Threshold of Thioglycoside Reactivity Difference Is Critical for Efficient Synthesis of Type i Oligosaccharides by Chemoselective Glycosylation

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Threshold of Thioglycoside Reactivity Diﬀerence Is Critical for

Eﬃcient Synthesis of Type I Oligosaccharides by Chemoselective

Glycosylation

Nitish Verma, Zhijay Tu, Ming-Shiuan Lu, Shih-Hao Liu, Septila Renata, Riping Phang, Peng-Kai Liu,

Bhaswati Ghosh, and Chun-Hung Lin *

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ABSTRACT: Synthesis of type I LacNAc (Galβ1 → 3GlcNAc) oligosaccharides usually suﬀers from low yields. We herein report

the eﬃcient synthesis of type I LacNAc oligosaccharides by chemoselective glycosylation. With 16 relative reactivity values (RRVs)

measured thiotoluenyl-linked disaccharide donors and acceptors, chemoselective glycosylations were investigated to obtain optimal

conditions. In these reactions, the RRV diﬀerence between the donors and acceptors had to be more than 6311 to obtain type I

LacNAc tetrasaccharides in 72−86% yields, with minimal occurrence of aglycon transfer. The threshold of RRV diﬀerence was

further applied to plan the synthesis of longer glycans. Because it is challenging to measure the RRVs of tetrasaccharides, anomeric

proton chemical shifts were utilized to predict the corresponding RRVs, which consequently explained the outcome of glycosylations

for the synthesis of type I LacNAc hexasaccharides. The result supported the idea that elongation of glycan chains has to proceed

from the reducing to the nonreducing end for a better yield.

to assemble type I LacNAc oligomers with variable lengths.^6,7

INTRODUCTION

■

Nevertheless, it was still a concern to yield those glycans at a

Type I LacNAc (Galβ1 → 3GlcNAc)-repeating oligosacchar-

milligram scale, not to mention that the work was not trivial to

ides are known as tumor-associated carbohydrate antigens,

separate a desired product from reaction mixtures, especially

owing to the aberrant glycosylation pattern particularly in

for the glycans longer than a pentasaccharide. In contrast,

colon cancer.¹⁻³For example, Hakomori et al. identiﬁed the

chemical synthesis was shown to avoid the disadvantages and

dimeric Lewis antigen, Lewis a−Lewis a, on the surface of

additionally to provide these biologically important oligosac-

human colonic adenocarcinoma cell line Colo205.⁴Moreover,

charides in a suﬃcient quantity with ﬂexibility. Kobayashi et al.,

type I oligosaccharides act as a novel antigen for colon cancer

for example, recently synthesized the fucosylated oligosacchar-

cells, especially when the glycan chains are longer than

ide that contained four Le^a-tandem repeats by using (N-

octasaccharides and are decorated with additional fucose and

phenyl) triﬂuoroacetimidate donors⁸with a convergent

sialic acid residues in their nonreducing end.⁵Furthermore,

approach. These growing research eﬀorts signify the urgency

Lewis a-tandem repeat is known to bind with highly expressed

to produce type I-repeating oligomers.

cancer-related proteins, such as mannose-binding protein⁵and

At the current stage, there are several formidable barriers in

galectin 3.⁶However, biological study is limited by the

chemical synthesis of type I oligosaccharides. For example, the

availability of pure oligosaccharides. Methods leading to the

3-hydroxyl GlcNAc acceptor is less active than the 4-hydroxyl

accessibility of these oligosaccharides would not only help to

obtain these glycans in a suﬃcient amount but could also pave

the way for further investigations and applications. Hence, it is

Received: October 13, 2020

necessary to rapidly aﬀord those structurally well-deﬁned

oligosaccharides.

There have been few chemical and enzymatic approaches to

synthesize type I LacNAc-related oligosaccharides. For

instance, Henze and co-workers applied enzymatic synthesis

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GlcNAc acceptor in glycosylation reactions.⁹⁻¹²The glyco-

sylation with Galβ1 → 3GlcNAc donor gave a lower yield, as

compared to that with Galβ1 → 4GlcNAc donor.¹⁰

Furthermore, when the thioglycoside donor and acceptor

with similar reactivity are subjected to chemoselective

glycosylation, the transfer of the anomeric thiotoluenyl group

usually occurs from the thioglycoside acceptor to the activated

donor, leading to donor regeneration, and formation of

acceptor oligomerization or/and acceptor hydrolysis. The

problem, known as aglycon transfer, accounts for commonly

observed low yields.^10,13,14

Scheme 1. Structures of Type I LacNAc Disaccharide

Donors and Acceptors Used for [2 + 2] Chemoselective

Glycosylations

In the past, diﬀerent approaches were used to minimize the

aglycon transfer. Mong and co-workers utilized reactivity-based

[2 + 2] glycosylation between disaccharide donor and acceptor

to synthesize type II LacNAc (Galβ1 → 4GlcNAc)

tetrasaccharide, which was further activated to yield hexa-

and octasaccharides with one-pot glycosylations.¹⁵Addition-

ally, several studies developed sophisticated, less reactive

sulfur-based leaving groups by using either sterically hindered

or electron-withdrawing substituents on sulfur, such as 4-nitro-

thiophenyl,¹⁶dicyclohexylmethanethio,¹⁷2,6-dimethyl-thio-

phenyl,¹⁴thio-ortho-tolyl,¹⁸and 2-triﬂuoromethyl-thiophen-

yl.¹⁹In spite of less aglycon transfer, these methods were

limited to the synthesis of di- or trisaccharides.

Despite eﬀorts of procuring similar oligosaccharides,^9,10,15,20

there is a lack of systematic study on the factors diminishing or

avoiding the aforementioned problems, for example, stereo-

electronic eﬀects of protecting groups on the reactivity of type

I LacNAc disaccharides. Moreover, it is equally important to

know which direction for the type I glycan elongation is suited

most to obtain satisfying yields. For instance, desired

oligosaccharides can either be constructed from the reducing

to nonreducing end or the other way around. Without in-depth

understanding of associated factors, it is challenging to

synthesize desirable oligosaccharides in useful quantities.

Herein, we report the chemoselective glycosylation in which

various type I LacNAc thioglycoside disaccharides were ﬁrst

prepared with their measured relative reactivity values (RRVs).

A linear correlation was found between product yields vs

diﬀerence in the reactivity of disaccharide donors and

acceptors. The result is useful to predict the threshold

reactivity diﬀerence required for satisfying yields. The

threshold RRV diﬀerence was shown applicable for preparation

of longer glycan chains and useful to identify several factors to

eliminate the occurrence of aglycon transfer and thus increase

the reaction yields. Additionally, anomeric proton chemical

shifts of glycosides were shown useful to predict the RRVs and

the outcome of chemoselective glycosylation.

protecting groups introduced at O4 and O6 positions in the

GlcNTCA residue in a divergent manner (see Schemes S4 −

S7), including ester (OAc, OBz), ether (OBn, benzylidene),

and silyl ether (OTBS and OTBDPS) groups. The purpose

was to exploit their diﬀerence in steric and electronic

properties to create a spectrum of thioglycoside disaccharides.

For example, benzylidene was used to tortionally disarm²¹the

disaccharide to generate the less reactive acceptor 15. On the

other hand, acetyl was chosen in combination with OBn to

aﬀord a moderately disarmed disaccharide donor (4) and

acceptor (13). Likewise, two benzyl ethers were used to

protect O4 and O6 of GlcNTCA, owing to the arming

(electron-donating) behavior, to yield the reactive donor 8.

Furthermore, trichloroacetyl (TCA) was installed as the

amine-protecting group to achieve β-stereoselectivity via

neighboring group participation.²²

The reactivity of each disaccharide donor and acceptor was

shown as an RRV (Scheme 1), initially established by Wong

and co-workers.²³⁻²⁶Competition reactions were done

between a thioglycoside with an unknown RRV and the

reference thioglycoside with a known RRV in the presence of a

limiting amount of promoter to determine the RRV of each

disaccharide (please see Experimental Section for details). For

example, compound 2a (Figure S1) was used as a reference

donor to measure the RRV of disaccharide 2. Because

tetrasaccharide products would be possibly elongated to

hexasaccharides or longer glycans at a later stage, the

protecting groups installed in the reducing end of tetrasac-

charides appeared to be critical. To explore the possibility of

RESULTS AND DISCUSSION

■

We ﬁrst performed the synthesis of type I LacNAc

tetrasaccharides by [2 + 2] glycosylation. Several Galβ1 →

3GlcNTCA thioglycoside disaccharides (1−16, see the

inserted structure and Scheme 1) were prepared with

B

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deriving tetrasaccharide products into reactive donors or

acceptors in one step, a diester combination was avoided, and

rather orthogonal protecting groups were employed at O4 and

O6 positions in GlcNTCA.

Four most reactive disaccharides (6−9) were chosen as

donors, whereas seven disaccharide acceptors (10−16) were

synthesized from their corresponding Nap-protected precur-

sors (see Schemes S5 and S6). [2 + 2] Chemoselective

glycosylations were then conducted in the presence of

TMSOTf (0.2 equiv) and 3 Å molecular sieves and an equal

concentration of donor and NIS in CH₂Cl₂(Table 1). Since

both the donor and acceptor are thioglycosides, it is important

to selectively activate the donor STol without aﬀecting the

acceptor STol; that is, there has to be diﬀerential reactivity to

obtain a satisfying yield.²⁷Isolated yields were measured for

the tetrasaccharide products and unreacted starting material/

side product by puriﬁcation with ﬂash column chromatography

on silica gel (see Experimental Section for related procedures).

The structure of each tetrasaccharide was conﬁrmed and

characterized in a vigorous manner by high-resolution mass

spectroscopy (HRMS) and various 1D and 2D NMR

techniques. For example, a detailed assignment is shown in

the Supporting Information (pages S34−S37) for the

representative tetrasaccharide 27.

A donor with OTBS at O6 in GlcNTCA (6, RRV = 7389)

was found to be less reactive (entry 1, Table 1) than the

corresponding O6-OBn-protected donor (7, RRV = 7657,

entry 2). The bulkier silyl-protecting group (OTBDPS) at O6

in GlcNTCA makes donor 5 (RRV = 4433) even less reactive

than donor 6. Hence, the lowest reactivity of O6-OTBDPS

plus an ester protection at O4 in GlcNTCA resulted in the less

reactive acceptors 14 (RRV = 1299) and 16 (RRV = 2060),

which appeared to be beneﬁcial to [2 + 2] glycosylation (e.g.,

comparison of entries 2−5). For reactions with insuﬃcient

reactivity diﬀerence between the donor and acceptor, low

yields were observed (entries 6−8), and about one-third of the

donor was recovered (33−37%) because of aglycon transfer.

The desired product and the recovered donor were also

accompanied with several more polar compounds according to

TLC analysis. With an increase in reactivity diﬀerence between

the donor and acceptor, improved yields were observed. It was

achieved by changing the reactivity of either donor or acceptor.

For instance, the glycosylation of diﬀerent acceptors 13−16

with donor 7 generated tetrasaccharides 18−21 (entries 2−5),

respectively, while acceptors 13−16 reacted with donor 8 to

aﬀord products 25−28 (entries 9 and 14−16), respectively.

Glycosylations of acceptors 14 and 16 produced the best

yields, even though 16 was not the least reactive. Likewise,

when the same acceptor was glycosylated with diﬀerent donors

(e.g., acceptor 13 reacting with diﬀerent donors 6−8; see

entries 1, 2, and 9), the reactive donor (8) had the highest

yield. Apparently, the presence of two OBn groups at O4 and

O6 in GlcNTCA rendered 8 an excellent donor. Please also

refer to entries 3 and 14, entries 4 and 15, and entries 5 and 16

for a similar comparison. Therefore, obtaining good yields has

to make either donor more reactive or acceptor less reactive.

High reaction yields were often in company with low/no

recovery of donor and decreased decomposition of acceptor,

which was easily shown by TLC analysis.

Although it is well known that the silyl protecting group

increases the donor reactivity,^20,28to the best of our

knowledge, herein for the ﬁrst time we found that silyl

protection is decreasing the reactivity, compared to the benzyl

ether protection, when the silyl group is present at O6 of

GlcNTCA, for example, donor 3 (RRV = 3202) versus donor 4

(RRV = 3762), donors 5 (RRV = 4433) and 6 (RRV = 7389)

versus donor 7 (RRV = 7657), acceptor 12 (RRV = 5329)

versus acceptor 11 (RRV = 5441), and acceptor 14 (RRV =

1299) versus acceptor 13 (RRV = 2888). In contrast, an

opposite trend was observed at O4 in GlcNTCA; TBS ether at

O4 in GlcNTCA (e.g., compound 9, RRV = 9404) appeared to

increase the reactivity in comparison with 8 (RRV = 8351).

However, no signiﬁcant diﬀerence in yield was observed in the

glycosylation of acceptor 13 with donor 9 (29, 65%, entry 18,

Table 1) in comparison with the same acceptor glycosylation

with donor 8 (25, 63%, entry 12, Table 1). A trace amount of

Table 1. [2 + 2] Chemoselective Glycosylations to

a

Synthesize Type I LacNAc Tetrasaccharides

donor

(equiv),

RRV

acceptor

(1 equiv),

RRV

temp

time

(h)

product

b

c

entry

1

ln(RRV_D)

8.41

(°C)

(% yield)

d

6 (1.3),

7389

7 (1.3),

7657

7 (1.3),

7657

7 (1.3),

7657

7 (1.3),

7657

8 (1.3),

8351

8 (1.3),

8351

8 (1.3),

8351

8 (1.3),

8351

8 (1.3),

8351

8 (1.3),

8351

8 (1.1),

8351

8 (1.6),

8351

8 (1.3),

8351

8 (1.3),

8351

8 (1.3),

8351

13, 2888

14, 1299

15, 1903

16, 2060

10, 9740

11, 5441

12, 5329

13, 2888

14, 1299

15, 1903

16, 2060

13, 2888

16, 2060

−50

−70

−60

−50

−60

−70

−60

2.5

2

17 (54)

18 (58)

19 (63)

20 (60)

21 (67)

22 (19)

23 (20)

24 (25)

25 (60)

25 (72)

25 (68)

25 (63)

25 (69)

26 (79)

27 (75)

28 (86)

28 (75)

29 (65)

29 (61)

30 (52)

2

8.47

8.76

8.66

3

4

5

8.63

2.5

21

e

f

6

g

h

7

7.98

8.01

8.61

8.86

8.77

8.75

8.78

8.90

8

9

i

10

11

12

13

14

15

16

17

18

19

20

2.5

2

j

2.5

21

8 (1.1),

8351

9 (1.1),

9404

9 (1.1),

9404

9 (1.1),

9404

i

k

4.5

a

Glycosylation conditions: NIS (same as donor equiv), TMSOTf (0.2

b

equiv), 3 Å MS, and CH₂Cl₂(50 mM). RRV_D= RRV_Donor

RRV_Acceptor. Isolated yield. 18% acceptor recovered. ln(RRV_D) for

this entry is not valid, as RRV_Dis a negative number. 34%, donor

recovered. 33%, donor recovered. 37% donor recovered. Acceptor

−

c

d

e

f

g

h

i

13 remained after 2.5 h (entry 10)/2 h (entry 19); hence, the

j

reactions were continued for longer time. 14% oxazoline recovered.

k

Donor spot disappeared with one-third acceptor remained unreacted

(based on TLC).

C

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acceptor 13 remained unreacted during the reaction with

donor 9. In fact, the eﬀort to glycosylate the less reactive

acceptor 16 with donor 9 was ineﬃcient to form product 30 in

52% yield and one-third acceptor was found unconsumed as

can be seen by TLC (entry 20). Moreover, we applied a

preactivation method to activate donor 9 before the addition of

acceptor 13. However, product 29 was obtained in a moderate

yield (58%) even after several trials (see Scheme S8). These

moderate yields from donor 9 were attributed to the oxazoline

formation to a signiﬁcant degree, suggesting that RRV serves as

a reactivity index of glycoside donors but cannot be directly

linked to reaction yield.

The RRV-based analysis also helped to identify other factors

to improve reaction yields. For instance, we compared the

reactions of 8 with acceptors 13 and 16. With a relatively

smaller RRV diﬀerence between donor 8 and acceptor 13, we

were able to increase the yields by either reducing the amount

of donor/NIS or lowering the temperature (entries 9−13).

Likewise, because there was a relatively larger RRV diﬀerence

between donor 8 and acceptor 16, increasing the amount of

donor/NIS helped to improve the yield from 75 to 86%

(entries 17 and 16, respectively).

To precisely delineate the required reactivity diﬀerence

between glycosyl donor and acceptor, quantitative analysis

becomes indispensable. To examine if the reactivity diﬀerence

correlated with the yield of desired product, a graph was

plotted between the yields (%) of tetrasaccharides formed in

Table 1 and the corresponding ln(RRV diﬀerence) (Figure 1).

The RRV diﬀerence (RRV_D) is deﬁned as the diﬀerence in the

RRVs between donor and acceptor disaccharides. As shown in

Figure 1, there are red and blue lines generated by ﬁtting

diﬀerent sets of data points with linear regression. The red line

corresponded all entries in Table 1 (R²value: 0.68), except for

entry 6, where ln(RRV_D) is not valid because of the negative

value of RRV_D. It was noted that several entries in Table 1

were performed at a diﬀerent temperature or donor equivalents

(entries 10−13 and 17−20 that are shown as red numbers and

data points in Figure 1). In contrast, the blue line is only

corresponding to the entries that were performed under the

same glycosylation conditions (−50 °C and the use of 1.3

equiv of donor), explaining a better linear correlation (R²

value: 0.91). The following conclusions are made according to

the data points of blue line (Figure 1). First, with an RRV_Dof

less than 3641, low yields (<25%) were observed because of

aglycon transfer (entries 7 and 8, Table 1). Second, moderate

to good yields (50−67%) were found when the RRV_Dis in the

range of 4447−6003 (entries 1, 2, and 5). Additionally,

excellent yields (75−86%) of tetrasaccharides were obtained

for the reactions with RRV_D> 6311 (entries 14−16).

Because in this work all the acceptors were derived by

removing the Nap ether from corresponding precursors, it

would be interesting to use the precursors’ RRVs as an

estimate of the acceptors’ RRVs. By this way, we could

understand if Nap plays a role in aﬀecting the RRVs. We thus

plotted the graph between tetrasaccharide yields vs estimated

ln(RRV_D) (Table S3 and Figure S2). The estimated RRV_Dwas

obtained by the diﬀerence in the RRVs of donors A and B

disaccharides (see Figure S2 for the deﬁnition). Interestingly,

the threshold RRV_D(6634) to obtain 75−86% yields was

similar to the aforementioned RRV_D(6311) derived from

Figure 1. How Nap aﬀects the RRVs is not clear because the

Nap deprotection was found to increase or decrease the RRVs.

The estimated RRV_Dcould be timesaving and applicable for

cases where it is challenging to measure the RRV of every

glycoside. The comparison of Figures 1 and S2 indicated that

the Nap existence only marginally changed the threshold RRV

diﬀerence.

Having prepared type I LacNAc tetrasaccharides in good

yields (entries 13−16 in Table 1), we next proceeded with

chain elongation to synthesize hexasaccharide by [2 + 4] and

[4 + 2] chemoselective glycosylations. We thus selected

tetrasaccharide 27 because it was readily converted in one step

to either disarmed tetrasaccharide acceptor 31 by Nap

deprotection or armed tetrasaccharide donor 23 by regiose-

lective opening of the benzylidene (Scheme 2). [2 + 4]

Chemoselective glycosylation was ﬁrst performed between

donor 8 (RRV = 8351, 1.3 equiv) and acceptor 31 (1 equiv) in

the presence of NIS (1.3 equiv) and TMSOTf (0.2 equiv) at

−50 °C (Scheme 2). The desired hexasaccharide 32 was

obtained in 70% yield with concomitant formation of oxazoline

33 (19%). This reaction was analogous to the glycosylation of

acceptor 15 (RRV = 1903, entry 15, Table 1) with 8 because

both acceptors contained the identical disaccharide in the

reducing end. Presumably, the RRV of 31 is smaller than that

of 15 because the former one is less reactive owing to its longer

chain, suggesting that the resulting RRV diﬀerence should be

larger than that of the analogous [2 + 2] reaction, that is, the

RRV_Dof the [2 + 4] reaction should be >6448.

Figure 1. Linear relationship was found between ln(RRV_D) and yields

of tetrasaccharide products shown in Table 1. Blue line was generated

with linear regression by ﬁtting the blue data points that were

performed under the same conditions (−50 °C and 1.3 equiv of

donor). Red line was generated by ﬁtting the red and blue data points

(representing all the entries in Table 1, except for entry 6). Numbers

next to data points designate the entry numbers in Table 1.

Although RRV is a good index to predict the reactivity in

glycosylation reactions, the measurement is not trivial,

especially for longer oligosaccharides. Finding another quick

way is convenient and useful to determine the reactivity of

glycosides. Wong and co-workers are the ﬁrst to correlate the

reactivity of glycosides with the H-1 chemical shift, providing

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Scheme 2. Glycosylations to Synthesize Type I LacNAc Hexa- and Octasaccharides

that the glycosides contain the same protecting group at the C-

2 position.^23,29We thus plotted between the RRVs of

glycosides 1−16 versus their H-1 chemical shifts (Table 2

and Figure 2). The resulting data points resulted in a roughly

linear correlation (in correspondence to the red line in Figure

2) with an R²value of 0.67 because three disaccharides (6, 7,

and 14) appeared to deviate more from the red line. Removal

of these data points indeed led to a better linear correlation

(blue line with an R²value of 0.92). As shown in Figure 2,

disaccharides of higher reactivity (8−10) have their H-1 more

upﬁeld-shifted (4.92, 4.84, and 4.91 ppm, respectively). In

contrast, less reactive disaccharides (1, 15, and 16) possess the

H-1 in a relatively downﬁeld-shifted region (5.32, 5.32, and

5.31 ppm, respectively). The RRV−chemical shift relationship

helped us to explain the result of [2 + 4] and [4 + 2]

glycosylation reactions. In the [2 + 4] glycosylation of

tetrasaccharide acceptor 31 with donor 8 (RRV = 8351), the

RRV of 31 was predicted to be 2591 because of its H-1

chemical shift (δ_H‑1= 5.30 ppm), leading to a calculated RRV_D

of 5760. On the basis of the linear correlation between

ln(RRV_D) and reaction yield (blue line in Figure 1), an RRV_D

of 5760 corresponded to 67% yield that is close to what we

observed for this [2 + 4] reaction (70%).

Table 2. Listed RRVs of Disaccharides with the

Corresponding Anomeric Proton Chemical Shifts

a

b

RRV (compd)

δ (ppm)

1299 (14)

1411 (1)

1903 (15)

2060 (16)

2239 (2)

2888 (13)

3202 (3)

3762 (4)

4433 (5)

5329 (12)

5441 (11)

7389 (6)

7657 (7)

8351 (8)

9404 (9)

9740 (10)

5.17

5.32

5.31

5.36

5.20

5.23

5.22

5.23

5.19

5.21

5.19

5.22

4.92

4.84

4.91

a

b

Values shown in the ascending order. Chemical shift of anomeric

proton.

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presumably because of the aglycon transfer). The usage of

donor 22 indeed gave a better yield, as compared to the [4 +

2] glycosylation of acceptor 16 with tetrasaccharide donor 23

(28% yield). Therefore, the RRV-based analysis was shown

applicable to improve the [4 + 2] glycosylation.

Furthermore, the H-1 chemical shift is a direct and

convenient way to index the glycoside reactivity. In the

aforementioned [2 + 4] glycosylation, the H-1 chemical shifts

of donor 8 and acceptor 31 are 4.92 and 5.30 ppm,

respectively. In the [4 + 2] glycosylation, the H-1 chemical

shifts of donor 23 and acceptor 16 are 5.14 and 5.31 ppm,

respectively. With the established RRV−chemical shift

relationship, judging the diﬀerence of H-1 chemical shifts is

able to predict if glycosylations of interest likely aﬀord good

yields; for example, the [2 + 4] glycosylation has a higher

feasibility than the [4 + 2] glycosylation. Therefore, the

importance of using anomeric proton chemical shifts can be

best demonstrated when measuring RRV becomes labor-

intensive.

