H₆₄NO₁₁

[M + NH₄]⁺m/z 914.4474. Obsd. m/z 914.4469.

Allyl (3,4,6-tri-O-Benzyl-α-^D-glucopyranosyl)-(1→4)-α-L-rhamno-

pyranoside (16-α). Colorless oil, ¹H NMR, CDCl₃, 400 MHz, δ 7.33−

7.24 (m, Ar−H); 7.15−7.13 (m, Ar−H); 5.95−5.86 (m, 1H,

OCH₂CHCH₂); 5.27 (d, J = 17.4 Hz, 1H, OCH₂CHCH₂);

5.19 (d, J = 10.6 Hz, 1H, OCH₂CHCH₂); 4.98 (bs, 1H, gH-1); 4.86

(d, J = 11.1 Hz, OCH₂Ph × 1); 4.83 (m, 2H, OCH₂Ph × 2); 4.78 (d,

J = 11.5 Hz, 1H, OCH₂Ph × 1); 4.57 (d, J = 12.1 Hz, 1H, OCH₂Ph ×

1); 4.50−4.47 (m, 2H, OCH₂Ph × 2); 4.45 (s, 1H, rH-1); 4.37 (dd,

J = 12.7 and 4.9 Hz, 1H, OCH₂CHCH₂× 1); 4.12−4.07 (m, 2H,

OCH₂CHCH₂× 1, gH-5); 3.98 (bs, 1H, rH-2); 3.92 (bs, 1H, r−

OH); 3.74−3.60 (m, 4H, gH-2, gH-3, gH-6_a, gH-6_b); 3.54−3.43 (m,

3H, gH-4, rH-3, rH-4); 3.37−3.30 (m, 1H, rH-5); 2.51 (bs, 1H, r−

OH); 2.06 (bs,1H, g−OH); 1.38 (d, J = 6.0 Hz, 3H, r-CH₃). ¹³C

NMR, CDCl₃, 100 MHz, δ 138.30, 138.10, 138.0 (ipso-C); 133.66

(OCH₂-CHCH₂); 129.10−128.05 (Ar−C); 117.96 (CH₂CH−

OCH₂); 99.93 (gC-1); 98.51 (rC-1); 83.76 (rC-4); 82.68 (gC-3);

77.91 (rC-3); 75.50 (OCH₂Ph); 75.07 (OCH₂Ph); 73.77 (OCH₂Ph);

72.74 (gC-2); 72.49 (gC-4); 71.50 (gC-5); 71.24 (rC-2); 70.96 (rC-

5); 70.04 (OCH₂−CHCH₂); 68.77 (gC-6); 18.02 (rCH₃). ESI-

HRMS: Calcd. for C₃₆H₄₈NO₁₀[M + NH₄]⁺m/z 654.3272. Obsd. m/

z 654.3235.

Allyl (3,4,6-tri-O-Benzyl-β-^D-glucopyranosyl)-(1→4)-α-L-rhamno-

pyranoside (16-β). Colorless oil, ¹H NMR, CDCl₃, 400 MHz, δ 7.33−

7.23 (m, Ar−H); 7.19−7.17 (m, Ar−H); 5.93−5.84 (m, 1H, CH₂

CH-OCH₂); 5.26 (d, J = 17.2 Hz, 1H, CH₂CH−OCH₂); 5.18 (d,

J = 10.3 Hz, 1H, CH₂CH−OCH₂); 4.83 (m, 2H, OCH₂Ph × 2);

4.79 (d, J = 10.9 Hz, 1H, OCH₂Ph × 1); 4.57 (d, J = 12.1 Hz, 1H,

OCH₂Ph × 1); 4.56 (d, J = 10.9 Hz, 1H, OCH₂Ph × 1); 4.50 (d, J =

12.3 Hz, 1H, OCH₂Ph × 1); 4.46−4.45 (m, 2H, gH-1, rH-1); 4.38−

4.34 (m, 1H, OCH₂CHCH₂× 1); 4.10−4.06 (dd, J = 12.7 and 6.4

Hz, 1H, OCH₂CHCH₂× 1); 3.99 (d, J = 2.4 Hz, 1H, rH-2); 3.68−

3.67 (m, 2H, gH-6_a, gH-6_b); 3.62−3.59 (m, 2H, rH-3, gH-4); 3.55−

3.42 (m, 4H, gH-2, rH-4, gH-3, gH-5); 3.33−3.26 (m, 1H, rH-5); 1.41

(d, J = 6.0 Hz, 3H, rCH₃). ¹³C NMR, CDCl₃, 100 MHz, δ138.49,

138.10, 138.01 (ipso-C); 133.65 (OCH₂-CHCH₂); 128.56−127.57

(Ar−C); 117.97 (CH₂CH−OCH₂); 105.45 (gC-1); 98.24 (rC-1);

84.62 (rC-4); 84.51 (gC-3); 77.42 (rC-3); 75.19 (gC-5); 75.16 (gC-

2); 75.02 (OCH₂Ph); 74.90 (OCH₂Ph); 73.70 (gC-4); 73.44

(OCH₂Ph); 70.82 (rC-2); 70.78 (rC-5); 69.84 (OCH₂−CHCH₂);

68.72 (gC-6); 17.53 (rCH₃). ESI-HRMS: Calcd. for C₃₆H₄₈NO₁₀[M

+ NH₄]⁺m/z 654.3272. Obsd. m/z 654.3269.

