Influence of Configuration at the 4- And 6-Positions on the Conformation and Anomeric Reactivity and Selectivity of 7-Deoxyheptopyranosyl Donors: Discovery of a Highly Equatorially Selective l - glycero- d - gluco-Heptopyranosyl Donor

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Inﬂuence of Conﬁguration at the 4- and 6‑Positions on the

Conformation and Anomeric Reactivity and Selectivity of

7

‑Deoxyheptopyranosyl Donors: Discovery of a Highly Equatorially

Selective L -glycero -D -gluco -Heptopyranosyl Donor

Kapil Upadhyaya, Rahul S. Bagul, and David Crich*

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sı Supporting Information

ABSTRACT: The preparation of four per-O-benzyl-D- or L-

glycero-D-galacto and D- or L-glycero-D-gluco heptopyranosyl

sulfoxides and the inﬂuence of their side-chain conformations on

reactivity and stereoselectivity in glycosylation reactions are

described. The side-chain conformation in these donors is

determined by the relative conﬁguration of its point of attachment

to the pyranoside ring and the two ﬂanking centers in agreement

with a recent model. In the D- and L-glycero-D-galacto glycosyl donors, the D-glycero-D-galacto isomer with the more electron-

withdrawing trans,gauche conformation of its side chain was the more equatorially selective isomer. In the D- and L-glycero-D-gluco

glycosyl donors, the L-glycero-D-gluco isomer with the least disarming gauche,gauche side-chain conformation was the most

equatorially selective donor. Variable temperature NMR studies, while supporting the formation of intermediate glycosyl triﬂates at

−

80 °C in all cases, were inconclusive owing to a change in the decomposition mechanism with the change in conﬁguration. It is

suggested that the equatorial selectivity of the L-glycero-D-gluco isomer arises from H-bonding between the glycosyl acceptor and O6

of the donor, which is poised to deliver the acceptor antiperiplanar to the glycosyl triﬂate, resulting in a high degree of S 2 character

N

in the displacement reaction.

INTRODUCTION

We deﬁne the three staggered conformations of the

exocyclic bond to the side chain (hereinafter the side-chain

conformation) as being either gauche,gauche (gg), gauche,trans

(gt), or trans,gauche (tg) (Figures 1 and 2), where the ﬁrst

and second terms refer to the position of the C6−O6 bond

■

Oligosaccharides are important structural motifs in many

biological systems and are involved in a vast array of

1

biological processes, and consequently, the construction of

glycosidic bonds in an eﬃcient and stereocontrolled manner

is of great interest and importance to glycobiology. Most

12−14

2

relative to C5−O5 and C5−C4 bonds, respectively.

As

ﬁrst determined by Marchessault and Perez on the basis of

glycosylation reactions, however, occur at the boundary

between S 1 and S 2 processes, which makes stereoselective

15

analysis of crystal structure databases and subsequently by

many groups using NMR spectroscopy, conformationally

mobile glucopyranosides can typically be considered as an

∼50:50 equilibrating mixture of gg and gt conformers, while

the isomeric galactopyranosides can populate an ∼15:55:30

N

glycosylation a complex and sometimes unpredictable task,

necessitating further study of the numerous factors aﬀecting

3

selectivity.

In recent years, it has become increasingly apparent that

the conformation of the side chain of glycosyl donors

contributes signiﬁcantly to their reactivity and selectivity, with

the initial ground rules determined using conformationally

12−14,16

gg/gt/tg mixture (Figure 2).

Our studies with the 5- and/or 7-epi-sialic acid and Kdo

series (Figure 1) revealed that the conformational space

available to the side chains of higher carbon sugars (here

deﬁned as those with a longer side chain than the

hydroxymethyl group of typical hexopyranosides) is signiﬁ-

4

−6

locked bicyclic donors.

More recently, we have demon-

strated by the study of a series of sialic acid and Kdo donors

isomeric at the 5- and/or 7-positions that side-chain

conformation also contributes to reactivity and selectivity in

7

−10

Received: June 29, 2021

monocyclic donors (Figure 1).

Finally, recent studies

have highlighted the role of side-chain conformation in glycan

recognition and as a contributing factor to catalysis by the

glycosyl hydrolases, glycosyltransferases, transglycosidases,

and glycoside phosphorylases during enzymatic cleavage and

11

the formation of glycosidic bonds.

©

XXXX American Chemical Society

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A

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Figure 1. Predominant side-chain conformation of glycosyl donors in the neuraminic acid and ulosonic series and their relative conﬁgurations

from C5 −C7, as depicted on Fischer projection formulas of the parent sugar.

center at the point of attachment of the side chain to the

pyranose ring and by the two ﬂanking centers, that is, by a

simple stereotriad comprising C5, C6, and C7 in the sialic

17

acids. On this basis and comparison with the solution- and

crystal-phase conformations of the four pentitol sugars, we

devised a simple model whereby the arabino conﬁguration of

the three centers in question leads to the predominant tg

conformation of the side chain, while the lyxo conﬁguration

results in the predominant population of the gg conformation.

The ribo and xylo conﬁgurations, on the other hand, result in

the predominant population of the two gt conformations

17

(

Figure 1).

In spite of the patterns evident in our studies on the

inﬂuence of conﬁguration and conformation of sialic acid side

chains on reactivity and selectivity at the anomeric center,

comparisons were marred to some extent by the diﬀerent

protecting groups employed, which in turn was a function of

the complex synthesis required to access the donors in some

series. Seeking to generalize the models and standardize them

to other higher carbon sugars, we set out to construct and

analyze a series of four 7-deoxyheptopyranosyl donors

diﬀering in conﬁgurations at the 4- and 6-positions, that is,

Figure 2. Staggered conformation of the hexopyranose side chain

illustrated for D-glucose and D-galactose and their relative

populations in free solution.

cantly restricted by the presence of the extra C−C bond that

extends the side chain and that the predominant

conformation of these higher carbon sugar side chains is

controlled by the relative conﬁgurations of the stereogenic

Figure 3. D- and L-glycero-D-gluco and D- and L-glycero-D-galacto heptopyranoses and the predicted conformations of their exocyclic bonds.

B

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comprising the arabino, lyxo, ribo, and xylo conﬁgurations of

the three contiguous stereogenic centers thought to control

side-chain conformation, and all carrying the same suite of

protecting groups. We report here on the synthesis and

conformational analysis of this series of four such donors

Scheme 1. Synthesis of 7-Deoxy-D-glycero-D-

galactoheptopyranose and 7-Deoxy-L-glycero-D-

galactoheptopyranose Donors 9 and 12

(

Figure 3) and conﬁrm the predictions of side-chain

conformation from our model. Based on a comparative

study of the same four donors with a standard series of

acceptor alcohols, we determine that the D-glycero-D-galacto

and L-glycero-D-galacto donors conform to expectation with

the former isomer having the tg conformation of its side

chain being more equatorially selective than the latter with its

gt side-chain conformation. Unexpectedly, however, the

model fails with regard to selectivity in the D- and L-

glycero-D-gluco series where the L-glycero-D-gluco-conﬁgured

donors exhibit unanticipatedly high equatorial selectivity

despite the gg conformation of its side chain. This unexpected

and novel selectivity, which reveals the pitfalls in extrap-

olation from one series (Figure 1) of donors to another

(Figure 3), appears to arise from donor−acceptor hydrogen

bonding involving the benzyl ether at the 6-position of the L-

glycero-D-gluco conﬁgured donor and potentially opens the

way for the design of further series of selective glycosyl

donors.

RESULTS AND DISCUSSION

■

Donor Synthesis. Intermediate 6 was obtained from

penta-O-acetyl-β-D-galactopyranose by the literature proto-

1

8

col.

Dess−Martin periodinane oxidation to give the

corresponding aldehyde followed by treatment with MeMgBr

at −78 °C gave a complex reaction mixture from which only

1

6% of the desired product could be isolated. In contrast,

reaction with the less basic methylcerium reagent, derived by

19

reaction of MeMgBr with cerium chloride, aﬀorded the

required C-6-methyl-substituted compound 7 in 71% yield

and as a 11:1 mixture of diastereomers. After protection of

the so-formed alcohol as the benzyl ether 8 in 89% yield,

oxidation with mCPBA aﬀorded the corresponding sulfoxide

additions in going from the galactose to the glucose series

(Schemes 1 and 2) is consistent with literature observations

and the changes from a chelation model involving O4 in the

galactose series to the one invoking the ring oxygen in the

21,22

(9) as a mixture of two stereoisomers in 81% yield. The

glucose series.

donor 12, epimeric with 9 at the 6-postion, was obtained

from 7 by Dess−Martin oxidation followed by sodium

borohydride reduction, giving 10 in 90% yield as a 1:22

mixture of isomers. Subsequent benzylation and mCPBA

oxidation then aﬀorded the sulfoxide 12 in 79% yield as a

mixture of isomers (Scheme 1).

Side-Chain Conformation. Side-chain conformations

were determined at the level of the 6-hydroxy thioglycosides

before ﬁnal benzylation and conversion to the ultimate

sulfoxides, because of the less complex nature of the NMR

spectra, by a combination of coupling constant analysis and

NOE measurements (Figure 4). Thus, the D-glycero-D-galacto

3

The D-glycero-D-gluco- and L-glycero-D-gluco-conﬁgured

donors were obtained analogously from 13, which was

system 7 displayed a

JH5,H6 of 8.0 Hz and an NOE

interaction between H

and the terminal methyl group

5

20

obtained by the literature protocol. Thus, oxidation of 13

employing the Dess−Martin periodinane followed by

immediate treatment with methyl magnesium chloride in

THF furnished the C6-methyl-substituted products 14 and

consistent with the very predominant population of the tg

conformation. The L-glycero-D-galacto thioglycoside 10, on the

3

other hand, had a JH5,H6 of 7.5 Hz and an NOE interaction

between H

gt conformation. In the D-gluco series, the D-glycero isomer 15

had an NOE interaction between the methyl group and H

and the methyl group, indicative of a dominant

4

1

5 in a 3:1 ratio. Protection of the remaining hydroxyl group

as the benzyl ether resulted in the thiogycosides 16 and 18,

which were subjected to standard mCPBA oxidation

conditions to aﬀord sulfoxides 17 and 19 in good yield

4

3

and a JH5,H6 of 3.9 Hz consistent with the gt conformation,

while the L-glycero isomer 14 had an NOE interaction

3

(

Scheme 2).

between the methyl group and H

5

and a JH5,H6 of 1.6 Hz

The conﬁguration at C6 of the donors 9 , 12 , 17 , and 19

indicative of the gg conformation. While the magnitudes of

3

was assigned as described in Supporting Information by

conversion to a set of rigid bicyclic congeners carrying the

JH5,H6 in 7 and 10 at ﬁrst sight appear small for a pair of

antiperiplanar vicinal hydrogens on the side chain of a

hexopyranoside, after correction for the presence of the

additional C−C bond, they are consistent with literature

4

,6-O-benzylidene protecting group (Schemes S1 and S2 )

3

and analysis of their NOE and ROE spectra, and J

H5,H6

2

3,24

coupling constants, in the usual manner (Figures S1 and S2).

The reversal of stereoselectivity observed in the Grignard

values derived from rigid bicyclic systems.

Similarly, the

3

discrepancy between the two J_H₅_,_H₆coupling constants

C

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Scheme 2. Synthesis of 7-Deoxy-L-glycero-D-

glucoheptopyranose (17) and 7-Deoxy-D-glycero-D-

glucoheptopyranose (19) Donors

The assignment of a predominant tg conformation to the

side chain of the D-glycero-D-galacto donor 7 is consistent with

the tg side-chain conformation of the pseudoenantiomeric

sialic acid donors 4 and 5, while the predominant gt

conformation assigned to the side chain of its L-glycero-D-

galacto isomer 10 is consistent with that of the

pseudoenantiomeric sialic acid donor 2. Similarly, the

assignments of the gg conformation to the side chain of the

L-glycero-D-gluco isomer 14 and of the gt conformation to the

side chain of the D-glycero-D-gluco donor 15 are consistent

with those of the pseudoenantiomeric sialic acids 1 and 3,

respectively, that is, the predictions of side-chain conforma-

tions based on the analysis of the relative conﬁgurations of

the C4−C6 stereotriad presented in Figure 3 are fully borne

out. It follows that the diﬀering side-chain conformations in

the sialic acids 1−5 are predominantly determined by the

relative conﬁgurations of the C5−C7 stereotriads and not by

the diﬀerences in alcohol protecting (acetyl vs benzoyl) nor

by the diﬀerences in electronegative group at the 5 and 7-

positions (esters, amides, and azides).

Glycosylation. Glycosylation reactions were carried out

by activating sulfoxides 9, 12, 17, and 19 with triﬂic

anhydride in the presence of the hindered non-nucleophilic

base TTBP at −78 °C in 0.20 M CH Cl followed by the

2

addition of 1.1 equiv of acceptor alcohols in the form of 0.5

M solutions in dichloromethane, giving rise to the coupled

25

products in good yield, as presented in Tables 1 and 2.

The anomeric conﬁguration of the various glycosides

3

obtained was assigned based on the J coupling constant

1

,2

in the usual manner, with that for the equatorial isomers

found in the range of 7.6−7.8 Hz, as compared to the 3.7−

3

.9 Hz of the axial anomers.

In the galactose-derived series, the D-glycero-D-galacto-

conﬁgured donor 9 with its predominant tg side-chain

conformation showed excellent selectivity for the formation

of the equatorial glycoside with simple primary, secondary,

and tertiary alcohols (Table 1, entries 1−3), modest

equatorial selectivity with primary carbohydrate acceptors

(

Table 1, entries 4 and 5), modest to poor equatorial

selectivity with two secondary carbohydrate acceptors (Table

, entries 6 and 7), and ﬁnally modest axial selectivity with

1

diacetone-D-glucose as the acceptor (Table 1, entry 8). With

epimeric L-glycero-D-galacto-conﬁgured donor 12, with the

predominant gt side-chain conformation, the analogous trend

in selectivities was seen with the same series of acceptors;

however, the overall equatorial selectivity was generally lower

than that seen with 9, and the switch over from equatorial to

axial selectivity began with the glucopyranose 4-OH acceptor

(

Table 1, entry 7) and was much more pronounced with the

glucofuranose 3-OH acceptor (Table 1, entry 8). This pattern

is consistent with equatorial selectivity being promoted, to a

greater extent, in a donor with the tg conformation of the

side chain than with the more arming gt conformation and

matches that seen in the sialic acid series. The fall-oﬀ in

equatorial selectivity with decreased nucleophilicity of the

acceptor alcohols is consistent with the patterns observed by

Figure 4. Assigned side-chain conformations with diagnostic data.

between pairs of gauche protons spanning a hexopyranoside

side chain is consistent with the presence and location of the

addition C−C bond as determined with rigid bicyclic

26

Codee and others in the hexopyranoside series of donors.

́

2

3

models. No signiﬁcant diﬀerences in the J

coupling

Turning to the glucose-derived series, we were surprised to

discover that the L-glycero-D-gluco-conﬁgured donor 17, with

the predominant gg conformation of its side chain, was highly

equatorially selective in its couplings with simple alcohols and

with a primary carbohydrate acceptor (Table 2, entries 1−3).

Signiﬁcant equatorial selectivity was maintained with two

H5,H6

constants of the subsequent members of each series were

observed, indicating that neither benzylation of O6 nor

conversion of the thioglycosides to the corresponding

sulfoxides resulted in an appreciable change in side-chain

conformation.

D

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a

Table 1. Glycosylation Reactions with D-glycero-D-galacto Donor 9 and L-glycero-D-galacto Donor 12

a

b

c

All reactions were carried out at −78 °C with activation by Tf O/TTBP. The donor to acceptor ratio is 1.0:1.1. Isolated yield. Anomeric ratios

2

1

were determined by integration of the H NMR spectra of the crude reaction mixtures.

E

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a

Table 2. Glycosylation Reactions with L-glycero-D-gluco Donor 17 and D-glycero-D-gluco Donor 19

a

b

c

All reactions were carried out at −78 °C with activation by Tf O/TTBP. The donor to acceptor ratio is 1.0:1.1. Isolated yield. Anomeric ratios

2

1

were determined by integration of the H NMR spectra of the crude reaction mixtures.

secondary carbohydrate acceptors (Table 2, entries 4 and 5),

whereas poor equatorial selectivity was observed with the

glucofuranose 3-OH acceptor (Table 2, entry 6). On the

other hand, the D-glycero-D-gluco donor 19, with the

predominant gt conformation of its side chain, showed little

to no selectivity with the two simple alcohols and a primary

carbohydrate-based acceptor (Table 2, entries 1−3) and

accordingly was not pursued further.

Overall, the relationships between relative conﬁguration,

side-chain conformation, and anomeric selectivity in the

series of isomeric donors 9, 12, 17, and 19 studied here are

consistent with the patterns established previously in the

sialic acid series (Figure 1), with the one major exception of

the highly equatorially selective 17. Thus, the exocyclic bonds

of the D-glycero-D-galacto donor 9 and the pseudaminic acid

and Kdo donors 4 and 5 all have the arabino conﬁguration of

the branch point and its two ﬂanking centers, the tg

conformation of the side chain and, with the exception of

17, the highest equatorial selectivity. The L-glycero-D-galacto

donor 12 has the xylo conﬁguration of the same three

stereogenic centers as does the 5-epi-neuraminic acid donor

2, similarly adopts the gt conformation of the side chain, and

has somewhat reduced anomeric selectivity. The D-glycero-D-

gluco-conﬁgured donor 19, like the 7-epi-neuraminic acid

donor 3, has the ribo conﬁguration of the three stereogenic

centers that control side-chain conformation and also shares

the gt conformation of the side chain and modest anomeric

selectivity in its glycosylation reactions. The exception to the

overall trend of conﬁguration, conformation, and selectivity

seen with the sialic acids and the simpliﬁed models studied

F

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1

Figure 5. H NMR spectra of donor 9 (a) at −80 °C prior to the addition of Tf O; the anomeric proton appears at δ 3.80 and (b) after the

2

3

addition of Tf O and warming to −50 °C; the anomeric proton of the glycosyl triﬂate appears at 6.19 as a doublet ( J = 3.82 Hz).

2

1,2

here is the L-glycero-D-gluco-conﬁgured donor 17: like the

neuraminic acid donor 1, it has the lyxo conﬁguration of the

three key stereogenic centers and the anticipated gg

conformation of its side chain, but contrary to our initial

expectations based on the selectivity observed with 1 and

analogous systems, it displays the highest equatorial

selectivity among the isomeric donors studied here.

10 °C increments resulted in decomposition of the glycosyl

triﬂate intermediate between −20 and −10 °C, at which

point analysis of the reaction mixture by electrospray mass

spectrometry revealed the presence of one predominant

+

product with m/z = 559 [M + Na ], which we attribute to

the glycal (54). Unfortunately, all attempts to isolate 54

failed but aﬀorded instead the 1,1′-disaccharides 56 and 57 in

43% yield as a mixture of two isomers (α/β, 1:1.5), which

nevertheless supports the formation of glycal 54 as the

immediate decomposition product from 9.

Low-Temperature NMR Studies. In an attempt to

understand the unexpected selectivity of donor 17, we turned

to the use of variable temperature NMR spectroscopy to

probe the nature of the activated donors and their relative

In the case of the L-glycero-D-galacto donor 12, a diﬀerent

pattern of reactivity was observed (Figure 6). A glycosyl

triﬂate (58) was clearly formed at −80 °C, characterized by

2

7

stabilities. Accordingly, the four donors 9, 12, 17, and 19

were activated at −80 °C in deuteriodichloromethane

1

13

19

3

solution in the presence of TTBP by the addition of Tf O,

H, C, and F chemical shifts of δ 6.26 (d, J1,2 = 3.41 Hz),

2

1

13

and H and C NMR spectra were recorded at −80 °C. The

temperature of the NMR probe was then increased in 10 °C

increments, with H NMR spectra recorded at each step,

109.0, and −76.21 for the anomeric proton, carbon, and

triﬂate resonances, respectively, but decomposition was

almost complete by −70 °C when only traces of the glycosyl

triﬂate remained and the 1,6-anhydro derivative 59 was

observed as the major product. Subsequent isolation aﬀorded

59 in 53% yield.

1

until −10 °C (Supporting Information, Pages S153, S161,

S171, S179 ). Finally, decomposition products were isolated

and characterized in each case.

Starting with the D-glycero-D-galacto donor 9, conversion

Analogous study of the NMR study of the L-glycero-D-gluco

donor 17 showed the clean formation of an axial glycosyl

triﬂate (60) by −60 °C, with characteristic resonances at δ

into the corresponding glycosyl triﬂate (53) began at −80 °C

1

but was not complete until −50 °C when a clean H NMR

3

1

spectrum was observed (Figure 5). The anomeric proton of

6.15 (d, J = 3.14 Hz), δ 107.5, and δ −76.18 in the H,

1

,2

3

13

19

this glycosyl triﬂate appears at δ 6.19 as a doublet ( J

=

C, and F NMR spectra (Figure 7b). On gradual warming,

1

,2

3

1

.82 Hz), whereas the corresponding carbon resonated at δ

this glycosyl triﬂate decomposed around −40 °C with the

formation of the 1,6-anhydro sugar 61, which was isolated in

43% yield.

Finally, the D-glycero-D-gluco donor 19 was observed to

cleanly form a glycosyl triﬂate (62) by −60 °C as indicated

19

07.7. A peak was observed at δ −76.19 in the F NMR

1

13

19

spectrum (SI). These H, C, and F chemical shifts are

fully consistent with the very predominant formation of a

covalent axial glycosyl triﬂate. Warming the NMR probe by

27

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1

Figure 6. H NMR spectra of donor 12 (a) at −80 °C prior to the addition of Tf O; the anomeric proton appears at δ 4.43 ppm and (b) after

2

3

the addition of Tf O and warming to −70 °C; the anomeric proton of the residual triﬂate appears at δ 6.26 ppm as a doublet ( J = 3.41 Hz).

2

1,2

by the anomeric proton that resonated at δ 6.16 (d, ³J₁_,₂

=

group and the pseudoequatorial benzyloxy group at the 4-

position in either of the proposed transition states for ring

closure. The evidently more facile closure of the L-glycero-D-

galacto triﬂate to the corresponding 1,6-anhydrogalactose

derivative 59 also appears to be the result of steric

interactions between the terminal methyl group and the

benzyloxy group at the 6-position and the pseudoequatorial

benzyloxy group at the 4-position, which, in this case,

3

.08 Hz), the anomeric carbon at δ 107.1, and the glycosyl

1

13

19

triﬂate CF resonance at δ −75.27 in the H, C, and

F

3

NMR spectra, respectively (Figure 8b). On warming,

decomposition of this triﬂate began around −40 °C and

was complete by −30 °C and aﬀorded primarily the 1,6-

anhydro sugar 63 (Figure 9) which could be isolated in 29%

yield.

2

,5

Overall, all four donors aﬀorded an axial glycosyl triﬂate on

activation with triﬂic anhydride, but the decomposition

temperatures of these triﬂates varied considerably. Three of

the four glycosyl triﬂates decomposed preferentially to give

favorably orient the side for ring closure in both the B and

4

H₃conformers. Any favorable or unfavorable steric

interactions between the side chain and the benzyloxy

group at the 4-position are alleviated in the D- and L-

glycero-D-gluco triﬂates, leading to the formation of the 6-endo

methyl-1,6-anhydroglucose derivative because of the pseu-

doaxial nature of the substituent at the 4-position. 1,6-

Anhydroglucose derivatives substituted at the 6-endo-position

1

,6-anhydro sugars, whereas the fourth underwent apparent

elimination to give a glycal, which in turn underwent partial

hydration and coupling on attempted isolation. The

formation of 1,6-anhydro sugars, side products in many

glycosylation reactions, is best explained by intramolecular

attack of the side-chain benzyl ether on the glycosyl triﬂate

through an exploded transition state with signiﬁcant

28

30

have been described previously, albeit prepared by a

diﬀerent method involving substitution on a pre-existing

bicyclic framework.