Figure 2. Linear relationship was observed between the RRVs of

disaccharides vs anomeric proton chemical shifts. Red line was

produced by ﬁtting all the data points (shown in red or blue color) in

Table 2. Blue line was produced by ﬁtting the blue data points (after

excluding red data points that correspond to compounds 6, 7, and

14).

Alternatively, the synthesized di- and tetra-thioglycoside

donors were available to react with acceptors that were

protected with the OTBS group at the reducing-end anomeric

center. The aforementioned tetrasaccharide 25 was used as the

donor for the [4 + 2] glycosylation of disaccharide acceptor 35

(see Scheme S1). Hexasaccharide 36 was produced in 70%

yield (Scheme S1). Additionally, [2 + 4] glycosylation was

pursued by glycosylating tetrasaccharide acceptor 37 with

donor 8 (see Scheme S9 for the preparation of 37) in the

presence of NIS and TfOH, leading to the formation of

hexasaccharide 38 in 82% yield (Scheme 2). The resulting

product was then subjected to the Nap removal (39, 62%

yield), followed by the further [2 + 6] glycosylation with

disaccharide donor 8. The desired octasaccharide (40) was

produced in 61% yield (Scheme 2).

Meanwhile, we also examined [4 + 2] glycosylation of

thioglycoside disaccharide acceptor 16 (RRV = 2060) (1.2

equiv) with tetrasaccharide donor 23 (1 equiv) in the presence

of NIS (1 equiv) and TMSOTf (0.2 equiv) under −50 °C

(Scheme 2). A low yield (28%) of hexasaccharide 34 was

observed in addition to the recovered acceptor 16 (55%) and

aglycon transfer (26%).³⁰Although this reaction is comparable

to the [2 + 2] glycosylation of 16 (RRV = 2060) with 7 (RRV

= 7657, entry 5, Table 1), it is likely that the RRV of donor 23

became signiﬁcantly smaller than that of 7. The estimated

RRV_Dof this [4 + 2] glycosylation should be thus much

smaller than that of entry 5; that is, the RRV_Dof the [4 + 2]

reaction is predicted to be <5597 (RRV_Dfor entry 5 from

Table 1). Moreover, according to the RRV−chemical shift

relationship, donor 23 (δ_H‑1= 5.14 ppm) was predicted to

have an RRV of 5175, leading to the estimated RRV_Dof 3115

in the [4 + 2] glycosylation (5175 − 2060 = 3115). As a

consequence, the comparison in Scheme 2 supported the idea

that [2 + 4] is superior to [4 + 2] glycosylation. Our RRV-

based analysis explained why it is better to elongate glycan

chains from the reducing to the nonreducing end.

Notably, the predicted RRV of benzylated thioglycoside

tetrasaccharide 22 (see the structure in Scheme 1) is 10343,

predicted by the RRV−chemical shift relationship (δ_H‑1of 22

= 4.82 ppm). The calculated RRV_Dbetween the RRVs of

tetrasaccharide 22 and disaccharide acceptor 16 turned out to

be 8283, indicating the tendency for a possible improvement in

glycosylation yield. We thus performed [4 + 2] chemoselective

glycosylation of disaccharide acceptor 16 (1.2 equiv) with

tetrasaccharide donor 22 (1.0 equiv) in the presence of NIS

(1.0 equiv) and TMSOTf (0.2 equiv) (Scheme 2). Our initial

trial to conduct this glycosylation at −50 °C did not yield any

major product. Instead, the donor was decomposed in

company with recovered acceptor 16 after column chromatog-

raphy. Because tetrasaccharide 22 is a reactive donor, we thus

lowered the temperature to −70 °C for addition of the

promoter, gradually increased the temperature to −60 °C, and

ﬁnally stirred the reaction for another 2 h at −50 °C to allow

the glycosylation. Desired hexasaccharide 34a was obtained in

52% yield, in conjunction with recovery of acceptor 16 (0.49

equiv recovered, with respect to the amount of acceptor 16

initially added to the reaction) and donor 22 (22%,

CONCLUSIONS

■

In conclusion, with systematic investigation on the reactivity of

glycosides and the direction of oligosaccharide chain

elongation, we successfully accomplished the synthesis of

arduous type I LacNAc hexa- and octasaccharides in good

yields. Cautious and judicious protecting group design allowed

us to create type I LacNAc disaccharides with varying

reactivities, which were used to synthesize orthogonally

protected type I tetrasaccharides. Through the graph of

tetrasaccharide yields vs RRV_D, we were able to predict the

threshold RRV_Drequired for fruitful chemoselective glyco-

sylation. The correlation helped to access the type I LacNAc

hexasaccharide 32 by [2 + 4] glycosylation and also explained

the reason why reducing to nonreducing end synthesis is better

than the other way. We additionally demonstrated that the H-1

chemical shifts of glycosides could be useful to predict not only

their RRVs but also the feasibility of chemoselective

glycosylations.

EXPERIMENTAL SECTION

■

General Experimental Procedure. All reactions were performed

in an oven-dried glassware under the nitrogen atmosphere unless

otherwise mentioned. The reaction mixtures were puriﬁed by using

silica gel ﬂash column chromatography. Anhydrous solvents and

moisture-sensitive materials were transferred by using an oven-/

vacuum-dried syringe or cannula through a rubber septum. Analytical

TLC was performed on the precoated glass plates of TLC Silica gel 60

F₂₅₄from Merck and was detected by UV visualization (254 nm) and/

F

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or by staining with reagents that contained ceric molybdate (for

general use), para-anisaldehyde (for carbohydrates), or ninhydrin (for

amino-group-containing samples). Column chromatography was

performed on silica gel (Geduran Silicagel 60, 0.040−0.063 mm,

from Geduran). Puriﬁcation of the bulk building blocks was

performed either on a Teledyne Isco CombiFlash Rf that was

equipped with a UV detector (for compounds with UV-active

chromophores) or on a Grace Davison Reveleris ﬂash system that was

equipped with an evaporative light scattering detector (for

compounds without UV-active chromophores). ¹H NMR spectra

were recorded on Bruker AV-400 (400 MHz) or AVII-500 (500

MHz) spectrometers by using tetramethylsilane (δ_H= 0.00 ppm) and

CDCl₃(δ_H= 7.26 ppm) as internal standards. ¹³C NMR spectra were

recorded on Bruker AV-400 (100 MHz) or AVII-500 (125 MHz)

spectrometers by using CDCl₃(δ_C= 77.23 ppm, central line of a

triplet) as an internal standard. Structural assignments were made

with additional information from 2D-COSY, 2D-HMQC, and 2D-

HMBC experiments using gradient pulses for coherence pathway

selection, which were acquired on Bruker AV-400 or AVII-500

spectrometers. HRMS was performed on Bruker Bio-TOF III (ESI-

TOF) or Bruker Ultraﬂex (MALDI-TOF/TOF) spectrometers and is

reported as mass/charge (m/z) ratios with percentage relative

abundance. Optical rotations were measured at the sodium D-line

(589 nm) at 25 °C or 20.0 °C on a PerkinElmer model 341

polarimeter. Speciﬁc rotations were reported as [α]²_D⁵after dividing

the observed values by the sample concentration (C, in g mL⁻¹) and

the path length (l, in dm). The solvents for extraction and

chromatography were of ACS grade. CH₂Cl₂and CH₃CN were

predried by using molecular sieves and then percolated through an

active Al₂O₃column. Anhydrous DMF and MeOH were purchased

from Aldrich Chemical Co. and J-T Baker, respectively, in sealed

packages. Diphenylsulfoxide (Ph₂SO) and 2,4,6-tri-tert-butylpyrimi-

dine were purchased from Aldrich Chemical Co. All the chemicals

were used without further puriﬁcation unless otherwise speciﬁed.

Celite 545 and 3 Å molecular sieves (powder < 50 μm) were

purchased from Acros Co. and Alfa Aesar Co., respectively. 1,2,3,4,6-

Penta-O-acetyl-β-^D-galactopyranoside and D-glucosamine hydrochlor-

ide were purchased from Carbosynth Ltd. in a bulk package.

General Procedure to Determining RRVs of Thioglycoside

Donors. In a 10 mL reaction tube, a solution of two thioglycoside

donors (0.055 mmol of each, D_refis the reference donor and D_xis any

other donor molecule), absolute MeOH (0.275 mmol), and

molecular sieves [AW-300; 2xwt (D_ref+ D_x)] in CH₂Cl₂(1.1 mL)

was stirred at rt for 10 min. An aliquot of this mixture (0.1 mL) was

taken, diluted to 10.0 mL with CH₂Cl₂, and separately injected (20

μL for each injection) into the HPLC in order to determine the time

= 0 absorbance (A_x)₀and (A_ref)₀at 254 nm at the initial concentration

of the donor molecules. The HPLC conditions must allow baseline

separation of D_refand D_x. The NIS (0.055 mmol) and TfOH (0.005

mmol) were added to the reaction, and the reaction was kept at rt for

2 h. The mixture was quenched with Et₃N, diluted with CH₂Cl₂,

ﬁltered, washed with saturated NaHCO₃aqueous and Na₂S₂O₃

aqueous solution, dried over MgSO₄, and concentrated to dryness

by evaporation. The residue was redissolved in CH₂Cl₂(1.0 mL) and

diluted to 100.0 mL with CH₂Cl₂. The concentrations of the

remaining unreacted donors ([D_x] and [D_ref]) were measured by

HPLC with the same conditions (20 μL for each injection) as

determined for the mixture before the addition of reagents. The ratio

of RRVs for D_xand D_ref, k_x/k_ref, was calculated by applying the HPLC

absorbance values to the formula k_x/k_ref= [ln(A_x)_t− ln(A_x)₀]/

[ln(A_ref)_t− ln(A_ref)₀].

dried over MgSO₄, ﬁltered, and concentrated by evaporation to yield

viscous yellow crude. The crude was subjected to column

chromatography on silica gel to yield a desired tetrasaccharide

product (w.r.t: with respect to).

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-4-O-benzo-

yl-6-O-tert-butyldiphenylsilyl-2-deoxy-2-trichloroacetamido-

1-thio-β-^D-glucopyranoside (1). For reaction details, please see

Scheme S6. 4-DMAP (73 mg, 0.60 mmol), Et₃N (420 μL, 3.0 mmol),

and BzCl (251 μL, 2.16 mmol) were sequentially added to a solution

of compound 5 (1.50 g, 1.20 mmol) in anhydrous CH₂Cl₂(12 mL).

After stirring at rt for 1.5 h, the reaction was quenched by addition of

MeOH (2 mL) and concentrated by evaporation to yield a pale-

yellow thick crude. The crude was redissolved in CH₂Cl₂(20 mL)

and washed with saturated NaHCO₃solution (20 mL, two times).

The CH₂Cl₂layer was collected, dried over MgSO₄, ﬁltered, and

concentrated by evaporation to yield a thick crude that was subjected

to column chromatography on silica gel with EtOAc/hexanes (1/5 to

1/4, v/v) to yield the desired pure product 1 (1.62 g, 99%) as a white

amorphous solid. R_f0.26 (EtOAc/hexanes = 1/4, v/v); [α]²_D⁰−2.0 (c

1.5, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, J = 7.2 Hz, 2H,

Ar-H), 7.76−7.69 (m, 3H, Ar-H), 7.63 (d, J = 6.6 Hz, 2H, Ar-H), 7.58

(d, J = 6.9 Hz, 2H, Ar-H), 7.54 (d, J = 7.8 Hz, 1H, Ar-H), 7.52−7.46

(m, 3H, Ar-H), 7.44−7.37 (m, 3H, Ar-H), 7.37−7.31 (m, 4H, Ar-H),

7.31−7.25 (m, 8H, Ar-H), 7.24−7.20 (m, 6H, Ar-H), 7.19−7.11 (m,

5H, Ar-H), 6.95 (d, J = 6.8 Hz, 1H, N−H), 6.92 (d, J = 7.9 Hz, 2H,

Ar-H), 5.48 (dd, J = 9.9, 7.9 Hz, 1H, H-2′), 5.32 (d, J = 10.2 Hz, 1H,

H-1), 5.12 (t, J = 8.8 Hz, 1H, H-4), 4.89 (d, J = 11.6 Hz, 1H,

CH₂Ph), 4.74−4.63 (m, 2H, H-3, CH₂group of Nap), 4.57 (d, J = 7.8

Hz, H-1′), 4.45 (m, 2H, CH₂Ph, CH₂group of Nap), 4.25 (dd, J =

30.8, 11.7 Hz, 2H, 2× CH₂Ph), 3.87 (d, J = 2.1 Hz, 1H, H-4′), 3.79−

3.68 (m, 3H, H-5, H-6a, H-6b), 3.48 (dd, J = 10.1, 2.4 Hz, 1H, H-3′),

3.43−3.36 (m, 1H, H-5′), 3.29−3.18 (m, 1H, H-2), 3.11−3.07 (m,

1H, H-6a′), 2.95 (t, J = 8.3 Hz, 1H, H-6b′), 2.25 (s, 3H, PhCH₃),

0.99 (s, 9H, TBDPS-t-Bu); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ

165.2 (C), 165.02 (C), 161.6 (C), 138.8 (C), 138.6 (C), 137.9 (C),

135.7 (CH), 134.9 (C), 133.7 (CH), 133.3 (C), 133.19 (C), 133.16

(C), 133.1 (C), 133.0 (CH), 132.7 (CH), 130.2 (C), 130.0 (CH),

129.7 (CH), 128.6 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH),

128.0 (CH), 127.9 (CH), 127.75 (CH), 127.72 (CH), 127.5 (CH),

126.8 (CH), 126.2 (CH), 126.1 (CH), 125.9 (CH), 100.1 (CH),

92.6 (C), 84.0 (CH), 79.7 (CH), 79.6 (CH), 76.4 (CH), 74.5 (CH₂),

73.5 (CH₂), 73.4 (CH), 72.5 (CH), 71.9 (CH), 71.8 (CH₂), 69.2

(CH), 67.6 (CH₂), 63.4 (CH₂), 58.2 (CH), 26.8 (CH₃), 21.3 (CH₃),

19.3 (C); HRMS (ESI-TOF) m/z: calcd for C₇₆H₇₄Cl₃NO₁₂SSiNa

[M + Na]⁺, 1382.3635; found, 1382.3701.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-4,6-O-ben-

zylidene-2-deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyra-

noside (2). For reaction details, please see Scheme S4. A solution of

45 (3.28 g, 4.61 mmol) and 49^9,31,32(2.0 g, 3.85 mmol) in anhydrous

CH₂Cl₂(64 mL) was stirred with 3 Å pulverized molecular sieves

(11.0 g) at rt for 30 min under the N₂atmosphere. After cooling to

−60 °C, NIS (1.04 g, 4.61 mmol) was added to the reaction mixture,

followed by the addition of TMSOTf (140.0 μL, 0.77 mmol). After 4

h, the reaction was quenched by dropwise addition of Et₃N to

neutralize the reaction mixture and ﬁltered through a pad of Celite.

The ﬁltrate was washed with saturated Na₂S₂O₃solution (60 mL, two

times), dried over MgSO₄, ﬁltered, and concentrated by evaporation

to yield a viscous yellow residue. The residue was puriﬁed by column

chromatography on silica gel with EtOAc/hexanes (1/6 to 1/4, v/v)

to yield the pure disaccharide 2 (3.39 g, 80% yield) as a white

amorphous foam. R_f0.44 (EtOAc/hexanes = 1/3, v/v); [α]²_D⁵+5.9 (c

General Procedure for [2 + 2] Glycosylations in Table 1. A

solution of disaccharide donor (see Table 1 for the equiv) and

acceptor (1 equiv) in anhydrous CH₂Cl₂(50 mM w.r.t acceptor) was

stirred with 3 Å molecular sieves (D + A, wt/wt) at rt for 30 min.

After cooling to low temperature, the promoter (NIS of the same

equiv as donor; and TMSOTf, 0.2 equiv) was added. After stirring for

a period of time (see Table 1), the reaction was quenched by

dropwise addition of Et₃N to neutralize the pH and ﬁltered to remove

insoluble. The ﬁltrate was washed with saturated Na₂S₂O₃solution,

1

1.0, CHCl₃); H NMR (500 MHz, CDCl₃): δ 7.89 (d, J = 8.15 Hz,

2H, Ar-H), 7.71 (d, J = 7.75 Hz, 1H, Ar-H), 7.55−7.47 (m, 4H, Ar-

H), 7.45−7.37 (m, 5H, Ar-H), 7.36−7.27 (m, 12H, Ar-H), 7.26−7.21

(m, 4H, Ar-H), 7.14 (d, J = 8.4 Hz, 1H, Ar-H), 7.06 (d, J = 8 Hz, 2H,

Ar-H), 6.95 (d, J = 6.85 Hz, 1H, N−H), 5.57 (dd, J = 10.0, 8.1 Hz,

1H, H-2′), 5.43 (s, 1H, PhCH benzylidene), 5.36 (d, J = 10.4 Hz, 1H,

H-1), 4.96 (d, J = 11.7 Hz, 1H, CH₂Ph), 4.73 (d, J = 8.1 Hz, 1H, H-

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1′), 4.70 (d, J = 12.3 Hz, 1H, CH₂group of Nap), 4.61 (d, J = 11.7

Hz, 1H, CH₂Ph), 4.55 (t, J = 9.1 Hz, 1H, H-3), 4.49 (d, J = 12.3 Hz,

1H, CH₂group of Nap), 4.31 (m, 3H, H-6a, CH₂Ph), 3.94 (d, J = 2.3

Hz, 1H, H-4′), 3.67 (m, 2H, H-4, H-6b), 3.63−3.56 (m, 1H, H-6a′),

3.54 (dd, J = 10.0, 2.8 Hz, 1H, H-3′), 3.51−3.44 (m, 2H, H-5, H-6b′),

3.38 (t, J = 6.5 Hz, 1H, H-5′), 3.21−3.14 (td, J = 9.9, 7.1 Hz, 1H, H-

2), 2.33 (s, 3H, PhCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.5

(C), 161.7 (C), 139.2 (C), 138.6 (C), 137.9 (C), 137.5 (C), 135.0

(C), 134.2 (CH), 133.2 (CH), 133.1 (C), 130.2 (CH), 130.1 (CH),

129.1 (CH), 128.7 (CH), 128.5 (CH), 128.44 (CH), 128.4 (CH),

128.3 (CH), 128.2 (CH), 128.0 (CH), 127.8 (CH), 127.2 (C), 126.7

(CH), 126.34 (CH), 126.3 (CH), 126.1 (CH), 125.9 (CH), 101.3

(CH), 100.0 (CH), 92.2 (C), 84.1 (CH), 80.2 (CH), 80.0 (CH),

76.3 (CH), 74.7 (CH₂), 73.8 (CH₂), 73.5 (CH), 72.4 (CH), 72.2

(CH), 72.0 (CH₂), 70.8 (CH), 68.8 (CH₂), 57.7 (CH), 29.9 (CH₂),

21.4 (CH₃); HRMS (ESI-TOF) m/z: calcd for C₆₀H₅₆Cl₃NO₁₁SNa

[M + Na]⁺, 1126.2532; found, 1126.2556.

yield the viscous crude. The crude was redissolved in CH₂Cl₂(15

mL) and neutralized by addition of saturated NaHCO₃solution (15

mL) under the ice bath. Organic layer was separated, washed with

saturated NaHCO₃solution (15 mL), dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure. Pure product 4 was obtained

after puriﬁcation by column chromatography on silica gel with

EtOAc/hexanes (1/4, v/v) in 94% yield (0.95 g) as a white

amorphous foam. R_f0.30 (EtOAc/hexanes = 1/3, v/v, run two

times); [α]²_D⁰−2.913 (c 1.03, CHCl₃); ¹H NMR (500 MHz, CDCl₃):

δ 7.92 (d, J = 7.45 Hz, 2H, Ar-H), 7.74 (d, J = 7.5 Hz, 1H, Ar-H),

7.61−7.52 (m, 4H, Ar-H), 7.48−7.4 (m, 2H, Ar-H), 7.4−7.32 (m,

5H, Ar-H), 7.31−7.30 (m, 3H, Ar-H), 7.30−7.29 (m, 5H, Ar-H),

7.29−7.23 (m, 6H, Ar-H), 7.19 (d, J = 8.55 Hz, 1H, Ar-H), 7.0 (d, J =

6.9 Hz, 1H, N−H), 6.93 (d, J = 7.85 Hz, 2H, Ar-H), 5.53 (dd, J = 9.7,

8.1 Hz, 1H, H-2′), 5.22 (d, J = 10.1 Hz, 1H, H-1), 4.99 (d, J = 11.6

Hz, 1H, CH₂Ph), 4.88 (t, J = 9.4 Hz, 1H, H-4), 4.73 (d, J = 12.25 Hz,

1H, CH₂Ph), 4.62 (d, J = 7.8 Hz, 1H, H-1′), 4.58−4.45 (m, 6H,

CH₂Ph, H-3), 4.42 (d, J = 11.8 Hz, 1H, CH₂Ph), 3.95 (d, J = 1.8 Hz,

1H, H-4′), 3.64−3.46 (m, 7H, H-5, H-5′, H-6a, H-6b, H-6a′, H-6b′,

H-3′), 3.27 (td, J = 9.8, 7.3 Hz, 1H, H-2), 2.25 (s, 3H, PhCH₃), 1.62

(s, 3H, COCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 169.8 (C),

165.2 (C), 161.5 (C), 138.6 (C), 138.5 (C), 138.2 (C), 137.8 (C),

135.0 (C), 133.5 (CH), 133.2 (CH), 133.1 (C), 130.2 (CH), 130.0

(C), 129.9 (CH), 128.7 (CH), 128.5 (CH), 128.4 (CH), 128.3 (C),

128.2 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 127.8 (CH),

127.7 (CH), 126.9 (CH), 126.3 (CH), 126.2 (CH), 125.9 (CH),

99.3 (CH), 92.6 (C), 84.4 (CH), 79.8 (CH), 78.0 (CH), 75.8 (CH),

74.6 (CH₂), 73.80 (CH), 73.78 (CH₂), 73.6 (CH₂), 72.8 (CH), 72.2

(CH₂), 71.9 (CH), 69.7 (CH₂), 68.6 (CH), 68.5 (CH₂), 57.6 (CH),

21.3 (CH₃), 20.6 (CH₃); HRMS (ESI-TOF) m/z: calcd for

C₆₂H₆₀Cl₃NO₁₂SNa [M + Na]⁺, 1172.2783; found, 1172.2801.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-6-O-tert-bu-

tyldiphenylsilyl-2-deoxy-2-trichloroacetamido-1-thio-β-^D-glu-

copyranoside (5). For reaction details, please see Scheme S6. To a

solution of compound 52 (1.0 g, 0.98 mmol) in DMF (10 mL),

imidazole (200 mg, 2.94 mmol) and TBDPSCl (0.64 mL, 2.46 mmol)