9.4 Hz, 1H, H-2 S), 3.12 (m, 2H, CH-mcpm R, CH-mcpm S), 2.03−

1.95 (m, 18H, Ac-CH₃), 1.26 (d, J = 6.2 Hz, 3H, CH₃-mcpm R), 1.15

(d, J = 6.2 Hz, 3H, CH₃-mcpm S), 0.92 (m, 1H, CH-ring S), 0.60 (m,

1H,CH-ring R), 0.24 (m, 1H,CH₂-ring S), 0.22 (m, 1H, CH₂-ring R),

0.16 (m, 5H,CH₂-ring R,S), −0.01 (m, 1H, CH₂-ring S). ¹³C NMR,

CDCl₃, 100 MHz, δ170.6, 170.0, 169.81, 169.77 169.6 (CO, Ac),

133.6 (SPh_ip), 131.9, 131.8 (SPh_o), 128.9 (SPh_m), 127.7 (SPh_p), 88.5

(C-1 R, C-1 S), 81.5 (CH-mcpm S), 81.2 (CH-mcpm R), 75.7 - 75.3

(6C, C-2, C-4, C-5 (R,S)), 69.7 (C-3 S), 67.9 (C-3 R), 62.5 (C-6 S),

61.5 (C-6 R), 21.0 (MCPM-CH₃S), 20.8, 20.7, 20.6 (Ac-CH₃), 20.1

(MCPM-CH₃R), 17.1 (MCPM-CH S), 16.5 (MCPM-CH R), 5.3

(MCPM-CH₂R), 4.4 (MCPM-CH₃S), 1.9 (MCPM-CH₃S), 0.5

(MCPM-CH₂R). ESI-HRMS: Calcd. for C₂₃H₃₄NO₈S [M + NH₄]⁺

m/z 484.2005. Obsd. m/z 484.1996.

Phenyl 3,4,6-tri-O-Acetyl-2-O-(R,S-1-methyl 1′-Cyclopropylmeth-

yl)-1-thio-α-^D-glucopyranoside (7a-α). Colorless amorphous solid,

¹H NMR, CDCl₃, 400 MHz, δ 7.49 (m, 4H, ArH), 7.30 (m, 6H, ArH),

5.81 (d, J_1,2= 5.6 Hz, 1H, H-1 R), 5.75 (d, J_1,2= 5.6 Hz, 1H, H-1 S),

5.28 (m, 2H, H-3 R, H-3 S), 5.01 (m, 2H, H-4 R, H-4 S), 4.55 (m, 2H,

H-5 R,H-5 S), 4.29 (dd, J_5,6= 5.3 Hz, J_6,6′= 12.3 Hz, 2H, H-6 R, H-6

S), 4.08 (dd, J_2,3= 10.0 Hz, 1H, H-2 R), 4.02 (brd, 2H, H-6′ R, H-6′ S),

3.90 (dd, J_2,3= 10.0 Hz, 1H, H-2 S), 3.03 (m, 1H, MCPM-CHO R),

2.90 (m, 1H, MCPM-CHO S), 2.10−2.01 (18H, Ac-CH₃), 1.27 (d, J =

6.2 Hz, 3H, MCPM-CH₃R), 1.23 (d, J = 6.2 Hz, 3H, MCPM-CH₃S),

0.85 (m, 1H, MCPM-CH R), 0.57 (m, 1H, MCPM-CH S), 0.51, 0.47,

0.38, 0.33, 0.13 (m, 8H, MCPM-CH₂R, MCPM-CH₂S). ¹³C NMR,

CDCl₃, 100 MHz, δ 170.6, 170.0, 169.9 (CO, Ac), 133.7 (SPh_ip),

131.6 (SPh_o), 129.0 (SPh_m), 127.3 (SPh_p), 87.5 (C-1 R), 87.0 (C-1 S),

81.9 (MCPM-CHO S), 79.8 (MCPM-CHO R), 76.0 (C-2 S), 74.7 (C-

2 R), 72.4 (C-3 S), 72.3 (C-2 R), 68.8 (C-4 R, C-4 S), 68.0 (C-5 R, C-

5 S), 62.2 (C-6 R, C-6 S), 21.1 (MCPM-CH₃R), 20.78, 20.74, 20.69

(Ac-CH₃), 20.6 (MCPM-CH₃S), 17.1 (MCPM-CH S), 16.2 (MCPM-

CH R), 4.8 (MCPM-CH₂R), 4.3 (MCPM-CH₃S), 1.8 (MCPM-CH₃S),

1.0 (MCPM-CH₂R). ESI-HRMS: Calcd. for C₂₃H₃₄NO₈S [M + NH₄]⁺

m/z 484.2005. Obsd. m/z 484.2021.