3

2,5

oxocarbenium ion character and a H or B conformation

The fact that the signiﬁcant diﬀerence in stabilities of the

D- and L-glycero-D-galacto triﬂates can be attributed to steric

interactions in the transition states for ring closure to the

corresponding 1,6-anhydro derivatives prevents us from

drawing any ﬁrm conclusions correlating the stability of the

two diastereomeric triﬂates and their inﬂuence on selectivity

in their respective glycosylation reactions. Similarly, little of

any use regarding the inﬂuence of the side chain on

intermolecular reactivity and glycosylation selectivity can be

gleaned from the comparable decomposition temperatures of

4

of the pyranose ring (Scheme 3). The formulation of these

ring closure reactions as S 2-like reactions with exploded

N

transition states is consistent with current thinking on O-

3d,29

glycosylation reactions

and avoids the need to write a

disfavored 5-endo-trig ring closure as would be required by a

pure S 1 mechanism. It is apparent that the failure of the D-

N

glycero-D-galacto conﬁgured triﬂate 53 to undergo ring closure

to the endo-substituted 1,6-anhydro derivative 55 is the result

of an unfavorable steric interaction by the terminal methyl

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1

Figure 7. H NMR spectra of donor 17 (a) at −80 °C prior to the addition of Tf O; the anomeric proton appears at δ 3.91 and (b) after the

2

3

addition of Tf O and warming to −60 °C; the anomeric proton of the glycosyl triﬂate appears at δ 6.15 (d, J = 3.14 Hz).

2

1,2

the two D- and L-glycero-D-gluco triﬂates as obviously the

transition states for ring closure do not resemble those for O-

glycosylation.

gg conformation ideal for the key donor−acceptor hydrogen

bond, which reduces the entropy of activation and so

increases selectivity with respect to other transition states

giving rise to the opposite anomer of the product. Donor−

acceptor hydrogen-bond-mediated aglycone delivery, in

general, is a much-discussed concept in recent years, albeit

the focus is typically on the use of basic protecting groups in

Ultimately, the most interesting and unexpected observa-

tion in this study is the highly selective formation of

equatorial glycosides with the L-glycero-D-gluco-conﬁgured

donor 17 with the preferred gg conformation of the side

5

,6

32

chain which, according to the earlier bicyclic models,

the donor as the hydrogen-bond acceptor.

should have been the most reactive and least equatorially

selective of the compounds studied. We suggest that this

observation is best explained by donor−acceptor hydrogen

bonding involving the benzyloxy group in the side chain of

the donor in its gg conformation serving as the H-bond

acceptor and directing group. Thus, as the C1 to the OTf

bond lengthens and oxocarbenium character develops, the

To test the hypothesis that donor−acceptor hydrogen-

bonding factors into the equatorial selectivity observed with

donor 17, we prepared the corresponding 6-O-acetyl

thioglycoside 66 by acetylation of 14 under standard

conditions in 90% yield and converted it to the sulfoxide

3

67 by mCPBA oxidation in 83% yield. The J₅coupling

,6

constants of 1.78 Hz in the 6-O-acetyl glycosyl donor 66 and

those of 1.71 and 1.92 Hz for two isomers of sulfoxide 67 are

consistent with that of 1.60 Hz seen in the analogous 6-O-

benzyl donor 16, indicating that the nature of the protecting

group at the 6-position has no signiﬁcant inﬂuence of side-

chain conformation in the L-glycero-D-gluco series and that 66

and 67 retain the gg conformation. Coupling of 67 to 1-

adamantanol under the standard conditions gave 61% of a

1.94:1 axial to equatorial mixture of glycosides 68 (Scheme

5), which diﬀers signiﬁcantly from the exclusive formation of

the equatorial glycoside observed on coupling of 17 to the

same acceptor alcohol (Table 2, entry 2). Clearly, the nature

of the protecting group, ether or ester, at the 6-position has a

very signiﬁcant inﬂuence on the stereochemical outcome of

glycosylations in the L-glycero-D-gluco series, consistent with

the more basic benzyl ether in 17 serving as a better

4

C chair conformer will undergo distortion toward an E

1

4

envelope 64 and/or the closely related H₃half-chair

conformation 65 in either of which O6 is ideally placed to

accept a hydrogen bond from the acceptor and stabilize a

loose S 2-like transition state (Scheme 4). This hypothesis is

N

consistent with Whitﬁeld and Guo’s DFT computations,

including proton transfer from the acceptor to O6 at the

transition state, on the reaction of methanol with a tetra-O-

methyl-α-D-glucopyranosyl donor, and with Liu’s recent

31

molecular dynamics study on glycosylation mechanisms.

The main diﬀerence between the models proposed by

Whitﬁeld and Liu and their respective co-workers on with

prototypical tetra-O-alkyl-α-D-glucopyranosyl donors and that

proposed here for the L-glycero-β-D-glucopyranosyl triﬂate 60

is the preorganization of the side chain in the latter into the

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1

Figure 8. H NMR spectra of donor 19 (a) at −80 °C prior to the addition of Tf O; the anomeric proton appears at δ 3.91 and (b) after the

2

3

addition of Tf O and warming to −60 °C; the anomeric proton of the glycosyl triﬂate appears at δ 6.16(d, J = 3.08 Hz).

2

1,2

A ﬁnal issue concerns the diﬀerence between the sialic acid

series with which we began and the simple 7-deoxyheptopyr-

anosyl series of donors studied here, namely, that the L-

glycero-D-gluco donor 17 is the most selective in the present

series, whereas the neuraminic acid donor 1 is among the

least selective in its series despite the fact that both have the

same lyxo relative conﬁguration at the point of attachment of

the side chain to the pyranose ring and its two ﬂanking

centers and both have the gg conformation of the side chain.

The two series are clearly not the same and diﬀer most

prominently not only by the presence of the carboxylate ester

at the anomeric position and the absence of a C−O bond at

the 2-position of the pyranose ring in the sialic acid series but

also by the nature of the protecting groups. If donor−

acceptor hydrogen bonding is accepted as the underlying

reason for the equatorial selectivity of 17 (Schemes 4 and 5),

it is apparent that it cannot play a signiﬁcant role in the

reactions of 1, which in turn is consistent with the less basic

nature of the acetate protecting groups in 1 than the benzyl

ethers in 2. Unfortunately, while research into the use of

ethers as protecting groups in sialic acid donors has been

Figure 9. Structures of intermediates and the decomposition

products obtained during low-temperature NMR studies.

hydrogen-bond acceptor than the less basic acetate ester of

34

initiated, it has not yet been extended under comparable

6

7. The alternative possibility of stereodirecting participation

conditions to comparisons of reactivity and selectivity across

a spectrum of diastereomeric donors such as those employed

here.

by the ester in 67 steering the glycosylation toward

preferential axial glycoside formation is considered unlike-

3

d,33

ly.

J

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Scheme 3. Mechanism of 1,6-Anhydro Product Formation

Scheme 4. Mechanistic Hypothesis for the Equatorial

Selectivity of L-glycero-D-gluco Donor 17

Scheme 5. Unselective Glycosylation with the 6-O-Acetyl-L-

glycero-D-gluco Heptopyranosyl Donor 67

CONCLUSIONS

■

Continuing our studies on the role of side-chain conforma-

tional eﬀects in anomeric reactivity and selectivity, we report

the synthesis, conformational analysis, reactivity, and

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selectivity of a series of four diastereomeric 6-C-methyl

galacto and glucopyranosyl donors. Consistent with expect-

ations based on earlier studies in the sialic series, the D-

glycero-D-galacto and L-glycero-D-galacto isomers have the tg

and gt conformations of the side chain, while the D-glycero-D-

gluco and L-glycero-D-gluco isomers have the gt and gg

conformations: side-chain conformations of higher carbon

sugars can be reliably predicted based on a simple model

coupled with inspection of Fischer projection formulas.

Somewhat to our surprise, however, while the D-glycero-D-

galacto conﬁgured donor exhibited signiﬁcantly greater

equatorial selectivity than the L-glycero-D-galacto isomer

consistent with the model, the D-glycero-D-gluco isomer was

more reactive than the L-glycero-D-gluco isomer which

generally exhibited the greatest equatorial selectivity of the

whole series. This observation is rationalized in terms of

stereodirecting donor−acceptor hydrogen bonding in the L-

glycero-D-gluco isomer with O6 of the donor serving as a H-

bond acceptor. Transition states involving E or H₃

conformations of the activated donor encompassing this

type of donor−acceptor hydrogen are consistent with recent

DFT and metadynamics studies of the reactions of simple

per-O-methylated glucopyranosyl donors with simple alcohols

and are especially favored in the present case by the gg side-

chain conformation very predominantly adopted in the

ground state by the L-glycero-D-gluco donor which results in

a decrease in entropy of activation and so of the activation

energy for the formation of the equatorial glycoside.

p-Methylphenyl 2,3,4-Tri-O-benzyl-1-thio-β-D-galactopyr-

18

anoside (6). This compound was prepared according to the

literature method (2.60 g, 91%) as white foam. The spectral

data are consistent with the literature.

p-Methylphenyl 2,3,4-Tri-O-benzyl-7-deoxy-1-thio-D-glyc-

ero-α-D-galacto-heptopyranoside (7). To a solution of 6

(0.60 g, 1.08 mmol) in dry CH Cl (5 mL) was added Dess−

2 2

Martin periodinane (0.51 g, 1.19 mmol). The mixture was

stirred at room temperature for 3 h until complete

consumption of the starting material as observed by TLC

^aⁿ^a^l^y^sⁱ^s^.^T^h^e^r^e^a^c^tⁱ^oⁿ^w^a^s^dⁱ^l^u^t^e^d^wⁱ^t^h⁵^m^L^o^f^s^a^t^.^N^a^H^C^O3

and 5 mL of Na S O solution, the layers were separated, and

2

3

the aqueous layer was extracted three times with CH Cl (3

2

×

10 mL). The combined organic layers were washed with

brine, dried over Na SO , ﬁltered, and concentrated under

2

4

reduced pressure to aﬀord the crude residue which was used

immediately without further puriﬁcation.

THF (5 mL) was added at room temperature to vigorously

4

stirred anhydrous CeCl (0.31 g, 1.25 mmol, 2.0 equiv) to

3

form a uniform white suspension, which was stirred for 2 h.

The resulting suspension was cooled to 0 °C, and the

addition of methylmagnesium bromide (1.88 mL, 1.0 M in

THF, 1.88 mmol, 3.0 equiv) was carried out in a dropwise

manner over 10 min to form an oﬀ-white suspension. The

resulting suspension was stirred for 1 h, whereupon glycosyl

aldehyde (0.35 g, 0.63 mmol, 1.0 equiv) in THF (3.0 mL)

was added dropwise over 5 min, and the reaction mixture

warmed gradually to room temperature. After 1 h, the

reaction mixture was cooled to 0 °C, quenched with sat.

General Experimental Details. All reactions were

carried out under argon unless otherwise stated. Solvents

used for column chromatography were of analytical grade and

were purchased from commercial suppliers. Thin-layer

chromatography was carried out with 250 μm glass-backed

silica (XHL) plates. Detection of compounds was achieved by

UV absorption (254 nm) and by staining with 10% sulfuric

acid in ethanol. Puriﬁcation of crude residues was performed

by silica gel chromatography using 230−400 mesh grade 60

silica. Speciﬁc rotations were measured in chloroform on an

automatic polarimeter with a path length of 10 cm. NMR

spectra were recorded in C D and CDCl at either 500, 600,

NH Cl (10 mL), and extracted with EtOAc (2 × 15 mL).

4

The organic extracts were combined, washed with brine (15

mL), dried over Na SO , ﬁltered, and evaporated under

2

4

reduced pressure, and the resulting residue was puriﬁed by

ﬂash column chromatography on silica gel (hexane/ethyl

acetate; 4:1) to yield 7 and 10 stereoisomers in a 11:1 ratio

20

(

−

7

5

(

9

4

combined yield: 0.44 g, 71%) as colorless syrup. 7: [α]

D

1

8.3 (c 1.4, CHCl ); H NMR (500 MHz, CDCl ): δ 7.46−

3

.41 (m, 4H), 7.39−7.27 (m, 13H), 7.04 (d, J = 8.0 Hz, 2H),

.01 (d, J = 11.7 Hz, 1H), 4.87 (d, J = 10.2 Hz, 1H), 4.78

d, J = 12.0 Hz, 3H), 4.73 (d, J = 11.8 Hz, 1H), 4.56 (d, J =

6

3

.7 Hz, 1H), 4.10 (d, J = 2.7 Hz, 1H), 3.91 (td, J = 9.5, 8.9,

.4 Hz, 2H), 3.58 (dd, J = 9.2, 2.7 Hz, 1H), 2.94 (d, J = 8.0

or 900 MHz as indicated. High-resolution (HRMS) mass

spectra were recorded in the electrospray mode using an

orbitrap mass analyzer (Thermo Fisher ESI-Orbitrap). The

chemical shifts (δ) are recorded in ppm, and the multi-

plicities are abbreviated as follows: s (singlet), m (multiplet),

br (broad), d (doublet), t (triplet), and q (quartet).

13

1

Hz, 1H), 2.30 (s, 3H), 1.18 (d, J = 6.3 Hz, 3H); C{ H}

NMR (126 MHz, CDCl ): δ 138.7, 138.4, 138.3, 137.4,

3

1

6

32.5, 130.4, 129.6, 128.66, 128.60, 128.5, 128.4, 128.0,

27.8, 127.7, 88.6, 84.6, 82.4, 77.9, 75.8, 74.0, 73.1, 71.8,

5.7, 21.2, 20.7. HRMS (ESI): m/z calcd for C H O SNa

3

5

38

5

Preparation of Acceptors. Methyl 2,3,4-Tri-O-benzyl-α-

[

M + Na], 593.2332; found, 593.2307.

p-Methylphenyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-1-thio-D-

glycero-α-D-galacto-heptopyranoside (8). To a solution of 7

0.50 g, 0.87 mmol) in dry DMF (3 mL) were added sodium

hydride (49.10 mg, 1.22 mmol) and BnBr (130 μL, 1.05

mmol) at 0 °C. The reaction mixture was gradually warmed

to room temperature and stirred until completion with

2

0

D-glucopyranoside (23).

This acceptor was prepared

according to the literature method (1.40 g, 98%) as colorless

syrup. The spectral data are consistent with the literature.

(

1

,2:3,4-O-Di-isopropylidene-α-D-galactopyranoside

35

(

24). This acceptor was prepared according to the literature

method (0.80 g, 74%) as colorless syrup. The spectral data

are consistent with the literature.

Methyl 2,3-O-Isopropylidene-α-L-rhamnoside (25). This

monitoring by TLC (hexane/ethyl acetate 4:1, R = 0.8) and

f

36

then quenched with methanol (0.5 mL). It was diluted with

ethyl acetate, washed with water and brine, dried over

anhydrous Na SO , ﬁltered, and evaporated under reduced

acceptor was prepared according to the literature method

(

4.62 g, 94%) as colorless syrup. The spectral data are

2

4

consistent with the literature.

Methyl 2,3,6-Tri-O-benzyl-α-D-glucopyranoside (26).

pressure. The residual syrup was puriﬁed by silica gel column

chromatography (hexane/ethyl acetate 9:1) to aﬀord 8 (0.51

3

7

2

0

1

This acceptor was prepared according to the literature

method (4.51 g, 90%) as colorless syrup. The spectral data

are consistent with the literature.

g, 89%) as colorless syrup. [α] −9.6 (c 1.0, CHCl ); H

D

3

NMR (500 MHz, CDCl ): δ 7.46 (d, J = 7.8 Hz, 2H), 7.40

3

(d, J = 7.7 Hz, 2H), 7.37−7.21 (m, 18H), 7.03 (d, J = 7.8

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Hz, 2H), 5.03 (d, J = 11.4 Hz, 1H), 4.82 (d, J = 10.2 Hz,

9.7 Hz, 1H), 4.67−4.52 (m, 3H), 3.94 (t, J = 9.5 Hz, 1H),

3.93−3.81 (m, 2H), 3.61 (dd, J = 9.2, 2.6 Hz, 1H), 3.31 (d, J

= 8.0 Hz, 1H), 2.24 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H);

1

H), 4.76−4.71 (m, 3H), 4.59−4.54 (m, 2H), 4.52 (d, J =

1.4 Hz, 1H), 4.22 (d, J = 11.2 Hz, 1H), 4.19 (d, J = 2.6 Hz,

H), 3.95−3.87 (m, 2H), 3.60 (dd, J = 9.3, 2.6 Hz, 1H), 3.15

1

3

1

C{ H} NMR (126 MHz, CDCl ): δ 139.1, 138.7, 138.4,

3

(

d, J = 8.7 Hz, 1H), 2.31 (s, 3H), 1.30 (d, J = 6.0 Hz, 3H);

138.3, 136.9, 131.6, 130.9, 129.6, 128.5, 128.49, 128.44,

128.3, 128.0, 127.8, 127.66, 127.63, 127.4, 88.3, 85.3, 83.4,

77.8, 75.7, 75.1, 74.2, 74.0, 73.4, 73.1, 21.1, 16.7. HRMS

(ESI): m/z calcd for C H O SNa [M + Na], 683.2801;

1

3

1

C{ H} NMR (126 MHz, CDCl ): δ 139.2, 138.5, 138.4,

3

1

8

1

6

37.3, 132.3, 130.4, 129.6, 128.5, 128.48, 128.42, 128.2,

27.89, 127.81, 127.78, 127.70, 127.6, 127.5, 127.3, 88.4,

4.7, 81.7, 77.6, 75.7, 74.4, 73.4, 72.86, 72.81, 70.7, 21.2,

6.7. HRMS (ESI): m/z calcd for C H O SNa [M + Na],

4

2

44

5

found, 683.2784.

General Protocol A for the Oxidation of Thioglyco-

sides to Glycosyl Sulfoxides. To a stirred solution of

thioglycoside (0.35 g, 0.53 mmol) in anhydrous dichloro-

methane (2 mL), mCPBA (0.12 g, 0.53 mmol, 77%) was

added portionwise at −78 °C under argon. After 3 h, the

reaction mixture was neutralized with saturated aqueous

42

44

5

83.2801; found, 683.2789.

p-Methylphenyl 2,3,4-Tri-O-benzyl-7-deoxy-1-thio-L-glyc-

ero-α-D-galacto-heptopyranoside (10). To a solution of 7

0.20 g, 0.36 mmol) in dry CH Cl (2 mL) was added Dess−

(

2

Martin periodinane (0.30 g, 0.72 mmol). The mixture was

stirred at room temperature for 3 h until complete

consumption of the starting material as observed by TLC

analysis. The reaction was diluted with 2 mL of sat. NaHCO₃

and 2 mL of Na S O solution, the layers were separated, and

NaHCO solution (2 mL) and then warmed up to room

3

temperature. The mixture was extracted with dichloro-

methane (2 × 10 mL); all combined organic phases were

washed with brine, dried over Na SO , ﬁltered, and

2

3

2

4

the aqueous layer was extracted three times with CH Cl (3

evaporated under reduced pressure to give a crude residue.

Puriﬁcation by ﬂash column chromatography on silica gel

(hexane/ethyl acetate, 1:1) aﬀorded the corresponding

glycosyl sulfoxides.

2

×

5 mL). The combined organic layers were washed with

brine, dried over Na SO , ﬁltered, and concentrated under

2

4

reduced pressure to aﬀord the crude residue which was used

immediately without further puriﬁcation.

To a solution of galactosyl ketone (0.19 g, 0.33 mmol) in

methanol (2 mL) was added sodium borohydride (26.00 mg,

p-Methylphenyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-1-thio-D-

glycero-α-D-galacto-heptopyranosyl Sulfoxide (9). It was

obtained following the general protocol A as colorless syrup

(0.29 g, 81%) in a 1:1.51 ratio of two unidentiﬁed isomers.

0

.67 mmol) in two portions at 0 °C. The mixture was stirred

2

3

at 0 °C for 15 min until complete consumption of the

starting material as observed by TLC analysis. It was diluted

with 10 mL of ethyl acetate, washed with water and brine,

dried over anhydrous Na SO , ﬁltered, and evaporated under

Isomer a. White amorphous solid; [α] −37.3 (c 1.0,

D

1

CHCl ); H NMR (500 MHz, CDCl ): δ 7.50 (d, J = 7.8

3

Hz, 2H), 7.41 (d, J = 7.4 Hz, 2H), 7.37−7.21 (m, 18H), 7.16

(d, J = 7.3 Hz, 2H), 5.04−4.93 (m, 3H), 4.80−4.64 (m, 2H),

4.53 (d, J = 11.6 Hz, 1H), 4.46 (t, J = 9.6 Hz, 1H), 4.40 (d, J

= 11.1 Hz, 1H), 4.17−4.04 (m, 2H), 3.85 (d, J = 9.8 Hz,

1H), 3.77 (dt, J = 12.2, 6.1 Hz, 1H), 3.66 (dd, J = 9.5, 2.7

Hz, 1H), 2.92 (d, J = 8.6 Hz, 1H), 2.38 (s, 3H), 0.71 (d, J =

2

4

reduced pressure. The residual syrup was puriﬁed by silica gel

column chromatography (hexane/ethyl acetate 4:1) to aﬀord

1

0 and 7 stereoisomers in a 22:1 ratio (combined yield: 0.18

20

g, 90%) as colorless syrup. 10: [α] +11.6 (c 1.0, CHCl );

D

3

1

13

1

H NMR (500 MHz, CDCl ): δ 7.48−7.44 (m, 2H), 7.43−

5.9 Hz, 3H); C{ H} NMR (126 MHz, CDCl ): δ 141.0,

3

.40 (m, 2H), 7.39−7.28 (m, 13H), 7.05 (d, J = 7.9 Hz, 2H),

.04 (d, J = 11.5 Hz, 1H), 4.86 (d, J = 10.3 Hz, 1H), 4.83−

.74 (m, 3H), 4.63 (d, J = 11.6 Hz, 1H), 4.60 (d, J = 9.6 Hz,

H), 4.08−4.01 (m, 1H), 3.94 (t, J = 9.4 Hz, 1H), 3.85 (d, J

138.9, 138.3, 138.1, 138.0, 136.9, 129.4, 128.6, 128.5, 128.4,

128.3, 128.2, 128.07, 128.03, 127.9, 127.8, 127.78, 127.74,

127.6, 127.5, 127.4, 125.1, 94.7, 84.7, 82.8, 76.0, 74.6, 74.0,

73.2, 72.6, 72.3, 70.4, 21.4, 15.8. HRMS (ESI): m/z calcd for

C H O SNa [M + Na], 699.2751; found, 699.2745.

2.6 Hz, 1H), 3.60 (dd, J = 9.2, 2.7 Hz, 1H), 3.00 (d, J =

4

2

44

6

2

3

1

Isomer b. Colorless syrup; [α] −6.0 (c 0.4, CHCl ); H

D

3

1

3

1

H); C{ H} NMR (126 MHz, CDCl ): δ 138.3, 138.2,

NMR (500 MHz, CDCl ): δ 7.47 (d, J = 8.2 Hz, 2H), 7.28

3

(m, 16H), 7.19 (d, J = 8.1 Hz, 4H), 7.14−7.06 (m, 2H), 4.92

(d, J = 11.7 Hz, 1H), 4.87 (d, J = 10.7 Hz, 1H), 4.82 (d, J =

10.7 Hz, 1H), 4.72 (d, J = 11.7 Hz, 1H), 4.64 (d, J = 11.6

Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 4.44−4.33 (m, 2H), 4.13

(d, J = 11.1 Hz, 1H), 4.10 (d, J = 2.5 Hz, 1H), 3.98 (t, J =

9.3 Hz, 1H), 3.75−3.63 (m, 2H), 3.19 (d, J = 8.6 Hz, 1H),

35

38

5

1

3

1

2.36 (s, 3H), 1.21 (d, J = 6.1 Hz, 3H); C{ H} NMR (126

MHz, CDCl ): δ 141.6, 139.1, 138.2, 138.07, 138.01, 137.0,

3

1

.05 mmol) at 0 °C. The reaction mixture was gradually

129.3, 128.56, 128.52, 128.3, 128.2, 128.1, 127.88, 127.84,

127.81, 127.78, 127.70, 127.1, 126.8, 126.3, 95.7, 84.9, 82.0,

74.7, 74.4, 74.1, 72.8, 72.6, 72.5, 70.6, 21.6, 16.5. HRMS

(ESI): m/z calcd for C H O SNa [M + Na], 699.2751;

warmed to room temperature and stirred until completion

with monitoring by TLC (hexane/ethyl acetate 4:1, R =

f

0

.70) and then quenched with methanol (0.50 mL). It was

4

2

44

6

diluted with ethyl acetate, washed with water and brine, dried

found, 699.2747.

over anhydrous Na SO , ﬁltered, and evaporated under

reduced pressure. The residual syrup was puriﬁed by silica

p-Methylphenyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-1-thio-L-

glycero-α-D-galacto-heptopyranosyl Sulfoxide (12). It was

obtained following the general protocol A as colorless syrup

2

4

gel column chromatography (hexane/ethyl acetate 4:1) to

2

0

aﬀord 11 (0.49 g, 85%) as colorless syrup. [α] −8.8 (c 1.0,

(0.28 g, 79%) in a 1:1.63 ratio of two unidentiﬁed isomers.