were added at rt with continuous stirring. After 1 h, the reaction was

quenched by addition of MeOH (4 mL) and concentrated by

evaporation to yield a viscous white crude. The crude was redissolved

in EtOAc (15 mL) and washed with dd. H₂O (15 mL, two times) and

saturated NaHCO₃solution (15 mL, two times). The organic layer

was collected, dried over MgSO₄, ﬁltered, and concentrated under

reduced pressure to collect the crude product. The crude product was

subjected to puriﬁcation by column chromatography on silica gel with

EtOAc/hexanes (1/6, v/v, with 1% Et₃N) to yield pure 5 in 92% yield

(1.13 g) as a white amorphous solid. R_f0.51 (EtOAc/hexanes = 1/2,

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-4-O-acetyl-

6-O-tert-butyldiphenylsilyl-2-deoxy-2-trichloroacetamido-1-

thio-β-^D-glucopyranoside (3). For reaction details, please see

Scheme S6. A solution of compound 5 (2.60 g, 2.07 mmol) in dry

CH₂Cl₂(21 mL) was stirred with 4-DMAP (25 mg, 0.20 mmol) in an

ice bath for 5 min. Then, Et₃N (0.72 mL, 5.17 mmol) and Ac₂O (488

μL, 5.17 mmol) were sequentially added, and the reaction mixture

was stirred for 1.5 h. After completion of the reaction, as checked by

TLC, MeOH (4 mL) was added to the mixture and concentrated by

evaporation to yield a viscous white crude. The crude was redissolved

in CH₂Cl₂(20 mL) and neutralized by the addition of saturated

NaHCO₃solution (20 mL) under the ice bath. The organic layer was

collected, washed with saturated NaHCO₃solution (20 mL), dried

over MgSO₄, ﬁltered, and concentrated by evaporation to yield a thick

white crude. The crude was subjected to column chromatography on

silica gel with EtOAc/hexanes (1/4, v/v) to obtain pure 3 (2.61 g,

97%) as a white amorphous solid. R_f0.38 (EtOAc/hexanes = 1/4, v/v,

run two times); [α]²_D⁰+6.0 (c 1.0, CHCl₃); H NMR (500 MHz,

1

CDCl₃): δ 7.90 (d, J = 7.3 Hz, 2H, Ar-H), 7.72 (d, J = 7.3 Hz, 1H, Ar-

H), 7.65 (d, J = 6.9 Hz, 4H, Ar-H), 7.60−7.50 (m, 4H, Ar-H), 7.45−

7.40 (m, 2H, Ar-H), 7.39−7.36 (m, 2H, Ar-H), 7.36−7.34 (m, 2H,

Ar-H), 7.34−7.31 (m, 7H, Ar-H), 7.31−7.27 (m, 7H, Ar-H), 7.26−

7.23 (m, 1H, Ar-H), 7.22−7.16 (m, 2H, Ar-H), 6.98 (d, J = 6.7 Hz,

1H, N−H), 6.91 (d, J = 7.8 Hz, 2H, Ar-H), 5.51 (dd, J = 9.9, 7.9 Hz,

1H, H-2′), 5.23 (d, J = 10.1 Hz, 1H, H-1), 5.00 (d, J = 11.6 Hz, 1H,

CH₂Ph), 4.84 (t, J = 9.5 Hz, 1H, H-4), 4.72 (d, J = 12.2 Hz, 1H, CH₂

group of Nap), 4.63−4.40 (m, 6H, H-3, H-1′, 3× CH₂Ph, CH₂group

of Nap), 3.95 (d, J = 1.8 Hz, 1H, H-4′), 3.73−3.61 (m, 2H, H-6a, H-

6b), 3.60−3.50 (m, 5H, H-5, H-3′, H-5′, H-6a′, H-6b′), 3.30−3.21

(m, 1H, H-2), 2.24 (s, 3H, PhCH₃), 1.56 (s, 3H, COCH₃), 1.02 (s,

9H, TBDPS-t-Bu); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 169.5 (C),

165.1 (C), 161.4 (C), 138.6 (C), 138.4 (C), 137.8 (C), 135.8 (CH),

134.9 (C), 133.44 (CH), 133.38 (C), 133.3 (C), 133.2 (CH), 133.1

(C), 130.1 (CH), 130.0 (C), 129.9 (CH), 129.78 (CH), 129.76

(CH), 128.68 (CH), 128.4 (CH), 128.13 (CH), 128.11 (CH), 128.0

(CH), 127.8 (CH), 127.77 (CH), 127.7 (CH), 126.8 (CH), 126.3

(CH), 126.1 (CH), 125.9 (CH), 99.4 (CH), 92.7 (C), 84.5 (CH),

79.8 (CH), 79.6 (CH), 76.0 (CH), 74.6 (CH₂), 74.0 (CH), 73.8

(CH₂), 72.8 (CH), 72.1 (CH₂), 71.9 (CH), 68.4 (CH₂), 68.1 (CH),

63.4 (CH₂), 57.7 (CH), 26.9 (CH₃), 21.3 (CH₃), 20.5 (CH₃), 19.3

(C); HRMS (ESI-TOF) m/z: calcd for C₇₁H₇₂Cl₃NO₁₂SSiNa [M +

Na]⁺, 1320.3478; found, 1320.3540.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-4-O-acetyl-

6-O-benzyl-2-deoxy-2-trichloroacetamido-1-thio-β-^D-gluco-

pyranoside (4). For reaction details, please see Scheme S5. A

solution of compound 7 (0.97 g, 0.88 mmol) in dry CH₂Cl₂(8.13

mL) was stirred with 4-DMAP (10 mg, 0.08 mmol) in an ice bath for

5 min. Then, Et₃N (227 μL, 1.75 mmol) and Ac₂O (153 μL, 1.75

mmol) were sequentially added, and the reaction mixture was stirred

for 2 h. After reaction completion, as checked by TLC, MeOH (2

mL) was added, and the mixture was concentrated by evaporation to

v/v); [α]²_D⁰+5.21 (c 0.96, CHCl₃); H NMR (500 MHz, CDCl₃): δ

1

7.90 (d, J = 7.4 Hz, 2H, Ar-H), 7.74 (d, J = 6.3 Hz, 5H, Ar-H), 7.60−

7.51 (m, 4H, Ar-H), 7.48−7.42 (m, 2H, Ar-H), 7.39−7.32 (m, 10H,

Ar-H), 7.31−7.24 (m, 10H, Ar-H), 7.19 (d, J = 8.1 Hz, 1H, Ar-H),

6.93 (d, J = 7.6 Hz, 2H, Ar-H), 6.70 (d, J = 6.5 Hz, 1H, N−H), 5.63

(dd, J = 9.8, 7.8 Hz, 1H, H-2′), 5.23 (d, J = 10.3 Hz, 1H, H-1), 4.95

(d, J = 11.6 Hz, 1H, CH₂Ph), 4.74 (d, J = 12.0 Hz, 1H, CH₂group of

Nap), 4.63−4.51 (m, 3H, H-1′, CH₂group of Nap, CH₂Ph), 4.45 (d,

J = 11.7 Hz, 1H, CH₂Ph), 4.41−4.29 (m, 2H, H-3, CH₂Ph), 4.05−

3.93 (m, 3H, H-4′, H-6a, O−H), 3.87 (dd, J = 10.9, 4.9 Hz, 1H, H-

6b), 3.69−3.41 (m, 6H, H-4, H-5, H-3′, H-5′, H-6a′, H-6b′), 3.11−

3.02 (m, 1H, H-2), 2.26 (s, 3H, PhCH₃), 1.05 (s, 9H, TBDPS-t-Bu);

¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.7 (C), 161.7 (C), 138.5

(C), 138.2 (C), 137.6 (C), 135.9 (CH), 134.7 (C), 133.8 (C), 133.5

(CH), 133.4 (CH), 133.2 (C), 133.17 (C), 130.2 (CH), 130.0 (CH),

129.9 (C), 129.7 (CH), 128.7 (CH), 128.6 (CH), 128.53 (CH),

128.50 (CH), 128.3 (C), 128.2 (CH), 128.1 (CH), 128.05 (CH),

128.02 (CH), 127.8 (CH), 127.0 (CH), 126.4 (CH), 126.3 (CH),

126.0 (CH), 101.2 (CH), 92.2 (C), 83.5 (CH), 81.9 (CH), 80.9

(CH), 80.0 (CH), 74.8 (CH₂), 74.2 (CH), 73.8 (CH₂), 72.5 (CH₂),

72.4 (CH), 72.0 (CH), 69.1 (CH), 68.5 (CH₂), 63.6 (CH₂), 57.3

(CH), 27.0 (CH₃), 21.3 (CH₃), 19.5 (C); HRMS (ESI-TOF) m/z:

H

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Article

calcd for C₆₉H₇₀Cl₃NO₁₁SSiNa [M + Na]⁺, 1278.3365; found,

1278.3372.

4H, H-3′, H-6b, H-5′, H-6a′), 3.55−3.50 (m, 2H, H-4, H-5), 3.48

(dd, J = 4.3, 7.66 Hz, 1H, H-6b′), 3.09 (td, J = 10.0, 7.0 Hz, 1H, H-2),

2.28 (s, 3H, PhCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.6

(C), 161.6 (C), 138.7 (C), 138.6 (C), 138.1 (C), 137.6 (C), 134.7

(C), 133.5 (CH), 133.4 (CH), 133.2 (C), 133.1 (C), 130.2 (CH),

129.9 (CH), 129.8 (C), 128.6 (CH), 128.59 (CH), 128.50 (CH),

128.47 (CH), 128.41 (CH), 128.2 (CH), 128.1 (CH), 128.0 (CH),

127.8 (CH), 127.7 (CH), 127.5 (CH), 127.0 (CH), 126.3 (CH),

126.2 (CH), 126.0 (CH), 101.1 (CH), 92.1 (C), 83.6 (CH), 81.9

(CH), 80.0 (CH), 79.8 (CH), 74.7 (CH₂), 74.1 (CH), 73.8 (CH₂),

73.5 (CH₂), 72.5 (CH₂), 72.4 (CH), 72.0 (CH), 69.9 (CH₂), 69.6

(CH), 68.7 (CH₂), 57.2 (CH), 21.3 (CH₃); HRMS (ESI-TOF) m/z:

calcd for C₆₀H₅₈Cl₃NO₁₁SNa [M + Na]⁺, 1130.2663; found,

1130.2670.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-6-O-tert-bu-

tyldimethylsilyl-2-deoxy-2-trichloroacetamido-1-thio-β-^D-glu-

copyranoside (6). For reaction details, please see Scheme S5.

Imidazole (155 mg, 2.27 mmol) and TBMSCl (191.4 mg, 1.27 mmol)

were added to a solution of compound 52 (0.92 g, 0.91 mmol) in

DMF (9 mL) at rt and stirred for 2.5 h. After complete consumption

of the starting material, the reaction was quenched by adding MeOH

(2 mL). The reaction mixture was concentrated by evaporation to

yield the viscous white crude. The crude product was extracted with

EtOAc (15 mL) and saturated NaHCO₃solution (15 mL, two times).

The EtOAc layer was collected, dried over MgSO₄, ﬁltered, and

concentrated by evaporation to aﬀord a thick crude. The crude was

subjected to column chromatography on silica gel with EtOAc/

hexanes (1/3, v/v, with 1% Et₃N) to yield the pure product 6 as a

white amorphous solid (0.98 g, 96%). R_f0.62 (EtOAc/hexanes = 1/2,

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-4,6-di-O-

benzyl-2-deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyra-

noside (8). For reaction details, please see Scheme S5. Tetrabutyl

ammonium iodide (545 mg, 1.47 mmol), BnBr (525 μL, 4.42 mmol),

and NaH (60% in mineral oil, 206 mg, 5.15 mmol) were sequentially

added to the ice-cold solution of compound 51 (1.63 g, 1.47 mmol)

in anhydrous DMF (14.75 mL) under N₂. After 2 h, the reaction was

quenched by adding dd. H₂O (4 mL) under the ice bath and diluted

with CH₂Cl₂(20 mL). Solvent extraction was done to wash the

CH₂Cl₂layer with saturated NaHCO₃solution (20 mL, three times).

The organic layer was collected, dried over MgSO₄, ﬁltered, and

concentrated by evaporation to yield the pale-yellow viscous crude.

The crude was puriﬁed by column chromatography on silica gel with

EtOAc/hexanes (1/5, v/v) to aﬀord the pure product 8 (1.14 g, 65%)

as a white amorphous foam. R_f0.57 (EtOAc/hexanes = 1/2, v/v);

1

v/v); [α]²_D⁰+4.95 (c 1.01, CHCl₃); H NMR (500 MHz, CDCl₃): δ

7.90 (d, J = 7.2 Hz, 2H, Ar-H), 7.75 (d, J = 7.5 Hz, 1H, Ar-H), 7.63−

7.51 (m, 4H, Ar-H), 7.44 (td, J = 10.3, 5.0 Hz, 2H, Ar-H), 7.39−7.27

(m, 14H, Ar-H), 7.19 (dd, J = 8.2, 1.6 Hz, 1H, Ar-H), 7.00 (d, J = 7.8

Hz, 2H, Ar-H), 6.68 (d, J = 6.7 Hz, 1H, N−H), 5.62 (dd, J = 9.8, 8.0

Hz, 1H, H-2′), 5.19 (d, J = 10.3 Hz, 1H, H-1), 4.96 (d, J = 11.6 Hz,

1H, CH₂Ph), 4.74 (d, J = 12.0 Hz, 1H, CH₂group of Nap), 4.64−

4.52 (m, 3H, H-1′, CH₂group of Nap, CH₂Ph), 4.5 (d, J = 11.7 Hz,

1H, CH₂Ph), 4.4 (d, J = 11.7 Hz, 1H, CH₂Ph), 4.31 (t, J = 9.0 Hz,

1H, H-3), 4.05−3.89 (m, 3H, H-4′, H-6a, O−H), 3.77 (dd, J = 11.2,

5.2 Hz, 1H, H-6b), 3.71−3.58 (m, 3H, H-3′, H-5′, H-6a′), 3.57−3.43

(m, 2H, H-4, H-6b′), 3.41−3.30 (m, 1H, H-5), 3.03 (td, J = 10.1, 6.8

Hz, 1H, H-2), 2.30 (s, 3H, PhCH₃), 0.90 (s, 9H, TBS-t-Bu), 0.071 (s,

3H, TBS-CH₃), 0.06 (s, 3H, TBS-CH₃); ¹³C{¹H} NMR (125 MHz,

CDCl₃): δ 165.7 (C), 161.7 (C), 138.5 (C), 138.2 (C), 137.7 (C),

134.8 (C), 133.4 (CH), 133.24 (C), 133.20 (C), 130.3 (CH), 130.0

(CH), 129.9 (C), 128.7 (CH), 128.6 (CH), 128.55 (CH), 128.52

(CH), 128.4 (C), 128.2 (CH), 128.17 (CH), 128.1 (CH), 128.0

(CH), 127.9 (CH), 127.1 (CH), 126.4 (CH), 126.3 (CH), 126.0

(CH), 101.2 (CH), 92.2 (C), 83.6 (CH), 81.9 (CH), 81.0 (CH),

80.0 (CH), 74.8 (CH₂), 74.2 (CH), 73.9 (CH₂), 72.5 (CH₂), 72.4

(CH), 72.0 (CH), 69.2 (CH), 68.7 (CH₂), 63.0 (CH₂), 57.3 (CH),

26.2 (CH₃), 21.4 (CH₃), 18.6 (C), −5.0 (2× CH₃); HRMS (ESI-

TOF) m/z: calcd for C₅₉H₆₇Cl₃NO₁₁SSi [M + H]⁺, 1132.3253;

found, 1132.3252.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-6-O-benzyl-

2-deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyranoside

(7). For reaction details, please see Scheme S5. A solution of

compound 2 (0.50 g, 0.45 mmol) in dry CH₂Cl₂(4.52 mL) was

stirred in an ice bath, followed by the addition of Et₃SiH (445 μL,

2.78 mmol) and TFAA (64 μL, 0.45 mmol). After stirring for 5 min,

TFA (168 μL, 2.26 mmol) was added to the reaction mixture. After 3

h, the reaction was neutralized by dropwise addition of Et₃N under

the ice bath. The neutralized reaction mixture was concentrated by

evaporation to aﬀord the solid residue. The residue was then

redissolved in CH₂Cl₂(10 mL) and washed with saturated NaHCO₃

solution (10 mL, two times). The CH₂Cl₂layer was collected, dried

over MgSO₄, ﬁltered, and concentrated by evaporation. Pure product

7 was isolated as a white solid after puriﬁcation of crude by column

chromatography on silica gel with EtOAc/hexanes (1/5 to 1/3, v/v)

in 85% yield (0.43 g). R_f0.34 (EtOAc/hexanes = 1/2, v/v); [α]_D²⁰

+10.99 (c 0.91, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ 7.91 (d, J =

7.72 Hz, 2H, Ar-H), 7.75 (d, J = 7.24 Hz, 1H, Ar-H), 7.62−7.51 (m,

4H, Ar-H), 7.49−7.40 (m, 2H, Ar-H), 7.39−7.34 (m, 2H, Ar-H),

7.34−7.25 (m, 17H, Ar-H), 7.19 (dd, J = 8.46, 1.34 Hz, 1H, Ar-H),

6.96 (d, J = 8.0 Hz, 2H, Ar-H), 6.72 (d, J = 6.9 Hz, 1H, N−H), 5.62

(dd, J = 10, 8.0 Hz, 1H, H-2′), 5.22 (d, J = 10.4 Hz, 1H, H-1), 4.95

(d, J = 11.6 Hz, 1H, CH₂), 4.74 (d, J = 12.1 Hz, 1H, CH₂), 4.66−4.52

(m, 5H, H-1′, CH₂), 4.46 (d, J = 11.8 Hz, 1H, CH₂), 4.40 (d, J = 11.8

Hz, 1H, CH₂), 4.34−4.26 (m, 1H, H-3), 4.12 (s, 1H, O−H), 3.94 (d,

J = 2.5 Hz, 1H, H-4′), 3.82 (d, J = 11.0 Hz, 1H, H-6a), 3.70−3.60 (m,

[α]²_D⁰−6.62 (c 1.36, CHCl₃); H NMR (500 MHz, CDCl₃): δ 7.93

1

(d, J = 7.72 Hz, 2H, Ar-H), 7.73 (d, J = 8 Hz, 1H, Ar-H), 7.62−7.53

(m, 4H, Ar-H), 7.46−7.40 (m, 2H, Ar-H), 7.39−7.33 (m, 4H, Ar-H),

7.31−7.14 (m, 18H, Ar-H), 7.11−7.07 (m, 2H, Ar-H), 6.87 (d, J = 8

Hz, 2H, Ar-H), 6.82 (d, J = 7.85 Hz, 1H, N−H), 5.69 (dd, J = 10.1,

7.9 Hz, 1H, H-2′), 5.05 (d, J = 11.45 Hz, 1H, CH₂Ph), 4.93 (d, J =

10.15 Hz, 1H, CH₂Ph), 4.92 (d, J = 9.5 Hz, 1H, H-1), 4.76 (d, J =

12.4 Hz, 1H, CH₂Ph), 4.68 (d, J = 7.9 Hz, 1H, H-1′), 4.61 (d, J =

11.5 Hz, 1H, CH₂Ph), 4.56 (d, J = 11.7 Hz, 1H, CH₂Ph), 4.54−4.46

(m, 2H, CH₂Ph), 4.46−4.40 (m, 2H, H-3, CH₂Ph), 4.38 (d, J = 11.8

Hz, 1H, CH₂Ph), 4.29 (d, J = 11.8 Hz, 1H, CH₂Ph), 4.03 (d, J = 2.5

Hz, 1H, H-4′), 3.75 (dd, J = 10.7, 2.3 Hz, 1H, H-6a), 3.71 (d, J =

10.7, 4.65 Hz, 1H, H-6b), 3.60−3.52 (m, 4H, H-3′, H5, H-5′, H-6a′),

3.52−3.46 (m, 2H, H-4, H-6b′), 3.38−3.24 (m, 1H, H-2), 2.20 (s,

3H, PhCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.5 (C), 161.1

(C), 138.7 (C), 138.4 (C), 138.2 (C), 138.0 (C), 134.9 (C), 133.2

(CH), 133.1 (C), 133.09 (CH), 130.0 (C), 129.97 (CH), 129.7

(CH), 128.6 (CH), 128.5 (CH), 128.46 (CH), 128.4 (CH), 128.37

(CH), 128.1 (CH), 128.0 (CH), 127.97 (CH), 127.9 (CH), 127.8

(CH), 127.7 (CH), 127.66 (CH), 127.6 (CH), 127.56 (CH), 126.9

(CH), 126.2 (CH), 126.1 (CH), 126.0 (CH), 100.4 (CH), 92.7 (C),

84.4 (CH), 79.4 (CH), 78.8 (CH), 77.4 (CH), 75.9 (CH), 74.9

(CH₂), 74.8 (CH₂), 74.0 (CH), 73.7 (CH₂), 73.4 (CH₂), 73.0 (CH),

72.0 (CH), 71.8 (CH₂), 69.3 (CH₂), 68.4 (CH₂), 57.1 (CH), 21.2

(CH₃); HRMS (ESI-TOF) m/z: calcd for C₆₇H₆₄Cl₃NO₁₁SNa [M +

Na]⁺, 1220.3149; found, 1220.3079.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-4-O-tert-bu-

tyldimethylsilyl-6-O-benzyl-2-deoxy-2-trichloroacetamido-1-

thio-β-^D-glucopyranoside (9). For reaction details, please see

Scheme S7. 2,6-Lutidine (257 μL, 2.22 mmol) and TBSOTf (170 μL,

0.74 mmol) were added to a solution of compound 7 (328 mg, 0.30

mmol) in CH₂Cl₂(3 mL) at rt and stirred for 2.5 h. After complete

consumption of the starting material, the reaction was quenched by

addition of MeOH (2 mL). The reaction mixture was concentrated by

evaporation, and the crude product was extracted by using CH₂Cl₂

(10 mL) and saturated NaHCO₃solution (10 mL, three times). The

organic layer was collected, dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure to yield a thick viscous crude.