4.8. General Procedure for the Removal of MCPM

Protection. To the ice cooled solution of the glycosylated compound

in DCM was added trifluoroacetic acid (10% by volume) under argon

atmosphere and the reaction was allowed to stir for 1.5 h. After

reaction completion, more DCM and sat. sodium bicarbonate solution

was added and stirred for 30 min. The solution was transferred to a

separating funnel and the organic layer was extracted with DCM. The

organic layer was dried with anhyd. sodium sulfate and concentrated to

give the crude product. The crude was column purified over silica gel

to afford the pure MCPM deprotected product.

Methyl (3,4,6-tri-O-Benzyl-α-^D-glucopyranosyl)-(1→6)-2,3,4-tri-

O-benzyl-α-^D-mannopyranoside (15-α). Colorless oil, ¹H NMR,

CDCl₃, 400 MHz, δ 7.37−7.22 (m, Ar−H); 7.15−7.13 (m, Ar−H);

4.99 (bs, 1H, gH-1); 4.96 (d, J = 11.1 Hz, 1H, OCH₂Ph × 1); 4.90 (d,

J = 11.4 Hz, 1H, OCH₂Ph × 1); 4.83 (d, J = 10.5 Hz, 1H, OCH₂Ph × 1);

4.71−4.68 (m, 4H, mH-1, OCH₂Ph × 3); 4.62−4.58 (m, 4H,

OCH₂Ph × 4); 4.47 (d, J = 11.4 Hz, 2H, OCH₂Ph × 2); 4.08−4.01

(m, 2H, mH-4, gH-6_a); 3.89 (dd, J = 9.4 and 7 Hz, 1H, mH-3); 3.79−

3.77 (m, 2H, mH-2, gH-5); 3.71−3.57 (m, 7H, gH-2, gH-3, gH-4, gH-

6b, mH-5, mH-6_a, mH-6_b); 3.28 (s, 3H, OCH₃). ¹³C NMR, CDCl₃,

100 MHz, δ 138.93, 138.51, 138.38 (2C); 138.01 (2C)(ipso-C × 6);

128.38−127.43 (Ar−C); 100.61 (gC-1); 98.94 (mC-1); 83.38 (gC-3);

79.92 (mC-3); 77.26 (gC-4); 75.16 (OCH₂Ph); 75.08 (OCH₂Ph);

74.96 (OCH₂Ph); 74.32 (gC-5); 74.18 (mC-4); 73.80 (mC-2); 73.44

(OCH₂Ph); 72.81 (OCH₂Ph); 72.07 (OCH₂Ph); 71.33 (mC-5);

70.69 (gC-2); 68.53 (mC-6); 67.78 (gC-6); 54.90 (OCH₃). ESI-HRMS:

Calcd. for C₅₅H₆₄NO₁₁[M + NH₄]⁺m/z 914.4474. Obsd. m/z 914.4472.

Methyl (3,4,6-tri-O-Benzyl-β-^D-glucopyranosyl)-(1→6)-2,3,4-tri-O-

benzyl-α-^D-mannopyranoside (15-β). Colorless oil, ¹H NMR,

CDCl₃, 400 MHz, δ 7.40−7.25 (m, 29H, Ar−H); 7.18−7.16 (m,

1H, Ar−H); 4.99 (d, J = 11.1 Hz, 1H, OCH₂Ph × 1); 4.94 (d, J =

10.9 Hz, 1H, OCH₂Ph × 1); 4.85 (d, J = 10.7 Hz, 1H, OCH₂Ph × 1);

4.76 (d, J = 12.5 Hz, 1H, OCH₂Ph × 1); 4.71 (d, J = 1.8 Hz, 1H, mH-

1); 4.70 (d, J = 12.5 Hz, 1H, OCH₂Ph × 1); 4.65−4.60 (m, 4H,

ASSOCIATED CONTENT

* Supporting Information

NMR spectra and computational details. This material is

available free of charge via the Internet at http://pubs.acs.org.

■

S

AUTHOR INFORMATION

Corresponding Author

*E-mail: dennis.whitfield@nrc-cnrc.gc.ca.

■

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS

■

We gratefully acknowledge the help of the NRC computer

support group and the Mass Spectral group. This is NRC

publication #50014.

3737

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The Journal of Organic Chemistry

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Could diastereoselectivity in the presence of O-2 chiral nonparticipating groups be an indicator of glycopyranosyl oxacarbenium ions in glycosylation reactions?

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