D

1

23

CHCl ); H NMR (500 MHz, CDCl ): δ 7.51−7.21 (m,

Isomer a. White amorphous solid; [α] −109.2 (c 1.0,

3

D

1

2

4

2H), 6.90 (d, J = 7.9 Hz, 2H), 5.09 (d, J = 11.5 Hz, 1H),

.87 (d, J = 10.3 Hz, 1H), 4.85−4.72 (m, 3H), 4.67 (d, J =

CHCl ); H NMR (500 MHz, CDCl ): δ 7.55 (d, J = 7.9

3

Hz, 2H), 7.49−7.18 (m, 18H), 7.14 (d, J = 8.0 Hz, 2H),

M

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Article

7

.11−7.03 (m, 2H), 5.11 (d, J = 11.7 Hz, 1H), 5.02 (d, J =

.4 Hz, 2H), 4.84 (s, 2H), 4.63−4.50 (m, 2H), 4.12−4.03

75.8, 75.6, 75.3, 65.5, 21.2, 20.5; HRMS: m/z calcd for

+

2

C H O SNa [M + Na] , 593.2332; found, 593.2318.

3

5

38

5

(

m, 2H), 3.96 (d, J = 12.0 Hz, 1H), 3.81 (d, J = 2.5 Hz,

p-Methylphenyl 2,3,4-Tri-O-benzyl-7-deoxy-1-thio-D-glyc-

2

0

1

3

H), 3.79−3.68 (m, 2H), 3.20 (d, J = 7.8 Hz, 1H), 2.15 (s,

ero-α-D-gluco-heptopyranoside (15). [α] +9.0 (c 0.6,

D

H), 0.84 (d, J = 6.4 Hz, 3H); ¹C{ H} NMR (126 MHz,

3

1

CHCl ); H NMR (600 MHz, CDCl ): δ 7.39−7.31 (m,

1

3

CDCl ): δ 141.1, 139.2, 138.5, 138.04, 138.00, 136.7, 129.7,

4H), 7.33−7.22 (m, 13H), 7.13 (d, J = 7.7 Hz, 2H), 4.97−

4.90 (m, 3H), 4.84 (d, J = 10.9 Hz, 1H), 4.75 (d, J = 10.3

Hz, 1H), 4.65 (d, J = 11.1 Hz, 1H), 4.61 (d, J = 9.7 Hz, 1H),

3.99 (m, 1H), 3.74 (t, J = 8.8 Hz, 1H), 3.47 (td, J = 9.4, 4.3

Hz, 2H), 3.31 (dd, J = 9.8, 4.1 Hz, 1H), 2.52 (d, J = 7.0 Hz,

3

1

7

28.68, 128.64, 128.5, 128.3, 128.2, 128.1, 128.0, 127.6,

27.2, 125.1, 94.5, 85.4, 76.1, 75.1, 74.1, 74.08, 74.02, 73.2,

3.0, 21.3, 17.1. HRMS (ESI): m/z calcd for C H O SNa

42

44

6

[M + Na], 699.2751; found, 699.2747.

2

3

13

1

Isomer b. White amorphous solid; [α] +17.1 (c 1.0,

1H), 2.34 (s, 3H), 1.15 (d, J = 6.5 Hz, 3H); C{ H} NMR

D

1

CHCl ); H NMR (500 MHz, CDCl ): δ 7.48 (d, J = 8.0

(151 MHz, CDCl ): δ 138.2, 138.1, 137.9, 137.5, 133.0,

3

Hz, 2H), 7.36−7.21 (m, 18H), 7.18−7.13 (m, 2H), 7.10 (d, J

8.0 Hz, 2H), 5.01 (d, J = 11.7 Hz, 1H), 4.87 (s, 2H), 4.75

d, J = 11.6 Hz, 1H), 4.69 (d, J = 11.5 Hz, 1H), 4.60 (d, J =

129.7, 128.6, 128.56, 128.54, 128.2, 128.07, 128.00, 127.9,

127.8, 127.7, 87.7, 87.0, 81.4, 81.3, 79.4, 75.8, 75.4, 74.8,

68.1, 21.1, 17.7. HRMS: m/z calcd for C H O SNa [M +

=

(

3

5

38

5

+

1

1.7 Hz, 1H), 4.55−4.45 (m, 3H), 4.12 (t, J = 9.2 Hz, 1H),

Na] , 593.2332; found, 593.2318.

3

.84 (d, J = 2.4 Hz, 1H), 3.79 (p, J = 6.5 Hz, 1H), 3.68 (dd,

p-Methylphenyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-1-thio-L-

glycero-α-D-gluco-heptopyranoside (16). To a solution of

14 (0.34 g, 0.60 mmol) in dry DMF (2 mL) were added

sodium hydride (28 mg, 0.90 mmol) and BnBr (85 μL, 0.72

mmol) at 0 °C. The reaction mixture was gradually warmed

to room temperature and stirred until completion with

J = 9.1, 2.5 Hz, 1H), 3.39 (d, J = 7.6 Hz, 1H), 2.29 (s, 3H),

13

1

0

.97 (d, J = 6.5 Hz, 3H); C{ H} NMR (126 MHz,

CDCl ): δ 141.4, 139.0, 138.6, 138.1, 137.8, 137.3, 129.4,

3

1

7

28.6, 128.4, 128.3, 128.2, 128.0, 127.9, 127.9, 127.7, 127.6,

27.5, 127.4, 127.3, 125.9, 96.1, 85.4, 83.2, 74.9, 74.6, 74.0,

3.7, 73.5, 72.9, 21.5, 16.6. HRMS (ESI): m/z calcd for

monitoring by TLC (hexane/ethyl acetate 4:1, R = 0.8) and

f

C H O SNa [M + Na], 699.2751; found, 699.2742.

then quenched with methanol (0.50 mL). It was diluted with

ethyl acetate, washed with water and brine, dried over

anhydrous Na SO , ﬁltered, and evaporated under reduced

4

2

44

6

Preparation of L-glycero-α-D-gluco and D-glycero-α-D-

gluco Donors. To a solution of p-methylphenyl 2,3,4-tri-O-

2

4

20

benzyl-1-thio-β-D-glucopyranoside 13 (2.07 g, 3.70 mmol)

in anhydrous DCM (20 mL) was added Dess−Martin

periodinane (3.15 g, 7.40 mmol). The mixture was stirred

at room temperature for 2 h until complete consumption of

the starting material as observed by TLC analysis. The

pressure. The residual syrup was puriﬁed by silica gel column

chromatography (hexane/ethyl acetate 95:5) to aﬀord 16

2

0

(0.36 g, 92%) as colorless syrup. [α] +4.3 (c 0.6, CHCl );

D

3

1

H NMR (500 MHz, CDCl ): δ 7.52−7.47 (m, 2H), 7.44−

3

7.38 (m, 2H), 7.38−7.21 (m, 16H), 7.16 (dd, J = 7.6, 1.8 Hz,

2H), 7.04 (d, J = 8.0 Hz, 2H), 4.90 (dd, J = 10.5, 9.0 Hz,

2H), 4.81 (dd, J = 10.9, 5.6 Hz, 2H), 4.71 (dd, J = 11.0, 6.2

Hz, 2H), 4.54 (d, J = 9.8 Hz, 1H), 4.47 (d, J = 10.9 Hz, 1H),

4.36 (d, J = 11.7 Hz, 1H), 3.99 (qd, J = 6.3, 1.6 Hz, 1H),

3.85 (t, J = 9.3 Hz, 1H), 3.68 (t, J = 9.0 Hz, 1H), 3.49 (t, J =

9.3 Hz, 1H), 3.19 (dd, J = 9.5, 1.9 Hz, 1H), 2.31 (s, 3H),

reaction was diluted with 25 mL of sat. NaHCO and 25 mL

3

of Na S O solution, the layers were separated, and the

2

3

aqueous layer was extracted three times with CH Cl (3 × 30

2

mL). The combined organic layers were washed with brine,

dried over Na SO , ﬁltered, and concentrated under reduced

2

4

pressure to aﬀord crude aldehyde (2.00 g) which was used

immediately without further puriﬁcation. Crude aldehyde was

dissolved in THF (10 mL), and the solution was cooled to 0

1

3

1

1.34 (d, J = 6.4 Hz, 3H); C{ H} NMR (126 MHz,

CDCl ): δ 138.9, 138.5, 138.3, 137.7, 133.1, 129.9, 129.6,

3

°

C. To this mixture, a solution of methyl magnesium chloride

128.5, 128.5, 128.46, 128.41, 127.9, 127.9, 127.8, 127.7,

127.6, 127.5, 88.1, 87.2, 82.1, 80.9, 77.7, 75.9, 75.4, 74.9,

71.6, 70.2, 21.2, 15.6; HRMS: m/z calcd for C H O SN [M

(

5.41 mL, 1.0 M in THF, 5.41 mmol, 1.5 equiv) was added

in a dropwise manner over 10 min, and the reaction mixture

was stirred for 2 h at the same temperature. The reaction was

4

2

48

5

+

+ NH ] , 678.3231; found, 678.3234.

4

quenched with the dropwise addition of saturated aq. NH Cl

solution (10 mL) until eﬀervescence stopped. The mixture

p-Methylphenyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-1-thio-D-

glycero-α-D-gluco-heptopyranoside (18). To a solution of

15 (0.15 g, 0.26 mmol) in dry DMF (2 mL) were added

sodium hydride (16 mg, 0.40 mmol) and BnBr (38 μL, 0.32

mmol) at 0 °C. The reaction mixture was gradually warmed

to room temperature and stirred until completion with

4

was then diluted with H O (50 mL) and extracted with

2

EtOAc (3 × 30 mL). The organic layer was separated and

dried over Na SO , and solvents were evaporated under

2

4

reduced pressure. The crude mixture was subjected to

column puriﬁcation (eluent: hexane/ethyl acetate) (93:7) to

aﬀord 14 (1.14 g, 54%) and 15 (0.38 g, 18%) stereoisomers

in a 3:1 ratio as a white amorphous solid.

monitoring by TLC (hexane/ethyl acetate 4:1, R = 0.7) and

f

then quenched with methanol (0.5 mL). It was diluted with

ethyl acetate, washed with water and brine, dried over

anhydrous Na SO , ﬁltered, and evaporated under reduced

p-Methylphenyl 2,3,4-Tri-O-benzyl-7-deoxy-1-thio-L-glyc-

2

4

2

0

ero-α-D-gluco-heptopyranoside (14). [α] −4.7 (c l.9,

pressure. The residual syrup was puriﬁed by silica gel column

chromatography (hexane/ethyl acetate 95:5) to aﬀord 18

D

1

CHCl ); H NMR (500 MHz, CDCl ): δ 7.42 (m, 4H),

3

2

0

7

.91−6.78 (m, 13H), 7.13 (d, J = 7.9 Hz, 2H), 5.27−4.84

(0.16 g, 90%) as colorless syrup. [α] +3.0 (c 0.2, CHCl );

D 3

1

(

m, 4H), 4.78 (d, J = 10.3 Hz, 1H), 4.73 (d, J = 10.8 Hz,

H NMR (500 MHz, CDCl ): δ 7.50−7.45 (m, 2H), 7.39 (d,

3

1

3

H), 4.63 (d, J = 9.6 Hz, 1H), 4.03 (qd, J = 6.6, 1.7 Hz,

H), 3.76−3.67 (m, 2H), 3.47 (dt, J = 4.8, 2.7 Hz, 1H),

J = 7.8 Hz, 2H), 7.37−7.24 (m, 16H), 7.16 (dd, J = 7.3, 2.4

Hz, 2H), 7.00 (d, J = 7.9 Hz, 2H), 4.90 (dd, J = 10.6, 7.5

Hz, 2H), 4.81 (d, J = 10.8 Hz, 2H), 4.71 (d, J = 10.3 Hz,

1H), 4.65−4.55 (m, 4H), 4.54 (d, J = 4.7 Hz, 1H), 3.85 (qd,

J = 6.6, 1.5 Hz, 1H), 3.54 (dd, J = 10.0, 1.5 Hz, 1H), 3.44

.13−3.10 (m, 1H), 2.34 (s, 3H), 1.27 (d, J = 6.5 Hz, 3H);

1

3

1

C{ H} NMR (126 MHz, CDCl ): δ 138.5, 138.2, 138.1,

3

1

38.1, 133.0, 129.8, 129.6, 128.6, 128.5, 128.4, 128.1, 128.07,

28.00, 127.9, 127.85, 127.80, 88.1, 86.7, 81.6, 81.3, 77.9,

1

3

1

(m, 2H), 2.28 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H); C{ H}

N

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

NMR (126 MHz, CDCl ): δ 139.0, 138.4, 138.2, 138.0,

1H), 3.35 (dd, J = 9.8, 1.5 Hz, 1H), 2.32 (s, 3H), 1.11 (d, J

3

1

3

1

7

37.7, 132.9, 129.9, 129.7, 128.6, 128.5, 128.4, 128.3, 128.1,

27.94, 127.92, 127.8, 127.6, 127.4, 87.5, 87.4, 81.0, 80.8,

= 6.7 Hz, 3H); C{ H} NMR (151 MHz, CDCl ): δ 141.5,

3

138.9, 138.3, 137.7, 137.6, 136.3, 129.5, 128.54, 128.51,

128.44, 128.40, 128.2, 128.1, 127.9, 127.7, 127.6, 127.4,

127.2, 125.6, 93.1, 86.9, 81.7, 75.7, 75.6, 74.7, 74.1, 70.2,

8.2, 75.9, 75.3, 74.7, 74.2, 70.9, 29.8, 21.2, 14.8; HRMS: m/

+

z calcd for C H O SNa [M + Na] , 683.2801; found,

4

2

44

5

+

6

83.2797.

General Protocol B for the Oxidation of Thioglyco-

21.4, 14.8; HRMS: m/z calcd for C H O SNa [M + Na] ,

4

2

44

6

699.2751; found, 699.2729.

2

0

1

sides to Glucosyl Sulfoxides. To a stirred solution of

thioglycoside (0.20 g, 0.30 mmol) in anhydrous dichloro-

methane (2 mL), mCPBA (68 mg, 0.30 mmol, 77%) was

added portionwise at −78 °C under argon followed by

warming to −30 °C in 30 min. The reaction mixture was

Isomer b. [α] +7.2 (c 0.8, CHCl ); H NMR (600 MHz,

D

3

CDCl ): δ 7.54−7.45 (m, 2H), 7.42−7.23 (m, 16H), 7.21−

3

7.13 (m, 6H), 4.89−4.75 (m, 4H), 4.75 (d, J = 11.0 Hz, 1H),

4.62 (d, J = 11.0 Hz, 1H), 4.50 (d, J = 12.2 Hz, 1H), 4.46

(d, J = 8.9 Hz, 1H), 4.41 (d, J = 12.2 Hz, 1H), 3.88−3.80

(m, 2H), 3.76 (t, J = 8.5 Hz, 1H), 3.62 (dd, J = 9.6, 1.4 Hz,

1H), 3.47 (dd, J = 9.7, 8.4 Hz, 1H), 2.31 (s, 3H), 1.16 (d, J

neutralized with saturated aqueous NaHCO solution (5 mL)

3

and then warmed up to room temperature. The mixture was

extracted with dichloromethane (2 × 10 mL); all combined

organic phases were washed with brine, dried over Na SO ,

1

3

1

= 6.7 Hz, 3H); C{ H} NMR (151 MHz, CDCl ): δ 141.5,

3

138.7, 137.9, 137.7, 136.7, 129.5, 128.5, 128.4, 128.39,

128.32, 128.27, 128.0, 127.9, 127.9, 127.83, 127.80, 127.7,

127.69, 127.63, 127.5, 127.4, 127.3, 125.6, 95.5, 86.6, 81.5,

77.4, 76.2, 75.5, 74.7, 74.4, 74.0, 71.3, 29.7, 21.3, 15.6;

2

4

ﬁltered, and evaporated under reduced pressure to give a

crude residue. Puriﬁcation by ﬂash column chromatography

on silica gel (hexane/ethyl acetate, 2:1) aﬀorded the

corresponding glucosyl sulfoxides.

+

HRMS: m/z calcd for C H O SNa [M + Na] , 699.2751;

4

2

44

6

p-Methylphenyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-1-thio-L-

glycero-α-D-gluco-heptopyranosyl Sulfoxide (17). It was

obtained following the general protocol B as colorless syrup

found, 699.2733.

p-Methoxyphenyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-D-glyc-

ero-α/β-D-galacto-heptopyranoside (S1). A mixture of

donor 8 (90 mg, 0.14 mmol), p-methoxyphenol (21 mg,

0.16 mmol), and activated 4 Å acid-washed powdered

molecular sieves (90 mg) in anhydrous CH Cl (1.5 mL,

0.1 M) was stirred for 30 min at rt under argon and then

cooled to −40 °C. The reaction mixture was then treated

with N-iodosuccinimide (37 mg, 0.16 mmol) and AgOTf (7

mg, 0.03 mmol) and stirred at −40 °C until completion and

then quenched with triethylamine (20 μL) at −40 °C, and

gradually, temperature was increased to rt. The reaction

mixture was diluted with CH Cl (5 mL), ﬁltered through

(

0.16 g, 79%) in a 2.1:1 ratio of two unidentiﬁed isomers.

2

0

1

Isomer a. [α]_D+4.4 (c l.0, CHCl ); H NMR (600 MHz,

3

CDCl ): δ 7.58 (d, J = 8.0 Hz, 2H), 7.50−7.26 (m, 20H),

3

2

7

1

4

.19 (d, J = 7.6 Hz, 2H), 4.92−4.80 (m, 5H), 4.76 (d, J =

0.8 Hz, 1H), 4.56−4.50 (m, 2H), 4.45 (d, J = 8.5 Hz, 1H),

.29 (d, J = 11.5 Hz, 1H), 3.98 (q, J = 6.7 Hz, 1H), 3.82 (q,

J = 8.6 Hz, 1H), 3.78 (t, J = 9.0 Hz, 1H), 3.36 (d, J = 9.4

Hz, 1H), 2.35 (s, 3H), 1.28 (d, J = 6.7 Hz, 3H); C{ H}

1

3

1

NMR (151 MHz, CDCl ): δ 138.7, 138.11, 138.10, 137.9,

3

1

7

37.6, 129.4, 128.6, 128.57, 128.53, 128.47, 128.44, 128.38,

28.35, 128.2, 128.0, 127.9, 127.88, 127.83, 127.76, 127.72,

27.66, 127.64, 127.4, 126.6, 94.9, 86.3, 81.7, 77.3, 75.3, 74.6,

2

Celite, and washed with 20% aqueous Na S O (5 mL). The

aqueous layer was extracted with CH Cl (5 mL) twice, and

the combined organic layers were dried over Na SO and

2

3

2

4.2, 71.5, 69.8, 21.4, 15.2; HRMS: m/z calcd for

2 4

+

C H O SNa [M + Na] , 699.2751; found, 699.2728.

concentrated under reduced pressure to aﬀord the crude

residue. Puriﬁcation by silica gel column chromatography

eluting with ethyl acetate/hexane (1:19 to 1:9) aﬀorded the

desired product as colorless syrup (83 mg, 92%) in a 1:2.4

ratio of α/β anomers.

4

2

44

6

2

1

Isomer b. [α]_D−15.1 (c 0.7, CHCl ); H NMR (500

3

MHz, CDCl ): δ 7.56 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 7.0

3

Hz, 2H), 7.39−7.22 (m, 18H), 7.13 (dd, J = 7.4, 2.0 Hz,

2

H), 5.04 (d, J = 10.3 Hz, 1H), 4.99−4.93 (m, 2H), 4.89 (d,

2

3

1

J = 11.1 Hz, 1H), 4.78 (d, J = 10.9 Hz, 1H), 4.60 (d, J =

1.8 Hz, 1H), 4.48 (d, J = 10.9 Hz, 1H), 4.30 (d, J = 11.8

Hz, 1H), 4.10 (t, J = 9.4 Hz, 1H), 3.78 (t, J = 9.1 Hz, 1H),

.97 (dd, J = 9.5, 2.1 Hz, 1H), 2.40 (s, 3H), 0.78 (d, J = 6.5

S1β. [α] +30.8 (c 1.0, CHCl ); H NMR (500 MHz,

D 3

1

CDCl ): δ 7.40 (d, J = 6.8 Hz, 2H), 7.36−7.20 (m, 18H),

3

6.97 (d, J = 9.0 Hz, 2H), 6.82−6.78 (m, 2H), 5.44 (d, J =

3.6 Hz, 1H), 5.05 (s, 1H), 4.90 (d, J = 11.6 Hz, 1H), 4.87−

4.76 (m, 2H), 4.71 (d, J = 12.0 Hz, 1H), 4.51 (dd, J = 11.2,

3.7 Hz, 2H), 4.27 (d, J = 2.6 Hz, 1H), 4.24−4.13 (m, 2H),

4.13 (dd, J = 10.0, 2.7 Hz, 1H), 3.86−3.73 (m, 4H), 3.65 (d,

2

1

3

1

Hz, 3H); C{ H} NMR (126 MHz, CDCl ): δ 141.2, 138.8,

3

1

2

6

38.4, 138.3, 137.8, 136.4, 129.5, 128.6, 128.59, 128.55,

28.47, 128.41, 128.1, 127.8, 127.75, 127.71, 127.6, 127.5,

25.3, 93.9, 87.0, 83.2, 77.4, 77.0, 75.1, 75.7, 74.9, 71.2, 69.7,

1

3

1

J = 9.1 Hz, 1H), 1.08 (d, J = 6.1 Hz, 3H); C{ H} NMR

(126 MHz, CDCl ): δ 154.8, 150.8, 139.0, 138.9, 138.5,

+

1.5, 14.5. HRMS: m/z calcd for C H O SNa [M + Na] ,

42

44

6

3

99.2751; found, 699.2761.

p-Methylphenyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-1-thio-D-

138.4, 128.4 (2C), 128.3, 128.1, 127.9, 127.7 (2C), 127.5,

127.5, 118.1, 114.4, 96.7, 79.5, 76.2, 74.8, 74.7, 74.2, 73.5,

73.3, 72.6, 70.5, 55.7, 16.4. HRMS (ESI): m/z calcd for

C H O Na [M + Na], 683.2979; found, 683.2966.

glycero-α-D-gluco-heptopyranosyl Sulfoxide (19). It was

obtained following the general protocol B as colorless syrup

4

2

44

7

2

3

1

(

0.16 g, 80%) in a 2.3:1 ratio of two unidentiﬁed isomers.

S1α. [α] −7.8 (c 0.4, CHCl ); H NMR (500 MHz,

D

3

2

0

1

Isomer a. [α]_D−55.0 (c l.0, CHCl ); H NMR (600

CDCl ): δ 7.38−7.21 (m, 20H), 7.02−6.93 (m, 2H), 6.86−

3

MHz, CDCl ): δ 7.60−7.55 (m, 2H), 7.45−7.40 (m, 2H),

6.76 (m, 2H), 5.04 (d, J = 11.5 Hz, 1H), 5.00 (d, J = 10.9

Hz, 1H), 4.88−4.81 (m, 2H), 4.78 (d, J = 11.8 Hz, 1H), 4.74

(d, J = 11.8 Hz, 1H), 4.55 (dd, J = 11.3, 6.8 Hz, 2H), 4.23−

4.16 (m, 2H), 4.08 (dd, J = 9.7, 7.7 Hz, 1H), 3.92 (dq, J =

8.7, 6.1 Hz, 1H), 3.76 (s, 3H), 3.59 (dd, J = 9.7, 2.8 Hz,

1H), 3.21 (d, J = 9.0 Hz, 1H), 1.31 (d, J = 6.0 Hz, 3H);

3

7

4

.40−7.24 (m, 16H), 7.20 (dd, J = 7.3, 2.2 Hz, 2H), 7.18−

.14 (m, 2H), 5.05 (d, J = 10.3 Hz, 1H), 5.01−4.94 (m, 2H),

.91 (d, J = 11.1 Hz, 1H), 4.84 (d, J = 11.0 Hz, 1H), 4.66

(

d, J = 11.0 Hz, 1H), 4.59−4.24 (m, 2H), 4.11 (t, J = 9.4

Hz, 1H), 3.92 (d, J = 9.7 Hz, 1H), 3.82 (t, J = 8.9 Hz, 1H),

.71 (qd, J = 6.7, 1.5 Hz, 1H), 3.55 (dd, J = 9.8, 8.8 Hz,

1

3

1

3

C{ H} NMR (126 MHz, CDCl ): δ 155.1, 151.7, 139.0,

3

O

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1

7

38.6, 138.6, 138.4, 128.5, 128.4, 128.39, 128.34, 128.2,

28.0, 127.9, 127.8, 127.7, 127.69, 127.64, 127.5, 127.4,

18.2, 114.5, 103.2, 82.6, 79.3, 78.0, 75.4, 74.6, 73.3, 73.1,

2.6, 70.6, 55.7, 16.7. HRMS (ESI): m/z calcd for

saturated NaHCO . The organic layer was separated, dried

3

over Na SO , ﬁltered, and concentrated under reduced

2

4

pressure. The residue was then subjected to column

chromatography over silica (EtOAc/Hexane, 5:95) to aﬀord

S3β (minor compound) and S3α (major compound) as

colorless syrups (combined yield: 57. mg, 73%, α/β = 2:1,

separated after column chromatography).