The crude was puriﬁed by column chromatography on silica gel with

I

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Article

EtOAc/hexanes (1/6 to 1/4, v/v, with 0.5−1% Et₃N) to obtain the

pure product 9 as a white amorphous foam (257 mg, 70%). R_f0.31

(EtOAc/hexanes = 1/4, v/v); [α]²_D⁰−7.14 (c 0.98, CHCl₃); ¹H NMR

(500 MHz, CDCl₃): δ 7.96 (d, J = 7.8 Hz, 2H, Ar-H), 7.72 (d, J = 7.7

Hz, 1H, Ar-H), 7.60−7.56 (m, 2H, Ar-H), 7.53 (d, J = 8.8 Hz, 2H,

Ar-H), 7.46−7.40 (m, 2H, Ar-H), 7.38 (t, J = 7.7 Hz, 2H, Ar-H),

7.35−7.31 (m, 3H, Ar-H), 7.31−7.24 (m, 11H, Ar-H), 7.23−7.19 (m,

2H, Ar-H), 7.19−7.16 (m, 2H, Ar-H), 7.00 (d, J = 7.7 Hz, 1H, N−H),

6.85 (d, J = 7.8 Hz, 2H, Ar-H), 5.72−5.58 (m, 1H, H-2′), 5.05 (d, J =

11.4 Hz, 1H, CH₂Ph), 4.84 (d, J = 8.6 Hz, 1H, H-1), 4.77 (d, J = 12.4

Hz, 1H, CH₂group of Nap), 4.72 (d, J = 7.9 Hz, 1H, H-1′), 4.58 (d, J

= 12.5 Hz, 1H, CH₂group of Nap), 4.57 (d, J = 11.4 Hz, 1H,

CH₂Ph), 4.51 (d, J = 11.9 Hz, 1H, CH₂Ph), 4.47−4.39 (m, 3H,

3xCH₂Ph), 4.16−4.10 (m, 1H, H-3), 3.99 (d, J = 1.3 Hz, 1H, H-4′),

3.81−3.73 (m, 1H, H-4), 3.67−3.48 (m, 8H, H-2, H-5, H-3′, H-5′, H-

6a, H-6b, H-6a′, H6b′), 2.20 (s, 3H, PhCH₃), 0.79 (s, 9H, TBS-t-Bu),

0.15 (s, 3H, TBS-CH₃), −0.03 (s, 3H, TBS-CH₃); ¹³C{¹H} NMR

(125 MHz, CDCl₃): δ 165.5 (C), 161.0 (C), 138.7 (C), 138.6 (C),

137.84 (C), 137.80 (C), 135.0 (C), 133.2 (C), 133.1 (C), 133.08

(CH), 132.4 (CH), 130.2 (C), 130.1 (CH), 129.7 (CH), 128.7

(CH), 128.5 (CH), 128.4 (CH), 128.37 (CH), 128.3 (CH), 128.2

(CH), 128.1 (CH), 128.0 (CH), 127.8 (CH), 127.6 (CH), 127.5

(CH), 126.9 (CH), 126.2 (CH), 126.1 (CH), 126.0 (CH), 99.7

(CH), 92.8 (C), 84.9 (CH), 80.7 (CH), 79.6 (CH), 76.4 (CH), 74.8

(CH₂), 73.9 (CH), 73.8 (CH₂), 73.4 (CH₂), 73.1 (CH), 71.9 (CH₂),

71.6 (CH), 70.0 (CH₂), 69.8 (CH), 68.7 (CH₂), 56.1 (CH), 26.2

(CH₃), 21.2 (CH₃), 18.1 (C), −3.5 (CH₃), −4.7 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₆₆H₇₃Cl₃NO₁₁SSi [M + H]⁺, 1222.3725;

found, 1222.3661.

continuously under the argon atmosphere. After 5 h, the reaction was

quenched by addition of saturated NaHCO₃solution (3 mL) under

the ice bath. The organic layer was washed with saturated NaHCO₃

solution (15 mL, two times), dried over MgSO₄, ﬁltered, and

concentrated by evaporation to yield the yellow viscous crude. The

crude was puriﬁed by column chromatography on silica gel with

EtOAc/hexanes (1/4 to 1/2, v/v) to isolate the desired product 11 as

a white amorphous solid (128 mg, 70%). R_f0.24 (EtOAc/hexanes =

1/2, v/v); [α]²_D⁰+3.66 (c 0.82, CHCl₃); ¹H NMR (500 MHz,

CDCl₃): δ 8.0 (d, J = 7.35 Hz, 2H, Ar-H), 7.63−7.54 (m, 1H, Ar-H),

7.47−7.41 (m, 2H, Ar-H), 7.38−7.27 (m, 17H, Ar-H), 6.98 (d, J = 7.9

Hz, 2H, Ar-H), 6.77 (d, J = 7.0 Hz, 1H, N−H), 5.26 (dd, J = 9.6, 8.3

Hz, 1H, H-2′), 5.21 (d, J = 10.3 Hz, 1H, H-1), 4.68−4.65 (m, 2H, 2×

CH₂Ph), 4.61 (d, J = 7.9 Hz, 1H, H-1′), 4.58−4.55 (m, 2H, 2×

CH₂Ph), 4.51 (d, J = 11.8 Hz, 1H, CH₂Ph), 4.45 (d, J = 11.7 Hz, 1H,

CH₂Ph), 4.37−4.30 (m, 1H, H-3), 4.04 (s, 1H, O−H), 3.88−3.81

(m, 2H, H-4′, H-6a), 3.76 (t, J = 6.5 Hz, 1H, H-5′), 3.73−3.64 (m,

3H, H-3′, H-6a′, H-6b), 3.60−3.50 (m, 3H, H-4, H-5, H-6b′), 3.18

(dd, J = 17.2, 10.1 Hz, 1H, H-2), 2.32−2.25 (m, 4H, PhCH₃, O−H);

¹³C{¹H} NMR (125 MHz, CDCl₃): δ 166.8 (C), 161.8 (C), 138.7

(C), 138.6 (C), 137.7 (C), 137.5 (C), 133.7 (CH), 133.6 (CH),

130.2 (CH), 130.0 (CH), 129.7 (C), 128.9 (CH), 128.73 (CH),

128.7 (CH), 128.5 (CH), 128.4 (CH), 128.37 (CH), 128.29 (C),

128.2 (CH), 128.18 (CH), 127.7 (CH), 127.6 (CH), 100.6 (CH),

92.3 (C), 83.9 (CH), 81.8 (CH), 79.9 (CH), 76.5 (CH), 75.8 (CH₂),

74.1 (CH), 73.92 (CH), 73.90 (CH₂), 73.6 (CH₂), 73.2 (CH), 69.9

(CH₂), 69.6 (CH), 68.3 (CH₂), 57.3 (CH), 21.3 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₄₉H₅₀Cl₃NO₁₁SNa [M + Na]⁺, 990.2046;

found, 990.2051.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galacto-

pyranosyl)-(1 → 3)-4,6-di-O-benzyl-2-deoxy-2-trichloroaceta-

mido-1-thio-β-^D-glucopyranoside (10). For reaction details,

please see Scheme S5. To a solution of compound 8 (410 mg, 0.34

mmol) in a 10:1 (v/v) mixture of CH₂Cl₂(31 mL) and PBS (3.1 mL,

pH = 7.4), DDQ (233 mg, 1.02 mmol) was added with continuous

stirring at 0 °C under the argon atmosphere. After 6 h, the reaction

mixture was quenched by addition of saturated NaHCO₃solution (5

mL) under the ice bath. The organic layer was washed with saturated

NaHCO₃solution (30 mL, two times), dried over MgSO₄, ﬁltered,

and concentrated by evaporation to aﬀord the pale-yellow viscous

crude. The crude was puriﬁed by column chromatography on silica gel

with EtOAc/hexanes (1/5 to 1/4, v/v) to yield the desired product

10 (228 mg, 63%) as a white amorphous solid. R_f0.28 (EtOAc/

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galacto-

pyranosyl)-(1 → 3)-6-O-tert-butyldimethylsilyl-2-deoxy-2-tri-

chloroacetamido-1-thio-β-^D-glucopyranoside (12). For reaction

details, please see Scheme S5. To a solution of compound 6 (298 mg,

0.26 mmol) in a 10:1 (v/v) mixture of CH₂Cl₂(24 mL) and PBS (2.4

mL, pH = 7.4), DDQ (180 mg, 0.79 mmol) was added at 0 °C under

the argon atmosphere and stirred continuously. After 6 h, the reaction

mixture was quenched by addition of saturated NaHCO₃solution (5

mL) under the ice bath. The organic layer was washed with saturated

NaHCO₃solution (20 mL, two times), dried over MgSO₄, ﬁltered,

and concentrated by evaporation to yield a yellow viscous crude. The

crude was puriﬁed by column chromatography on silica gel with

EtOAc/hexanes (1/4 to 1/3, v/v) to yield the desired product 12 in

80% (209 mg) yield as a white amorphous solid. R_f₁0.38 (EtOAc/

hexanes = 1/2, v/v); [α]_D²⁰−8.26 (c 1.21, CHCl₃); H NMR (400

MHz, CDCl₃): δ 8.01 (d, J = 7.4 Hz, 2H, Ar-H), 7.57 (t, J = 7.3 Hz,

1H, Ar-H), 7.43 (t, J = 7.6 Hz, 2H, Ar-H), 7.39−7.26 (m, 12H, Ar-

H), 7.02 (d, J = 7.7 Hz, 2H, Ar-H), 6.75 (d, J = 6.9 Hz, 1H, N−H),

5.31−5.23 (m, 1H, H-2′), 5.19 (d, J = 10.4 Hz, 1H, H-1), 4.67 (m,

2H, 2× CH₂Ph), 4.59 (d, J = 7.9 Hz, 1H, H-1′), 4.54 (d, J = 14.7 Hz,

1H, CH₂Ph), 4.46 (d, J = 14.7 Hz, 1H, CH₂Ph), 4.33 (t, J = 9.0 Hz,

1H, H-3), 3.99−3.90 (m, 2H, H-6a, O−H), 3.86 (d, J = 2.6 Hz, 1H,

H-4′), 3.83−3.73 (m, 2H, H-6b, H-5′), 3.73−3.63 (m, 2H, H-3′, H-

6a′), 3.62−3.54 (m, 1H, H-6b′), 3.49 (t, J = 8.9 Hz, 1H, H-4), 3.40−

3.32 (m, 1H, H-5), 3.18−3.07 (m, 1H, H-2), 2.33−2.24 (m, 4H,

PhCH₃, O−H), 0.91 (s, 9H, TBS-t-Bu), 0.086 (s, 3H, TBS-CH₃),

0.075 (s, 3H, TBS-CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 166.8

(C), 161.7 (C), 138.5 (C), 137.8 (C), 137.5 (C), 133.6 (CH), 133.4

(CH), 130.2 (CH), 130.0 (CH), 129.7 (C), 128.9 (CH), 128.7

(CH), 128.66 (CH), 128.5 (C), 128.4 (CH), 128.3 (CH), 128.2

(CH), 128.1 (CH), 100.6 (CH), 92.3 (C), 83.9 (CH), 81.7 (CH),

80.9 (CH), 76.5 (CH), 75.8 (CH₂), 74.1 (CH), 73.93 (CH), 73.89

(CH₂), 73.2 (CH), 69.2 (CH), 68.2 (CH₂), 62.9 (CH₂), 57.2 (CH),

26.1 (CH₃), 21.3 (CH₃), 18.6 (C), −5.0 (2× CH₃); HRMS (ESI-

TOF) m/z: calcd for C₄₈H₅₉Cl₃NO₁₁SSi [M + H]⁺, 992.2612; found,

992.2592.

hexanes = 1/3, v/v); [α]_D²⁰−20.29 (c 0.69, CHCl₃); H NMR (500

1

MHz, CDCl₃): 8.06 (d, J = 7.7 Hz, 2H, Ar-H), 7.57 (t, J = 7.3 Hz, 1H,

Ar-H), 7.49−7.40 (m, 2H, Ar-H), 7.36−7.24 (m, 17H, Ar-H), 7.23−

7.18 (m, 3H, Ar-H), 7.17−7.13 (m, 2H, Ar-H), 7.05 (d, J = 8.0 Hz,

1H, N−H), 6.93 (d, J = 7.8 Hz, 2H, Ar-H), 5.33−5.21 (m, 1H, H-2′),

4.99−4.87 (m, 2H, H-1, CH₂Ph), 4.79 (d, J = 7.8 Hz, 1H, H-1′), 4.74

(d, J = 11.7 Hz, 1H, CH₂Ph), 4.65 (d, J = 11.6 Hz, 1H, CH₂Ph), 4.55

(d, J = 12.0 Hz, 1H, CH₂Ph), 4.52−4.40 (m, 4H, H-3, 3× CH₂Ph),

4.34 (d, J = 11.8 Hz, 1H, CH₂Ph), 3.87 (d, J = 2.6 Hz, 1H, H-4′),

3.80−3.67 (m, 3H, H-3′, H-6a, H-6b), 3.66−3.60 (m, 1H, H-5′),

3.59−3.44 (m, 5H, H-2, H-4, H-5, H-6a′, H-6b′), 2.56 (s, 1H, O−H),

2.24 (s, 3H, PhCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 167.1

(C), 161.3 (C), 138.4 (C), 138.3 (C), 138.1 (C), 137.8 (C), 133.5

(CH), 133.1 (CH), 130.1 (CH), 129.8 (CH), 129.76 (C), 128.7

(CH), 128.6 (CH), 128.5 (CH), 128.46 (CH), 128.2 (CH), 128.1

(CH), 128.0 (CH), 127.9 (CH), 127.7 (CH), 99.9 (CH), 92.9 (C),

85.0 (CH), 78.9 (CH), 77.7 (CH), 76.8 (CH), 76.0 (CH), 75.7

(CH₂), 74.8 (CH₂), 74.5 (CH), 74.0 (CH), 73.7 (CH₂), 73.5 (CH₂),

73.4 (CH), 69.3 (CH₂), 68.3 (CH₂), 57.0 (CH), 21.2 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₅₆H₅₆Cl₃NO₁₁SNa [M + Na]⁺,

1080.2506; found, 1080.2544.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galacto-

pyranosyl)-(1 → 3)-6-O-benzyl-2-deoxy-2-trichloroacetamido-

1-thio-β-^D-glucopyranoside (11). For reaction details, please see

Scheme S5. Compound 7 (210 mg, 0.19 mmol) was stirred in a 10:1

(v/v) mixture of CH₂Cl₂(17.2 mL) and PBS (1.72 mL, pH = 7.4) in

an ice bath. Then, DDQ (129 mg, 0.57 mmol) was added and stirred

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galacto-

pyranosyl)-(1 → 3)-4-O-acetyl-6-O-benzyl-2-deoxy-2-trichlor-

oacetamido-1-thio-β-^D-glucopyranoside (13). For reaction de-

tails, please see Scheme S5. Compound 4 (0.85 g, 0.74 mmol) was

stirred in a 10:1 (v/v) mixture of CH₂Cl₂(67.20 mL) and PBS (6.72

J

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mL, pH = 7.4) in an ice bath. Then, DDQ (503 mg, 2.22 mmol) was

added and stirred continuously under the argon atmosphere. After 5

h, the reaction was quenched by addition of saturated NaHCO₃

solution (8 mL) under the ice bath. The organic layer was washed

with saturated NaHCO₃solution (60 mL, two times), dried over

MgSO₄, ﬁltered, and concentrated by evaporation to yield a thick

yellow crude. The crude was subjected to column chromatography on

silica gel with EtOAc/hexanes (1/4, v/v) to aﬀord pure 13 (0.57 g,

75% yield) as a white amorphous foam. R_f0.31 (EtOAc/hexanes = 1/

2, v/v); [α]²_D⁰−9.71 (c 1.03, CHCl₃); ¹H NMR (500 MHz, CDCl₃):

δ 8.2 (d, J = 7.4 Hz, 2H, Ar-H), 7.57 (t, J = 7.4 Hz, 1H, Ar-H), 7.43

(t, J = 7.7 Hz, 2H, Ar-H), 7.37−7.26 (m, 17H, Ar-H), 7.08 (d, J = 7.2

Hz, 1H, N−H), 6.96 (d, J = 7.9 Hz, 2H, Ar-H), 5.20 (d, J = 10.1 Hz,

1H, H-1), 5.11 (dd, J = 9.8, 7.8 Hz, 1H, H-2′), 4.89 (t, J = 9.4 Hz, 1H,

H-4), 4.73 (d, J = 11.7 Hz, 1H, CH₂Ph), 4.67 (d, J = 7.8 Hz, 1H, H-

1′), 4.61 (d, J = 11.7 Hz, 1H, CH₂Ph), 4.55 (d, J = 11.8 Hz, 1H,

CH₂Ph), 4.52−4.44 (m, 4H, H-3, 2× CH₂Ph), 3.84 (d, J = 3.3 Hz,

1H, H-4′), 3.70−3.59 (m, 4H, H3′, H5, CH₂Ph), 3.59−3.48 (m, 3H,

H6a, H6b), 3.39 (td, J = 9.6, 7.5 Hz, 1H, H2), 2.52 (d, J = 8.6 Hz, 1H,

OH), 2.26 (s, 3H, PhCH₃), 1.7 (s, 3H, COCH₃); ¹³C{¹H} NMR

(125 MHz, CDCl₃): δ 169.8 (C), 166.8 (C), 161.6 (C), 138.6 (C),

138.14 (C), 138.1 (C), 137.6 (C), 133.5 (CH), 130.2 (CH), 130.0

(CH), 129.8 (C), 128.7 (CH), 128.6 (CH), 128.5 (CH), 128.4 (C),

128.2 (CH), 128.13 (CH), 128.1 (CH), 127.95 (CH), 127.92 (CH),

127.8 (CH), 99.1 (CH), 92.7 (C), 84.8 (CH), 78.0 (CH), 76.7

(CH), 75.8 (CH), 75.6 (CH₂), 74.2 (CH), 73.8 (CH₂), 73.7 (CH),

73.6 (CH₂), 73.5 (CH), 69.6 (CH₂), 68.8 (CH), 68.3 (CH₂), 57.5

(CH), 21.3 (CH₃), 20.7 (CH₃); HRMS (ESI-TOF) m/z: calcd for

C₅₁H₅₂Cl₃NO₁₂SNa [M + Na]⁺, 1032.2152; found, 1032.2054.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galacto-

pyranosyl)-(1 → 3)-4-O-acetyl-6-O-tert-butyldiphenylsilyl-2-

deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyranoside (14).

For reaction details, please see Scheme S6. To a solution of

compound 3 (391 mg, 0.30 mmol) in a 10:1 (v/v) mixture of CH₂Cl₂

(27 mL) and PBS (2.7 mL, pH = 7.4), DDQ (205 mg, 0.903 mmol)

was added under the argon atmosphere at 0 °C. After 5 h, the reaction

was completed as observed by TLC. Saturated NaHCO₃solution (4

mL) was slowly added to the reaction mixture under the ice bath to

quench the reaction. The organic layer was washed with saturated

NaHCO₃solution (20 mL, two times), dried over MgSO₄, ﬁltered,

and concentrated by evaporation to yield a thick yellow crude. The

crude was subjected to column chromatography on silica gel with

EtOAc/hexanes (1/5 to 1/3, v/v) to yield the desired pure product

14 (278 mg, 80%) as a white amorphous foam. R_f₁0.35 (EtOAc/

hexanes = 1/2, v/v); [α]_D²⁰−4.71 (c 0.85, CHCl₃); H NMR (500

MHz, CDCl₃): δ 8.00 (d, J = 7.2 Hz, 2H, Ar-H), 7.67 (dd, J = 6.3, 4.6

Hz, 4H, Ar-H), 7.57 (t, J = 6.8 Hz, 1H, Ar-H), 7.46−7.39 (m, 4H, Ar-

H), 7.38−7.31 (m, 12H, Ar-H), 7.31−7.26 (m, 4H, Ar-H), 7.01 (d, J

= 6.8 Hz, 1H, N−H), 6.95 (d, J = 7.5 Hz, 2H, Ar-H), 5.17 (d, J = 9.9

Hz, 1H, H-1), 5.09 (dd, J = 9.4, 8.0 Hz, 1H, H-2′), 4.87 (t, J = 9.3 Hz,

1H, H-4), 4.74 (d, J = 11.5 Hz, 1H, CH₂Ph), 4.67−4.59 (m, 2H, H-

1′, CH₂Ph), 4.56 (d, J = 11.7, 1H, CH₂Ph), 4.52−4.45 (m, 2H, H-3,

CH₂Ph), 3.85 (d, J = 2.4 Hz, 1H, H-4′), 3.72−3.52 (m, 7H, H-5, H-

6a, H-6b, H-3′, H-5′, H-6a′, H-6b′), 3.41−3.30 (m, 1H, H-2), 2.60−

2.44 (m, 1H, O−H), 2.26 (s, 3H, PhCH₃), 1.66 (s, 3H, COCH₃),

1.03 (s, 9H, TBDPS-t-Bu); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ

169.5 (C), 166.9 (C), 161.6 (C), 138.6 (C), 138.1 (C), 137.7 (C),

135.9 (CH), 133.5 (CH), 133.47 (CH), 133.43 (C), 133.3 (C), 130.2

(CH), 130.0 (CH), 129.85 (CH), 129.82 (CH), 128.76 (CH), 128.6

(CH), 128.5 (C), 128.2 (CH), 128.1 (CH), 128.07 (CH), 127.9

(CH), 127.87 (CH), 99.3 (CH), 92.8 (C), 84.8 (CH), 79.5 (CH),

76.7 (CH), 76.1 (CH), 75.6 (CH₂), 74.3 (CH), 73.8 (CH₂), 73.7

(CH), 73.6 (CH), 68.3 (CH), 68.26 (CH₂), 63.4 (CH₂), 57.7 (CH),

26.9 (CH₃), 21.3 (CH₃), 20.7 (CH₃), 19.4 (C); HRMS (ESI-TOF)

m/z: calcd for C₆₀H₆₄Cl₃NO₁₂SSiNa [M + Na]⁺, 1180.2851; found,

1180.2802.

mmol) in a 10:1 (v/v) mixture of CH₂Cl₂(47 mL) and PBS (4.70

mL, pH = 7.4), DDQ (349 mg, 1.54 mmol) was added under the

argon atmosphere at 0 °C. After 5 h, the reaction was completed as

observed by TLC. To quench the reaction, saturated NaHCO₃

solution (5 mL) was slowly added to the reaction mixture under

the ice bath. Solvent extraction was done to wash the organic layer

with saturated NaHCO₃solution (40 mL, three times). The organic

layer was collected, dried over MgSO₄, ﬁltered, and concentrated by

evaporation. The residue was puriﬁed by column chromatography on

silica gel with EtOAc/hexanes (1/4, v/v) to yield the pure product 15

(366 mg, 74%) as a white amorphous foam. R_f0.38 (EtOAc/hexanes

= 1/2, v/v); [α]²_D⁵−0.9 (c 1.2, CHCl₃); ¹H NMR (500 MHz,

CDCl₃): δ 7.97 (d, J = 7.3 Hz, 2H, Ar-H), 7.53 (t, J = 7.4 Hz, 1H, Ar-

H), 7.46−7.41 (m, 2H, Ar-H), 7.41−7.36 (m, 2H, Ar-H), 7.36−7.26

(m, 15H, Ar-H), 7.08 (d, J = 7.8 Hz, 2H, Ar-H), 6.92 (d, J = 6.9 Hz,

1H, N−H), 5.47 (s, 1H, PhCH benzylidene), 5.32 (d, J = 10.4 Hz,

1H, H-1), 5.18 (dd, J = 9.6, 8.3 Hz, 1H, H-2′), 4.80 (d, J = 8.0 Hz,

1H, H-1′), 4.67 (m, 2H, 2xCH₂Ph), 4.59 (t, J = 9.1 Hz, 1H, H-3),

4.40 (d, J = 11.6 Hz, 1H, CH₂Ph), 4.36−4.28 (m, 2H, H-6a, CH₂Ph),

3.80 (d, J = 3.1 Hz, 1H, H-4′), 3.74−3.66 (m, 2H, H-4, H-6b), 3.65−

3.57 (m, 2H, H-3′, H-6a′), 3.56−3.44 (m, 3H, H-5, H-5′, H-6b′),

3.33−3.23 (m, 1H, H-2), 2.39−2.35 (m, 1H, O−H), 2.33 (s, 3H,

PhCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 166.9 (C), 161.7 (C),

139.2 (C), 138.1 (C), 137.8 (C), 137.4 (C), 134.1 (CH), 133.5

(CH), 130.2 (CH), 129.8 (C), 129.2 (CH), 128.8 (CH), 128.7

(CH), 128.6 (CH), 128.4 (CH), 128.2 (CH), 127.4 (C), 126.3

(CH), 101.3 (CH), 99.5 (CH), 92.3 (C), 84.6 (CH), 80.1 (CH),

76.6 (CH), 76.3 (CH), 75.6 (CH₂), 74.5 (CH), 73.8 (CH₂), 73.6

(CH), 73.4 (CH), 70.8 (CH), 68.7 (CH₂), 68.5 (CH₂), 57.7 (CH),

21.4 (CH₃); HRMS (ESI-TOF) m/z: calcd for C₄₉H₄₈Cl₃NO₁₁SNa

[M + Na]⁺, 986.1906; found, 986.1952.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galacto-

pyranosyl)-(1 → 3)-4-O-benzoyl-6-O-tert-butyldiphenylsilyl-2-

deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyranoside (16).

For reaction details, please see Scheme S6. To a solution of

compound 1 (408 mg, 0.30 mmol) in a 10:1 (v/v) mixture of CH₂Cl₂

(27 mL) and PBS (2.7 mL, pH = 7.4), DDQ (204 mg, 0.90 mmol)

was added at 0 °C under the argon atmosphere and stirred

continuously. After 5 h, the reaction mixture was quenched by

addition of saturated NaHCO₃solution (4 mL) under the ice bath.

The organic layer was washed with saturated NaHCO₃solution (20

mL, two times), dried over MgSO₄, ﬁltered, and concentrated by

evaporation to aﬀord the viscous yellow crude. The crude was puriﬁed

by column chromatography on silica gel with EtOAc/hexanes (1/5 to

1/3, v/v) to yield the desired product 16 (273 mg, 75%) as a white

amorphous foam. R_f0.31 (EtOAc/hexanes = 1/3, v/v); [α]²_D⁰−24.79

(c 1.17, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.93 (d, J = 7.1 Hz,

2H, Ar-H), 7.83 (d, J = 7.4 Hz, 2H, Ar-H), 7.66 (d, J = 6.7 Hz, 2H,

Ar-H), 7.58 (d, J = 6.9 Hz, 2H, Ar-H), 7.52 (t, J = 7.3 Hz, 1H, Ar-H),

7.46 (t, J = 7.3 Hz, 1H, Ar-H), 7.41−7.37 (m, 2H, Ar-H), 7.37−7.32

(m, 5H, Ar-H), 7.31−7.27 (m, 5H, Ar-H), 7.27−7.22 (m, 5H, Ar-H),

7.21−7.13 (m, 5H, Ar-H), 7.00 (d, J = 7.0 Hz, 1H, N−H), 6.95 (d, J

= 7.9 Hz, 2H, Ar-H), 5.31 (d, J = 10.3 Hz, 1H, H-1), 5.17 (t, J = 8.8

Hz, 1H, H-4), 5.09 (dd, J = 9.9, 7.9 Hz, 1H, H-2′), 4.71 (t, J = 9.4 Hz,

1H, H-3), 4.62 (d, J = 7.8 Hz, 1H, H-1′), 4.54 (d, J = 11.8 Hz, 1H,

CH₂Ph), 4.46 (d, J = 11.8 Hz, 1H, CH₂Ph), 4.30 (d, J = 11.8 Hz, 1H,

CH₂Ph), 4.24 (d, J = 11.8 Hz, 1H, CH₂Ph), 3.80−3.70 (m, 4H, H, H-

4′, H-5, H-6a, H-6b), 3.59−3.52 (m, 1H, H-3′), 3.47 (dd, J = 7.4, 6.0

Hz, 1H, H-5′), 3.37−3.28 (m, 1H, H-2), 3.13 (dd, J = 8.9, 5.5 Hz,

1H, H-6a′), 2.92−2.83 (m, 1H, H-6b′), 2.38 (d, J = 8.2 Hz, 1H, O−

H), 2.26 (s, 3H, PhCH₃), 1.01 (s, 9H, TBDPS-t-Bu); ¹³C{¹H} NMR

(125 MHz, CDCl₃): δ 166.7 (C), 164.9 (C), 161.7 (C), 138.7 (C),

138.2 (C), 137.8 (C), 135.73 (CH), 135.70 (CH), 133.7 (CH), 133.3

(CH), 133.2 (C), 133.1 (C), 132.8 (CH), 130.3 (C), 130.0 (CH),

129.96 (CH), 129.9 (C), 129.7 (CH), 128.65 (CH), 128.62 (CH),

128.5 (CH), 128.2 (CH), 128.1 (CH), 127.9 (CH), 127.8 (CH),

127.7 (CH), 127.66 (CH), 99.8 (CH), 92.7 (C), 84.2 (CH), 79.5

(CH), 76.5 (CH), 76.4 (CH), 75.3 (CH₂), 74.2 (CH), 73.4 (CH₂),

73.3 (CH), 73.2 (CH), 69.2 (CH), 67.4 (CH₂), 63.3 (CH₂), 58.1

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galacto-

pyranosyl)-(1 → 3)-4,6-O-benzylidene-2-deoxy-2-trichloroa-

cetamido-1-thio-β-^D-glucopyranoside (15). For reaction details,

please see Scheme S5. To a solution of compound 2 (567 mg, 0.51

K

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(CH), 26.8 (CH₃), 21.3 (CH₃), 19.3 (C); HRMS (ESI-TOF) m/z:

calcd for C₆₅H₆₇Cl₃NO₁₂SSi [M + H]⁺, 1220.3189; found, 1220.3174.

Compounds 17 to 30 Are the Tetrasaccharide Products of

[2 + 2] Reactions from Table 1. 4-Methylphenyl(2-O-benzoyl-4,6-

di-O-benzyl-3-O-(naphthalen-2-ylmethyl)-β-^D-galactopyranosyl)-

(1 → 3)-(6-O-tert-butyldimethylsilyl-2-deoxy-2-trichloroacetami-

do-β-^D-glucopyranosyl)-(1 → 3)-(2-O-benzoyl-4,6-di-O-benzyl-β-D-

galactopyranosyl)-(1 → 3)-4-O-acetyl-6-O-benzyl-2-deoxy-2-tri-

chloroacetamido-1-thio-β-^D-glucopyranoside (17). A solution of 6

(70 mg, 0.062 mmol) and 13 (50 mg, 0.05 mmol) in anhydrous

CH₂Cl₂(1 mL) was stirred with 3 Å pulverized molecular sieves (120

mg) at rt for 30 min under the N₂atmosphere. After cooling to −50

°C, NIS (14 mg, 0.062 mmol) and TMSOTf (1.8 μL, 0.01 mmol)

were added to the reaction mixture. After 2.5 h, the reaction mixture

was quenched by dropwise addition of Et₃N, diluted with CH₂Cl₂(5

mL), and ﬁltered through ﬁlter paper. The ﬁltrate was washed with

saturated Na₂S₂O₃solution (10 mL), dried over MgSO₄, ﬁltered, and

concentrated by evaporation to aﬀord yellow viscous residue that was

subjected to column chromatography on silica gel with EtOAc/

toluene (1/16 to 1/13, v/v) to obtain the desired product 17 (55 mg,

54%) as a white amorphous solid. R_f0.38 (EtOAc/toluene = 1/8, v/v,

run two times); [α]²_D⁰−10.49 (c 1.43, CHCl₃); ¹H NMR (500 MHz,

CDCl₃): δ 7.90 (t, J = 7.5 Hz, 4H, Ar-H), 7.73 (d, J = 7.6 Hz, 1H, Ar-

H), 7.57−7.48 (m, 5H, Ar-H), 7.46−7.37 (m, 4H, Ar-H), 7.37−7.32

(m, 6H, Ar-H), 7.31−7.26 (m, 17H, Ar-H), 7.25−7.23 (m, 1H, Ar-

H), 721−7.18 (m, 2H, Ar-H), 7.18−7.13 (m, 3H, Ar-H), 7.11−7.05

(m, 1H, Ar-H), 6.93 (d, J = 7.7 Hz, 3H, Ar-H, N−H), 6.43 (d, J = 6.7

Hz, 1H, N−H), 5.61 (dd, J = 9.8, 8.1 Hz, 1H, H-2‴), 5.27 (dd, J =

9.9, 7.9 Hz, 1H, H-2′), 5.12 (d, J = 10.0 Hz, 1H, H-1), 4.94 (m, 2H,

CH₂Ph, H-1″), 4.80 (t, J = 9.4 Hz, 1H, H-4), 4.70 (m, 2H, CH₂Ph,

CH₂group of Nap), 4.60−3.37 (m, 12H, H-1′, H-3, H1‴, CH₂group

of Nap, 8× CH₂Ph), 4.17 (dd, J = 9.7, 8.1 Hz, 1H, H-3″), 3.99−3.90

(m, 4H, O−H, H-6a″, H-4′, H-4‴), 3.83 (dd, J = 10.0, 2.6 Hz, 1H, H-

3′), 3.71 (dd, J = 11.0, 5.8 Hz, 1H, H-6b″), 3.61−3.45 (m, 9H, H-3‴,

H-5‴, H-5′, H-6a, H-6b, H-6a′, H-6b′, H-6a‴, H-6b‴), 3.43−3.34

(m, 2H, H-4″, H-5), 3.33−3.27 (m, 1H, H-5″), 3.24−3.16 (m, 1H,

H-2), 2.76−2.68 (m, 1H, H-2″), 2.26 (s, 3H, PhCH₃), 1.58 (s, 3H,

COCH₃), 0.86 (s, 9H, TBS-t-Bu), 0.02 (s, 3H, TBS-CH₃), 0.01 (s,

3H, TBS-CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 169.85 (C),

165.6 (C), 164.9 (C), 161.6 (C), 161.4 (C), 139.1 (C), 138.4 (C),

138.3 (C), 138.2 (C), 137.9 (C), 137.7 (C), 134.7 (C), 133.5 (CH),

133.4 (CH), 133.3 (CH), 133.2 (C), 133.1 (C), 130.4 (CH), 130.2

(CH), 129.9 (CH), 129.8 (C), 128.7 (CH), 128.64 (CH), 128.61

(CH), 128.59 (CH), 128.52 (CH), 128.5 (CH), 128.4 (CH), 128.2

(CH), 128.14 (CH), 128.11 (CH), 128.0 (CH), 127.96 (CH), 127.8

(CH), 127.76 (CH), 127.6 (CH), 127.0 (CH), 126.4 (CH), 126.3

(CH), 125.9 (CH), 101.0 (CH), 99.7 (CH), 98.9 (CH), 92.7 (C),

91.8 (C), 84.8 (CH), 79.7 (CH), 78.0 (CH), 77.97 (CH), 77.3

(CH), 76.6 (CH), 75.5 (CH), 75.1 (CH₂), 74.9 (CH₂), 74.0 (CH),

73.99 (CH), 73.8 (CH₂), 73.6 (CH₂), 72.58 (CH), 72.4 (CH₂), 72.2

(CH), 71.7 (CH), 69.7 (CH₂), 69.4 (CH), 68.8 (CH), 68.7 (CH₂),

68.4 (CH₂), 62.9 (CH₂), 59.4 (CH), 57.7 (CH), 26.1 (CH₃), 21.33

(CH₃), 20.54 (CH₃), 18.5 (C), −5.1 (2xCH₃); HRMS (ESI-TOF)

m/z: calcd for C₁₀₃H₁₁₁Cl₆N₂O₂₃SSi [M + H]⁺, 2017.5182; found,

2017.5184.

product 18 (46 mg, 58%) as a white amorphous foam. R_f0.16

(EtOAc/toluene = 1/8, v/v, run two times); [α]²_D⁰−13.41 (c 1.79,

1

CHCl₃); H NMR (500 MHz, CDCl₃): δ 7.89 (dd, J = 6.7, 4.8 Hz,

4H, Ar-H), 7.73 (d, J = 7.7 Hz, 1H, Ar-H), 7.58−7.52 (m, 3H, Ar-H),

7.52−7.48 (m, 2H, Ar-H), 7.46−7.40 (m, 2H, Ar-H), 7.40−7.35 (m,

2H, Ar-H), 7.35−7.32 (m, 4H, Ar-H), 7.31−7.29 (m, 5H, Ar-H),

7.29−7.26 (m, 13H, Ar-H), 7.26−7.21 (m, 7H, Ar-H), 7.20−7.14 (m,

5H, Ar-H), 7.13−7.08 (m, 1H, Ar-H), 6.93 (d, J = 7.9 Hz, 2H, Ar-H),

6.89 (d, J = 7.1 Hz, 1H, N−H), 6.47 (d, J = 6.8 Hz, 1H, N−H), 5.61

(dd, J = 9.8, 8.2 Hz, 1H, H-2‴), 5.28 (dd, J = 9.9, 7.8 Hz, 1H, H-2′),

5.11 (d, J = 10.1 Hz, 1H, H-1), 4.96 (dd, J = 15.8, 9.9 Hz, 2H, H-1″,

CH₂Ph), 4.79 (t, J = 9.4 Hz, 1H, H-4), 4.72 (m, 2H, CH₂Ph, CH₂

group of Nap), 4.59−4.34 (m, 14H, H-1′, H-1‴, H-3, CH₂group of

Nap, 10× CH₂Ph), 4.19 (dd, J = 9.7, 8.0 Hz, 1H, H-3″), 4.04−3.98

(m, 2H, O−H, H-4′), 3.93 (d, J = 1.8 Hz, 1H, H-4‴), 3.86−3.79 (m,

2H, H-3′, H-5‴), 3.62−3.35 (m, 13H, H-3‴, H-4″, H-5, H-5″, H-5′,

H-6a, H-6b, H-6a′, H-6b′, H-6a″, H-6b″, H-6a‴, H-6b‴), 3.24−3.14

(m, 1H, H-2), 2.85−2.76 (m, 1H, H-2″), 2.26 (s, 3H, PhCH₃), 1.58

(s, 3H, COCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 169.8 (C),

165.6 (C), 164.9 (C), 161.7 (C), 161.5 (C), 139.1 (C), 138.4 (C),

138.3 (C), 138.2 (C), 137.9 (C), 137.7 (C), 134.7 (C), 133.5 (CH),

133.4 (CH), 133.3 (CH), 133.2 (C), 133.1 (C), 130.4 (CH), 130.2

(CH), 129.9 (CH), 129.7 (C), 128.7 (CH), 128.6 (CH), 128.59

(CH), 128.52 (CH), 128.5 (CH), 128.4 (CH), 128.2 (CH), 128.1

(CH), 128.08 (CH), 128.01 (CH), 127.96 (CH), 127.8 (CH), 127.7

(CH), 127.6 (CH), 127.5 (CH), 126.9 (CH), 126.4 (CH), 126.3

(CH), 125.9 (CH), 101.0 (CH), 99.6 (CH), 98.9 (CH), 92.7 (C),

91.7 (C), 84.7 (CH), 79.8 (CH), 79.7 (CH), 78.5 (CH), 78.0 (CH),

77.0 (CH), 75.4 (CH), 75.1 (CH), 75.0 (CH₂), 74.9 (CH₂), 74.1

(CH), 73.83 (CH), 73.8 (CH₂), 73.64 (CH₂), 73.6 (CH₂), 72.6

(CH), 72.4 (CH₂), 72.2 (CH), 71.7 (CH), 69.9 (CH₂), 69.7 (CH),

68.8 (CH), 68.7 (CH₂), 68.4 (CH₂), 59.4 (CH), 57.7 (CH), 21.3

(CH₃), 20.6 (CH₃); HRMS (ESI-TOF) m/z: calcd for

C₁₀₄H₁₀₃Cl₆N₂O₂₃S [M + H]⁺, 1993.4787; found, 1993.4806.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(6-O-benzyl-2-deoxy-2-

trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-benzoyl-4,6-

di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4-O-acetyl-6-O-tert-bu-

tyldiphenylsilyl-2-deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyr-

anoside (19). A solution of 7 (62 mg, 0.056 mmol) and 14 (50 mg,

0.043 mmol) in anhydrous CH₂Cl₂(0.9 mL) was stirred with 3 Å

pulverized molecular sieves (112 mg) at rt for 30 min under the N₂

atmosphere. After cooling to −50 °C, NIS (12.6 mg, 0.056 mmol)

and TMSOTf (1.6 μL, 0.009 mmol) were added to the reaction

mixture. After 2.5 h, the reaction was quenched by dropwise addition

of Et₃N, diluted with CH₂Cl₂(5 mL), and ﬁltered through ﬁlter

paper. The ﬁltrate was washed with saturated Na₂S₂O₃solution (10

mL), dried over MgSO₄, ﬁltered, and concentrated by evaporation to

aﬀord a yellow viscous residue that was subjected to column

chromatography on silica gel with EtOAc/hexanes (1/5 to 1/3, v/v)

to yield the pure desired product 19 (58 mg, 63%) as a white

amorphous solid. R_f0.45 (EtOAc/toluene = 1/8, v/v, run two times);

[α]²_D⁰−8.33 (c 1.92, CHCl₃); H NMR (500 MHz, CDCl₃): δ 7.88

1

(dd, J = 11.8, 7.7 Hz, 4H, Ar-H), 7.72 (d, J = 7.5 Hz, 1H, Ar-H), 7.63

(d, J = 3.6 Hz, 4H, Ar-H), 7.58−7.47 (m, 5H, Ar-H), 7.46−7.36 (m,

6H, Ar-H), 7.35−7.27 (m, 22H, Ar-H), 7.26−7.21 (m, 6H, Ar-H),

7.20−7.13 (m, 5H, Ar-H), 7.13−7.08 (m, 1H, Ar-H), 6.98−6.86 (m,

3H, Ar-H, N−H), 6.54 (d, J = 6.5 Hz, 1H, N−H), 5.60 (dd, J = 9.7,

8.0 Hz, 1H, H-2′), 5.25 (dd, J = 9.6, 7.8 Hz, 1H, H-2‴), 5.10 (d, J =

10.1 Hz, 1H, H-1), 5.00−4.90 (m, 2H, H-1″, CH₂Ph), 4.79−4.67 (m,

3H, H-4, 2× CH₂group of Nap), 4.59−4.35 (m, 12H, H-1′, H-1‴, H-

3, 9× CH₂Ph), 4.20 (t, J = 8.7 Hz, 1H, H-3″), 4.06−3.98 (m, 2H, H-

4‴, O−H), 3.94−3.90 (m, 1H, H-4′), 3.87−3.77 (m, 2H, H-3‴, H-

5‴), 3.69−3.35 (m, 13H, H-3′, H-5, H-4″, H-5′, H-5″, H-6a, H-6b,

H-6a′, H-6b′, H-6a″, H-6b″, H-6a‴, H-6b‴), 3.23−3.13 (m, 1H, H-

2), 2.86−2.77 (m, 1H, H-2″), 2.26 (s, 3H, PhCH₃), 1.51 (s, 3H,

COCH₃), 1.01 (s, 9H, TBDPS-t-Bu); ¹³C{¹H} NMR (125 MHz,

CDCl₃): δ 169.6 (C), 165.6 (C), 164.9 (C), 161.7 (C), 161.5 (C),

139.1 (C), 138.4 (C), 138.2 (C), 137.9 (C), 137.7 (C), 135.8 (CH),

134.7 (C), 133.5 (CH), 133.3 (CH), 133.2 (C), 133.1 (C), 130.3

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(6-O-benzyl-2-deoxy-2-

trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-benzoyl-4,6-

di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4-O-acetyl-6-O-benzyl-

2-deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyranoside (18). A

solution of 7 (57 mg, 0.052 mmol) and 13 (40 mg, 0.04 mmol) in

anhydrous CH₂Cl₂(0.8 mL) was stirred with 3 Å pulverized

molecular sieves (100 mg) at rt for 30 min under the N₂atmosphere.

After cooling to −50 °C, NIS (11.6 mg, 0.052 mmol) and TMSOTf

(1.4 μL, 0.008 mmol) were added to the reaction mixture. After 2.5 h,

the reaction was quenched by dropwise addition of Et₃N, diluted with

CH₂Cl₂(5 mL), and ﬁltered through ﬁlter paper. The ﬁltrate was

washed with saturated Na₂S₂O₃solution (10 mL), dried over MgSO₄,

ﬁltered, and concentrated by evaporation to aﬀord a yellow viscous

residue that was subjected to column chromatography on silica gel

with EtOAc/hexanes (1/5 to 1/3, v/v) to yield the pure desired

L

https://dx.doi.org/10.1021/acs.joc.0c02422

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(CH), 130.2 (CH), 129.9 (CH), 129.8 (CH), 129.7 (C), 128.8 (C),

128.7 (CH), 128.6 (CH), 128.57 (CH), 128.5 (CH), 128.4 (CH),

128.2 (CH), 128.1 (CH), 128.09 (CH), 128.0 (CH), 127.8 (CH),

127.6 (CH), 127.5 (CH), 126.9 (CH), 126.3 (CH), 126.2 (CH),

125.9 (CH), 101.0 (CH), 99.6 (CH), 98.9 (CH), 92.7 (C), 91.7 (C),

84.8 (CH), 79.7 (CH), 79.6 (CH), 78.6 (CH), 77.0 (CH), 75.5

(CH), 75.1 (CH), 75.0 (CH₂), 74.8 (CH₂), 74.0 (CH), 73.8 (CH₂),

73.6 (CH₂), 73.57 (CH₂), 72.6 (CH), 72.4 (CH₂), 72.2 (CH), 71.7

(CH), 69.9 (CH₂), 69.7 (CH), 68.7 (CH₂), 68.3 (CH₂), 68.2 (CH),

63.6 (CH₂), 59.3 (CH), 57.8 (CH), 26.9 (CH₃), 21.3 (CH₃), 20.5

(CH₃), 19.3 (C); HRMS (ESI-TOF) m/z: calcd for

C₁₁₃H₁₁₄Cl₆N₂O₂₃SSiNa [M + Na]⁺, 2163.5319; found, 2163.5297.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(6-O-benzyl-2-deoxy-2-

trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-benzoyl-4,6-

di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4,6-O-benzylidene-2-

deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyranoside (20). A

solution of 7 (119 mg, 0.11 mmol) and 15 (80 mg, 0.083 mmol)

in anhydrous CH₂Cl₂(1.66 mL) was stirred with 3 Å pulverized

molecular sieves (200 mg) at rt for 30 min under the N₂atmosphere.