C H O Na [M + Na], 683.2979; found, 683.2962.

4

2

44

7

p-Methoxyphenyl 2,3-Di-O-benzyl-4,6-O-benzylidende-7-

deoxy-D-glycero-β-D-galacto-heptopyranoside (S2). To a

solution of the compound S1β (40 mg, 47.56 μmol) in 2

mL of MeOH under a hydrogen atmosphere (balloon

pressure) was added 10% Pd/C (53 mg, 47.56 μmol) and

stirred for 24 h at room temperature. The reaction mixture

was ﬁltered through a pad of Celite, and the ﬁltrate was

evaporated under reduced pressure to aﬀord the crude

residue which was used subsequently without puriﬁcation for

the next step.

2

0

1

S3β. [α] +4.3 (c 0.9, CHCl ); H NMR (600 MHz,

D

3

CDCl ): δ 7.42−7.20 (m, 18H), 7.18−7.13 (m, 2H), 7.03−

3

6.97 (m, 2H), 6.83−6.79 (m, 2H), 5.44 (d, J = 3.5 Hz, 1H),

5.05 (d, J = 10.6 Hz, 1H), 4.87 (d, J = 10.6 Hz, 2H), 4.79

(

3

d, J = 12.0 Hz, 1H), 4.66 (dd, J = 17.1, 11.8 Hz, 2H), 4.32

dd, J = 11.3, 6.0 Hz, 2H), 4.19 (t, J = 9.3 Hz, 1H), 3.97−

.91 (m, 1H), 3.85 (t, J = 9.4 Hz, 1H), 3.78 (s, 3H), 3.73

(

=

dd, J = 9.7, 3.4 Hz, 1H), 3.62 (d, J = 9.9 Hz, 1H), 1.12 (d, J

To a stirred solution of unprotected galactoside (22.0 mg,

9.96 μmol) in dry acetonitrile (1.5 mL) were added pTSA

13

1

6.4 Hz, 3H); C{ H} NMR (151 MHz, CDCl ): δ 154.8,

3

1

7

50.5, 138.6, 138.4, 138.1, 138.0, 128.5, 128.4, 128.1, 127.9,

27.7, 127.69, 127.62, 117.7, 114.4, 95.6, 82.4, 79.7, 77.5,

(

2 mg, 11.99 μmol) and benzaldehyde dimethylacetal (7.20

μL, 47.95 μmol). The reaction mixture was stirred at room

temperature until completion and then quenched with

triethylamine (20 μL). The reaction mixture was diluted

with ethyl acetate (10 mL) and washed with saturated

solution of NaHCO₃(5 mL). The aqueous layer was

extracted with EtOAc (5 mL) twice, and the combined

organic layers were dried over Na SO and concentrated

under reduced pressure to aﬀord the crude residue. The

crude residue obtained was dissolved in dry DMF (1.5 mL).

The addition of sodium hydride (8.4 mg, 0.21 mmol) and

BnBr (4.8 μL, 0.21 mmol) was carried out at 0 °C. The

reaction mixture was gradually warmed to room temperature

and stirred until completion with monitoring by TLC

5.9, 74.9, 74.0, 73.3, 71.0, 70.8, 29.7, 15.6; HRMS: m/z

+

calcd for C H O Na [M + Na] , 683.2961; found,

4

2

44

7

683.2961.

S3α. White solid [α]_D²⁰+10.6 (c 0.5, CHCl ); H NMR

1

3

(

2

1

600 MHz, CDCl ): δ 7.41−7.23 (m, 18H), 7.23−7.12 (m,

3

H), 7.03 (m, 2H), 6.88−6.82 (m, 2H), 5.10 (d, J = 10.9 Hz,

H), 4.98 (d, J = 10.8 Hz, 1H), 4.90−4.79 (m, 4H), 4.72 (d,

2

4

J = 11.8 Hz, 1H), 4.45 (d, J = 10.8 Hz, 1H), 4.41 (d, J =

1

9

1.8 Hz, 1H), 4.06 (qd, J = 6.4, 2.0 Hz, 1H), 3.96 (dd, J =

.7, 8.7 Hz, 1H), 3.81 (s, 3H), 3.80−3.49 (m, 2H), 3.31 (dd,

13

1

J = 9.6, 2.0 Hz, 1H), 1.40 (d, J = 6.4 Hz, 3H); C{ H}

NMR (151 MHz, CDCl ): δ 155.2, 151.6, 138.5, 138.44,

3

1

7

38.42, 128.4, 128.38, 128.33, 128.0, 127.9, 127.8, 127.7,

27.67, 127.63, 127.5, 118.3, 114.5, 103.1, 85.1, 82.0, 78.1,

(

hexane/ethyl acetate 4:1, R = 0.6) and then quenched

f

with methanol (0.2 mL). It was diluted with ethyl acetate,

washed with water and brine, dried over anhydrous Na SO ,

7.4, 75.8, 75.0, 74.8, 71.2, 70.5, 55.7, 15.7; HRMS: m/z

2

4

+

calcd for C H O Na [M + Na] , 683.2961; found,

4

2

44

7

ﬁltered, and evaporated under reduced pressure. The residual

syrup was puriﬁed by silica gel column chromatography

6

83.2953.

p-Methoxyphenyl 4,6-Di-O-benzylidene-7-deoxy-L-glyc-

(

hexane/ethyl acetate 9:1) to aﬀord S2 (27.0 mg, 71%) as

2

3

1

ero-α-D-gluco-heptopyranoside (S4). To a solution of the

compound S3α (8.7 mg, 0.01 mmol) in MeOH (0.5 mL)

under a hydrogen atmosphere (balloon pressure) was added

colorless syrup. [α] +41.5 (c 1.0, CHCl ); H NMR (500

MHz, CDCl ): δ 7.56−7.48 (m, 2H), 7.49−7.41 (m, 2H),

D

3

7

2

1

2

1

.40−7.19 (m, 11H), 7.06−6.97 (m, 2H), 6.86−6.76 (m,

H), 5.75 (s, 1H), 5.49 (d, J = 3.5 Hz, 1H), 4.88 (dd, J =

3.9, 12.0 Hz, 2H), 4.81 (d, J = 12.1 Hz, 1H), 4.68 (d, J =

2.0 Hz, 1H), 4.36 (dd, J = 3.3, 1.0 Hz, 1H), 4.30−4.18 (m,

H), 4.16 (dd, J = 10.1, 3.3 Hz, 1H), 3.77 (s, 3H), 3.53 (s,

10% Pd/C (11 mg, 0.01 mmol) and stirred for 24 h at room

temperature. The reaction mixture was ﬁltered through a pad

of Celite, and the ﬁltrate was evaporated under reduced

pressure to aﬀord the crude debenzylated product (3.7 mg),

which was dissolved in acetonitrile (0.2 mL) and treated with

dimethyl acetal (2.6 mg, 0.02 mmol) and pTSA (1.0 mg, 4.3

μmol). The reaction was then stirred for 4 h at room

temperature before being quenched with saturated aq.

_H₎_,₁_.₃₉₍_d_,_J₌₇_.₂_H_z_,₃_H₎_;1 C{ H} NMR (126 MHz,

3

1

CDCl ): δ 154.9, 151.2, 138.9, 138.5, 138.2, 128.8, 128.4,

3

1

7

28.2, 128.0, 127.7, 127.6, 126.5, 117.7, 114.6, 97.4, 93.9,

6.3, 75.6, 73.6, 72.3, 72.2, 70.7, 66.3, 55.7, 15.3. HRMS

NaHCO and extracted with EtOAc (5 mL). The organic

(

ESI): m/z calcd for C H O Na [M + Na], 591.2353;

3

35

36

7

layer was separated, collected, dried over Na SO , ﬁltered,

found, 591.2335.

2

4

and concentrated under reduced pressure to aﬀord a crude

residue which was puriﬁed over silica (eluent: EtOAc/hexane,

4-Methoxyphenyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glyc-

ero-α/β-D-gluco-heptopyranoside (S3). A mixture of sulf-

oxide 17 (80.0 mg, 0.11 mmol), TTBP (58.7 mg, 0.23

mmol), and activated 4 Å powdered molecular sieves (160.0

mg) in CH Cl (0.25 mL) was stirred for 1 h at room

temperature under argon and then cooled to −78 °C and

treated with Tf O (21.0 μL, 0.13 mmol). After stirring for 10

min, a solution of p-methoxy phenol (16.0 mg, 0.13 mmol)

in CH Cl (50 μL) was added and continued stirring for 10

h before the reaction was quenched with triethylamine (15.0

μL) at −78 °C. The reaction mixture was diluted with

dichloromethane (10 mL), molecular sieves were ﬁltered oﬀ

through a pad of Celite, and the ﬁltrate was washed with

2

0

1

(

:3) to aﬀord S4 as a white solid (3 mg, 61%). [α] −33.3

D

1

c 0.2, CHCl ); H NMR (900 MHz, CDCl ): δ 7.51−7.48

3

m, 2H), 7.37 (m, 3H), 7.04−7.00 (m, 2H), 6.84 (d, J = 9.1

2

Hz, 2H), 5.86 (s, 1H), 4.88 (d, J = 7.7 Hz, 1H), 4.58 (p, J =

.8 Hz, 1H), 3.90−3.86 (m, 2H), 3.79 (s, 3H), 3.78−3.74

m, 1H), 3.72 (t, J = 7.6 Hz, 1H), 1.49 (d, J = 6.9 Hz, 3H);

6

2

(

1

3

1

C{ H} NMR (226 MHz, CDCl ): δ 155.7, 150.9, 143.1,

2

3

137.3, 129.2, 128.4, 126.4, 118.8, 114.6, 102.5, 94.4, 77.2,

74.1, 73.9, 73.8, 70.4, 68.8, 55.6, 29.7, 11.4; HRMS: m/z

+

calcd for C H O Na [M + Na] , 411.1414; found,

2

1

24

7

411.1400.

P

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

General Procedure C for the Coupling of Glycosyl

J = 7.7 Hz, 1H), 4.15 (d, J = 11.1 Hz, 1H), 4.11 (d, J = 2.8

Hz, 1H), 3.97 (hept, J = 6.2 Hz, 1H), 3.88 (dq, J = 9.0, 6.0

Hz, 1H), 3.79 (dd, J = 9.8, 7.7 Hz, 1H), 3.50 (dd, J = 9.8,

2.9 Hz, 1H), 3.08 (d, J = 8.8 Hz, 1H), 1.29 (d, J = 6.0 Hz,

3H), 1.27 (d, J = 6.3 Hz, 3H), 1.23 (d, J = 6.1 Hz, 3H);

Donors with Acceptors with TTBP/Tf O. A mixture of the

2

donor (1.0 equiv), TTBP (2.0 equiv), and activated 4 Å

powdered molecular sieves (2 g/mmol of the donor) in

CH Cl (0.2 M in the substrate) was stirred for 1 h at room

2

1

3

1

temperature under argon and then cooled to −78 °C and

C{ H} NMR (126 MHz, CDCl ): δ 139.1, 138.9, 138.8,

3

treated with Tf O (1.1 equiv). After 15 min of stirring at −78

2

138.5, 128.4, 128.39, 128.33, 128.17, 128.14, 128.0, 127.8,

127.7, 127.56, 127.52, 127.3, 103.0, 82.8, 79.7, 77.8, 75.2,

°

C, a solution of the glycosyl acceptor (1.1 equiv) in CH Cl

2 2

(

0.5 M in acceptor) was added slowly. The reaction mixture

7

4.5, 73.5, 73.2, 72.8, 72.5, 70.6, 23.6, 22.3, 16.6. HRMS

was stirred for further 4−5 h at −78 °C and then quenched

with triethylamine (0.2 mL). The reaction mixture was

diluted with dichloromethane (10 mL), molecular sieves were

ﬁltered oﬀ through a pad of Celite, and the ﬁltrate was

(

ESI): m/z calcd for C H O Na [M + Na], 619.3030;

3

8

44

6

found, 619.3030.

Adamantyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-D-glycero-α/

β-D-galacto-heptopyranoside (30). 30α and 30β were

obtained from the reaction of donor 9 (30.0 mg, 44.30

μmol) and 1-adamantanol (7.4 mg, 48.7 μmol) following the

general procedure for glycosylation (ethyl acetate/hexane,

washed with saturated NaHCO . The organic layer was

3

separated, dried over Na SO , ﬁltered, and concentrated

2

4

under reduced pressure. Puriﬁcation by ﬂash column

chromatography on silica gel (hexane/ethyl acetate) aﬀorded

the corresponding α/β-glycopyranosides. The anomeric ratio

1

:19); combined yield (24.1 mg, 79%), α/β = 14.2:1.

22

1

3

0β. Colorless syrup; [α]_D+33.2 (c 0.4, CHCl ); H

3

1

of the products was determined by integration of the H

NMR (500 MHz, CDCl ): δ 7.37−7.18 (m, 20H), 5.31 (d, J

3

NMR spectrum of the crude product mixture.

=

3.7 Hz, 1H), 5.01 (d, J = 11.2 Hz, 1H), 4.82 (d, J = 11.6

Benzyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-D-glycero-α/β-D-

galacto-heptopyranoside (28). 28α and 28β were obtained

from the reaction of donor 9 (40.0 mg, 59.10 μmol) and

benzyl alcohol (6.76 μL, 65.0 μmol) following the general

procedure for glycosylation (ethyl acetate/hexane, 1:9);

combined yield (24.0 mg, 64%), α/β = 6:1.

Hz, 1H), 4.77−4.66 (m, 3H), 4.56 (d, J = 11.1 Hz, 1H), 4.47

(

d, J = 11.2 Hz, 1H), 4.26−4.18 (m, 2H), 4.03 (dd, J = 10.2,

3

2

1

.7 Hz, 1H), 3.97 (dd, J = 10.2, 2.7 Hz, 1H), 3.87−3.76 (m,

H), 2.13 (p, J = 3.2 Hz, 3H), 1.90−1.83 (m, 3H), 1.80−

.70 (m, 3H), 1.66−1.57 (m, 6H), 1.27 (d, J = 5.6 Hz, 3H);

13

1

C{ H} NMR (126 MHz, CDCl ): δ 139.3, 139.2, 138.9,

₈_β_._C_o_l_o_r_l_e_s_s_s_y_r_u_p_;_[_α_]2 +15.9 (c 1.0, CHCl ); H

3

1

3

2

D 3

1

7

38.6, 128.5, 128.3, 128.2, 128.0, 127.84, 127.81, 127.6,

27.5, 127.3, 127.3, 90.5, 79.6, 76.4, 75.0, 74.7, 74.3, 73.3,

3.2, 73.1, 72.8, 70.7, 42.7, 36.4, 30.7, 16.8. HRMS (ESI): m/

NMR (500 MHz, CDCl ): δ 7.40−7.19 (m, 25H), 5.02 (d, J

3

=

1

(

1

=

11.2 Hz, 1H), 4.93−4.85 (m, 2H), 4.75 (d, J = 11.7 Hz,

H), 4.71 (dd, J = 12.1, 5.6 Hz, 2H), 4.57 (d, J = 1.7 Hz,

H), 4.55 (d, J = 2.5 Hz, 1H), 4.51 (d, J = 7.3 Hz, 1H), 4.48

z calcd for C H O Na [M + Na], 711.3656; found,

4

5

52

6

7

11.3649.

3

d, J = 6.4 Hz, 1H), 4.24 (d, J = 2.6 Hz, 1H), 4.20 (d, J =

1.1 Hz, 1H), 4.04 (dd, J = 10.1, 3.5 Hz, 1H), 4.00 (dd, J =

0α. Colorless syrup; [α]²+6.8 (c 1.0, CHCl ); H NMR

2

1

D

3

(

500 MHz, CDCl ): δ 7.41−7.20 (m, 20H), 5.01 (d, J = 11.5

3

0.1, 2.5 Hz, 1H), 3.83 (dq, J = 9.1, 6.0 Hz, 1H), 3.62 (d, J

₉_.₁_H_z_,₁_H₎_,₁_.₃₀₍_d_,_J₌₆_.₀_H_z_,₃_H₎_;1 C{ H} NMR

3

1

Hz, 1H), 4.97 (d, J = 10.9 Hz, 1H), 4.79−4.73 (m, 2H), 4.71

(

d, J = 11.9 Hz, 1H), 4.61 (d, J = 7.8 Hz, 1H), 4.55 (d, J =

(

126 MHz, CDCl ): δ 139.1, 139.0, 138.6, 138.4, 137.1,

3

6

1

.8 Hz, 1H), 4.53 (d, J = 6.3 Hz, 1H), 4.17 (d, J = 11.2 Hz,

H), 4.12 (d, J = 2.8 Hz, 1H), 3.89 (dq, J = 8.9, 6.0 Hz,

H), 3.80 (dd, J = 9.7, 7.7 Hz, 1H), 3.10 (d, J = 9.1 Hz,

H), 2.15 (t, J = 3.3 Hz, 3H), 1.98−1.89 (m, 3H), 1.85−1.73

1

7

28.5, 128.4, 128.39, 128.33, 128.2, 127.96, 127.90, 127.8,

27.7, 127.5, 127.48, 127.42, 95.6, 79.7, 76.4, 74.8, 74.7, 73.7,

3.3, 73.2, 72.8, 70.6, 68.6, 16.5. HRMS (ESI): m/z calcd for

C H O Na [M + Na], 667.3030; found, 667.3016.

4

2

44

6

23

1

(m, 3H), 1.71−1.57 (m, 6H), 1.29 (d, J = 6.0 Hz, 3H);

2

8α. Colorless syrup; [α] −21.7 (c 0.6, CHCl ); H

D

3

1

3

1

C{ H} NMR (126 MHz, CDCl ): δ 139.2, 139.0, 138.9,

3

NMR (500 MHz, CDCl ): δ 7.36 (d, J = 6.9 Hz, 2H), 7.37−

3

1

7

38.6, 128.4, 128.39, 128.32, 128.16, 128.13, 127.8, 127.7,

27.57, 127.53, 127.50, 127.3, 96.9, 83.1, 79.6, 77.8, 75.3,

4.9, 74.6, 73.6, 73.2, 72.7, 70.6, 42.8, 36.4, 30.8, 16.8.

7

5

4

.17 (m, 23H), 5.01 (d, J = 11.4 Hz, 1H), 4.93 (dd, J = 11.4,

.4 Hz, 2H), 4.80−4.71 (m, 2H), 4.70 (d, J = 11.9 Hz, 1H),

.65 (d, J = 12.0 Hz, 1H), 4.55 (d, J = 3.4 Hz, 1H), 4.43 (d,

HRMS (ESI): m/z calcd for C H O Na [M + Na],

J = 7.7 Hz, 1H), 4.17 (d, J = 11.2 Hz, 1H), 4.13 (d, J = 2.8

Hz, 1H), 3.98−3.84 (m, 2H), 3.51 (dd, J = 9.7, 2.9 Hz, 1H),

45 52

6

7

11.3656; found, 711.3638.

Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-7-

1

3

1

3

.10 (d, J = 8.8 Hz, 1H), 1.33 (d, J = 6.0 Hz, 3H); C{ H}

deoxy-D-glycero-α/β-D-galacto-heptopyranosyl)-α-D-gluco-

pyranoside (31). 31α and 31β were obtained from the

reaction of donor 9 (30.0 mg, 44.30 μmol) and acceptor 23

NMR (126 MHz, CDCl ): δ 139.1, 138.8, 138.7, 138.4,

3

1

7

37.6, 128.5, 128.44, 128.41, 128.3, 128.2, 128.0, 127.8,

27.7, 127.5, 127.4, 103.0, 95.5, 82.8, 79.6, 77.8, 75.2, 74.6,

3.4, 73.2, 72.7, 70.9, 70.6, 16.6. HRMS (ESI): m/z calcd for

20

(22.7 mg, 48.8 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:4); combined yield

(31.0 mg, 70%), α/β = 4.0:1.

C H O Na [M + Na], 667.3030; found, 667.3021.

4

2

44

6

Isopropyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-D-glycero-α-D-

2

1

galacto-heptopyranoside (29α). 29α and 29β were obtained

from the reaction of donor 9 (40.0 mg, 59.10 μmol) and

isopropyl alcohol (5.0 μL, 65.00 μmol) following the general

procedure for glycosylation (ethyl acetate/hexane, 1:9);

combined yield (26.0 mg, 73%), α/β = 16.7:1.

31β. Colorless syrup; [α]

D 3

+32.0 (c 0.5, CHCl ); H

NMR (500 MHz, CDCl ): δ 7.35−7.17 (m, 35H), 5.01−4.98

3

(m, 2H), 4.95 (d, J = 10.9 Hz, 1H), 4.85 (d, J = 11.0 Hz,

1H), 4.80 (d, J = 4.0 Hz, 1H), 4.78 (d, J = 5.0 Hz, 1H),

4.72−4.65 (m, 4H), 4.59 (d, J = 11.0 Hz, 1H), 4.55 (d, J =

5.4 Hz, 1H), 4.54−4.51 (m, 2H), 4.48 (d, J = 11.3 Hz, 1H),

4.20 (d, J = 11.3 Hz, 1H), 4.16 (d, J = 2.8 Hz, 1H), 4.03

(dd, J = 10.0, 3.6 Hz, 1H), 3.96 (t, J = 9.2 Hz, 1H), 3.89

(dd, J = 10.1, 2.8 Hz, 1H), 3.83−3.71 (m, 3H), 3.68 (d, J =

2

Only 29α data given here: colorless syrup; [α] −4.0 (c

D

1

0

2

4

.2, CHCl ); H NMR (500 MHz, CDCl ): δ 7.38−7.19 (m,

3

0H), 4.99 (d, J = 11.5 Hz, 1H), 4.92 (d, J = 10.7 Hz, 1H),

.80−4.66 (m, 3H), 4.53 (dd, J = 11.4, 7.2 Hz, 2H), 4.38 (d,

Q

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1

=

0.4 Hz, 1H), 3.59 (t, J = 9.4 Hz, 1H), 3.52 (d, J = 9.1 Hz,

Methyl 4-O-(2,3,4,6-Tetra-O-benzyl-7-deoxy-D-glycero-α/

β-D-galacto-heptopyranosyl)-2,3-O-isopropylidene-α-L-

rhamnopyranoside (33). 33α and 33β were obtained from

the reaction of 9 (40.0 mg, 59.10 μmol) and acceptor 25

H), 3.40 (dd, J = 9.6, 3.6 Hz, 1H), 3.28 (s, 3H), 1.21 (d, J

1

3

1

5.9 Hz, 3H); C{ H} NMR (126 MHz, CDCl ): δ 139.2,

3

1

7

39.0, 138.9, 138.6, 138.4, 138.3, 128.47, 128.43, 128.3,

28.2, 128.1, 128.0, 128.0, 127.95, 127.90, 127.7, 127.66,

27.62, 127.5, 127.4, 127.3, 97.9, 97.8, 82.1, 80.3, 78.9, 78.0,

6.5, 75.7, 75.1, 74.8, 74.7, 73.6, 73.4, 72.89, 72.84, 72.53,

0.50, 70.3, 66.0, 55.1, 16.4. HRMS (ESI): m/z calcd for

36

(14.2 mg, 65.00 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:9); combined yield

(34.3 mg, 77%), α/β = 5.1:1.

2

1

33β. Colorless syrup; [α] +21.5 (c 0.4, CHCl ); H

D

3

C H O Na [M + Na], 1023.4653; found, 1023.4644.