After cooling to −50 °C, NIS (24.3 mg, 0.11 mmol) and TMSOTf (3

μL, 0.017 mmol) were added to the reaction mixture. After 2 h, the

reaction was quenched by dropwise addition of Et₃N, diluted with

CH₂Cl₂(5 mL), and ﬁltered through ﬁlter paper. The ﬁltrate was

washed with saturated Na₂S₂O₃solution (10 mL), dried over MgSO₄,

ﬁltered, and concentrated by evaporation to aﬀord a yellow viscous

residue that was subjected to column chromatography on silica gel

with EtOAc/hexanes (1/5 to 1/3, v/v) to yield the pure desired

product 20 (97 mg, 60%) as a white amorphous solid. R_f0.23

(EtOAc/toluene = 1/8, v/v, run two times); [α]²_D⁰−5.83 (c 3.6,

CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.90 (d, J = 7.3 Hz, 2H, Ar-

H), 7.83 (d, J = 7.3 Hz, 2H, Ar-H), 7.72 (d, J = 7.5 Hz, 1H, Ar-H),

7.57−7.48 (m, 4H, Ar-H), 7.46−7.39 (m, 3H, Ar-H), 7.38−7.26 (m,

21H, Ar-H), 7.24−7.20 (m, 10H, Ar-H), 7.19−7.07 (m, 6H, Ar-H),

7.03 (d, J = 7.8 Hz, 2H, Ar-H), 6.90 (d, J = 6.8 Hz, 1H, N−H), 6.41

(d, J = 6.7 Hz, 1H, N−H), 5.60 (dd, J = 9.8, 8.1 Hz, 1H, H-2‴),

5.42−5.33 (m, 2H, H-2′, PhCH benzylidene), 5.28 (d, J = 10.3 Hz,

1H, H-1), 4.98−4.89 (m, 2H, H-1″, CH₂Ph), 4.77−4.64 (m, 3H, H-

1′, CH₂Ph), 4.59−4.35 (m, 9H, H-1‴, H-3, CH₂group of Nap, 6×

CH₂Ph), 4.31−4.20 (m, 2H, 2× CH₂Ph), 4.12 (dd, J = 9.5, 7.8 Hz,

1H, H-3″), 4.06 (s, 1H, O−H), 4.00 (d, J = 2.2 Hz, 1H, H-4′), 3.95−

3.89 (m, 1H, H-4‴), 3.85 (dd, J = 10.0, 2.6 Hz, 1H, H-3′), 3.79 (d, J

= 10.0 Hz, 1H, H-5‴), 3.68−3.37 (m, 14H, H-4, H-4″, H-3‴, H-5, H-

5′, H-5″, H-6a, H-6b, H-6a′, H-6b′, H-6a″, H-6b″, H-6a‴, H-6b‴),

3.21−3.12 (m, 1H, H-2), 2.86−2.77 (m, 1H, H-2″), 2.31 (s, 3H,

PhCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.5 (C), 165.1 (C),

161.6 (C), 139.1 (C), 138.9 (C), 138.4 (C), 138.2 (C), 138.0 (C),

137.6 (C), 137.4 (C), 134.7 (C), 133.9 (CH), 133.4 (CH), 133.3

(CH), 133.1 (C), 133.09 (C), 130.2 (CH), 130.1 (CH), 129.7 (C),

128.9 (CH), 128.6 (CH), 128.5 (CH), 128.47 (CH), 128.4 (CH),

128.2 (CH), 128.1 (CH), 128.0 (CH), 127.8 (CH), 127.6 (CH),

127.5 (CH), 126.9 (CH), 126.3 (CH), 126.25 (CH), 126.2 (CH),

125.9 (CH), 100.9 (CH), 99.7 (CH), 98.7 (CH), 92.3 (C), 91.7 (C),

84.5 (CH), 80.0 (CH), 79.7 (CH), 79.1 (CH), 78.4 (CH), 76.9

(CH), 75.8 (CH), 75.1 (CH), 74.9 (CH₂), 74.8 (CH₂), 74.0 (CH),

73.74 (CH₂), 73.71 (CH₂), 73.7 (CH), 73.5 (CH₂), 72.5 (CH), 72.4

(CH₂), 72.36 (CH), 71.7 (CH), 70.8 (CH), 69.9 (CH₂), 69.7 (CH),

69.0 (CH₂), 68.5 (CH₂), 68.4 (CH₂), 59.1 (CH), 58.0 (CH), 21.3

(CH₃); HRMS (ESI-TOF) m/z: calcd for C₁₀₂H₉₉Cl₆N₂O₂₂S [M +

H]⁺, 1949.4520; found, 1949.4540.

diluted with CH₂Cl₂(5 mL) and ﬁltered through ﬁlter paper. The

ﬁltrate was washed with saturated Na₂S₂O₃solution (10 mL), dried

over MgSO₄, ﬁltered, and concentrated by evaporation to aﬀord a

yellow viscous residue that was subjected to column chromatography

on silica gel with EtOAc/hexanes (1/5 to 1/3, v/v) to yield the pure

desired product 21 (61 mg, 67%) as a white amorphous solid. R_f0.47

(EtOAc/toluene = 1/8, v/v, run two times); [α]²_D⁰−11.33 (c 2.03,

CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.89 (d, J = 7.4 Hz, 2H, Ar-

H), 7.78 (d, J = 7.4 Hz, 2H, Ar-H), 7.74−7.71 (m, 3H, Ar-H), 7.60

(d, J = 6.9 Hz, 2H, Ar-H), 7.58−7.48 (m, 7H, Ar-H), 7.46−7.37 (m,

5H, Ar-H), 7.34−7.29 (m, 8H, Ar-H), 7.29−7.25 (m, 15H, Ar-H),

7.23−7.18 (m, 6H, Ar-H), 7.17−7.15 (m, 4H, Ar-H), 7.14−7.11 (m,

2H, Ar-H), 7.11−7.07 (m, 3H, Ar-H), 6.93 (d, J = 8.0 Hz, 2H, Ar-H),

6.81 (d, J = 6.9 Hz, 1H, N−H), 6.40 (d, J = 6.8 Hz, 1H, N−H), 5.59

(dd, J = 9.9, 8.1 Hz, 1H, H-2‴), 5.28−5.22 (m, 2H, H-1, H-2′), 5.06

(t, J = 9.0 Hz, 1H, H-4), 4.92 (m, 2H, H-1″, CH₂Ph), 4.70 (d, J =

12.2 Hz, 1H, CH₂group of Nap), 4.66−4.56 (m, 3H, H-3), 4.56−

4.53 (m, 1H), 4.53−4.45 (m, 2H, H-1′), 4.45−4.41 (m, 3H), 4.40−

4.33 (m, 3H, H-1‴), 4.23 (d, J = 12 Hz, 1H, CH₂Ph), 4.19−4.12 (m,

2H, H-3″, CH₂Ph), 3.97−3.90 (m, 3H, H-4′, H-4‴, O−H), 3.80−

3.75 (m, 2H, H-3′), 3.71−3.68 (m, 2H, H-5), 3.60−3.56 (m, 2H),

3.56−3.52 (m, 1H), 3.52−3.48 (m, 2H, H-3‴), 3.45−3.40 (m, 2H,

H-4″), 3.39−3.35 (m, 1H), 3.13 (td, J = 10, 7.1 Hz, 1H, H-2), 3.05

(dd, J = 9.0, 5.7 Hz, 1H, H-6a′), 2.86−2.80 (m, 1H, H-6b′), 2.71 (td,

J = 8.6, 7.1 Hz, 1H, H-2″), 2.27 (s, 3H, PhCH₃), 0.98 (s, 9H, TBDPS-

t-Bu); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.5 (C), 165.0 (C),

164.8 (C), 161.7 (C), 161.6 (C), 139.3 (C), 138.4 (C), 138.3 (C),

138.1 (C), 137.7 (C), 135.7 (CH), 134.7 (C), 133.6 (CH), 133.5

(CH), 133.3 (C), 133.2 (C), 133.17 (C), 133.12 (CH), 132.7 (CH),

130.2 (CH), 130.0 (CH), 129.97 (CH), 129.9 (C), 129.7 (C), 129.68

(CH), 128.7 (CH), 128.6 (CH), 128.53 (CH), 128.5 (CH), 128.4

(CH), 128.2 (CH), 128.1 (CH), 128.06 (CH), 127.98 (CH), 127.94

(CH), 127.9 (CH), 127.87 (CH), 127.8 (CH), 127.76 (CH), 127.7

(CH), 127.6 (CH), 127.3 (CH), 126.9 (CH), 126.3 (CH), 126.2

(CH), 125.9 (CH), 100.9 (CH), 100.2 (CH), 98.7 (CH), 92.6 (C),

91.7 (C), 84.1 (CH), 79.7 (CH), 78.1 (CH), 76.8 (CH), 75.9 (CH),

75.1 (CH), 74.82 (CH₂), 74.0 (CH), 73.8 (CH₂), 73.6 (CH₂), 73.34

(CH), 73.33 (CH₂), 72.6 (CH), 72.4 (CH₂), 72.3 (CH), 71.7 (CH),

69.9 (CH₂), 69.6 (CH), 69.1 (CH), 68.3 (CH₂), 67.7 (CH₂), 63.4

(CH₂), 59.3 (CH), 58.3 (CH), 26.9 (CH₃), 21.4 (CH₃), 19.3 (C);

HRMS (ESI-TOF) m/z: calcd for C₁₁₈H₁₁₇Cl₆N₂O₂₃SSi [M + H]⁺,

2203.5659; found, 2203.5620.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-

benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4,6-di-O-

benzyl-2-deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyranoside

(22). A solution of 8 (44 mg, 0.037 mmol) and 10 (30 mg, 0.028

mmol) in anhydrous CH₂Cl₂(570 μL) was stirred with 3 Å

pulverized molecular sieves (75 mg) at rt for 30 min under the N₂

atmosphere. After cooling to −50 °C, NIS (8.3 mg, 0.037 mmol) and

TMSOTf (1 μL, 0.006 mmol) were added to the reaction mixture.

After 2.5 h, the reaction was quenched by dropwise addition of Et₃N,

diluted with CH₂Cl₂(5 mL), and ﬁltered through ﬁlter paper. The

ﬁltrate was washed with saturated Na₂S₂O₃solution (10 mL), dried

over MgSO₄, ﬁltered, and concentrated by evaporation to aﬀord a

yellow viscous residue that was subjected to column chromatography

on silica gel with EtOAc/hexanes (1/5 to 1/3, v/v) to yield the pure

product 22 (11 mg, 19%) as a glassy solid and donor 8 recovered (16

mg, 34%). R_f0.49 (EtOAc/toluene = 1/8, v/v); [α]²_D⁰−18 (c 1.5,

CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.94 (d, J = 7.4 Hz, 2H, Ar-

H), 7.92 (d, J = 7.6 Hz, 2H, Ar-H), 7.72 (d, J = 7.8 Hz, 1H, Ar-H),

7.58−7.48 (m, 4H, Ar-H), 7.46−7.35 (m, 6H, Ar-H), 7.34−7.29 (m,

10H, Ar-H), 7.29−7.26 (m, 8H, Ar-H), 7.26−7.24 (m, 3H, Ar-H),

7.22−7.18 (m, 9H, Ar-H), 7.18−7.17 (m, 3H, Ar-H), 7.16−7.14 (m,

4H, Ar-H), 7.14−7.11 (m, 3H, Ar-H), 7.10−7.05 (m, 4H, Ar-H), 6.90

(d, J = 8.1 Hz, 2H, Ar-H), 6.77 (d, J = 7.8 Hz, 1H, N−H), 6.57 (d, J =

7.8 Hz, 1H, N−H), 5.63 (dd, J = 10.1, 8.0 Hz, 1H, H-2‴), 5.50 (dd, J

= 10.1, 7.9 Hz, 1H, H-2′), 5.03 (d, J = 11.4 Hz, 1H, CH₂Ph), 4.92 (d,

J = 10.3 Hz, 1H, CH₂Ph), 4.87 (d, J = 10.3 Hz, 1H, CH₂Ph), 4.82 (d,

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(6-O-benzyl-2-deoxy-2-

trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-benzoyl-4,6-

di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4-O-benzoyl-6-O-tert-

butyldiphenylsilyl-2-deoxy-2-trichloroacetamido-1-thio-β-^D-gluco-

pyranoside (21). A solution of 7 (59 mg, 0.053 mmol) and 16 (50

mg, 0.041 mmol) in anhydrous CH₂Cl₂(0.82 mL) was stirred with 3

Å pulverized molecular sieves (109 mg) at rt for 30 min under the N₂

atmosphere. After cooling to −50 °C, NIS (12 mg, 0.053 mmol) and

TMSOTf (1.5 μL, 0.008 mmol) were added to the reaction mixture.

After 2.5 h, the reaction was quenched by dropwise addition of Et₃N,

M

https://dx.doi.org/10.1021/acs.joc.0c02422

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

J = 9.7 Hz, 1H, H-1), 4.77 (d, J = 8.1 Hz, 1H, H-1″), 4.75−4.71 (m,

2H, CH₂group of Nap, CH₂Ph), 4.64−4.58 (m, 3H, H-1′, H-1‴),

4.56 (d, J = 2.7 Hz, 1H), 4.54−4.49 (m, 3H), 4.47 (s, 1H), 4.45−4.41

(m, 1H), 4.41−4.35 (m, 4H, H-3), 4.35−4.30 (m, 3H, H-3″), 4.25 (d,

J = 11.9 Hz, 1H, CH₂Ph), 4.22 (d, J = 11.8 Hz, 1H, CH₂Ph), 3.98−

3.94 (m, 2H, H-4′, H-4‴), 3.90 (dd, J = 10.2, 2.8 Hz, 1H, H-3′),

3.73−3.62 (m, 4H), 3.55 (t, J = 6.4 Hz, 1H), 3.52−3.46 (m, 4H, H-

3‴), 3.45−3.38 (m, 5H, H-4, H-4″), 3.26−3.14 (m, 2H, H-2, H-2″),

2.25 (s, 3H, PhCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.7

(C), 165.2 (C), 161.2 (C), 139.2 (C), 138.8 (C), 138.5 (C), 138.3

(C), 138.2 (C), 137.9 (C), 134.9 (C), 133.4 (CH), 133.3 (CH),

133.2 (C), 133.1 (C), 133.0 (CH), 130.1 (CH), 130.0 (CH), 129.8

(CH), 129.0 (C), 128.7 (CH), 128.6 (CH), 128.57 (CH), 128.5

(CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.16 (CH), 128.1

(CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.6

(CH), 127.5 (CH), 126.9 (CH), 126.3 (CH), 126.2 (CH), 126.0

(CH), 100.6 (CH), 100.3 (CH), 99.3 (CH), 92.8 (C), 92.4 (C), 84.8

(CH), 79.5 (CH), 78.9 (CH), 77.6 (CH), 76.3 (CH), 76.0 (CH),

75.2 (CH), 75.1 (CH₂), 75.0 (CH₂), 74.96 (CH₂), 74.9 (CH₂), 74.2

(CH), 73.8 (CH), 73.7 (CH₂), 73.6 (CH₂), 73.5 (CH₂), 73.2 (CH),

72.8 (CH), 72.1 (CH), 72.0 (CH₂), 69.4 (CH₂), 69.2 (CH₂), 68.6

(CH₂), 68.4 (CH₂), 59.3 (CH), 57.3 (CH), 21.3 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₁₁₆H₁₁₂Cl₆N₂O₂₂SNa [M + Na]⁺,

2153.5446; found, 2153.5446.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-

benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-6-O-ben-

zyl-2-deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyranoside

(23). A solution of 8 (72 mg, 0.06 mmol) and 11 (45 mg, 0.047

mmol) in anhydrous CH₂Cl₂(0.93 mL) was stirred with 3 Å

pulverized molecular sieves (117 mg) at rt for 30 min under the N₂

atmosphere. After cooling to −50 °C, NIS (13 mg, 0.06 mmol) and

TMSOTf (1.7 μL, 0.009 mmol) were added to the reaction mixture.

After 2.5 h, the reaction was quenched by dropwise addition of Et₃N,

diluted with CH₂Cl₂(5 mL), and ﬁltered through ﬁlter paper. The

ﬁltrate was washed with saturated Na₂S₂O₃solution (10 mL), dried

over MgSO₄, ﬁltered, and concentrated by evaporation to aﬀord a

yellow viscous residue that was subjected to column chromatography

on silica gel with EtOAc/hexanes (1/5 to 1/3, v/v) to yield the

product 23 (19 mg, 20%) as a white amorphous solid.

11.05 Hz, 1H), 3.70 (d, J = 9.9 Hz, 1H), 3.66−3.58 (m, 3H), 3.57−

3.38 (m, 10H, H-4, H-4″, H-3‴), 3.30 (dd, J = 9.2, 5.3 Hz, 1H),

3.27−3.18 (m, 1H, H-2″), 3.08−2.99 (m, 1H, H-2), 2.28 (s, 3H,

PhCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.7 (C), 165.0 (C),

161.7 (C), 161.1 (C), 138.8 (C), 138.5 (C), 138.2 (C), 138.1 (C),

137.9 (C), 137.7 (C), 134.9 (C), 133.6 (CH), 133.4 (CH), 133.3

(CH), 133.2 (C), 133.1 (C), 130.2 (CH), 130.0 (CH), 129.9 (CH),

129.8 (C), 128.9 (CH), 128.7 (CH), 128.66 (CH), 128.63 (CH),

128.6 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.2 (CH),

128.1 (CH), 128.09 (CH), 128.05 (CH), 127.9 (CH), 127.8 (CH),

127.79 (CH), 127.7 (CH), 127.6 (CH), 126.9 (CH), 126.3 (CH),

126.2 (CH), 126.0 (CH), 101.1 (CH), 100.2 (CH), 99.4 (CH), 92.4

(C), 92.1 (C), 83.8 (CH), 81.7 (CH), 79.8 (CH), 79.5 (CH), 77.2

(CH), 76.3 (CH), 76.29 (CH), 76.0 (CH), 75.4 (CH), 75.0 (CH₂),

74.9 (CH₂), 74.87 (CH₂), 74.1 (CH), 73.9 (CH), 73.74 (CH₂),

73.72 (CH₂), 73.6 (CH₂), 73.5 (CH₂), 73.1 (CH), 72.5 (CH), 72.1

(CH), 72.0 (CH₂), 70.0 (CH₂), 69.5 (CH), 69.4 (CH₂), 68.7 (CH₂),

68.5 (CH₂), 59.0 (CH), 57.3 (CH), 21.3 (CH₃); HRMS (ESI-TOF)

m/z: calcd for C₁₀₉H₁₀₇Cl₆N₂O₂₂S [M + H]⁺, 2041.5103; found,

2041.5178.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-

benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-6-O-tert-

butyldimethylsilyl-2-deoxy-2-trichloroacetamido-1-thio-β-^D-gluco-

pyranoside (24). A solution of 8 (79 mg, 0.066 mmol) and 12 (50

mg, 0.05 mmol) in anhydrous CH₂Cl₂(1 mL) was stirred with 3 Å

pulverized molecular sieves (130 mg) at rt for 30 min under the N₂

atmosphere. After cooling to −50 °C, NIS (15 mg, 0.066 mmol) and

TMSOTf (1.8 μL, 0.01 mmol) were added to the reaction mixture.

After 2.5 h, the reaction was quenched by dropwise addition of Et₃N,

diluted with CH₂Cl₂(5 mL), and ﬁltered through ﬁlter paper. The

ﬁltrate was washed with saturated Na₂S₂O₃solution (10 mL), dried

over MgSO₄, ﬁltered, and concentrated by evaporation to aﬀord a

yellow viscous residue that was subjected to column chromatography

on silica gel with EtOAc/hexanes (1/5 to 1/3, v/v) to yield the

product 24 (26 mg, 25%) as a white amorphous solid and donor 8

recovered (29 mg, 37%) as a glassy solid. R_f0.33 (EtOAc/toluene =

1/8, v/v); [α]²_D⁰−13.04 (c 1.15, CHCl₃); ¹H NMR (500 MHz,

CDCl₃): δ 7.88 (dd, J = 16.8, 7.3 Hz, 4H, Ar-H), 7.71 (d, J = 7.4 Hz,

1H, Ar-H), 7.58−7.38 (m, 8H, Ar-H), 7.37−7.31 (m, 6H, Ar-H),

7.31−7.26 (m, 13H, Ar-H), 7.24−7.14 (m, 13H, Ar-H), 7.14−7.11

(m, 2H, Ar-H), 7.11−7.07 (m, 2H, Ar-H), 6.99 (d, J = 7.6 Hz, 2H,

Ar-H), 6.50 (d, J = 6.7 Hz, 1H, N−H), 6.38 (d, J = 7.8 Hz, 1H, N−

H), 5.63 (t, J = 8.9 Hz, 1H, H-2‴), 5.39 (t, J = 8.7 Hz, 1H, H-2′),

5.12 (d, J = 10.3 Hz, 1H, H-1), 5.03 (d, J = 11.4 Hz, 1H, CH₂Ph),

4.91 (d, J = 10.2 Hz, 1H, CH₂Ph), 4.74 (m, 2H, H-1″, CH₂group of

Nap), 4.65−4.51 (m, 4H, H-1‴, CH₂Ph, CH₂group of Nap), 4.50−

4.19 (m, 11H, H-1′, H-3, H-3″, 8× CH₂Ph), 3.99−3.96 (m, 1H, H-

4‴), 3.95−3.89 (m, 3H, H-3′, H-6a, O−H), 3.88−3.84 (m, 1H, H-

4′), 3.78−3.66 (m, 2H, H-6b, H-6a″), 3.65−3.58 (m, 2H, H-5′, H-

5‴), 3.57−3.37 (m, 8H, H-4, H-4″, H-3‴, H-6a′, H-6b′, H-6b″, H-

6a‴, H-6b‴), 3.36−3.28 (m, 2H, H-5, H-5″), 3.24−3.16 (m, 1H, H-

2″), 3.03−2.94 (m, 1H, H-2), 2.30 (s, 3H, PhCH₃), 0.89 (s, 9H, TBS-

t-Bu), 0.062 (s, 3H, TBS-CH₃), 0.054 (s, 3H, TBS-CH₃); ¹³C{¹H}

NMR (125 MHz, CDCl₃): δ 165.7 (C), 164.9 (C), 161.6 (C), 161.1

(C), 138.7 (C), 138.5 (C), 138.4 (C), 138.1 (C), 138.08 (C), 137.9

(C), 137.7 (C), 134.9 (C), 133.5 (CH), 133.2 (CH), 133.16 (C),

133.1 (C), 130.2 (CH), 130.0 (CH), 129.9 (CH), 129.8 (C), 128.8

(CH), 128.7 (CH), 128.6 (CH), 128.58 (CH), 128.5 (CH), 128.4

(CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 128.08 (CH), 128.0

(CH), 127.9 (CH), 127.8 (CH), 127.77 (CH), 127.7 (CH), 126.9

(CH), 126.3 (CH), 126.2 (CH), 125.9 (CH), 101.1 (CH), 100.2

(CH), 99.3 (CH), 92.3 (C), 92.2 (C), 83.8 (CH), 81.7 (CH), 80.9

(CH), 79.5 (CH), 77.2 (CH), 76.3 (CH), 76.0 (CH), 75.5 (CH),

74.94 (CH₂), 74.9 (2× CH₂), 74.1 (CH), 73.8 (CH), 73.72 (CH₂),

73.7 (CH₂), 73.6 (CH₂), 73.1 (CH), 72.5 (CH), 72.1 (CH), 72.0

(CH₂), 69.3 (CH₂), 69.1 (CH), 68.6 (CH₂), 68.4 (CH₂), 63.1

(CH₂), 59.0 (CH), 57.3 (CH), 26.1 (CH₃), 21.3 (CH₃), 18.6 (C),

Synthesis of 23 from 27 by Regioselective Ring Opening

Reaction. For reaction details, please see Scheme 2.

A solution of compound 27 (100 mg, 0.05 mmol) was stirred in

anhydrous CH₂Cl₂(490 μL) at 0 °C. Et₃SiH (47 μL, 0.29 mmol) and

TFAA (21 μL, 0.15 mmol) were then added to the reaction mixture

and allowed it to stir for 10 min before adding TFA (15 μL, 0.20

mmol). After complete consumption of the starting material as seen

from TLC, the reaction mixture was diluted with CH₂Cl₂(5 mL).

The solvent extraction was done to wash the CH₂Cl₂layer

sequentially with dd. H₂O (5 mL) and saturated NaHCO₃solution

(5 mL). The CH₂Cl₂layer was collected, dried over MgSO₄, ﬁltered,

and concentrated by evaporation to yield the thick white crude that

was puriﬁed by column chromatography on silica gel with EtOAc/

hexanes (1/4, v/v) to yield the pure product 23 as a white amorphous

solid (80.4 mg, 80%). R_f0.40 (EtOAc/hexanes = 1/2, v/v); [α]_D²⁰

−7.21 (c 2.08, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.89 (dd, J =

15.1, 7.8 Hz, 4H, Ar-H), 7.72 (d, J = 7.8 Hz, 1H, Ar-H), 7.58−7.50

(m, 3H, Ar-H), 7.49−7.38 (m, 5H, Ar-H), 7.36−7.29 (m, 13H, Ar-

H), 7.29−7.26 (m, 8H, Ar-H), 7.26−7.24 (m, 4H, Ar-H), 7.23−7.20

(m, 4H, Ar-H), 7.19−7.14 (m, 7H, Ar-H), 7.14−7.11 (m, 3H, Ar-H),

7.11−7.06 (m, 2H, Ar-H), 6.95 (d, J = 7.9 Hz, 2H, Ar-H), 6.55 (d, J =

6.9 Hz, 1H, N−H), 6.45 (d, J = 8.0 Hz, 1H, N−H), 5.63 (t, J = 9.0

Hz, 1H, H-2‴), 5.38 (t, J = 8.7 Hz, 1H, H-2′), 5.14 (d, J = 10.4 Hz,

1H, H-1), 5.03 (d, J = 11.5 Hz, 1H, CH₂Ph), 4.91 (d, J = 10.3 Hz, 1H,

CH₂Ph), 4.79−4.70 (m, 2H, H-1″, CH₂group of Nap), 4.65−4.55

(m, 4H, H-1‴, 2× CH₂Ph, CH₂group of Nap), 4.51−4.42 (m, 3H,

H-1′), 4.40 (d, J = 5.4 Hz, 1H), 4.39−4.36 (m, 2H), 4.36−4.30 (m,

3H), 4.30−4.18 (m, 3H, H-3, H-3″), 4.06−3.95 (m, 2H, H-4‴, O−

H), 3.91 (d, J = 10 Hz, 1H, H-3′), 3.86 (s, 1H, H-4′), 3.80 (d, J =

N

https://dx.doi.org/10.1021/acs.joc.0c02422

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

−5.0 (CH₃), −5.1 (CH₃); HRMS (ESI-TOF) m/z: calcd for

C₁₀₈H₁₁₅Cl₆N₂O₂₂SSi [M + H]⁺, 2065.5548; found, 2065.5502.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-

benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4-O-ace-

tyl-6-O-benzyl-2-deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyr-

anoside (25). A solution of 8 (77 mg, 0.064 mmol) and 13 (50 mg,

0.05 mmol) in anhydrous CH₂Cl₂(1 mL) was stirred with 3 Å

pulverized molecular sieves (127 mg) at rt for 30 min under the N₂

atmosphere. After cooling to −50 °C, NIS (14 mg, 0.064 mmol) and

TMSOTf (1.8 μL, 0.01 mmol) were added to the reaction mixture.

After 2.5 h, the reaction was quenched by dropwise addition of Et₃N,

diluted with CH₂Cl₂(5 mL), and ﬁltered through ﬁlter paper. The

ﬁltrate was washed with saturated Na₂S₂O₃solution (10 mL), dried

over MgSO₄, ﬁltered, and concentrated by evaporation to aﬀord a

yellow viscous residue that was subjected to column chromatography

on silica gel with EtOAc/hexanes (1/5 to 1/3, v/v) to yield the

product 25 (62 mg, 60%) as a white amorphous foam. R_f0.32

(EtOAc/toluene = 1/8, v/v, run two times); [α]²_D⁰−27.5 (c 0.8,

CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.90 (d, J = 7.5 Hz, 4H, Ar-

H), 7.71 (d, J = 7.6 Hz, 1H, Ar-H), 7.6−7.5 (m, 3H, Ar-H), 7.49−

7.38 (m, 4H, Ar-H), 7.37−7.28 (m, 14H, Ar-H), 7.27−7.23 (m, 15H,

Ar-H), 7.21−7.13 (m, 11H, Ar-H), 7.10−7.03 (m, 2H, Ar-H), 6.98−

6.87 (m, 3H, Ar-H, N−H), 6.49 (d, J = 7.5 Hz, 1H, N−H), 5.62 (t, J

= 8.9 Hz, 1H, H-2‴), 5.3 (t, J = 8.6 Hz, 1H, H-2′), 5.14 (d, J = 10.0

Hz, 1H, H-1), 5.03 (d, J = 11.45 Hz, 1H, CH₂Ph), 4.90 (d, J = 10.2

Hz, 1H, CH₂Ph), 4.81 (t, J = 9.2 Hz, 1H, H-4), 4.77−4.70 (m, 2H, H-

1″, CH₂group of Nap), 4.66 (d, J = 12 Hz, 1H, CH₂Ph), 4.61−4.22

(m, 16H, H-1′, H-1‴, H-3, H-3″, CH₂group of Nap, 11× CH₂Ph),

3.97 (s, 1H, H-4‴), 3.9−3.84 (m, 2H, H-3′, H-4′), 3.72−3.33 (m,

14H, H-3‴, H-4″, H-5, H-5′, H-5″, H-5‴, H-6a, H-6b, H-6a′, H-6b′,

H-6a″, H-6b″, H-6a‴, H-6b‴), 3.24−3.11 (m, 2H, H-2, H-2″), 2.26

(s, 3H, PhCH₃), 1.54 (s, 3H, COCH₃); ¹³C{¹H} NMR (125 MHz,

CDCl₃): δ 169.8 (C), 165.7 (C), 164.7 (C), 161.4 (C), 161.2 (C),

138.9 (C), 138.8 (C), 138.4 (C), 138.2 (C), 138.15 (C), 137.9 (C),

137.85 (C), 134.9 (C), 133.4 (CH), 133.3 (CH), 133.2 (C), 133.1

(C), 130.2 (CH), 130.0 (CH), 129.9 (CH), 128.7 (CH), 128.6

(CH), 128.59 (CH), 128.54 (CH), 128.5 (CH), 128.4 (CH), 128.3

(CH), 128.2 (CH), 128.18 (CH), 128.1 (CH), 128.07 (CH), 128.0

(CH), 127.9 (CH), 127.88 (CH), 127.85 (CH), 127.8 (CH), 127.7

(CH), 127.68 (CH), 127.6 (CH), 127.5 (CH), 126.9 (CH), 126.3

(CH), 126.1 (CH), 126.0 (CH), 100.2 (CH), 99.5 (CH), 99.3 (CH),

92.7 (CH), 92.3 (CH), 84.6 (CH), 79.5 (CH), 78.0 (CH), 77.7

(CH), 76.7 (CH), 76.3 (CH), 76.2 (CH), 75.6 (CH), 75.2 (CH),

74.9 (CH₂), 74.88 (CH₂), 73.9 (CH), 73.8 (CH), 73.7 (CH₂), 73.6

(CH₂), 73.58 (CH₂), 73.5 (CH₂), 73.1 (CH), 72.5 (CH), 72.1 (CH),

72.0 (CH₂), 69.6 (CH₂), 69.2 (CH₂), 68.6 (CH), 68.59 (CH₂), 68.3

(CH₂), 59.2 (CH), 57.6 (CH), 21.3 (CH₃), 20.5 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₁₁₁H₁₀₉Cl₆N₂O₂₃S [M + H]⁺, 2083.5260;

found, 2083.5278.

4H, Ar-H), 7.56−7.50 (m, 3H, Ar-H), 7.49−7.31 (m, 6H, Ar-H),

7.36−7.26 (m, 22H, Ar-H), 7.25−7.22 (m, 6H, Ar-H), 7.21−7.13 (m,

11H, Ar-H), 7.11−7.04 (m, 2H, Ar-H), 6.92 (d, J = 7.6 Hz, 3H, Ar-H,

N−H), 6.61 (d, J = 7.7 Hz, 1H, N−H), 5.62 (dd, J = 9.7, 8.2 Hz, 1H,

H-2‴), 5.27 (dd, J = 10.0, 7.8 Hz, 1H, H-2′), 5.14 (d, J = 10.2 Hz,

1H, H-1), 5.03 (d, J = 11.4 Hz, 1H, CH₂Ph), 4.91 (d, J = 10.2 Hz, 1H,

CH₂Ph), 4.79−4.64 (m, 4H, H-4, H-1″, CH₂Ph, CH₂group of Nap),

4.63−4.22 (m, 14H, H-1′, H-1‴, H-3, H-3″, CH₂group of Nap, 9×

CH₂Ph), 4.00−3.93 (m, 1H, H-4‴), 3.91−3.83 (m, 2H, H-3′, H-4′),

3.71−3.33 (m, 14H, H-3‴, H-4″, H-5, H-5′, H-5″, H-5‴, H-6a, H-6b,

H-6a′, H-6b′, H-6a″, H-6b″, H-6a‴, H-6b‴), 3.24−3.13 (m, 2H, H-2,

H-2″), 2.26 (s, 3H, PhCH₃), 1.47 (s, 3H, COCH₃), 1.01 (s, 9H,

TBDPS-t-Bu); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 169.6 (C),

165.8 (C), 164.7 (C), 161.5 (C), 161.2 (C), 139.0 (C), 138.8 (C),

138.3 (C), 138.2 (C), 138.17 (C), 137.9 (C), 135.8 (CH), 134.9 (C),

133.4 (C), 133.3 (CH), 133.2 (C), 133.1 (C), 130.2 (CH), 130.0

(CH), 129.9 (CH), 129.8 (CH), 128.8 (CH), 128.7 (CH), 128.6

(CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.26 (CH), 128.22

(CH), 128.2 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 127.8

(CH), 127.7 (CH), 127.66 (CH), 127.5 (CH), 126.9 (CH), 126.3

(CH), 126.2 (CH), 126.0 (CH), 100.2 (CH), 99.6 (CH), 99.3 (CH),

92.7 (C), 92.4 (C), 84.8 (CH), 79.6 (CH), 79.5 (CH), 77.7 (CH),

76.6 (CH), 76.3 (CH), 76.2 (CH), 75.7 (CH), 75.2 (CH), 75.0

(2xCH₂), 74.9 (CH₂), 73.86 (CH), 73.8 (CH), 73.7 (CH₂), 73.6

(CH₂), 73.5 (CH₂), 73.2 (CH), 72.6 (CH), 72.1 (CH), 72.0 (CH₂),

69.3 (CH₂), 68.6 (CH₂), 68.5 (CH₂), 68.2 (CH), 63.6 (CH₂), 59.2

(CH), 57.8 (CH), 26.9 (CH₃), 21.3 (CH₃), 20.4 (CH₃), 19.4 (C);

HRMS (ESI-TOF) m/z: calcd for C₁₂₀H₁₂₁Cl₆N₂O₂₃SSi [M + H]⁺,

2231.5973; found, 2231.6005.

4-Methylphenyl (2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-

benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4,6-O-ben-

zylidene-2-deoxy-2-trichloroacetamido-1-thio-β-^D-glucopyrano-

side (27). A solution of 8 (240 mg, 0.20 mmol) and 15 (150 mg,

0.155 mmol) in anhydrous CH₂Cl₂(3.1 mL) was stirred with 3 Å

pulverized molecular sieves (383 mg) at rt for 30 min under the N₂

atmosphere. After cooling to −50 °C, NIS (44 mg, 0.20 mmol) and

TMSOTf (5.6 μL, 0.031 mmol) were added to the reaction mixture.

After 2.5 h, the reaction was quenched by dropwise addition of Et₃N,

diluted with CH₂Cl₂(5 mL), and ﬁltered through ﬁlter paper. The

ﬁltrate was washed with saturated Na₂S₂O₃solution (10 mL), dried

over MgSO₄, ﬁltered, and concentrated by evaporation to aﬀord a

yellow viscous residue that was subjected to column chromatography

on silica gel with EtOAc/hexanes (1/5 to 1/3, v/v) to yield the

product 27 (237 mg, 75%) as a white amorphous foam. R_f0.43

(EtOAc/toluene = 1/8, v/v); [α]²_D⁰−13.08 (c 3.9, CHCl₃); ¹H NMR

(500 MHz, CDCl₃): δ 7.91 (d, J = 7.4 Hz, 2H, Ar-H), 7.84 (d, J = 7.3

Hz, 2H, Ar-H), 7.70 (d, J = 7.7 Hz, 1H, Ar-H), 7.56−7.53 (m, 1H,

Ar-H), 7.52−7.49 (m, 2H, Ar-H), 7.46−7.37 (m, 5H, Ar-H), 7.36−

7.30 (m, 6H, Ar-H), 7.29−7.26 (m, 10H, Ar-H), 7.26−7.23 (m, 9H,

Ar-H), 7.22−7.19 (m, 7H, Ar-H), 7.16−7.10 (m, 7H, Ar-H), 7.09−

7.05 (m, 2H, Ar-H), 7.04−7.01 (m, 2H, Ar-H), 6.86 (d, J = 6.7 Hz,

1H, N−H), 6.37 (d, J = 7.8 Hz, 1H, N−H), 5.63 (dd, J = 10.4, 7.6 Hz,

1H, H-2‴), 5.40−5.35 (m, 2H, H-2′, PhCH benzylidene), 5.28 (d, J =

10.3 Hz, 1H, H-1), 5.03 (d, J = 11.4 Hz, 1H, CH₂Ph), 4.87 (d, J =

10.3 Hz, 1H, CH₂Ph), 4.74−4.68 (m, 2H, H-1″, CH₂group of Nap),

4.67−4.63 (m, 2H, H-1′, CH₂Ph), 4.60−4.53 (m, 3H, H-1‴, CH₂Ph,

CH₂group of Nap), 4.52−4.47 (m, 2H, H-3, CH₂Ph), 4.46−4.42 (m,

2H, 2× CH₂Ph), 4.41−4.38 (m, 1H, CH₂Ph), 4.37−4.31 (m, 4H, H-

5‴, 3× CH₂Ph), 4.30−4.25 (m, 2H, H-5″, CH₂Ph), 4.24−4.19 (m,

2H, H-3″, H-6a), 3.99 (s, 1H, H-4‴), 3.90−3.83 (m, 2H, H-3′, H-4′),

3.67−3.62 (m, 2H, H-6a″, H-6a‴), 3.61−3.57 (m, 2H, H-4, H-6b″),

3.54−3.51 (m, 1H, H-6b), 3.51−3.48 (m, 1H, H-3‴), 3.47−3.43 (m,

3H, H-4″, H-6a′, H-6b‴) 3.43−3.40 (m, 2H, H-5, H-5′), 3.39−3.34

(m, 1H, H-6b′), 3.22−3.10 (m, 2H, H-2, H-2″), 2.30 (s, 3H,

PhCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.6 (C), 165.0 (C),

161.5 (C), 161.1 (C), 138.9 (C), 138.8 (C), 138.7 (C), 138.1 (C),

137.9 (C), 137.4 (C), 134.9 (C), 133.9 (CH), 133.4 (CH), 133.2

(CH), 133.1 (C), 133.0 (C), 130.04 (CH), 130.0 (CH), 129.97

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-

benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4-O-ace-

tyl-6-O-tert-butyldiphenylsilyl-2-deoxy-2-trichloroacetamido-1-

thio-β-^D-glucopyranoside (26). A solution of 8 (63 mg, 0.052 mmol)

and 14 (47 mg, 0.04 mmol) in anhydrous CH₂Cl₂(0.8 mL) was

stirred with 3 Å pulverized molecular sieves (109 mg) at rt for 30 min

under the N₂atmosphere. After cooling to −50 °C, NIS (12 mg,

0.052 mmol) and TMSOTf (1.5 μL, 0.008 mmol) were added to the

reaction mixture. After 2.5 h, the reaction was quenched by dropwise

addition of Et₃N, diluted with CH₂Cl₂(5 mL), and ﬁltered through

ﬁlter paper. The ﬁltrate was washed with saturated Na₂S₂O₃solution

(10 mL), dried over MgSO₄, ﬁltered, and concentrated by

evaporation to aﬀord a yellow viscous residue that was subjected to

column chromatography on silica gel with EtOAc/hexanes (1/5 to 1/

3, v/v) to yield the product 26 (71 mg, 79%) as a white amorphous

solid. R_f0.32 (EtOAc/toluene = 1/10, v/v); [α]²_D⁰−12.37 (c 1.94,

1

CHCl₃); H NMR (500 MHz, CDCl₃): δ 7.89 (dd, J = 12.1, 7.5 Hz,

4H, Ar-H), 7.72 (d, J = 7.6 Hz, 1H, Ar-H), 7.63 (dd, J = 5.8, 4.4 Hz,

O

https://dx.doi.org/10.1021/acs.joc.0c02422

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(CH), 129.7 (C), 128.9 (CH), 128.6 (CH), 128.57 (CH), 128.5

(CH), 128.45 (CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.13

(CH), 128.11 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 127.8

(CH), 127.78 (CH), 127.7 (CH), 127.6 (CH), 127.5 (C), 127.4

(CH), 126.8 (CH), 126.2 (CH), 126.19 (CH), 126.1 (CH), 125.9

(CH), 100.9 (CH), 100.2 (CH), 99.8 (CH), 99.1 (CH), 92.3 (C),

92.26 (C), 84.4 (CH), 79.5 (CH), 79.2 (CH), 77.6 (CH), 76.33

(CH), 76.3 (CH), 76.2 (CH), 75.9 (CH), 75.2 (CH), 74.9 (CH₂),

74.8 (CH₂), 73.7 (CH₂), 73.6 (CH₂), 73.4 (CH₂), 73.0 (CH), 72.9

(CH), 72.0 (CH), 71.9 (CH₂), 70.7 (CH), 69.2 (CH₂), 68.9 (CH₂),

68.5 (CH₂), 68.1 (CH₂), 58.9 (CH), 57.9 (CH), 21.3 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₁₀₉H₁₀₅Cl₆N₂O₂₂S [M + H]⁺, 2039.4997;

found, 2039.5017.

mmol) and 13 (34 mg, 0.033 mmol) in anhydrous CH₂Cl₂(670 μL)

was stirred with 3 Å pulverized molecular sieves (79 mg) at rt for 30

min under the N₂atmosphere. After cooling to −60 °C, NIS (8.3 mg,

0.037 mmol) and TMSOTf (1.21 μL, 0.0068 mmol) were added to

the reaction mixture. After 2.5 h, the reaction was quenched by

dropwise addition of Et₃N, diluted with CH₂Cl₂(5 mL), and ﬁltered

through ﬁlter paper. The ﬁltrate was washed with saturated Na₂S₂O₃

solution (10 mL), dried over MgSO₄, ﬁltered, and concentrated by

evaporation to aﬀord a yellow viscous residue that was subjected to

column chromatography on silica gel with EtOAc/toluene (1/13, v/

v) to yield the pure product 29 (45 mg, 65%) as a white amorphous

solid.

Synthesis of 29 by Using Preactivation Method. For reaction

details, please see Scheme S8. Ph₂SO (4.9 mg, 0.024 mmol) and

TTBP (10.4 mg, 0.042 mmol) were added to a solution of 9 (45 mg,

0.037 mmol) in CH₂Cl₂(617 μL) at rt under N₂. After 30 min of

stirring at rt, the reaction mixture was cooled down to −60 °C, and

Tf₂O (4.1 μL, 0.024 mmol) was added to the reaction solution. After

1 h of stirring at −60 °C, a solution of 13 (34 mg, 0.034 mmol) in

CH₂Cl₂(0.5 mL) was added to the reaction mixture at −60 °C. Then,

TMSOTf (2.43 μL, 0.013 mmol) was added, and the reaction was

stirred for 2 h. The reaction was quenched by dropwise addition of

Et₃N at −60 °C, diluted with CH₂Cl₂(5 mL), and ﬁltered. Solvent

extraction was then done to wash the CH₂Cl₂layer with saturated

Na₂S₂O₃solution (10 mL) and saturated NaHCO₃solution (10 mL).

The ﬁltrate was collected, dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure to aﬀord a yellow viscous

residue that was puriﬁed by column chromatography on silica gel with

EtOAc/toluene (1/14, v/v) to yield pure 29 (41 mg, 58% yield) as a

white amorphous solid. R_f0.38 (EtOAc/toluene = 1/8, v/v); [α]_D²⁰

−10.81 (c 0.74, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.94 (d, J =

7.7 Hz, 2H, Ar-H), 7.83 (d, J = 7.8 Hz, 2H, Ar-H), 7.70 (d, J = 7.8 Hz,

1H, Ar-H), 7.55−7.47 (m, 4H, Ar-H), 7.43−7.39 (m, 2H, Ar-H),

7.39−7.36 (m, 3H, Ar-H), 7.36−7.33 (m, 1H, Ar-H), 7.33−7.29 (m,

8H, Ar-H), 7.29−7.24 (m, 16H, Ar-H), 7.22−7.15 (m, 8H, Ar-H),

7.12−7.07 (m, 2H, Ar-H), 7.02 (d, J = 7.1 Hz, 1H, N−H), 6.93 (d, J

= 8.0 Hz, 2H, Ar-H), 6.44 (d, J = 8.1 Hz, 1H, N−H), 5.60 (dd, J =

9.6, 8.4 Hz, 1H, H-2‴), 5.30 (dd, J = 9.8, 8.0 Hz, 1H, H-2′), 5.16 (d, J

= 10.1 Hz, 1H, H-1), 5.01 (d, J = 11.5 Hz, 1H, CH₂Ph), 4.83 (t, J =

9.4 Hz, 1H, H-4), 4.76−4.68 (m, 3H, H-1″, H-1‴, CH₂group of

Nap), 4.57−4.36 (m, 12H, H-1′, H-3, CH₂group of Nap, 9xCH₂Ph),

4.31 (d, J = 11.9 Hz, 1H, CH₂Ph), 4.16 (d, J = 12.0 Hz, 1H, CH₂Ph),

3.94 (d, J = 1.5 Hz, 1H, H-4‴), 3.89 (t, J = 5.9 Hz, 1H, H-3″), 3.81

(dd, J = 10.1, 2.5 Hz, 1H, H-3′), 3.77−3.74 (m, 1H, H-4′), 3.71−3.32

(m, 14H, H-2″, H-3‴, H-4″, H-5, H-5′, H-5″, H-5‴, H-6a, H-6b, H-

6a′, H-6b′, H-6a″, H-6a‴, H-6b‴), 3.27 (td, J = 10.1, 7.2 Hz, 1H, H-

2), 3.18 (dd, J = 9.1, 4.9 Hz, 1H, H-6b″), 2.25 (s, 3H, PhCH₃), 1.49

(s, 3H, COCH₃), 0.76 (s, 9H, TBS-t-Bu), 0.05 (s, 3H, TBS-CH₃),

−0.05 (s, 3H, TBS-CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ

169.8 (C), 165.6 (C), 164.5 (C), 161.4 (C), 161.2 (C), 138.8 (C),

138.7 (C), 138.4 (C), 138.2 (C), 137.9 (C), 135.0 (C), 133.4 (CH),

133.3 (CH), 133.2 (C), 133.1 (C), 133.0 (CH), 130.3 (CH), 130.0

(C), 129.9 (CH), 128.7 (CH), 128.66 (CH), 128.64 (CH), 128.6

(CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.28 (CH), 128.1

(CH), 128.07 (CH), 128.0 (CH), 127.97 (CH), 127.9 (CH), 127.8

(CH), 127.73 (CH), 127.7 (CH), 127.6 (CH), 127.5 (CH), 126.8

(CH), 126.2 (CH), 126.1 (CH), 125.9 (CH), 100.0 (CH), 99.7

(CH), 99.2 (CH), 92.7 (C), 92.2 (C), 84.9 (CH), 79.8 (CH), 78.5

(CH), 78.4 (CH), 78.0 (CH), 76.9 (CH), 76.2 (CH), 75.6 (CH),

74.8 (CH₂), 74.6 (CH₂), 74.0 (CH), 73.7 (CH₂), 73.6 (CH₂), 73.5

(CH), 73.4 (CH₂), 73.2 (CH), 72.3 (CH), 72.1 (CH₂), 71.6 (CH),

70.0 (CH₂), 69.99 (CH), 69.7 (CH₂), 68.9 (CH₂), 68.5 (CH₂), 68.47

(CH), 58.3 (CH), 57.4 (CH), 26.2 (CH₃), 21.3 (CH₃), 20.4 (CH₃),

18.0 (C), −3.7 (CH₃), −4.8 (CH₃); HRMS (ESI-TOF) m/z: calcd

for C₁₁₀H₁₁₇Cl₆N₂O₂₃SSi [M + H]⁺, 2107.5655; found, 2107.5675.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4-O-tert-butyldime-

thylsilyl-6-O-benzyl-2-deoxy-2-trichloroacetamido-β-^D-glucopyra-

nosyl)-(1 → 3)-(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyrano-

syl)-(1 → 3)-4-O-benzoyl-6-O-tert-butyldiphenylsilyl-2-deoxy-2-tri-

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-

benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4-O-ben-

zoyl-6-O-tert-butyldiphenylsilyl-2-deoxy-2-trichloroacetamido-1-

thio-β-^D-glucopyranoside (28). A solution of 8 (54 mg, 0.045 mmol)

and 16 (42 mg, 0.035 mmol) in anhydrous CH₂Cl₂(0.7 mL) was

stirred with 3 Å pulverized molecular sieves (96 mg) at rt for 30 min

under the N₂atmosphere. After cooling to −50 °C, NIS (10.1 mg,

0.045 mmol) and TMSOTf (1.25 μL, 0.007 mmol) were added to the

reaction mixture. After 2.5 h, the reaction was quenched dropwise

addition of Et₃N, diluted with CH₂Cl₂(5 mL), and ﬁltered through

ﬁlter paper. The ﬁltrate was washed with saturated Na₂S₂O₃solution

(10 mL), dried over MgSO₄, ﬁltered, and concentrated by

evaporation to aﬀord a yellow viscous residue that was subjected to

column chromatography on silica gel with EtOAc/hexanes (1/5 to 1/

3, v/v) to yield the product 28 (68 mg, 86%) as a white amorphous

foam. R_f0.51 (EtOAc/toluene = 1/10, v/v); [α]²_D⁰−17.46 (c 1.89,

CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.90 (d, J = 7.3 Hz, 2H, Ar-