NMR (500 MHz, CDCl ): δ 7.37−7.20 (m, 20H), 5.08 (d, J

6

3

68 11

3

22

1

3

1α. Colorless syrup; [α] +12.1 (c 1.1, CHCl ); H

= 3.7 Hz, 1H), 5.02 (d, J = 11.3 Hz, 1H), 4.83−4.72 (m,

4H), 4.67 (d, J = 11.8 Hz, 1H), 4.57 (d, J = 11.2 Hz, 1H),

4.47 (d, J = 11.3 Hz, 1H), 4.25−4.20 (m, 2H), 4.14 (t, J =

6.4 Hz, 1H), 4.11−4.03 (m, 2H), 3.92 (dd, J = 10.2, 2.7 Hz,

1H), 3.86 (dq, J = 9.1, 6.0 Hz, 1H), 3.74 (d, J = 9.0 Hz,

1H), 3.66 (dq, J = 9.9, 6.3 Hz, 1H), 3.34 (s, 3H), 3.29 (dd, J

= 9.9, 6.7 Hz, 1H), 1.46 (s, 3H), 1.34−1.31 (m, 6H), 1.28 (s,

D

3

NMR (500 MHz, CDCl ): δ 7.39−7.15 (m, 35H), 5.04−4.89

3

(

m, 3H), 4.83−4.67 (m, 6H), 4.65 (d, J = 12.1 Hz, 1H), 4.60

d, J = 3.5 Hz, 1H), 4.52 (q, J = 10.8 Hz, 3H), 4.27 (d, J =

7

9

1

.7 Hz, 1H), 4.20−4.14 (m, 2H), 4.11 (s, 1H), 3.98 (t, J =

.1 Hz, 1H), 3.87 (dt, J = 16.6, 7.8 Hz, 3H), 3.60 (dd, J =

0.7, 5.5 Hz, 1H), 3.56−3.42 (m, 3H), 3.32 (s, 3H), 3.06 (d,

13

1

13

1

J = 8.7 Hz, 1H), 1.27 (d, J = 6.2 Hz, 3H); C{ H} NMR

3H); C{ H} NMR (126 MHz, CDCl ): δ 139.3, 138.9,

3

(

126 MHz, CDCl ): δ 139.1, 139.0, 138.8, 138.6, 138.5,

138.7, 138.6, 128.4, 128.3, 128.2, 128.1, 127.7, 127.65,

127.61, 127.4, 127.3, 127.2, 109.1, 99.2, 98.2, 82.9, 79.4, 76.6,

75.6, 74.9, 74.6, 74.1, 73.9, 73.3, 72.6, 70.5, 64.6, 54.7, 28.0,

26.1, 17.9, 16.4. HRMS (ESI): m/z calcd for C H O Na

3

1

7

38.4, 138.2, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.97,

27.91, 127.86, 127.81, 127.7, 127.6, 127.5, 127.4, 127.3,

04.7, 98.0, 82.8, 82.2, 80.0, 79.4, 78.2, 77.8, 75.7, 75.2, 74.9,

4.6, 73.5, 73.4, 73.0, 72.7, 70.6, 70.3, 70.0, 68.8, 55.2, 16.6.

45

54 10

[M + Na], 777.3609; found, 777.3600.

2

1

HRMS (ESI): m/z calcd for C H O Na [M + Na],

33α. Colorless syrup; [α] −8.0 (c 0.9, CHCl ); H NMR

63

68 11

D

3

1

023.4653; found, 1023.4642.

-O-(2,3,4,6-Tetra-O-benzyl-7-deoxy-D-glycero-α/β-D-gal-

(500 MHz, CDCl ): δ 7.37 (d, J = 7.8 Hz, 2H), 7.36−7.19

3

6

(m, 18H), 5.01 (d, J = 11.5 Hz, 1H), 4.89 (d, J = 11.0 Hz,

1H), 4.83 (d, J = 9.4 Hz, 2H), 4.81−4.65 (m, 3H), 4.55−

4.50 (m, 2H), 4.25−4.15 (m, 2H), 4.12−4.04 (m, 2H), 3.89

(dq, J = 8.1, 6.0 Hz, 1H), 3.73 (dd, J = 9.8, 7.6 Hz, 1H),

3.60 (qd, J = 10.0, 5.5 Hz, 2H), 3.54 (dd, J = 9.7, 2.9 Hz,

1H), 3.38 (s, 3H), 3.09 (d, J = 8.7 Hz, 1H), 1.48 (s, 3H),

acto-heptopyranosyl)-1,2:3,4-O-diisopropylidene-α-D-galac-

topyranose (32). 32α and 32β were obtained from the

reaction of donor 9 (30.0 mg, 44.30 μmol) and acceptor 24

35

(

12.7 mg, 48.80 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:4); combined yield

1

3

(

22.0 mg, 62%), α/β = 3.2:1.

1.35−1.26 (m, 9H); C NMR (126 MHz, CDCl ): δ 139.3,

3

2

1

3

2β. Colorless syrup; [α]²+2.8 (c 0.5, CHCl ); H NMR

139.0, 138.9, 138.4, 128.5, 128.3, 128.2, 128.2, 127.8, 127.75,

127.72, 127.5, 127.4, 127.3, 109.3, 102.5, 98.1, 82.8, 79.8,

78.8, 78.3, 77.7, 75.9, 75.1, 74.6, 73.9, 73.3, 72.8, 70.6, 64.3,

54.9, 28.0, 26.3, 18.1, 16.7. HRMS (ESI): m/z calcd for

C H O Na [M + Na], 777.3609; found, 777.3607.

D

3

500 MHz, CDCl ): δ 7.38−7.18 (m, 20H), 5.51 (d, J = 5.1

3

Hz, 1H), 5.02 (d, J = 3.7 Hz, 1H), 4.99 (d, J = 11.3 Hz, 1H),

.83 (d, J = 11.7 Hz, 1H), 4.78−4.69 (m, 3H), 4.61−4.52

m, 2H), 4.49 (d, J = 11.2 Hz, 1H), 4.34 (dd, J = 8.0, 1.9

4

(

4

5

54 10

Hz, 1H), 4.26−4.16 (m, 2H), 4.10−3.98 (m, 2H), 3.95 (dd,

Methyl 2,3,6-Tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-7-

J = 10.1, 2.7 Hz, 1H), 3.87−3.72 (m, 2H), 3.66 (dd, J = 10.3,

deoxy-D-glycero-α/β-D-galacto-heptopyranosyl)-α-D-gluco-

pyranoside (34). 34α and 34β were obtained from the

reaction of 9 (30.0 mg, 44.30 μmol) and acceptor 26 (22.7

7

3

.7 Hz, 1H), 3.61 (d, J = 8.8 Hz, 1H), 1.53 (s, 3H), 1.43 (s,

H), 1.32 (s, 3H), 1.32−1.26 (m, 6H); C{ H} NMR (126

13

1

37

MHz, CDCl ): δ 139.2, 139.1, 138.8, 138.6, 128.4, 128.36,

mg, 48.80 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:4); combined yield

(25.0 mg, 55%), α/β = 2.1:1.

3

1

7

1

8

28.32, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3,

09.2, 108.6, 97.6, 96.3, 79.5, 76.3, 74.75, 74.72, 73.5, 73.0,

2.8, 72.7, 70.8, 70.7, 70.5, 65.8, 65.7, 26.2, 26.1, 24.9, 24.7,

6.4. HRMS (ESI): m/z calcd for C H O Na [M + Na],

2

1

34β. Colorless syrup; [α] +14.0 (c 0.8, CHCl ); H

D

3

NMR (500 MHz, CDCl ): δ 7.36−7.12 (m, 35H), 5.73 (d, J

47

56 11

3

19.3714; found, 819.3716.

3

= 3.8 Hz, 1H), 4.96 (d, J = 4.6 Hz, 1H), 4.94 (d, J = 4.3 Hz,

1H), 4.80 (d, J = 11.4 Hz, 1H), 4.68 (d, J = 12.0 Hz, 2H),

4.64 (d, J = 11.2 Hz, 2H), 4.65−4.50 (m, 6H), 4.46 (t, J =

11.4 Hz, 2H), 4.22 (d, J = 11.2 Hz, 1H), 4.16 (d, J = 3.7 Hz,

1H), 4.07−4.03 (m, 1H), 4.01 (dd, J = 10.3, 3.8 Hz, 1H),

3.92−3.87 (m, 1H), 3.86−3.78 (m, 2H), 3.75 (dd, J = 10.3,

2.6 Hz, 1H), 3.68 (dd, J = 10.3, 2.5 Hz, 1H), 3.61−3.52 (m,

2H), 3.47 (d, J = 8.9 Hz, 1H), 3.38 (s, 3H), 1.28 (d, J = 6.1

2α. Colorless syrup; [α]²−32.7 (c 1.0, CHCl ); H

2

1

D

3

NMR (500 MHz, CDCl ): δ 7.45−7.41 (m, 2H), 7.35−7.19

3

(

m, 18H), 5.55 (d, J = 5.0 Hz, 1H), 5.03 (d, J = 11.1 Hz,

1

4

H), 4.99 (d, J = 11.4 Hz, 1H), 4.80 (d, J = 11.9 Hz, 1H),

.76−4.68 (m, 2H), 4.58 (dd, J = 7.9, 2.4 Hz, 1H), 4.53 (dd,

J = 11.3, 6.5 Hz, 2H), 4.39 (d, J = 7.7 Hz, 1H), 4.30 (dd, J =

5

.0, 2.4 Hz, 1H), 4.22 (dd, J = 7.9, 1.8 Hz, 1H), 4.17 (d, J =

1.1 Hz, 1H), 4.15−4.04 (m, 3H), 3.93−3.78 (m, 2H), 3.69

1

3

1

Hz, 3H); C{ H} NMR (126 MHz, CDCl ): δ 139.0, 138.9,

3

(

dd, J = 10.1, 7.0 Hz, 1H), 3.51 (dd, J = 9.7, 2.8 Hz, 1H),

138.8, 138.7, 138.3, 138.1, 138.0, 128.5, 128.4, 128.3, 128.29,

128.22, 128.1, 128.0, 127.7, 127.67, 127.61, 127.5, 127.4,

127.3, 127.2, 127.0, 97.7, 97.0, 82.2, 80.3, 79.5, 75.6, 74.8,

74.7, 74.4, 74.1, 73.8, 73.5, 73.1, 72.9, 72.6, 70.5, 69.8, 69.4,

55.1, 16.4. HRMS (ESI): m/z calcd for C H O Na [M +

.10 (d, J = 8.6 Hz, 1H), 1.50 (s, 3H), 1.44 (s, 3H), 1.32−

1

3

1

.27 (m, 9H); C{ H} NMR (126 MHz, CDCl ): δ 139.16,

3

39.12, 138.8, 138.4, 128.6, 128.5, 128.3, 128.19, 128.12,

28.0, 127.8, 127.7, 127.54, 127.50, 127.3, 109.4, 108.7,

05.1, 96.5, 82.4, 79.1, 77.7, 74.7, 74.6, 73.5, 73.2, 72.7, 71.5,

0.9, 70.6, 69.4, 67.4, 26.1, 26.0, 25.1, 24.5, 16.6. HRMS

6

3

68 11

Na], 1023.4653; found, 1023.4657.

2

1

34α. Colorless syrup; [α] −3.1 (c 1.1, CHCl ); H NMR

D

3

(500 MHz, CDCl ): δ 7.39−7.19 (m, 32H), 7.19−7.15 (m,

47

56 11

3

found, 819.3725.

1H), 7.15−7.10 (m, 2H), 5.12−5.00 (m, 2H), 4.86 (d, J =

R

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1

3

2

1

3

9

3

1

2.2 Hz, 1H), 4.79 (s, 2H), 4.75−4.63 (m, 4H), 4.59 (d, J =

.7 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.47 (dd, J = 11.4,

.0 Hz, 2H), 4.38 (d, J = 12.0 Hz, 1H), 4.27 (d, J = 7.6 Hz,

H), 4.17 (d, J = 11.2 Hz, 1H), 4.10 (d, J = 2.8 Hz, 1H),

.91 (d, J = 9.2 Hz, 1H), 3.88−3.77 (m, 2H), 3.76 (dd, J =

.7, 7.7 Hz, 1H), 3.71−3.57 (m, 2H), 3.55−3.45 (m, 2H),

.38 (s, 3H), 3.34 (dd, J = 9.7, 2.9 Hz, 1H), 2.92 (s, 1H),

4.70 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 11.6 Hz, 1H), 4.61−

4.55 (m, 3H), 4.08 (dd, J = 10.0, 3.7 Hz, 1H), 4.02 (dd, J =

10.1, 2.6 Hz, 1H), 3.91 (d, J = 2.6 Hz, 1H), 3.83−3.73 (m,

1

3

1

2H), 0.99 (d, J = 6.1 Hz, 3H); C{ H} NMR (126 MHz,

CDCl ): δ 139.4, 138.9, 138.7, 138.6, 137.3, 128.6, 128.48,

3

128.41, 128.3, 128.2, 127.9, 127.8, 127.69, 127.63, 127.59,

127.55, 127.4, 94.6, 80.3, 76.6, 75.7, 75.56, 75.50, 74.3, 73.8,

73.0, 68.0, 16.7. HRMS (ESI): m/z calcd for C H O Na

13

1

.09 (d, J = 5.9 Hz, 3H); C{ H} NMR (126 MHz,

4

2

44

6

CDCl ): δ 139.7, 139.5, 139.1, 138.8, 138.7, 138.6, 138.0,

[M + Na], 667.3030; found, 667.3023.

3

2

1

7

28.49, 128.46, 128.42, 128.37, 128.30, 128.2, 128.1, 128.0,

27.9, 127.89, 127.86, 127.77, 127.72, 127.70, 127.5, 127.45,

27.43, 127.3, 127.2, 126.9, 102.9, 98.6, 83.0, 80.4, 80.2, 79.0,

7.6, 76.5, 75.5, 75.2, 74.5, 73.8, 73.6, 73.3, 72.8, 72.7, 70.5,

0.0, 67.9, 55.4, 16.5. HRMS (ESI): m/z calcd for

36α. Colorless syrup; [α] −12.4 (c 0.6, CHCl ); H

D

3

NMR (500 MHz, CDCl ): δ 7.45−7.19 (m, 25H), 5.07 (d, J

3

= 11.6 Hz, 1H), 5.01−4.93 (m, 2H), 4.83 (d, J = 11.7 Hz,

1H), 4.80−4.73 (m, 3H), 4.70−4.60 (m, 3H), 4.47 (d, J =

7.7 Hz, 1H), 3.94 (dd, J = 9.8, 7.7 Hz, 1H), 3.87 (dq, J =

8.2, 6.3 Hz, 1H), 3.78 (d, J = 2.8 Hz, 1H), 3.52 (dd, J = 9.8,

2.8 Hz, 1H), 3.24 (d, J = 8.2 Hz, 1H), 0.92 (d, J = 6.3 Hz,

C H O Na [M + Na], 1023.4653; found, 1023.4653.

6

3

68 11

3

-O-(2,3,4,6-Tetra-O-benzyl-7-deoxy-D-glycero-α/β-D-gal-

1

3

1

acto-heptopyranosyl)-1,2:5,6-di-O-isopropylidene-α-D-glu-

cofuranose (35). 35α and 35β were obtained from the

reaction of 9 (30.0 mg, 44.30 μmol) and acceptor 27 (12.7

mg, 48.80 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:4); combined yield

3H); C{ H} NMR (126 MHz, CDCl ): δ 139.2, 138.7,

3

138.5, 137.7, 128.5, 128.4, 128.3, 127.9, 127.75, 127.70,

127.6, 127.5, 102.8, 83.3, 79.8, 79.7, 75.2, 74.1, 74.1, 73.7,

73.3, 70.8, 16.8. HRMS (ESI): m/z calcd for C H O Na

4

2

44

6

[M + Na], 667.3030; found, 667.3021.

(

25.0 mg, 68%), α/β = 1:2.9.

Isopropyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glycero-α/β-D-

galacto-heptopyranoside (37). 37α and 37β were obtained

from the reaction of donor 12 (40.0 mg, 59.10 μmol) and

isopropyl alcohol (5.0 μL, 65.00 μmol) following the general

procedure for glycosylation (ethyl acetate/hexane, 1:9);

combined yield (20.0 mg, 58%), α/β = 5.9:1.

5β. Colorless syrup; [α]²+32.7 (c 1.0, CHCl ); H

2

1

3

D 3

NMR (500 MHz, CDCl ): δ 7.37−7.31 (m, 8H), 7.30−7.21

3

(

m, 12H), 5.88 (d, J = 3.5 Hz, 1H), 5.30 (d, J = 3.8 Hz,

1

4

1

H), 5.03 (d, J = 11.2 Hz, 1H), 4.82 (d, J = 11.7 Hz, 1H),

.79−4.70 (m, 3H), 4.59 (dd, J = 7.3, 3.7 Hz, 2H), 4.51−

.44 (m, 2H), 4.27−4.20 (m, 3H), 4.16−4.07 (m, 2H),

.06−3.98 (m, 2H), 3.95−3.79 (m, 2H), 3.57 (d, J = 9.0 Hz,

H), 1.48 (s, 3H), 1.40 (s, 3H), 1.35 (d, J = 6.0 Hz, 3H),

2

3

1

37β. Colorless syrup; [α] +20.9 (c 1.0, CHCl ); H

D

3

NMR (500 MHz, CDCl ): δ 7.41−7.38 (m, 2H), 7.38−7.32

3

(m, 4H), 7.32−7.21 (m, 14H), 5.08 (d, J = 11.4 Hz, 1H),

5.01 (d, J = 3.8 Hz, 1H), 4.92 (d, J = 11.5 Hz, 1H), 4.84−

4.73 (m, 2H), 4.68 (d, J = 11.4 Hz, 2H), 4.57 (dd, J = 11.6,

3.6 Hz, 2H), 4.07 (dd, J = 10.1, 3.9 Hz, 1H), 4.00−3.93 (m,

2H), 3.90 (dd, J = 2.7, 1.0 Hz, 1H), 3.78−3.70 (m, 2H), 1.21

(d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.1 Hz, 3H), 0.98 (d, J =

13

1

.27 (s, 3H), 1.24 (s, 3H); C{ H} NMR (126 MHz,

CDCl ): δ 139.0, 138.8, 138.6, 138.2, 128.6, 128.4, 128.36,

3

1

7

2

28.32, 127.9, 127.89, 127.80, 127.7, 127.6, 127.5, 127.48,

27.42, 111.8, 109.1, 105.2, 98.6, 84.1, 81.4, 80.0, 79.2, 76.3,

4.8, 74.7, 74.4, 73.5, 73.0, 72.9, 72.3, 70.9, 67.2, 27.1, 26.9,

6.3, 25.5, 16.6. HRMS (ESI): m/z calcd for C H O Na

1

3

1

5.9 Hz, 3H); C{ H} NMR (126 MHz, CDCl ): δ 139.5,

47

56 11

3

[

M + Na], 819.3714; found, 819.3703.

139.0, 138.83, 138.80, 128.45, 128.41, 128.3, 128.2, 128.1,

127.7, 127.6, 127.55, 127.50, 127.2, 94.9, 80.2, 76.7, 75.9,

75.5, 75.4, 74.3, 73.7, 73.2, 73.0, 68.7, 23.2, 21.1, 16.8.

HRMS (ESI): m/z calcd for C H O Na [M + Na],

22

1

3

5α. Colorless syrup; [α] −2.2 (c 0.8, CHCl ); H NMR

D

3

(

500 MHz, CDCl ): δ 7.34−7.22 (m, 20H), 5.75 (d, J = 3.7

3

Hz, 1H), 5.00 (d, J = 11.6 Hz, 1H), 4.79 (d, J = 11.1 Hz,

3

8

44

6

1

4

1

4

8

H), 4.74−4.65 (m, 3H), 4.55 (d, J = 11.2 Hz, 1H), 4.53−

.47 (m, 2H), 4.45−4.36 (m, 2H), 4.34 (dd, J = 4.8, 3.1 Hz,

H), 4.23 (d, J = 3.1 Hz, 1H), 4.20 (d, J = 11.1 Hz, 1H),

.12 (d, J = 2.7 Hz, 1H), 4.10−4.02 (m, 2H), 3.87 (dq, J =

.8, 6.1 Hz, 1H), 3.73 (dd, J = 9.7, 7.7 Hz, 1H), 3.51 (dd, J

619.3030; found, 619.3036.

2

3

1

37α. Colorless syrup; [α] +3.2 (c 1.0, CHCl ); H NMR

D

3

(500 MHz, CDCl ): δ 7.38−7.35 (m, 4H), 7.35−7.23 (m,

3

16H), 5.05 (d, J = 11.6 Hz, 1H), 4.96 (d, J = 10.8 Hz, 1H),

4.84 (d, J = 11.7 Hz, 1H), 4.79−4.68 (m, 3H), 4.60 (dd, J =

11.6, 10.0 Hz, 2H), 4.42 (d, J = 7.8 Hz, 1H), 4.04 (hept, J =

6.1 Hz, 1H), 3.88−3.79 (m, 2H), 3.75 (dd, J = 2.8, 1.1 Hz,

1H), 3.51 (dd, J = 9.8, 2.8 Hz, 1H), 3.22 (dd, J = 8.3, 1.0

Hz, 1H), 1.30 (d, J = 6.2 Hz, 3H), 1.22 (d, J = 6.1 Hz, 3H),

=

9.6, 2.8 Hz, 1H), 3.10 (d, J = 8.6 Hz, 1H), 1.47 (s, 3H),

1

3

1

7

.42 (s, 3H), 1.34 (s, 3H), 1.29 (d, J = 6.0 Hz, 3H), 1.21 (s,

H); C{ H} NMR (126 MHz, CDCl ): δ 139.1, 138.5,

1

3

1

3

38.4, 138.3, 129.7, 128.5, 128.4, 128.2, 127.87, 127.81,

27.7, 127.6, 127.58, 127.51, 127.4, 111.8, 108.5, 105.2,

02.5, 82.8, 82.7, 80.9, 80.4, 79.4, 78.0, 75.3, 74.5, 73.5, 73.0,

2.7, 70.6, 65.9, 26.7, 26.6, 26.1, 25.4, 16.5. HRMS (ESI): m/

1

3

1

0.89 (d, J = 6.4 Hz, 3H); C{ H} NMR (126 MHz,

CDCl ): δ 139.2, 138.9, 138.7, 128.5, 128.4, 128.37, 128.34,

3

128.30, 127.7, 127.69, 127.63, 127.60, 127.4, 102.5, 83.5,

79.7, 79.6, 75.24, 75.21, 74.2, 74.1, 73.8, 73.3, 72.1, 23.8,

22.2, 16.8. HRMS (ESI): m/z calcd for C H O Na [M +

z calcd for C H O Na [M + Na], 819.3714; found,

8

4

7

56 11

19.3703.

Benzyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glycero-α/β-D-

3

8

44

6

Na], 619.3030; found, 619.3016.

galacto-heptopyranoside (36). 36α and 36β were obtained

from the reaction of donor 12 (25.0 mg, 36.90 μmol) and

benzyl alcohol (4.2 μL, 40.60 μmol) following the general

procedure for glycosylation (ethyl acetate/hexane, 1:9);

combined yield (12.6 mg, 53%), α/β = 1.6:1.

Adamantyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glycero-α/β-

D-galacto-heptopyranoside (38). 38α and 38β were

obtained from the reaction of donor 12 (40.0 mg, 59.10

μmol) and 1-adamantanol (9.9 mg, 65.00 μmol) following

the general procedure for glycosylation (ethyl acetate/hexane,

1:19); combined yield (20.0 mg, 70%), α/β = 4.1:1.

6β. Colorless syrup; [α]²+64.4 (c 1.0, CHCl ); H

1

3

D 3

2

3

1

NMR (500 MHz, CDCl ): δ 7.43−7.21 (m, 25H), 5.08 (d, J

38β. Colorless syrup; [α] +23.1 (c 1.0, CHCl ); H

3

D 3

=

11.5 Hz, 1H), 4.97−4.91 (m, 2H), 4.81−4.72 (m, 3H),

NMR (500 MHz, CDCl ): δ 7.41−7.19 (m, 20H), 5.38 (d, J

3

S

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

3.9 Hz, 1H), 5.10 (d, J = 11.5 Hz, 1H), 4.89 (d, J = 11.5

pubs.acs.org/joc

Article

=

128.15, 128.0, 127.9, 127.67, 127.61, 127.5, 127.4, 104.3,

98.0, 83.3, 82.0, 79.9, 79.8, 79.4, 78.2, 75.7, 75.2, 74.9, 74.8,

74.3, 74.2, 73.5, 73.4, 73.2, 70.0, 68.6, 55.2, 17.0. HRMS

(ESI): m/z calcd for C H O Na [M + Na], 1023.4653;

Hz, 1H), 4.77 (d, J = 11.5 Hz, 1H), 4.72 (d, J = 4.1 Hz, 2H),

4

1

2

3

.65 (d, J = 11.3 Hz, 1H), 4.55 (dd, J = 11.5, 2.8 Hz, 2H),

.06 (dd, J = 10.2, 3.8 Hz, 1H), 3.98 (dd, J = 10.0, 2.7 Hz,

H), 3.92−3.87 (m, 2H), 3.74 (p, J = 6.4 Hz, 1H), 2.14−

.00 (m, 3H), 1.96−1.85 (m, 3H), 1.79 (dd, J = 9.0, 5.7 Hz,

6

3

68 11

found, 1023.4648.

6-O-(2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glycero-α/β-D-gal-

acto-heptopyranosyl)-1,2:3,4-O-diisopropylidene-α-D-galac-

topyranose (40). 40α and 40β were obtained from the

reaction of donor 12 (35.0 mg, 51.70 μmol) and acceptor 24

(14.8 mg, 56.90 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:4); combined yield

(24.7 mg, 60%), α/β = 1.7:1.

H), 1.54 (s, 6H), 1.02 (d, J = 6.3 Hz, 3H); ¹C{ H} NMR

3

1

(

126 MHz, CDCl ): δ 139.3, 139.1, 138.97, 138.90, 128.4,

3

1

7

28.35, 128.30, 128.2, 128.1, 128.0, 127.6, 127.57, 127.55,

27.54, 127.46, 127.44, 127.2, 90.2, 80.1, 76.7, 76.0, 75.7,

4.9, 74.45, 74.40, 73.4, 73.1, 72.9, 42.5, 36.3, 30.7, 16.8.

HRMS (ESI): m/z calcd for C H O Na [M + Na],

45

52

6

2

3

1

7

11.3656; found, 711.3646.

3

40β. Colorless syrup; [α] +28.3 (c 0.2, CHCl ); H

NMR (500 MHz, CDCl ): δ 7.38 (d, J = 6.9 Hz, 4H), 7.35−

D 3

8α. Colorless syrup; [α]²+17.3 (c 0.7, CHCl ); H

3

1

D

3

NMR (500 MHz, CDCl ): δ 7.37−7.22 (m, 20H), 5.05 (d, J

7.22 (m, 16H), 5.53 (d, J = 5.0 Hz, 1H), 5.15 (d, J = 3.8 Hz,

1H), 5.05 (d, J = 11.4 Hz, 1H), 4.91 (d, J = 11.7 Hz, 1H),

4.79 (d, J = 11.9 Hz, 1H), 4.76 (d, J = 11.7 Hz, 1H), 4.73−

4.68 (m, 2H), 4.58 (d, J = 4.4 Hz, 1H), 4.56 (d, J = 4.0 Hz,

1H), 4.53 (dd, J = 7.9, 2.4 Hz, 1H), 4.28 (dd, J = 5.1, 2.3

Hz, 1H), 4.16 (dd, J = 7.9, 1.9 Hz, 1H), 4.10 (dd, J = 10.0,

3.7 Hz, 1H), 4.04 (td, J = 6.9, 2.0 Hz, 1H), 3.97 (dd, J =

10.0, 2.7 Hz, 1H), 3.90−3.85 (m, 2H), 3.77−3.69 (m, 3H),

1.52 (s, 3H), 1.40 (s, 3H), 1.32 (s, 3H), 1.26 (s, 3H), 0.98

3

=

11.6 Hz, 1H), 4.99 (d, J = 10.9 Hz, 1H), 4.84 (d, J = 11.6

Hz, 1H), 4.74 (d, J = 11.3 Hz, 2H), 4.69 (d, J = 11.3 Hz,

1

4

2

H), 4.64 (d, J = 7.7 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H),

.56 (d, J = 11.2 Hz, 1H), 3.85−3.77 (m, 2H), 3.75 (d, J =

.8 Hz, 1H), 3.51 (dd, J = 9.9, 2.8 Hz, 1H), 3.20 (d, J = 8.3

Hz, 1H), 2.05 (br s, 3H), 1.95−1.89 (m, 3H), 1.86−1.79 (m,

1

3

1

3

H), 1.61−1.52 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H); C{ H}

NMR (126 MHz, CDCl ): δ 139.1, 138.9, 138.7, 128.5,

3

1

3

1

7

28.45, 128.41, 128.35, 128.30, 128.2, 127.8, 127.6, 127.5,

27.4, 96.6, 83.8, 79.7, 79.3, 75.3, 75.1, 75.0, 74.2, 74.1, 73.8,

3.2, 42.8, 36.3, 30.7, 16.7. HRMS (ESI): m/z calcd for

(d, J = 6.2 Hz, 3H); C{ H} NMR (126 MHz, CDCl ): δ

3

139.5, 139.0, 138.8, 138.7, 128.4, 128.3, 128.2, 128.1, 127.9,

127.8, 127.7, 127.6, 127.56, 127.52, 127.3, 127.2, 109.2,

108.5, 96.4, 96.1, 80.0, 76.4, 76.3, 75.7, 75.6, 75.35, 75.32,

75.2, 74.3, 73.7, 73.2, 72.9, 72.2, 70.9, 70.8, 70.7, 65.4, 65.1,

26.3, 26.1, 25.0, 24.6, 16.8. HRMS (ESI): m/z calcd for

C H O Na [M + Na], 819.3714; found, 819.3701.

C H O Na [M + Na], 711.3656; found, 711.3647.

4

5

52

6

Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-7-

deoxy-L-glycero-α/β-D-galacto-heptopyranosyl)-α-D-gluco-

pyranoside (39). 39α and 39β were obtained from the

reaction of donor 12 (30.0 mg, 44.30 μmol) and acceptor 23

4

7

56 11

2

3

1

40α. Colorless syrup; [α] −2.8 (c 1.0, CHCl ); H NMR

D

3

(

22.7 mg, 48.80 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:4); combined yield

24.0 mg, 54%), α/β = 1.1:1.

(500 MHz, CDCl ): δ 7.46−7.42 (m, 2H), 7.38−7.22 (m,

3

18H), 5.56 (d, J = 4.9 Hz, 1H), 5.06 (d, J = 11.2 Hz, 1H),

5.03 (d, J = 11.6 Hz, 1H), 4.87 (d, J = 11.7 Hz, 1H), 4.74

(dd, J = 11.6, 2.8 Hz, 3H), 4.61 (d, J = 5.1 Hz, 1H), 4.58 (d,

J = 5.1 Hz, 2H), 4.55 (dd, J = 7.9, 2.4 Hz, 1H), 4.45 (d, J =

7.6 Hz, 1H), 4.29 (dd, J = 5.0, 2.4 Hz, 1H), 4.24−4.17 (m,

2H), 4.14−4.07 (m, 1H), 3.87 (dd, J = 9.8, 7.6 Hz, 1H), 3.82

(dq, J = 8.5, 6.3 Hz, 1H), 3.78−3.70 (m, 2H), 3.52 (dd, J =

9.8, 2.7 Hz, 1H), 3.25 (d, J = 8.1 Hz, 1H), 1.49 (s, 3H), 1.40

(s, 3H), 1.30 (s, 3H), 1.29 (s, 3H), 0.90 (d, J = 6.4 Hz, 3H);

(

9β. Colorless syrup; [α]²+55.9 (c 0.3, CHCl ); H

3

1

3

D 3

NMR (500 MHz, CDCl ): δ 7.38−7.31 (m, 8H), 7.30−7.17

3

(

m, 27H), 5.10 (d, J = 3.7 Hz, 1H), 5.07 (d, J = 11.5 Hz,

1

4

3

8

H), 4.93 (d, J = 10.8 Hz, 1H), 4.85 (d, J = 11.8 Hz, 1H),

.79 (dd, J = 10.9, 5.9 Hz, 2H), 4.73 (d, J = 11.9 Hz, 1H),

.73−4.64 (m, 4H), 4.59−4.50 (m, 5H), 4.07 (dd, J = 10.1,

.6 Hz, 1H), 3.95 (t, J = 9.3 Hz, 1H), 3.94−3.83 (m, 2H),

.82 (d, J = 3.6 Hz, 1H), 3.78−3.68 (m, 3H), 3.65 (d, J =

.2 Hz, 1H), 3.61 (t, J = 9.5 Hz, 1H), 3.40 (dd, J = 9.6, 3.6

1

3

1

C{ H} NMR (126 MHz, CDCl ): δ 139.2, 139.1, 138.7,

3

138.6, 128.7, 128.5, 128.4, 128.3, 128.29, 128.20, 127.8,

127.7, 127.69, 127.63, 127.5, 127.45, 127.42, 109.3, 108.6,

104.8, 96.4, 83.0, 79.7, 79.2, 79.1, 75.2, 74.7, 74.2, 74.1, 73.8,

73.4, 71.5, 70.8, 70.6, 69.8, 67.6, 26.1, 26.0, 25.1, 24.5, 16.8.

HRMS (ESI): m/z calcd for C H O Na [M + Na],

1

3

1

Hz, 1H), 3.29 (s, 3H), 0.93 (d, J = 6.3 Hz, 3H); C{ H}

NMR (126 MHz, CDCl ): δ 139.6, 139.0, 138.9, 138.8,

3

1

7

1

38.5, 138.3, 128.49, 128.45, 128.42, 128.3, 128.2, 128.1,

28.09, 128.06, 127.97, 127.90, 127.7, 127.64, 127.60, 127.4,

27.3, 127.2, 98.0, 97.5, 82.1, 80.3, 79.4, 78.0, 75.8, 75.7,

5.5, 75.3, 75.1, 74.3, 73.4, 73.4, 72.8, 72.3, 70.6, 66.0, 55.0,

6.7. HRMS (ESI): m/z calcd for C H O Na [M + Na],

4

7

56 11

819.3714; found, 819.3698.

Methyl 4-O-(2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glycero-α/

β-D-galacto-heptopyranosyl)-2,3-O-isopropylidene-α-L-

rhamnopyranoside (41). 41α and 41β were obtained from

the reaction of 12 (30.0 mg, 44.30 μmol) and acceptor 25

(10.6 mg, 48.80 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:9); combined yield

(23.0 mg, 69%), α/β = 1.8:1.

63

68 11

023.4653; found, 1023.4648.

9α. Colorless syrup; [α]²+9.3 (c 1.0, CHCl ); H NMR

3

1

3

D 3

(

500 MHz, CDCl ): δ 7.36−7.16 (m, 33H), 7.13−7.06 (m,

3

2

4

7

H), 5.04 (d, J = 11.5 Hz, 1H), 4.98−4.91 (m, 2H), 4.84−

.73 (m, 5H), 4.71 (d, J = 11.7 Hz, 1H), 4.67−4.62 (m, 2H),

.59−4.52 (m, 3H), 4.45 (d, J = 11.2 Hz, 1H), 4.35 (d, J =

.6 Hz, 1H), 4.21 (dd, J = 10.8, 2.0 Hz, 1H), 3.96 (t, J = 9.3

2

3

1

41β. Colorless syrup; [α] +30.5 (c 0.2, CHCl ); H

NMR (500 MHz, CDCl ): δ 7.37−7.35 (m, 2H), 7.34−7.22

D

3

Hz, 1H), 3.89 (dd, J = 9.8, 7.6 Hz, 1H), 3.86−3.78 (m, 2H),

(m, 18H), 5.20 (d, J = 3.7 Hz, 1H), 5.04 (d, J = 11.2 Hz,

1H), 4.82−4.79 (m, 3H), 4.75−4.65 (m, 3H), 4.62−4.56 (m,

2H), 4.27 (dd, J = 7.2, 5.7 Hz, 1H), 4.09 (dd, J = 10.2, 3.7

Hz, 1H), 3.98 (d, J = 2.1 Hz, 1H), 3.97−3.93 (m, 2H),

3.96−3.94 (m, 2H), 3.67 (dq, J = 9.9, 6.3 Hz, 1H), 3.36 (dd,

J = 9.9, 7.1 Hz, 1H), 3.33 (s, 3H), 1.43 (s, 3H), 1.32 (d, J =

3

0

.76 (d, J = 2.7 Hz, 1H), 3.67 (dd, J = 10.8, 5.1 Hz, 1H),

.54−3.43 (m, 3H), 3.27 (s, 3H), 3.22 (d, J = 8.0 Hz, 1H),

13

1

.94 (d, J = 6.4 Hz, 3H); C{ H} NMR (126 MHz,

CDCl ): δ 139.2, 138.9, 138.7, 138.6, 138.5, 138.4, 138.2,

3

1

28.5, 128.48, 128.40, 128.37, 128.33, 128.30, 128.2, 128.19,

T

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

.3 Hz, 3H), 1.17 (s, 3H), 1.11 (d, J = 6.4 Hz, 3H); ¹³C{ H}

pubs.acs.org/joc

Article

1

6

3-O-(2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glycero-α/β-D-gal-

acto-heptopyranosyl)-1,2:5,6-di-O-isopropylidene-α-D-glu-

cofuranose (43). 43α and 43β were obtained from the

reaction of 12 (60.0 mg, 88.60 μmol) and acceptor 27 (25.4

mg, 97.60 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:4); combined yield

(44.0 mg, 61%), α/β = 1:10.2.

NMR (126 MHz, CDCl ): δ 139.7, 139.0, 138.9, 138.7,

3

1

7

2

28.4, 128.3, 128.29, 128.22, 127.98, 127.94, 127.6, 127.5,

27.45, 127.40, 127.3, 127.2, 109.0, 98.1 (2C), 81.6, 79.8,

5.7, 75.6, 75.4, 74.2, 73.9, 73.7, 73.0, 72.6, 64.5, 54.7, 28.2,

6.4, 17.9, 16.5. HRMS (ESI): m/z calcd for C H O Na

45

54 10

[M + Na], 777.3609; found, 777.3601.

2

3

1

23

1

4

1α. Colorless syrup; [α] −4.4 (c 1.0, CHCl ); H NMR

43β. Colorless syrup; [α]_D+14.0 (c 1.0, CHCl ); H

NMR (500 MHz, CDCl ): δ 7.39−7.19 (m, 20H), 5.83 (d, J

D

3

(

500 MHz, CDCl ): δ 7.40−7.37 (m, 2H), 7.36−7.23 (m,

3

1

4

3

8H), 5.07 (d, J = 11.6 Hz, 1H), 4.93 (d, J = 11.2 Hz, 1H),

.87 (d, J = 7.8 Hz, 1H), 4.85−4.81 (m, 2H), 4.76−4.68 (m,

H), 4.63−4.55 (m, 2H), 4.23 (t, J = 6.4 Hz, 1H), 4.07 (d, J

= 3.6 Hz, 1H), 5.19 (d, J = 3.7 Hz, 1H), 5.08 (d, J = 11.4

Hz, 1H), 4.91 (d, J = 3.6 Hz, 1H), 4.88 (d, J = 11.7 Hz, 1H),

4.78−4.72 (m, 3H), 4.71−4.66 (m, 1H), 4.55 (dd, J = 11.8,

5.7 Hz, 2H), 4.47 (q, J = 6.3 Hz, 1H), 4.19 (dd, J = 6.8, 2.8

Hz, 1H), 4.15 (d, J = 2.8 Hz, 1H), 4.11−4.04 (m, 2H), 4.01

(dd, J = 8.5, 5.3 Hz, 1H), 3.88−3.83 (m, 2H), 3.76 (dq, J =

8.2, 6.3 Hz, 1H), 3.61 (d, J = 8.3 Hz, 1H), 1.41 (s, 3H), 1.40

=

1

5.8 Hz, 1H), 3.85−3.70 (m, 5H), 3.65 (dq, J = 9.7, 6.1 Hz,

H), 3.55 (dd, J = 9.8, 2.9 Hz, 1H), 3.38 (s, 3H), 3.23 (d, J

7.9 Hz, 1H), 1.39 (s, 3H), 1.36 (d, J = 6.2 Hz, 3H), 1.29

=

13

1

(

s, 3H), 0.95 (d, J = 6.3 Hz, 3H); C{ H} NMR (126 MHz,

1

3

1

CDCl ): δ 139.1, 138.9, 138.7, 128.44, 128.41, 128.3, 128.28,

(s, 3H), 1.21 (s, 3H), 1.02−0.91 (m, 6H); C{ H} NMR

3

1

9

7

28.20, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 109.3, 102.3,

8.2, 83.3, 79.8, 79.3, 78.7, 78.4, 75.9, 75.1, 74.9, 74.8, 74.2,

3.7, 73.1, 64.5, 54.9, 27.9, 26.3, 18.1, 16.8. HRMS (ESI): m/

(126 MHz, CDCl ): δ 139.2, 138.76, 138.71, 138.6, 128.49,

3

128.40, 128.29, 128.25, 128.1, 127.7, 127.68, 127.61, 127.5,

127.3, 111.6, 108.8, 105.3, 99.5, 82.9, 82.8, 81.0, 79.5, 76.1,

75.6, 75.5, 74.4, 73.6, 73.2, 73.0, 72.8, 66.7, 26.9, 26.8, 26.0,

25.3, 16.7. HRMS (ESI): m/z calcd for C H O Na [M +

Na], 819.3714; found, 819.3712.

43α. Colorless syrup; [α] −14.8 (c 0.3, CHCl ); H

NMR (500 MHz, CDCl ): δ 7.37−7.26 (m, 20H), 5.73 (d, J

= 3.7 Hz, 1H), 5.06 (d, J = 11.6 Hz, 1H), 4.83−4.68 (m,

5H), 4.61 (d, J = 11.6 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H),

4.51 (d, J = 3.8 Hz, 1H), 4.43 (dd, J = 6.8, 4.1 Hz, 2H), 4.35

(d, J = 3.2 Hz, 1H), 4.30 (dd, J = 5.1, 3.1 Hz, 1H), 4.11−

4.02 (m, 2H), 3.85−3.74 (m, 3H), 3.52 (dd, J = 9.7, 2.8 Hz,

1H), 3.24 (d, J = 8.1 Hz, 1H), 1.46 (s, 3H), 1.34 (s, 3H),

z calcd for C H O Na [M + Na], 777.3609; found,

4

5

54 10

7

77.3592.

Methyl 2,3,6-Tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-7-

4

7

56 11

2

3

1

deoxy-L-glycero-α/β-D-galacto-heptopyranosyl)-α-D-gluco-

pyranoside (42). 42α and 42β were obtained from the

reaction of 12 (30.0 mg, 44.30 μmol) and acceptor 26 (22.7

mg, 48.80 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:4); combined yield

D

3

(

26.0 mg, 59%), α/β = 1:3.9.

3

1

4

2β. Colorless syrup; [α]²+28.2 (c 1.0, CHCl ); H

D 3

NMR (500 MHz, CDCl ): δ 7.33−7.15 (m, 35H), 5.70 (d, J

3

1

3

1

=

3.9 Hz, 1H), 5.02 (d, J = 11.4 Hz, 1H), 4.93 (d, J = 11.5

1.30 (s, 3H), 1.20 (s, 3H), 0.93 (d, J = 6.3 Hz, 3H); C{ H}

Hz, 1H), 4.82 (d, J = 11.6 Hz, 1H), 4.74 (d, J = 11.5 Hz,

NMR (126 MHz, CDCl ): δ 139.0, 138.6, 138.5, 138.3,

3

1

3

6

H), 4.69−4.61 (m, 4H), 4.59−4.49 (m, 6H), 4.37 (d, J =

2.3 Hz, 1H), 4.05−3.99 (m, 2H), 3.91−3.86 (m, 1H),

.82−3.76 (m, 3H), 3.75−3.65 (m, 2H), 3.60 (dd, J = 10.6,

.5 Hz, 1H), 3.56 (d, J = 8.2 Hz, 1H), 3.43 (dd, J = 9.6, 3.5

128.55, 128.50, 128.3, 128.04, 128.01, 127.8, 127.74, 127.70,

127.6, 127.5, 111.7, 108.6, 105.2, 101.7, 83.3, 82.7, 80.3, 80.1,

80.0, 79.3, 75.3, 74.5, 74.3, 74.2, 73.6, 73.3, 66.0, 26.7, 26.6,

26.1, 25.4, 16.9. HRMS (ESI): m/z calcd for C H O Na

47

56 11

1

3

1

Hz, 1H), 3.36 (s, 1H), 0.93 (d, J = 6.3 Hz, 3H); C{ H}

[M + Na], 819.3714; found, 819.3704.

Isopropyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glycero-α-D-

gluco-heptopyranoside (44). 44α was obtained from the

reaction of 17 (35.0 mg, 51.70 μmol) and acceptor isopropyl

alcohol (4.4 μL, 56.10 μmol) following the general procedure

for glycosylation (ethyl acetate/hexane, 3:97); yield (17.2 mg,

57%), only α.

3

2

0

1

44α. Colorless syrup; [α] +15.7 (c 0.2, CHCl ); H

D 3

NMR (500 MHz, CDCl ): δ 7.42−7.19 (m, 18H), 7.13 (d, J

3

= 7.2 Hz, 2H), 4.96 (d, J = 10.8 Hz, 1H), 4.92 (d, J = 10.8

Hz, 1H), 4.82 (d, J = 10.9 Hz, 1H), 4.76−4.63 (m, 3H), 4.39

(m, 3H), 4.06−3.93 (m, 2H), 3.83 (t, J = 9.2 Hz, 1H), 3.62

(t, J = 9.1 Hz, 1H), 3.46 (t, J = 8.5 Hz, 1H), 3.19−3.10 (m,

1H), 1.32 (d, J = 6.4 Hz, 3H), 1.30 (d, J = 6.1 Hz, 3H), 1.23

1

3

1

(d, J = 6.2 Hz, 3H); C{ H} NMR (126 MHz, CDCl ): δ

3

138.8, 138.73, 138.72, 128.44, 128.41, 128.3, 128.0, 127.9,

127.7, 127.65, 127.61, 127.5, 102.9, 85.4, 82.4, 78.0, 77.7,

75.7, 74.8, 74.7, 72.5, 71.4, 70.5, 23.8, 22.3, 15.6; HRMS

+

(ESI): m/z calcd for C H O Na [M + Na] , 619.3030;

38 44

6

1

9

7

40.2, 139.4, 139.0, 138.68, 138.62, 138.1, 129.0, 128.48,

28.40, 128.29, 128.25, 128.1, 128.0, 127.99, 127.93, 127.7,

27.67, 127.62, 127.5, 127.48, 127.42, 127.1, 126.7, 102.5,

8.7, 83.4, 80.5, 80.26, 80.21, 78.9, 75.9, 75.7, 75.2, 74.7,

4.6, 73.9, 73.5, 73.3, 73.2, 70.3, 68.1, 55.3, 17.7. HRMS

found, 619.3007.

Adamantyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glycero-α-D-

gluco-heptopyranoside (45). 45α was obtained from the

reaction of 17 (35.0 mg, 51.70 μmol) and 1-adamantanol

(8.6 mg, 56.10 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 5:95); yield (19.8 mg,

56%), only α.

(

ESI): m/z calcd for C H O Na [M + Na], 1023.4653;

63 68 11

found, 1023.4633.

U

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

5α. Colorless syrup; [α]²⁰+13.6 (c 0.8, CHCl ); H

pubs.acs.org/joc

Article

1

4

glycosylation (ethyl acetate/hexane, 7:93); combined yield

(57.4 mg, 63%), α/β = 7.9:1.

D

3

NMR (500 MHz, CDCl ): δ 7.40−7.18 (m, 18H), 7.14 (dd,

3

2

0

1

J = 8.8, 7.3 Hz, 2H), 5.00 (d, J = 11.0 Hz, 1H), 4.90 (d, J =

47β. Colorless syrup; [α] +7.4 (c 0.1, CHCl ); H NMR

D 3

1

4

6

1

0.8 Hz, 1H), 4.81 (d, J = 10.9 Hz, 1H), 4.75−4.64 (m, 3H),

.60 (d, J = 7.8 Hz, 1H), 4.42−4.33 (m, 2H), 3.96 (tt, J =

.4, 3.2 Hz, 1H), 3.82 (t, J = 9.3 Hz, 1H), 3.62 (dd, J = 12.2,

.0 Hz, 1H), 3.49−3.41 (m, 1H), 3.13 (dd, J = 9.6, 2.0 Hz,

H), 2.14 (s, 3H), 1.92 (d, J = 11.3 Hz, 3H), 1.80 (d, J =

(500 MHz, CDCl ): δ 7.71−7.06 (m, 20H), 5.11 (d, J = 3.4

3

Hz, 1H), 4.96 (d, J = 10.6 Hz, 1H), 4.90−4.73 (m, 4H), 4.68

(dd, J = 11.7, 4.4 Hz, 2H), 4.39−4.33 (m, 2H), 4.17−4.06 (t,

J = 6.5 Hz, 1H), 4.11−4.10 (d, J = 6.02 Hz, 1H), 4.05−3.98

(m, 2H), 3.85−3.79 (m, 2H), 3.74−3.69 (m, 1H), 3.61−3.59

(dd, J = 9.88, 3.42 Hz, 1H), 3.36 (s, 3H), 3.30 (dd, J = 10.0,

6.6 Hz, 1H), 1.48 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H), 1.35 (d,

1.4 Hz, 3H), 1.68−1.58 (m, 6H), 1.30 (t, J = 6.5 Hz, 3H);

1

3

1

C{ H} NMR (151 MHz, CDCl ): δ 138.73, 138.71, 138.69,

3

1

3

1

7

38.66, 134.5, 133.7, 130.2, 129.8, 129.0, 128.5, 128.35,

28.31, 128.27, 128.25, 128.24, 128.0, 127.95, 127.56, 127.54,

27.4, 96.8, 85.6, 82.2, 77.9, 77.7, 75.7, 74.9, 74.9, 74.6, 71.2,

J = 6.3 Hz, 3H), 1.29 (s, 3H); C{ H} NMR (126 MHz,

CDCl ): δ 138.7, 138.7, 138.5, 138.2, 129.7, 128.5, 128.4,

3

128.2, 128.17, 128.15, 127.8, 127.65, 127.61, 127.5, 109.1,

98.5, 98.2, 83.1, 82.2, 80.5, 78.1, 77.4, 75.7, 74.9, 74.1, 73.9,

0.4, 45.3, 45.3, 42.9, 42.8, 36.3, 36.1, 30.7, 30.7, 30.7, 15.9;

+

HRMS (ESI): m/z calcd for C H O Na [M + Na] ,

71.8, 70.7, 64.6, 54.8, 28.1, 26.2, 17.9, 15.7; HRMS (ESI):

45

52

6

+

7

11.3656; found, 711.3642.

Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-7-

m/z calcd for C45

H

O

54

10Na [M + Na] , 777.3609; found,

777.3598.

47α. Colorless syrup; [α]²

0

D

+13.5 (c l.0, CHCl

); H NMR

3

1

deoxy-L-glycero-α/β-D-gluco-heptopyranosyl)-α-D-glucopyr-

anoside (46). 46α and 46β were obtained from the reaction

of donor 17 (35.0 mg, 51.70 μmol) and acceptor 23 (26.0

mg, 56.93 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:9); combined yield

(500 MHz, CDCl

): δ 8.09−6.21 (m, 20H), 4.92 (dd, J =

3

11.0, 6.0 Hz, 2H), 4.88−4.80 (m, 3H), 4.74 (d, J = 10.9 Hz,

1H), 4.69−4.63 (m, 2H), 4.47 (d, J = 10.9 Hz, 1H), 4.40 (d,

J = 11.9 Hz, 1H), 4.21 (t, J = 6.0 Hz, 1H), 4.09 (d, J = 5.7

Hz, 1H), 4.00 (dd, J = 6.3, 2.1 Hz, 1H), 3.84 (t, J = 9.3 Hz,

1H), 3.71−3.60 (m, 3H), 3.42 (t, J = 8.5 Hz, 1H), 3.38 (s,

3H), 3.17 (dd, J = 9.7, 2.1 Hz, 1H), 1.49 (s, 3H), 1.36 (d, J

(

25.0 mg, 49%), α/β = 23.6:1.

0

1

4

6β. Colorless syrup; [α]²+6.0 (c 0.1, CHCl ); H NMR

D 3

(

900 MHz, CDCl ): δ 7.71−6.93 (m, 35H), 5.04 (d, J = 3.5

3

1

3

1

Hz, 1H), 4.98 (d, J = 10.8 Hz, 1H), 4.95 (dd, J = 10.9, 7.0

Hz, 2H), 4.87 (d, J = 11.1 Hz, 1H), 4.83 (d, J = 10.8 Hz,

= 4.9 Hz, 3H), 1.33−1.32 (m, 6H); C{ H} NMR (126

MHz, CDCl ): δ 138.9, 138.8, 138.7, 128.4, 128.4, 128.37,

3

1

4

3

H), 4.76 (d, J = 10.6 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H),

.70−4.63 (m, 4H), 4.60 (d, J = 12.0 Hz, 1H), 4.57 (d, J =

.6 Hz, 1H), 4.33 (dd, J = 11.5, 5.7 Hz, 2H), 4.01 (t, J = 9.3

128.32, 127.9, 127.7, 127.68, 127.64, 127.62, 127.57, 127.50,

109.4, 102.4, 98.1, 85.3, 82.4, 79.0, 78.4, 77.9, 77.7, 76.0,

75.6, 74.8, 74.7, 71.4, 70.1, 64.3, 54.9, 28.1, 26.3, 18.1, 15.7;

+

Hz, 1H), 3.97 (t, J = 9.3 Hz, 1H), 3.92 (q, J = 6.9 Hz, 1H),

HRMS (ESI): m/z calcd for C45

H

O

54

10Na [M + Na] ,

3

1

=

.83−3.77 (m, 2H), 3.77−3.73 (m, 1H), 3.71−3.65 (m, 2H),

.58 (dd, J = 9.6, 3.5 Hz, 1H), 3.54 (dd, J = 9.8, 1.7 Hz,

H), 3.47 (dd, J = 9.5, 3.5 Hz, 1H), 3.37 (s, 3H), 1.23 (d, J

777.3609; found, 777.3585.

Methyl 2,3,6-Tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-7-

deoxy-L-glycero-α/β-D-gluco-heptopyranosyl)-α-D-glucopyr-

anoside (48). 48α and 48β were obtained from the reaction

of 17 (80.0 mg, 0.12 mmol) and acceptor 26 (60.0 mg, 0.13

mmol) following the general procedure for glycosylation

(ethyl acetate/hexane, 1:9); combined yield (71.0 mg, 59%),

α/β = 7.7:1.

1

3

1

6.4 Hz, 3H); C{ H} NMR (226 MHz, CDCl ): δ 138.8,

3

1

7

6

38.79, 138.6, 138.5, 138.4, 138.3, 128.5, 128.45, 128.43,

28.41, 128.37, 128.33, 128.27, 128.21, 128.1, 128.02, 128.01,

28.0, 127.9, 127.8, 127.7, 127.66, 127.63, 127.61, 127.59,

27.57, 127.4, 127.3, 97.9, 97.0, 82.2, 80.2, 79.9, 77.8, 77.6,

7.2, 75.7, 75.6, 75.0, 74.6, 73.4, 73.4, 72.3, 71.2, 70.8, 70.3,

5.8, 55.1, 14.1; HRMS (ESI): m/z calcd for C H O N

48β. Colorless syrup; [α]²+30.0 (c 0.1, CHCl ); H

0

1

D

3

NMR (600 MHz, CDCl ): δ 7.98−6.79 (m, 35H), 5.70 (d, J

63

72 11

3

+

[M + NH ] , 1018.5073; found, 1018.5068.

= 3.5 Hz, 1H), 5.00 (d, J = 11.6 Hz, 1H), 4.92−4.83 (m,

2H), 4.80 (dd, J = 11.9, 8.9 Hz, 1H), 4.73 (d, J = 10.6 Hz,

1H), 4.68 (d, J = 12.1 Hz, 1H), 4.63−4.59 (m, 2H), 4.59−

4.53 (m, 3H), 4.51−4.45 (m, 2H), 4.37−4.32 (m, 2H), 4.06

(dd, J = 9.6, 8.4 Hz, 1H), 3.90 (dd, J = 9.9, 8.4 Hz, 1H),

3.88−3.82 (m, 2H), 3.81−3.71 (m, 2H), 3.69 (dd, J = 10.7,

2.3 Hz, 1H), 3.58 (ddd, J = 8.1, 6.0, 3.5 Hz, 2H), 3.54 (dd, J

= 9.8, 1.9 Hz, 1H), 3.51 (dd, J = 9.9, 3.5 Hz, 1H), 3.38 (s,

4

2

0

1

4

6α. Colorless syrup; [α] +25.3 (c 0.4, CHCl ); H

D

3

NMR (500 MHz, CDCl ): δ 7.71−6.93 (m, 35H), 4.97

3

(

1

ddd, J = 10.1, 7.3, 2.0 Hz, 2H), 4.90 (dd, J = 10.8, 2.0 Hz,

H), 4.83−4.60 (m, 8H), 4.58 (t, J = 2.8 Hz, 1H), 4.51 (dd,

J = 11.2, 2.0 Hz, 1H), 4.41 (dd, J = 10.9, 2.0 Hz, 1H), 4.35

dd, J = 12.0, 2.0 Hz, 1H), 4.28 (dd, J = 7.8, 2.0 Hz, 1H),

(

4

2

9

.18 (dd, J = 10.8, 2.3 Hz, 1H), 3.98 (td, J = 9.1, 2.2 Hz,

H), 3.90−3.79 (m, 2H), 3.66−3.57 (m, 2H), 3.50 (ddd, J =

.3, 6.2, 2.9 Hz, 2H), 3.47−3.40 (m, 1H), 3.30 (d, J = 1.9

1

3

1

3H), 1.19 (d, J = 6.4 Hz, 3H); C{ H} NMR (151 MHz,

CDCl ): δ 139.0, 138.9, 138.6, 138.3, 138.1, 138.0, 137.9,

3

Hz, 3H), 3.11 (d, J = 9.5 Hz, 1H), 1.31 (dd, J = 6.5 Hz,

128.4, 128.38, 128.34, 128.30, 128.26, 128.21, 128.19, 128.12,

128.0, 127.9, 127.7, 127.65, 127.64, 127.57, 127.50, 126.8,

97.8, 96.2, 82.3, 82.1, 80.2, 79.7, 77.8, 75.6, 74.7, 74.3, 74.1,

73.4, 73.4, 73.2, 72.4, 71.4, 70.6, 69.6, 69.1, 55.1, 15.2;

1

3

1

3

1

8

7

H); C{ H} NMR (126 MHz, CDCl ): δ 138.8, 138.6,

3

38.5, 138.4, 138.1, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8,

27.6, 127.6, 127.5, 127.49, 127.41, 104.6, 97.9, 85.2, 82.1,

2.0, 79.9, 78.2, 77.8, 77.6, 75.7, 75.6, 74.8, 74.8, 74.7, 73.3,

+

HRMS (ESI): m/z calcd for C H O Na [M + Na] ,

6

3

68 11

1.5, 70.3, 70.0, 68.9, 55.2, 15.4; HRMS (ESI): m/z calcd for

1023.4653; found, 1023.4615.

+

20

1

C H O Na [M + Na] , 1023.4653; found, 1023.4614.

48α. Colorless syrup; [α]_D+23.0 (c 0.2, CHCl ); H

6

3

68 11

3

Methyl 4-O-(2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glycero-α/

NMR (500 MHz, CDCl ): δ 7.44−7.38 (m, 2H), 7.34−7.21

3

β-D-gluco-heptopyranosyl)-2,3-O-isopropylidene-α-L-rham-

nopyranoside (47). 47α and 47β were obtained from the

reaction of 17 (80.0 mg, 0.12 mmol) and acceptor 25 (28.3

mg, 0.13 mmol) following the general procedure for

(m, 28H), 7.20−7.15 (m, 2H), 7.14−7.06 (m, 3H), 5.19 (d,

J = 11.4 Hz, 1H), 4.88 (d, J = 10.8 Hz, 1H), 4.85−4.71 (m,

6H), 4.65 (d, J = 12.0 Hz, 1H), 4.61 (m, 2H), 4.58−4.56 (m,

2H), 4.49 (d, J = 11.1 Hz, 1H), 4.41 (d, J = 12.1 Hz, 1H),

V

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

4

9

3

.34 (d, J = 7.8 Hz, 1H), 4.03−3.90 (m, 2H), 3.86 (q, J =

.5 Hz, 3H), 3.58 (d, J = 10.0 Hz, 1H), 3.52−3.45 (m, 3H),

.40 (t, J = 8.5 Hz, 1H), 3.35 (s, 3H), 3.02 (dd, J = 9.7, 2.1

1H), 3.35−3.29 (m, 1H), 1.27 (dd, J = 6.3, 1.7 Hz, 3H), 1.17

(dd, J = 6.2, 1.7 Hz, 3H), 1.07 (dd, J = 6.6, 1.8 Hz, 3H);

1

3

1

C{ H} NMR (151 MHz, CDCl ): δ 138.9, 138.7, 138.3,

3

13

1

Hz, 1H), 1.30 (d, J = 6.3 Hz, 3H); C{ H} NMR (126

MHz, CDCl ): δ 139.8, 138.9, 138.8, 138.7, 138.6, 138.0,

138.0, 128.45, 128.42, 128.38, 128.3, 128.2, 128.14, 128.12,

128.0, 127.9, 127.8, 127.64, 127.60, 127.5, 127.4, 94.2, 82.5,

80.3, 78.6, 76.8, 75.8, 74.8, 73.1, 73.0, 72.1, 70.9, 70.6, 69.5,

68.5, 23.3, 21.0, 13.9; HRMS (ESI): m/z calcd for

3

1

7

28.6, 128.5, 128.49, 128.41, 128.38, 128.32, 128.2, 128.1,

28.0, 127.91, 127.88, 127.75, 127.6, 127.5, 127.35, 127.31,

27.0, 102.9, 98.6, 85.4, 83.0, 80.9, 79.0, 77.9, 77.8, 75.7,

+

C H O Na [M + Na] , 619.3030; found, 619.3011.

3

8

44

6

2

0

1

5.7, 74.9, 74.7, 73.8, 73.5, 72.1, 70.3, 69.9, 67.9, 55.4, 15.3;

50α. Colorless syrup; [α] +6.9 (c 0.1, CHCl ); H NMR

D 3

+

HRMS (ESI): m/z calcd for C H O N [M + NH ] ,

(600 MHz, CDCl ): δ 7.66−7.17 (m, 18H), 7.17 (dd, J =

63

72 11

4

3

1

018.5100; found, 1018.5063.

-O-(2,3,4,6-Tetra-O-benzyl-7-deoxy-L-glycero-α/β-D-

6.7, 2.9 Hz, 2H), 5.00 (d, J = 10.8 Hz, 1H), 4.96 (d, J = 10.9

Hz, 1H), 4.84 (d, J = 10.9 Hz, 1H), 4.79 (d, J = 10.9 Hz,

1H), 4.72 (d, J = 10.9 Hz, 1H), 4.62−4.56 (m, 2H), 4.48 (d,

J = 7.8 Hz, 1H), 4.06−4.02 (m, 2H), 3.84 (qd, J = 6.6, 1.5

Hz, 1H), 3.67 (t, J = 9.0 Hz, 1H), 3.54 (dd, J = 9.9, 1.5 Hz,

1H), 3.42 (ddd, J = 9.9, 8.2, 3.4 Hz, 2H), 1.34 (d, J = 6.2

Hz, 3H), 1.27 (d, J = 6.1 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H);

3

gluco-heptopyranosyl)-1,2:5,6-di-O-isopropylidene-α-D-glu-

cofuranose (49). 49α and 49β were obtained from the

reaction of 17 (40.0 mg, 59.10 μmol) and acceptor 27 (16.9

mg, 65.00 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:9); combined yield

1

3

1

(

30.0 mg, 63%), α/β = 1.7:1.

C{ H} NMR (151 MHz, CDCl ): δ 138.9, 138.6, 138.5,

3

2

1

4

9β. Colorless syrup; [α]²+40.9 (c 0.5, CHCl ); H

138.0, 128.5, 128.4, 128.39, 128.31, 128.27, 128.21, 128.1,

127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 102.4, 85.3, 82.5,

78.1, 76.8, 76.0, 75.7, 74.8, 74.6, 73.6, 72.6, 70.6, 29.7, 23.9,

22.4, 14.4; ESI-HRMS: m/z calcd for C H O Na [M +

D

3

NMR (500 MHz, CDCl ): δ 7.35−7.22 (m, 18H), 7.16−7.12

3

(

m, 2H), 5.87 (d, J = 3.7 Hz, 1H), 5.39 (d, J = 3.5 Hz, 1H),

4

1

4

.96 (d, J = 10.8 Hz, 1H), 4.84 (d, J = 10.6 Hz, 1H), 4.79−

.74 (m, 2H), 4.71−4.64 (m, 2H), 4.58 (d, J = 3.7 Hz, 1H),

.46 (ddd, J = 8.6, 6.1, 4.5 Hz, 1H), 4.36 (d, J = 11.6 Hz,

H), 4.30 (d, J = 10.7 Hz, 1H), 4.25 (d, J = 2.8 Hz, 1H),

.09 (dd, J = 8.5, 2.8 Hz, 1H), 4.06−3.99 (m, 3H), 3.95 (t, J

3

8

44

6

+

Na] , 619.3030; found, 619.3009.

Adamantyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-D-glycero-α/

β-D-gluco-heptopyranoside (51). 51α and 51β were

obtained from the reaction of donor 19 (35.0 mg, 51.70

μmol) and 1-adamantanol (8.6 mg, 56.10 μmol) following

the general procedure for glycosylation (ethyl acetate/hexane,

5:95) as colorless syrup; combined yield (18.2 mg, 52%), α/β

=

9.4 Hz, 1H), 3.78 (t, J = 9.4 Hz, 1H), 3.60 (dd, J = 9.8,

3

1

.6 Hz, 1H), 3.54 (dd, J = 9.8, 1.4 Hz, 1H), 1.48 (s, 3H),

1

3

1

.42−1.34 (m, 6H), 1.27 (s, 3H), 1.24 (s, 3H). C{ H}

NMR (126 MHz, CDCl ): δ 138.6, 138.3, 138.1, 128.56,

= 1.1:1.

3

1

7

2

28.50, 128.1, 128.0, 127.9, 127.89, 127.84, 127.80, 127.7,

27.6, 111.8, 109.2, 105.2, 97.5, 84.2, 81.9, 81.4, 79.9, 79.6,

7.7, 75.7, 75.2, 74.5, 73.0, 72.3, 71.1, 70.9, 67.3, 27.1, 26.8,

6.2, 25.6, 15.7. HRMS (ESI): m/z calcd for C H O Na

51α/β. H NMR (600 MHz, CDCl ): δ 7.99−6.88 (m,

3

40H), 5.31 (d, J = 3.7 Hz, 1H), 5.04 (dd, J = 10.9, 4.5 Hz,

2H), 4.95 (d, J = 10.8 Hz, 1H), 4.88−4.79 (m, 4H), 4.72

(dd, J = 9.6, 6.7 Hz, 5H), 4.64−4.54 (m, 6H), 4.23 (dd, J =

10.4, 1.5 Hz, 1H), 4.09 (t, J = 9.2 Hz, 1H), 3.82 (qt, J = 7.3,

3.5 Hz, 2H), 3.68 (t, J = 8.9 Hz, 1H), 3.55 (dd, J = 10.1, 1.7

Hz, 1H), 3.49 (dd, J = 9.7, 3.7 Hz, 1H), 3.46−3.33 (m, 3H),

2.17−2.13 (m, 8H), 1.97−1.92 (m, 7H), 1.89−1.81 (m, 8H),

1.68−1.59 (m, 12H), 1.16 (d, J = 6.6 Hz, 3H), 1.13 (d, J =

47

56 11

[M + Na], 819.3714; found, 819.3724.

2

1

4

9α. Colorless syrup; [α]²+6.7 (c 1.0, CHCl ); H NMR

D 3

(

7

500 MHz, CDCl ): δ 7.34−7.21 (m, 18H), 7.17 (dd, J =

3

.8, 1.8 Hz, 2H), 5.76 (d, J = 3.7 Hz, 1H), 4.90 (d, J = 10.9

Hz, 1H), 4.85−4.76 (m, 2H), 4.73 (s, 2H), 4.65 (d, J = 11.7

1

3

1

Hz, 1H), 4.52−4.44 (m, 3H), 4.43−4.34 (m, 3H), 4.27 (d, J

6.6 Hz, 3H); C{ H} NMR (151 MHz, CDCl ): δ 139.0,

3

=

3.0 Hz, 1H), 4.12−4.03 (m, 2H), 4.01 (qd, J = 6.4, 2.0 Hz,

H), 3.85 (t, J = 9.3 Hz, 1H), 3.64 (t, J = 9.1 Hz, 1H), 3.40

138.9, 138.7, 138.6, 138.3, 138.1, 128.4, 128.39, 128.36,

128.24, 128.22, 128.14, 128.06, 128.0, 127.94, 127.90, 127.75,

127.72, 127.58, 127.54, 127.51, 127.4, 127.3, 127.28, 127.25,

96.5, 89.5, 85.7, 82.5, 82.4, 80.5, 78.9, 78.3, 77.2, 75.7, 75.6,

75.6, 74.8, 74.8, 74.6, 74.5, 73.7, 72.7, 70.7, 70.5, 70.5, 42.8,

42.5, 36.3, 36.3, 30.7, 30.7, 29.7, 22.7, 14.4, 14.3; HRMS

1

(

dd, J = 9.2, 7.8 Hz, 1H), 3.17 (dd, J = 9.6, 2.1 Hz, 1H),

1

3

1

7

1

8

.48 (s, 3H), 1.42 (s, 3H), 1.34 (d, J = 6.5 Hz, 3H), 1.29 (s,

H), 1.23 (s, 3H); ¹³C{ H} NMR (126 MHz, CDCl ): δ

1

3

38.7, 138.5, 138.4, 138.3, 128.5, 128.49, 128.40, 127.89,

27.86, 127.80, 127.77, 127.73, 127.70, 127.6, 127.5, 111.9,

08.5, 105.2, 102.2, 85.1, 82.9, 82.2, 80.8, 80.4, 78.1, 77.5,

5.7, 75.0, 74.9, 73.5, 71.4, 70.1, 65.9, 26.7, 26.7, 26.1, 25.2,

5.3. HRMS (ESI): m/z calcd for C H O Na [M + Na],

19.3714; found, 819.3729.

Isopropyl 2,3,4,6-Tetra-O-benzyl-7-deoxy-D-glycero-α/β-

+

(ESI): m/z calcd for C H O Na [M + Na] , 711.3656;

4

5

52

6

found, 711.3621.

Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-7-

deoxy-D-glycero-α/β-D-gluco-heptopyranosyl)-α-D-glucopyr-

anoside (52). 52α and 52β were obtained from the reaction

of donor 19 (35.0 mg, 51.70 μmol) and acceptor 23 (26.0

mg, 56.10 μmol) following the general procedure for

glycosylation (ethyl acetate/hexane, 1:9); combined yield

(45.0 mg, 60%), α/β = 1.1:1.

47

56 11

D-gluco-heptopyranoside (50). 50α and 50β were obtained

from the reaction of donor 19 (35.0 mg, 51.70 μmol) and

acceptor isopropyl alcohol (4.4 μL, 56.10 μmol) following

the general procedure for glycosylation (ethyl acetate/hexane,

2

0

1

52β. Colorless syrup; [α] +6.0 (c 0.7, CHCl ); H NMR

D

3

:97); combined yield (18.5 mg, 61%), α/β = 1.2:1.

(500 MHz, CDCl ): δ 8.48−6.58 (m, 35H), 4.99 (d, J = 3.5

3

0β. Colorless syrup; [α]²+38.4 (c 0.1, CHCl ); H

0

1

5

Hz, 1H), 4.94 (dd, J = 10.9, 2.0 Hz, 2H), 4.89 (d, J = 11.0

Hz, 1H), 4.84 (d, J = 11.1, 1H), 4.80 (d, J = 10.9 Hz, 1H),

4.75 (d, J = 10.8 Hz, 1H), 4.70−4.58 (m, 4H), 4.57−4.46

(m, 4H), 4.42 (d, J = 12.2 Hz, 1H), 4.03−3.92 (m, 3H), 3.85

(dd, J = 11.6, 4.7 Hz, 1H), 3.78−3.73 (m, 3H), 3.62 (t, J =

9.4 Hz, 1H), 3.51−3.44 (m, 1H), 3.41−3.38 (m, 1H), 3.34

D

3

NMR (600 MHz, CDCl ): δ 7.82−6.79 (m, 20H), 5.02 (d, J

=

Hz, 1H), 4.75 (d, J = 12.0 Hz, 1H), 4.66 (d, J = 11.3 Hz,

3

10.8 Hz, 1H), 4.89 (d, J = 3.6 Hz, 1H), 4.80 (d, J = 10.7

2

8

H), 4.59−4.51 (m, 3H), 4.07−4.00 (m, 2H), 3.96 (dd, J =

.8, 3.9 Hz, 1H), 3.78 (d, J = 6.7 Hz, 1H), 3.53−3.46 (m,

W

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(

s, 3H), 3.32−3.25 (m, 1H), 1.05 (d, J = 6.5 Hz, 3H);

4.25−4.13 (m, 3H), 4.12 (d, J = 2.9 Hz, 1H), 4.07 (dd, J =

6.3, 2.7 Hz, 2H), 3.93−3.77 (m, 4H), 3.52 (dd, J = 9.8, 2.8

Hz, 1H), 3.13 (d, J = 8.8 Hz, 1H), 1.31 (d, J = 6.0 Hz, 3H),

1

3

1

C{ H} NMR (126 MHz, CDCl ): δ 139.0, 138.8, 138.7,

3

1

8

7

38.6, 138.55, 138.53, 138.3, 128.5, 128.46, 128.43, 128.3,

28.2, 128.1, 128.0, 127.9, 127.7, 127.6, 127.5, 98.0, 96.8,

2.2, 80.4, 80.3, 78.3, 78.0, 75.8, 75.2, 74.6, 73.5, 73.3, 72.2,

1

3

1

1.25 (d, J = 5.7 Hz, 6H); C{ H} NMR (126 MHz,

CDCl ): δ 139.3, 139.2, 139.1, 138.9, 138.8, 138.7, 138.4,

3

1.0, 70.6, 70.5, 65.8, 55.2, 14.1; HRMS (ESI): m/z calcd for

128.5, 128.4, 128.3, 128.25, 128.20, 128.0, 127.86, 127.81,

127.7, 127.6, 127.56, 127.52, 127.4, 127.28, 127.25, 102.5,

98.6, 82.6, 80.0, 79.4, 78.2, 76.3, 74.88, 74.82, 74.5, 74.3,

73.5, 73.3, 72.9, 70.6, 70.3, 16.9, 16.3. HRMS (ESI): m/z

+

C H O Na [M + Na] , 1023.4653; found, 1023.4622.

6

3

68 11

2

0

1

5

2α. Colorless syrup; [α] −1.6 (c 0.7, CHCl ); H NMR

D

3

(

1

5

600 MHz, CDCl ): δ 7.67−6.28 (m, 35H), 4.99 (dd, J =

3

1.0, 5.7 Hz, 2H), 4.94 (d, J = 10.8 Hz, 1H), 4.89−4.76 (m,

H), 4.73−4.63 (m, 3H), 4.58 (d, J = 9.1 Hz, 2H), 4.51 (d, J

11.1 Hz, 1H), 4.34 (d, J = 7.7 Hz, 1H), 4.25 (dd, J = 10.6,

calcd for C70

1113.5083.

H O11Na [M + Na], 1113.5123; found,

74

=

1,6-Anhydro-2,3,4-tri-O-benzyl-7-deoxy-L-glycero-α-D-gal-

acto-heptopyranose (59). This compound was obtained

from the decomposition of donor 12 when variable

temperature NMR studies were carried out following the

general procedure for VT study. The reaction mixture was

quenched with triethylamine (20.0 μL) at rt, diluted with

dichloromethane (5 mL), and washed with saturated

1

3

1

.6 Hz, 1H), 4.01 (t, J = 9.3 Hz, 1H), 3.86−3.81 (m, 2H),

.75−3.65 (m, 2H), 3.63−3.45 (m, 4H), 3.43 (d, J = 9.2 Hz,

H), 3.36 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H); ¹C{ H} NMR

3

1

(

151 MHz, CDCl ): δ 138.9, 138.8, 138.5, 138.4, 138.3,

3

1

8

7

1

38.1, 137.9, 128.5, 128.4, 128.38, 128.36, 128.33, 128.24,

28.20, 128.1, 128.08, 128.03, 128.01, 127.96, 127.92, 127.89,

27.85, 127.78, 127.75, 127.6, 127.5, 127.4, 103.8, 98.1, 85.3,

2.2, 82.0, 79.7, 78.1, 77.9, 76.3, 75.8, 75.7, 74.9, 74.9, 74.6,

3.7, 73.4, 70.7, 69.8, 68.3, 55.2, 53.4, 53.2, 53.0, 52.9, 52.7,

NaHCO

over Na

(2 mL). The organic layer was separated, dried

SO , ﬁltered, and concentrated under reduced

3

2

4

pressure. Puriﬁcation by ﬂash column chromatography on

silica gel (9:1, hexane/ethyl acetate) aﬀorded the decom-

posed product 59 (7.1 mg, 53%) as colorless syrup.

+

4.5; HRMS (ESI): m/z calcd for C H O Na [M + Na] ,

63

68 11

023.4653; found, 1023.4620.

General Procedure for VT H NMR Experiment. A

solution of 9, 12, 17, or 19 (20.0 mg, 0.03 mmol) in CD Cl

1

23

D

1

[α]

−32.1 (c 1.0, CHCl ); H NMR (500 MHz, CDCl ):

3

δ 7.36−7.26 (m, 13H), 7.25−7.22 (m, 2H), 5.36 (t, J = 1.6

Hz, 1H), 4.82 (q, J = 6.5 Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H),

4.57 (s, 2H), 4.51 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 12.3 Hz,

1H), 4.37 (d, J = 12.3 Hz, 1H), 3.98 (dd, J = 3.8, 1.4 Hz,

1H), 3.84 (dd, J = 5.2, 3.8 Hz, 1H), 3.79 (dt, J = 5.2, 1.5 Hz,

1H), 3.47 (t, J = 1.9 Hz, 1H), 1.15 (d, J = 6.4 Hz, 3H);

2

(

0.7 mL) containing TTBP (7.3 mg, 0.03 mmol) was placed

into an NMR tube and cooled to −80 °C in the NMR probe.

The ﬁrst H spectrum was obtained; then, the sample was

1

quickly removed from the probe, and the addition of Tf O

2

(

9.9 μL, 0.06 mmol) precooled at −78 °C was carried out

1

3

1

quickly. The sample was returned to the NMR probe, and

C{ H} NMR (126 MHz, CDCl ): δ 138.4, 138.2, 137.7,

3

1

the H spectrum was recorded after 10 min. The temperature

was increased by 10 °C increments every 10 min, and H

NMR spectra were acquired at each temperature.

128.5, 128.4, 128.1, 128.0, 127.9, 127.7, 100.8, 77.9, 76.6,

74.3, 73.5, 73.1, 72.1, 71.3, 71.2, 21.3. HRMS (ESI): m/z

1

calcd for C28H O Na [M + Na], 469.1985; found, 469.1985.

30 5

1

-O-(2,3,4,6-Tetra-O-benzyl-7-deoxy-D-glycero-α/β-D-gal-

1,6-Anhydro-2,3,4-tri-O-benzyl-7-deoxy-L-glycero-α-D-

gluco-heptopyranose (61). This compound was obtained

from the decomposition of donor 17 when variable

temperature NMR studies were carried out following the

general procedure for VT study. The reaction mixture was

quenched with triethylamine (20 μL) at rt, diluted with

dichloromethane (5 mL), and washed with saturated

acto-heptopyranosyl)-2,3,4,6-tetra-O-benzyl-7-deoxy-D-

glycero-β-D-galacto-heptopyranoside (56 & 57). These

compounds were obtained from the decomposition of

donor 9 when variable temperature NMR studies were

carried out following the general procedure for VT study.

The reaction mixture was quenched with triethylamine (20

μL) at rt, diluted with dichloromethane (5 mL), and washed

with saturated NaHCO₃(2 mL). The organic layer was

separated, dried over Na SO , ﬁltered, and concentrated

under reduced pressure. Puriﬁcation by ﬂash column

chromatography on silica gel (4:1, hexane/ethyl acetate)

aﬀorded the desired product as colorless syrup (7.0 mg, 43%)

in a 1:1.5 ratio of α/β anomers.

NaHCO

over Na

(2 mL). The organic layer was separated, dried

SO , ﬁltered, and concentrated under reduced

3

2

4

pressure. Puriﬁcation by ﬂash column chromatography on

silica gel (9:1, hexane/ethyl acetate) aﬀorded the decom-

2

4

2

0

posed product 61 (4.3 mg, 43%) as colorless syrup. [α]

D

1

−20.4 (c 0.21, CHCl ). H NMR (600 MHz, CDCl ): δ

3

7.36−7.24 (m, 15H), 5.47 (s, 1H), 4.61 (d, J = 12.5 Hz,

1H), 4.53−4.38 (m, 3H), 4.18 (qd, J = 6.2, 1.0 Hz, 1H),

4.14−4.10 (m, 1H), 3.60 (dq, J = 2.7, 1.3 Hz, 1H), 3.39−

3.34 (m, 1H), 3.32−3.28 (m, 1H), 1.16 (d, J = 6.3 Hz, 3H);

6β. Colorless syrup; [α]²+29.5 (c 1.0, CHCl ); H

3

1

5

D 3

NMR (500 MHz, CDCl ): δ 7.35−7.15 (m, 40H), 5.26 (d, J

3.5 Hz, 2H), 4.97 (d, J = 11.2 Hz, 2H), 4.75 (s, 8H), 4.53

d, J = 11.4 Hz, 2H), 4.46 (d, J = 11.2 Hz, 2H), 4.23 (d, J =

3

=

(

1

3

1

C{ H} NMR (151 MHz, CDCl ): δ 138.0, 137.9, 137.9,

3

2

3

4

.6 Hz, 2H), 4.19 (d, J = 11.4 Hz, 2H), 4.14 (dd, J = 10.1,

128.5, 128.43, 128.41, 128.0, 127.9, 127.9, 127.7, 101.2, 79.7,

.5 Hz, 2H), 4.06 (dd, J = 10.1, 2.6 Hz, 2H), 3.89−3.78 (m,

76.5, 72.7, 72.2, 71.7, 71.2, 29.7, 21.0; HRMS (ESI): m/z

13

1

+

H), 1.21 (d, J = 5.6 Hz, 6H). C{ H} NMR (126 MHz,

calcd for C H O Na [M + Na] , 469.1985; found,

2

8

30

5

CDCl ): δ 139.2, 138.96, 138.90, 138.6, 128.3, 128.2, 128.0,

469.1964.

3

1

7

27.7, 127.5, 127.49, 127.43, 127.3, 92.3, 79.5, 75.7, 74.7,

3.8, 73.6, 72.8, 72.6, 70.2, 16.2. HRMS (ESI): m/z calcd for

1,6-Anhydro-2,3,4-tri-O-benzyl-7-deoxy-D-glycero-α-D-

gluco-heptopyranose (63). This compound was obtained

from the decomposition of donor 19 when variable

temperature NMR studies were carried out following the

general procedure for VT study. The reaction mixture was

quenched with triethylamine (20.0 μL) at rt, diluted with

dichloromethane (5 mL), and washed with saturated

C H O Na [M + Na], 1113.5123; found, 1113.5115.

7

0

5

74 11

2

3

1

7α. Colorless syrup; [α] +4.9 (c 1.0, CHCl ); H NMR

D 3

(

500 MHz, CDCl ): δ 7.36−7.13 (m, 40H), 5.24 (d, J = 3.0

3

Hz, 1H), 5.05−4.94 (m, 3H), 4.77 (d, J = 11.8 Hz, 1H),

.76−4.66 (m, 5H), 4.67−4.57 (m, 2H), 4.56−4.47 (m, 4H),

4

X

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The Journal of Organic Chemistry

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Article

NaHCO (2 mL). The organic layer was separated, dried

16.4, 15.4; HRMS (ESI): m/z calcd for C H O SNa [M +

37 40 7

Na], 651.2387; found, 651.2386.

3

over Na SO , ﬁltered, and concentrated under reduced

2

4

pressure. Puriﬁcation by ﬂash column chromatography on

Adamantyl 6-O-Acetyl-2,3,4-tri-O-benzyl-7-deoxy-L-glyc-

ero-α/β-D-gluco-heptopyranoside (68). 68α and 68β were

obtained from the reaction of 67 (33.0 mg, 52.50 μmol) and

1-adamantanol (8.8 mg, 57.70 μmol) following the general

procedure for glycosylation (ethyl acetate/hexane, 1:9);

combined yield (21.0 mg, 61%), α/β = 1:1.94.

silica gel (9:1, hexane/ethyl acetate) aﬀorded the decom-

2

posed product 63 (8.0 mg, 29%) as colorless syrup. [α]

D

1

−

7

11.4 (c 1.0, CHCl ); H NMR (500 MHz, CDCl ): δ

3

.36−7.27 (m, 15H), 5.37 (s, 1H), 4.69−4.56 (m, 6H), 4.34

d, J = 4.3 Hz, 1H), 3.98 (qd, J = 6.5, 4.1 Hz, 1H), 3.70 (t, J

4.7 Hz, 1H), 3.60 (d, J = 4.9 Hz, 1H), 3.35 (d, J = 4.5 Hz,

(

2

1

6

8β. Colorless syrup; [α] +22.5 (c 0.9, CHCl ); H

=

1

D 3

13

1

NMR (500 MHz, CDCl ): δ 7.37−7.26 (m, 15H), 5.39 (qd,

H), 1.21 (d, J = 6.6 Hz, 3H); C{ H} NMR (126 MHz,

3

J = 6.6, 1.5 Hz, 1H), 5.36 (d, J = 3.6 Hz, 1H), 5.00 (d, J =

CDCl ): δ 138.3, 138.0, 137.9, 128.5, 128.4, 128.0, 127.97,

3

1

0.6 Hz, 1H), 4.85 (d, J = 9.8 Hz, 1H), 4.81 (d, J = 10.6 Hz,

H), 4.69 (d, J = 2.0 Hz, 2H), 4.40 (d, J = 9.9 Hz, 1H), 4.04

1

7

27.92, 127.7, 101.3, 81.1, 79.9, 78.8, 75.0, 73.5, 73.2, 71.9,

1.7, 14.7. HRMS (ESI): m/z calcd for C H O Na [M +

28

30

5

+

(t, J = 9.3 Hz, 1H), 3.84 (dd, J = 10.0, 1.6 Hz, 1H), 3.52

dd, J = 9.7, 3.6 Hz, 1H), 3.42 (dd, J = 10.0, 8.8 Hz, 1H),

Na] , 469.1985; found, 469.1988.

(

2

1

p-Methylphenyl 6-O-Acetyl-2,3,4,-tri-O-benzyl-7-deoxy-1-

thio-L-glycero-α-D-gluco-heptopyranoside (66). Acetic anhy-

dride (0.11 mL, 1.16 mmol) was added to a stirred solution

of 14 (0.33 g, 0.58 mmol) and 4-dimethylaminopyridine (7.0

mg, 0.06 mmol) in anhydrous pyridine (2.5 mL) at 0 °C.

After complete addition, it was shifted to room temperature

and stirred for 2 h. It was quenched with ice cold 1 N HCl

solution (5 mL) and diluted with ethyl acetate (10 mL). The

.23−2.10 (m, 3H), 2.07 (s, 3H), 1.88−1.74 (m, 6H), 1.68−

13 1

.51 (m, 8H), 1.29 (d, J = 6.4 Hz, 3H); C{ H} NMR (126

MHz, CDCl ): δ 170.5, 138.8, 138.2, 137.9, 128.6, 128.56,

3

1

8

3

28.53, 128.2, 128.1, 128.0, 127.98, 127.93, 127.7, 89.8, 82.0,

0.0, 78.1, 76.9, 75.7, 75.5, 74.8, 73.0, 71.8, 68.1, 42.9, 42.7,

6.3, 30.7, 21.3, 17.1. HRMS (ESI): m/z calcd for

C H O Na [M + Na], 663.3292; found, 663.3278.

4

0

48

7

2

1

6

8α. Colorless syrup; [α] +2.9 (c 0.7, CHCl ); H NMR

D 3

organic layer was washed with saturated NaHCO solution (5

3

(

500 MHz, CDCl ): δ 7.36−7.33 (m, 2H), 7.32−7.22 (m,

3

mL). The organic layer was dried over Na SO , ﬁltered,

2

4

1

4

3H), 5.27 (qd, J = 6.5, 2.0 Hz, 1H), 5.01 (d, J = 11.0 Hz,

H), 4.93 (d, J = 10.9 Hz, 1H), 4.79 (d, J = 10.1 Hz, 1H),

.76 (d, J = 10.9 Hz, 1H), 4.72 (d, J = 11.0 Hz, 1H), 4.63

concentrated, and puriﬁed by silica gel chromatography (1:4,

EtOAc/hexane) to give 66 (0.32 g, 90%) as a white solid.

2

1

mp: 130−134 °C, [α] −13.5 (c 1.0, CHCl ); H NMR

D

3

(

9

d, J = 7.8 Hz, 1H), 4.37 (d, J = 10.2 Hz, 1H), 3.64 (t, J =

.0 Hz, 1H), 3.54 (t, J = 9.3 Hz, 1H), 3.44 (dd, J = 9.2, 7.8

Hz, 1H), 3.19 (dd, J = 9.7, 2.0 Hz, 1H), 2.16 (p, J = 3.0 Hz,

(

500 MHz, CDCl ): δ 7.53−7.46 (m, 2H), 7.44−7.40 (m,

3

2

(

1

H), 7.37−7.25 (m, 13H), 7.11 (d, J = 7.9 Hz, 2H), 5.30

qd, J = 6.5, 1.8 Hz, 1H), 4.98−4.91 (m, 2H), 4.85 (d, J =

0.8 Hz, 1H), 4.82 (d, J = 10.0 Hz, 1H), 4.75 (d, J = 10.2

Hz, 1H), 4.57 (d, J = 9.7 Hz, 1H), 4.43 (d, J = 10.0 Hz, 1H),

3

2

6

1

7

H), 2.04 (s, 3H), 1.95−1.88 (m, 3H), 1.80 (dq, J = 11.4,

.6 Hz, 3H), 1.68−1.57 (m, 6H), 1.53 (s, 2H), 1.32 (d, J =

13

1

.3 Hz, 3H); C{ H} NMR (126 MHz, CDCl ): δ 170.7,

3

9

2

.70 (t, J = 8.9 Hz, 1H), 3.55 (t, J = 9.4 Hz, 1H), 3.50 (t, J =

38.6, 138.5, 137.8, 128.5, 128.49, 128.46, 128.3, 128.0,

27.9, 127.7, 96.7, 85.3, 82.2, 77.4, 76.3, 75.8, 75.3, 75.2,

5.0, 67.5, 42.9, 36.3, 30.7, 21.4, 16.7. HRMS (ESI): m/z

.3 Hz, 1H), 3.23 (dd, J = 9.7, 1.8 Hz, 1H), 2.34 (s, 3H),

13

1

.10 (s, 3H), 1.34 (d, J = 6.5 Hz, 3H); C{ H} NMR (126

MHz, CDCl ): δ 170.5, 138.3, 138.08, 138.04, 137.6, 133.0,

3

calcd for C H O Na [M + Na], 663.3292; found, 663.3290.

40 48 7

1

8

29.7, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.8, 88.2,

7.0, 81.0, 80.3, 75.9, 75.5, 75.3, 67.7, 21.4, 21.2, 16.5;

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01535.

■

HRMS (ESI): m/z calcd for C H O SNa [M + Na],

37

40

6

*

6

35.2437; found, 635.2443.

p-Methylphenyl 6-O-Acetyl-2,3,4-tri-O-benzyl-7-deoxy-1-

thio-L-glycero-α-D-gluco-heptopyranosyl Sulfoxide (67). It

was obtained following the general protocol B for sulfoxide as

a white solid (0.17 g, 83%) in a 1:1.6 ratio of two

unidentiﬁed isomers.

Copies of H and ¹³C NMR spectra for all compounds

1

(PDF)

1

Mixture of (R) and (S) sulfoxides: H NMR (500 MHz,

AUTHOR INFORMATION

Corresponding Author

■

CDCl ): δ 7.55 (d, J = 7.9 Hz, 5.8H), 7.41 (d, J = 6.9 Hz,

3

2

5

H), 7.38−7.18 (m, 48H), 5.23 (qd, J = 6.7, 1.7 Hz, 1.6H),

.11 (qd, J = 6.5, 1.9 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H),

.02−4.94 (m, 2H), 4.92 (d, J = 11.2 Hz, 1H), 4.89−4.76

David Crich − Department of Pharmaceutical and

Biomedical Sciences, University of Georgia, Athens, Georgia

3

0602, United States; Complex Carbohydrate Research

(

m, 8H), 4.72 (d, J = 10.2 Hz, 1.6H), 4.44−4.41 (m, 1.7H),

Center, University of Georgia, Athens, Georgia 30602,

United States; Department of Chemistry, University of

Georgia, Athens, Georgia 30602, United States;

orcid.org/0000-0003-2400-0083; Email: David.crich@

uga.edu

4

9

3

.41−4.35 (m, 2.3H), 4.13 (t, J = 9.4 Hz, 1H), 3.86 (d, J =

.8 Hz, 1H), 3.84−3.76 (m, 4.5H), 3.60 (t, J = 9.3 Hz, 1H),

.48−3.41 (m, 1.6H), 3.37 (dd, J = 9.8, 1.7 Hz, 1.6H), 2.99

(

dd, J = 9.7, 2.0 Hz, 1H), 2.40 (s, 3H), 2.38 (s, 5.1H), 2.06

s, 3H), 2.00 (s, 5.1H), 1.24 (d, J = 6.5 Hz, 5.4H), 0.75 (d, J

1

3

1

=

6.5 Hz, 3H). C{ H} NMR (151 MHz, CDCl ): δ 170.5,

Authors

3

1

7

70.2, 141.8, 141.5, 138.2, 137.9, 137.6, 137.4, 137.1, 136.0,

29.6, 129.4, 128.66, 128.63, 128.5, 128.47, 128.45, 128.3,

28.2, 128.1, 128.0, 127.96, 127.93, 127.90, 127.6, 126.1,

25.3, 95.0, 93.8, 86.9, 86.0, 81.4, 79.8, 77.3, 77.1, 76.9, 76.7,

5.9, 75.7, 75.4, 75.2, 74.9, 74.1, 67.6, 67.3, 21.5, 21.4, 21.2,

Kapil Upadhyaya − Department of Pharmaceutical and

Biomedical Sciences, University of Georgia, Athens, Georgia

30602, United States

Rahul S. Bagul − Department of Pharmaceutical and

Biomedical Sciences, University of Georgia, Athens, Georgia

Y

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

0602, United States; Complex Carbohydrate Research

pubs.acs.org/joc

Article

3

(10) (a) Ngoje, P.; Crich, D. Stereocontrolled Synthesis of the

Equatorial Glycosides of 3-Deoxy-D-manno-oct-2-ulosonic Acid

KDO): Role of Side Chain Conformation. J. Am. Chem. Soc.

020 , 142 , 7760 −7764. (b) Onobun, E.; Crich, D. Synthesis of 3-

Deoxy-D-manno-oct-2-ulosonic Acid (KDO) and Pseudaminic Acid

Center, University of Georgia, Athens, Georgia 30602,

United States

(

2

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01535

C-Glycosides. J. Org. Chem. 2020, 85, 16035−16042.

11) (a) McMahon, C. M.; Isabella, C. R.; Windsor, I. W.; Kosma,

(

Notes

P.; Raines, R. T.; Kiessling, L. L. Stereoelectronic Effects Impact

Glycan Recognition. J. Am. Chem. Soc. 2020 , 142 , 2386 −2395.

The authors declare no competing ﬁnancial interest.

(b) Quirke, J. C. K.; Crich, D. Glycoside hydrolases restrict the side

chain conformation of their substrates to gain additional transition

ACKNOWLEDGMENTS

■

state stabilization. J. Am. Chem. Soc. 2020 , 142 , 16965 −16973.

We thank the NIH (GM62160 and GM125271) for partial

support of this work.

(c) Quirke, J. C. K.; Crich, D. Side chain conformation restriction in

the catalysis of glycosidic bond formation by Leloir glycosyltrans-

ferases, glycoside phosphorylases, and transglycosidases. ACS Catal.

2021, 11, 5069−5078.

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AA

https://doi.org/10.1021/acs.joc.1c01535

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Influence of Configuration at the 4- And 6-Positions on the Conformation and Anomeric Reactivity and Selectivity of 7-Deoxyheptopyranosyl Donors: Discovery of a Highly Equatorially Selective l - glycero- d - gluco-Heptopyranosyl Donor

DOI: 10.1021/acs.joc.1c01535

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