H), 7.77 (d, J = 7.2 Hz, 2H, Ar-H), 7.73−7.65 (m, 3H, Ar-H), 7.62−

7.58 (m, 2H, Ar-H), 7.57−7.53 (m, 3H, Ar-H), 7.52−7.49 (m, 2H,

Ar-H), 7.48−7.42 (m, 2H, Ar-H), 7.42−7.40 (m, 1H, Ar-H), 7.40−

7.36 (m, 2H, Ar-H), 7.33−7.31 (m, 2H, Ar-H), 7.31−7.28 (m, 9H,

Ar-H), 7.27−7.25 (m, 6H, Ar-H), 7.24−7.22 (m, 5H, Ar-H), 7.22−

7.21 (m, 3H, Ar-H), 7.21−7.19 (m, 3H, Ar-H), 7.19−7.17 (m, 4H,

Ar-H), 7.16−7.10 (m, 9H, Ar-H), 7.09−7.03 (m, 4H, Ar-H), 6.91

(dd, J = 17.7, 7.3 Hz, 3H, Ar-H, N−H), 6.53 (d, J = 7.6 Hz, 1H, N−

H), 5.60 (dd, J = 9.8, 8.2 Hz, 1H, H-2‴), 5.32−5.22 (m, 2H, H-1, H-

2′), 5.11−4.98 (m, 2H, H-4, CH₂Ph), 4.90 (d, J = 10.0 Hz, 1H,

CH₂Ph), 4.76−4.61 (m, 3H, H-3, H-1′, CH₂group of Nap), 4.60−

4.19 (m, 13H, H-1′, H-1‴, H-3″, CH₂group of Nap, 9× CH₂Ph),

4.14 (d, J = 11.7 Hz, 1H, CH₂Ph), 3.98−3.91 (m, 1H, H-4‴), 3.86−

3.75 (m, 2H, H-3′, H-4′), 3.73−3.34 (m, 12H, H-3‴, H-4″, H-5, H-

5′, H-5″, H-5‴, H-6a, H-6b, H-6a″, H-6b″, H-6a‴, H-6b‴), 3.20−

3.02 (m, 3H, H-2, H-2″, H-6a′), 2.83 (t, J = 8.1 Hz, 1H, H-6b′), 2.27

(s, 3H, PhCH₃), 0.97 (s, 9H, TBDPS-t-Bu); ¹³C{¹H} NMR (125

MHz, CDCl₃): δ 165.8 (C), 165.1 (C), 164.7 (C), 161.7 (C), 161.2

(C), 139.2 (C), 138.8 (C), 138.4 (C), 138.2 (C), 138.1 (C), 138.0

(C), 137.9 (C), 135.7 (CH), 134.9 (C), 133.5 (CH), 133.3 (CH),

133.2 (CH), 133.1 (C), 132.7 (CH), 130.1 (C), 130.0 (CH), 129.9

(CH), 129.7 (CH), 128.7 (CH), 128.6 (CH), 128.58 (CH), 128.4

(CH), 128.3 (C), 128.2 (CH), 128.1 (CH), 127.9 (CH), 127.8

(CH), 127.7 (CH), 127.6 (CH), 127.3 (CH), 126.9 (CH), 126.3

(CH), 126.1 (CH), 126.0 (CH), 100.2 (CH), 100.1 (CH), 99.1

(CH), 92.6 (C), 92.3 (C), 84.2 (CH), 79.7 (CH), 79.5 (CH), 77.5

(CH), 76.4 (CH), 76.3 (CH), 76.2 (CH), 76.1 (CH), 75.1 (CH),

75.0 (CH₂), 74.9 (CH₂), 74.7 (CH₂), 73.8 (CH), 73.7 (CH₂), 73.5

(CH₂), 73.4 (CH), 73.3 (CH₂), 73.2 (CH), 72.6 (CH), 72.1 (CH),

72.0 (CH₂), 69.2 (CH₂), 69.1 (CH), 68.4 (CH₂), 67.8 (CH₂), 63.4

(CH₂), 59.2 (CH), 58.2 (CH), 26.9 (CH₃), 21.4 (CH₃), 19.3 (C);

HRMS (ESI-TOF) m/z: calcd for C₁₂₅H₁₂₃Cl₆N₂O₂₃SSi [M + H]⁺,

2293.6132; found, 2293.6093.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4-O-tert-butyldime-

thylsilyl-6-O-benzyl-2-deoxy-2-trichloroacetamido-β-^D-glucopyra-

nosyl)-(1 → 3)-(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyrano-

syl)-(1 → 3)-4-O-acetyl-6-O-benzyl-2-deoxy-2-trichloroacetamido-

1-thio-β-^D-glucopyranoside (29). A solution of 9 (45 mg, 0.037

P

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chloroacetamido-1-thio-β-D-glucopyranoside (30). A solution of 9

(55 mg, 0.045 mmol) and 16 (50 mg, 0.041 mmol) in anhydrous

CH₂Cl₂(0.82 mL) was stirred with 3 Å pulverized molecular sieves

(105 mg) at rt for 30 min under the N₂atmosphere. After cooling to

−60 °C, NIS (10.15 mg, 0.045 mmol) and TMSOTf (1.48 μL, 0.008

mmol) were added to the reaction mixture. After 4.5 h, the reaction

was quenched by dropwise addition of Et₃N, diluted with CH₂Cl₂(5

mL), and ﬁltered through ﬁlter paper. The ﬁltrate was washed with

saturated Na₂S₂O₃solution (10 mL), dried over MgSO₄, ﬁltered, and

concentrated by evaporation to aﬀord a yellow viscous residue that

was subjected to column chromatography on silica gel with EtOAc/

hexanes (1/5 to 1/3, v/v, with 1% Et₃N) to yield the product 30 (49

mg, 52%) as a white amorphous solid. R_f0.43 (EtOAc/hexanes = 1/3,

v/v); [α]²_D⁰−10.94 (c 1.46, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ

7.85−7.82 (m, 2H, Ar-H), 7.81−7.77 (m, 2H, Ar-H), 7.70 (d, J = 7.8

Hz, 1H, Ar-H), 7.66−7.63 (m, 2H, Ar-H), 7.59−7.58 (m, 1H, Ar-H),

7.58−7.57 (m, 1H, Ar-H), 7.56−7.55 (m, 1H, Ar-H), 7.55−7.54 (m,

1H, Ar-H), 7.53−7.48 (m, 3H, Ar-H), 7.43−7.39 (m, 3H, Ar-H),

7.39−7.35 (m, 3H, Ar-H), 7.33−7.32 (m, 2H, Ar-H), 7.32−7.30 (m,

4H, Ar-H), 7.30−7.28 (m, 3H, Ar-H), 7.28−7.27 (m, 1H, Ar-H),

7.27−7.26 (m, 2H, Ar-H), 7.26−7.25 (m, 3H, Ar-H), 7.23−7.22 (m,

5H, Ar-H), 7.22−7.21 (m, 3H, Ar-H), 7.20−7.19 (m, 4H, Ar-H),

7.18−7.17 (m, 3H, Ar-H), 7.16−7.15 (m, 3H, Ar-H), 7.15−7.14 (m,

2H, Ar-H), 7.13−7.10 (m, 2H, Ar-H), 7.03−7.00 (m, 2H, Ar-H),

6.95−6.91 (m, 3H, Ar-H, N−H), 6.38 (d, J = 8.1 Hz, 1H, N−H), 5.58

(dd, J = 9.9, 8.0 Hz, 1H, H-2‴), 5.30−5.24 (m, 2H, H-1, H-2′), 5.05

(t, J = 9.2 Hz, 1H, H-4), 5.00 (d, J = 11.5 Hz, 1H, CH₂Ph), 4.71 (d, J

= 12.4 Hz, 1H, CH₂group of Nap), 4.69−4.64 (m, 2H, H-1″, H-1‴),

4.64−4.60 (m, 1H, H-3), 4.56−4.49 (m, 3H, H-1′, CH₂Ph, CH₂

group of Nap), 4.47−4.35 (m, 5H, 5xCH₂Ph), 4.23 (d, J = 12.0 Hz,

1H, CH₂Ph), 4.12 (dd, J = 17.7, 12.0 Hz, 2H, 2× CH₂Ph), 3.92 (d, J

= 2.5 Hz, 1H, H-4‴), 3.86 (t, J = 6.4 Hz, 1H, H-3″), 3.77 (dd, J =

10.2, 2.9 Hz, 1H, H-3′), 3.70−3.33 (m, 13H, H-4′, H-5, H-4″, H-3″,

H-2″, H-5′, H-5″, H-5‴, H-6a, H-6b, H-6a″, H-6a‴, H-6b‴), 3.21 (td,

J = 10.0, 7.1 Hz, 1H, H-2), 3.09−3.01 (m, 2H, H-6a′, H-6b″), 2.77

(dd, J = 9.1, 6.9 Hz, 1H, H-6b′), 2.27 (s, 3H, PhCH₃), 0.97 (s, 9H,

TBDPS-t-Bu), 0.73 (s, 9H, TBS-t-Bu), 0.04 (s, 3H, TBS-CH₃), −0.08

(s, 3H, TBS-CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.6 (C),

165.1 (C), 164.5 (C), 161.6 (C), 161.1 (C), 139.0 (C), 138.8 (C),

138.4 (C), 138.1 (C), 137.9 (C), 135.7 (CH), 135.1 (C), 133.5

(CH), 133.3 (C), 133.25 (C), 133.2 (C), 133.16 (CH), 133.1 (C),

133.06 (CH), 132.7 (CH), 130.1 (C), 130.0 (CH), 129.9 (C), 129.7

(CH), 128.7 (CH), 128.6 (CH), 128.57 (CH), 128.5 (CH), 128.4

(CH), 128.39 (CH), 128.37 (CH), 128.3 (CH), 128.2 (CH), 128.1

(CH), 128.05 (CH), 128.0 (CH), 127.9 (CH), 127.74 (CH), 127.7

(CH), 127.6 (CH), 127.3 (CH), 126.8 (CH), 126.2 (CH), 126.1

(CH), 125.9 (CH), 99.8 (CH), 99.7 (CH), 99.6 (CH), 92.7 (C),

92.2 (C), 84.5 (CH), 79.8 (CH), 78.2 (CH), 78.1 (CH), 76.7 (CH),

76.2 (CH), 76.1 (CH), 74.8 (CH₂), 74.6 (CH₂), 73.7 (CH₂), 73.6

(CH), 73.5 (CH), 73.4 (CH₂), 73.3 (CH₂), 73.2 (CH), 72.5 (CH),

72.1 (CH₂), 71.6 (CH), 70.1 (CH), 69.9 (CH₂), 68.9 (CH), 68.6

(CH₂), 68.0 (CH₂), 63.5 (CH₂), 58.4 (CH), 58.1 (CH), 26.9 (CH₃),

26.2 (CH₃), 21.4 (CH₃), 19.3 (C), 18.0 (C), −3.6 (CH₃), −4.8

(CH₃); HRMS (ESI-TOF) m/z: calcd for C₁₂₄H₁₃₁Cl₆N₂O₂₃SSi₂[M

+ H]⁺, 2317.6527; found, 2317.6535.

column chromatography on silica gel with EtOAc/hexanes (1/5 to 1/

3, v/v) to yield the desired pure product 31 (203 mg, 60%) as a white

amorphous foam. R_f0.33 (EtOAc/hexanes = 1/2, v/v); [α]²_D⁰−20.25

(c 0.79, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 8.02 (d, J = 7.7 Hz,

2H, Ar-H), 7.88 (d, J = 7.8 Hz, 2H, Ar-H), 7.43 (t, J = 7.3 Hz, 2H, Ar-

H), 7.37−7.32 (m, 4H, Ar-H), 7.32−7.29 (m, 4H, Ar-H), 7.29−7.27

(m, 4H, Ar-H), 7.25−7.21 (m, 10H, Ar-H), 7.21−7.15 (m, 10H, Ar-

H), 7.15−7.10 (m, 4H, Ar-H), 7.04 (d, J = 7.6 Hz, 2H, Ar-H), 6.87

(d, J = 6.8 Hz, 1H, N−H), 6.50 (d, J = 8.0 Hz, 1H, N−H), 5.44−5.37

(m, 2H, H-2′, PhCH benzylidene), 5.30 (d, J = 10.3 Hz, 1H, H-1),

5.22 (t, J = 8.8 Hz, 1H, H-2‴), 4.85 (d, J = 10.2 Hz, 1H, CH₂Ph),

4.74−4.66 (m, 5H, H-1′, H-1″, H-1‴, 2× CH₂Ph), 4.62 (d, J = 11.6

Hz, 1H, CH₂× Ph), 4.53−4.19 (m, 10H, H-3, H-3″, 8× CH₂Ph),

3.94−3.89 (m, 1H, H-3′), 3.89−3.83 (m, 2H, H-4′, H-4‴), 3.67−3.41

(m, 15H, H-4, H-4″, H-3‴, H-5, H-5′, H-5″, H-5‴, H-6a, H-6b, H-

6a′, H-6b′, H-6a″, H-6b″, H-6a‴, H-6b‴), 3.38−3.32 (m, 1H, H-2″),

3.20−3.12 (m, 1H, H-2), 2.44 (d, J = 9.3 Hz, 1H, O−H), 2.31 (s, 3H,

PhCH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 167.1 (C), 165.0 (C),

161.5 (C), 161.3 (C), 138.9 (C), 138.8 (C), 138.2 (C), 138.1 (C),

138.0 (C), 137.9 (C), 137.7 (C), 137.4 (C), 133.9 (CH), 133.5

(CH), 133.4 (CH), 130.1 (CH), 130.0 (CH), 129.7 (C), 129.6 (C),

128.9 (CH), 128.7 (CH), 128.6 (CH), 128.58 (CH), 128.52 (CH),

128.48 (CH), 128.40 (CH), 128.3 (CH), 128.14 (CH), 128.10

(CH), 128.0 (CH), 127.9 (CH), 127.87 (CH), 127.83 (CH), 127.75

(CH), 127.70 (CH), 127.5 (CH), 127.4 (C), 126.2 (CH), 100.9

(CH), 99.7 (CH), 99.2 (CH), 92.4 (C), 92.2 (C), 84.3 (CH), 79.2

(CH), 77.7 (CH), 76.7 (CH), 76.3 (CH), 76.1 (CH), 75.9 (CH),

75.7 (CH₂), 75.3 (CH), 74.8 (CH₂), 74.7 (CH₂), 74.4 (CH), 73.7

(CH₂), 73.6 (CH), 73.57 (CH₂), 73.5 (CH), 73.4 (CH₂), 73.3 (CH),

73.0 (CH), 70.7 (CH), 69.1 (CH₂), 68.9 (CH₂), 68.5 (CH₂), 67.9

(CH₂), 58.8 (CH), 57.9 (CH), 21.3 (CH₃); HRMS (ESI-TOF) m/z:

calcd for C₉₈H₉₆Cl₆N₂O₂₂SNa [M + Na]⁺, 1921.4184; found,

1921.4174.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-

benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-

benzyl-2-deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 →

3)-(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-

4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-1-thio-β-^D-glu-

copyranoside (32). A solution of 8 (37 mg, 0.031 mmol) and 31 (45

mg, 0.024 mmol) in anhydrous CH₂Cl₂(474 μL) was stirred with 3 Å

pulverized molecular sieves (85 mg) at rt for 30 min under the N₂

atmosphere. After cooling to −50 °C, NIS (7 mg, 0.031 mmol) was

added to the reaction mixture, followed by the addition of TMSOTf

(0.9 μL, 0.005 mmol). After 1 h, the reaction was quenched by

dropwise addition of Et₃N, diluted with CH₂Cl₂(5 mL), and ﬁltered.

The ﬁltrate was washed with saturated Na₂S₂O₃solution (10 mL),

dried over MgSO₄, ﬁltered, and concentrated by evaporation to yield

the yellow residue that was puriﬁed by column chromatography on

silica gel with EtOAc/hexanes (1/4, v/v) to yield pure hexasaccharide

32 (49 mg, 70% yield) as a white amorphous foam and oxazoline 33

(6.1 mg, 19% w.r.t. donor 8) as a glassy solid. R_f0.33 (EtOAc/toluene

= 1/8, v/v); [α]²_D⁰−32.53 (c 0.83, CHCl₃); H NMR (500 MHz,

1

CDCl₃): δ 7.89 (t, J = 8.1 Hz, 4H, Ar-H), 7.84 (d, J = 7.6 Hz, 2H, Ar-

H), 7.70 (d, J = 7.7 Hz, 1H, Ar-H), 7.56−7.47 (m, 3H, Ar-H), 7.44−

7.37 (m, 4H, Ar-H), 7.35−7.29 (m, 6H, Ar-H), 7.27−7.23 (m, 21 H,

Ar-H), 7.22−7.21 (m, 4H, Ar-H), 7.21−7.17 (m, 11H, Ar-H), 7.17−

7.12 (m, 9H, Ar-H), 7.12−7.08 (m, 5H, Ar-H), 7.08−7.01 (m, 6H,

Ar-H), 6.86 (d, J = 6.6 Hz, 1H, N−H), 6.38 (dd, J = 15.0, 7.8 Hz, 2H,

N−H), 5.62 (t, J = 8.9 Hz, 1H, H-2‴″), 5.44 (t, J = 9.0 Hz, 1H, H-

2‴), 5.40−5.32 (m, 2H, H-2′, PhCH benzylidene), 5.31−5.23 (m,

1H, H-1), 5.02 (d, J = 11.5 Hz, 1H, CH₂Ph), 4.88 (d, J = 10.1 Hz, 1H,

CH₂Ph), 4.78 (d, J = 10.3 Hz, 1H, CH₂Ph), 4.75−4.59 (m, 6H, H-1′,

H-1″, H-1‴′, CH₂group of Nap), 4.58−4.39 (m, 9H, H-1‴, H-1‴″,

H-3, 5× CH₂Ph, CH₂group of Nap), 4.37−4.32 (m, 3H), 4.32−4.21

(m, 8H, H-3‴′), 4.21−4.13 (m, 2H, H-3″), 3.97 (s, 1H, H-4‴″), 3.90

(s, 1H, H-4‴), 3.88−3.81 (m, 2H, H-3′, H-3‴), 3.79 (s, 1H, H-4′),

3.66−3.53 (m, 6H, H-4, H-5‴′), 3.52−3.38 (m, 12H, H-3‴″, H-4″,

H-4‴′), 3.38−3.34 (m, 2H), 3.33−3.28 (m, 1H), 3.12 (m, 3H, H-2,

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyra-

nosyl)-(1 → 3)-(4,6-di-O-benzyl-2-deoxy-2-trichloroacetamido-β-^D-

glucopyranosyl)-(1 → 3)-(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galac-

topyranosyl)-(1 → 3)-4,6-O-benzylidene-2-deoxy-2-trichloroaceta-

mido-1-thio-β-^D-glucopyranoside (31). For reaction details, please

see Scheme 2. To a solution of compound 27 (362 mg, 0.18 mmol) in

a 2.4:1 (v/v) mixture of CH₂Cl₂(3.13 mL) and dd. H₂O (1.3 mL),

DDQ (60.4 mg, 0.27 mmol) was added at rt. After 1.5 h, an additional

30 mg (0.13 mmol) of DDQ was added, and let the reaction stir for

another 1 h. Saturated NaHCO₃solution (1 mL) was then slowly

added to the reaction mixture under the ice bath to quench the

reaction. Solvent extraction was done to wash the CH₂Cl₂layer with

saturated NaHCO₃solution (10 mL, two times). The CH₂Cl₂layer

was collected, dried over MgSO₄, ﬁltered, and concentrated by

evaporation to yield the yellow viscous crude that was puriﬁed by

Q

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H-2″, H-2‴′), 2.31 (s, 3H, PhCH₃); ¹³C{¹H} NMR (125 MHz,

CDCl₃): δ 165.7 (C), 165.3 (C), 165.0 (C), 161.5 (C), 161.1 (C),

161.0 (C), 139.1 (C), 139.0 (C), 138.9 (C), 138.8 (C), 138.2 (C),

138.1 (C), 138.09 (C), 138.0 (C), 137.96 (C), 137.4 (C), 134.93

(C), 133.89 (CH), 133.4 (CH), 133.2 (CH), 133.15 (C), 133.08

(C), 130.1 (CH), 130.0 (CH), 129.98 (CH), 129.8 (C), 129.7 (C),

128.9 (CH), 128.7 (CH), 128.6 (CH), 128.56 (CH), 128.5 (CH),

128.4 (CH), 128.23 (CH), 128.21 (CH), 128.17 (CH), 128.1 (CH),

128.05 (CH), 127.98 (CH), 127.9 (CH), 127.86 (CH), 127.81

(CH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 127.5 (CH), 127.4

(CH), 126.9 (CH), 126.3 (CH), 126.2 (CH), 126.1 (CH), 125.9

(CH), 100.9 (CH), 100.4 (CH), 100.3 (CH), 99.8 (CH), 99.2 (CH),

99.0 (CH), 92.4 (C), 92.3 (C), 92.28 (C), 84.4 (CH), 79.5 (CH),

79.2 (CH), 77.5 (CH), 76.8 (CH), 76.4 (CH), 76.37 (CH), 76.2

(CH), 75.9 (CH), 75.4 (CH), 75.2 (CH), 75.1 (CH₂), 74.94 (CH₂),

74.90 (CH₂), 74.8 (CH₂), 74.7 (CH₂), 73.8 (CH), 73.7 (CH₂), 73.66

(CH₂), 73.5 (CH₂), 73.4 (CH₂), 73.1 (CH), 73.0 (CH), 72.7 (CH),

72.1 (CH), 71.9 (CH₂), 70.8 (CH), 69.2 (CH₂), 69.0 (CH₂), 68.9

(CH₂), 68.6 (CH₂), 68.3 (CH₂), 68.2 (CH₂), 59.2 (CH), 59.0 (CH),

58.0 (CH), 21.4 (CH₃); HRMS (ESI-TOF) m/z: calcd for

C₁₅₈H₁₅₁Cl₉N₃O₃₃S [M − H]⁻¹, 2970.7146; found, 2970.7103.

2-Trichloromethyl-3-O-(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-4,6-di-O-benzyl-1,2-di-

deoxy-α-^D-glucopyrano-[2,1-d]-2-oxazoline (33). A solution of

compound 8 (250 mg, 0.21 mmol) in dry CH₂Cl₂(4.20 mL) was

stirred with 3 Å powdered molecular sieves (500 mg) at rt under N₂

for 30 min. NIS (56.3 mg, 0.25 mmol) and TMSOTf (7.6 μL, 0.042

mmol) were sequentially added to the reaction mixture after cooling

to −50 °C. The reaction was quenched after 30 min by dropwise

addition of Et₃N at −50 °C. Thereafter, the reaction mixture was

diluted with CH₂Cl₂(5 mL), ﬁltered, and extracted with saturated

Na₂S₂O₃solution (10 mL). The CH₂Cl₂layer was collected, dried

over MgSO₄, ﬁltered, and concentrated by evaporation to aﬀord the

viscous yellow crude that was puriﬁed by column chromatography on

silica gel with EtOAc/hexanes (1/5, v/v) to yield the pure product 33

(206 mg, 92%) as a white amorphous foam. R_f0.35 (EtOAc/hexanes

addition of Et₃N at −50 °C. The reaction mixture was diluted with

CH₂Cl₂(5 mL), ﬁltered, and washed with saturated Na₂S₂O₃solution

(10 mL). The CH₂Cl₂layer was collected, dried over MgSO₄, ﬁltered,

and concentrated by evaporation to yield a viscous yellow crude that

was puriﬁed by column chromatography on silica gel with EtOAc/

hexanes (1/3, v/v) to obtain the hexasaccharide 34 (25 mg, 28%) as a

glassy solid and unreacted acceptor 16 (24 mg, 55% w.r.t the initial

amount of acceptor 16 taken) as a glassy solid. R_f0.24 (EtOAc/

toluene = 1/8, v/v); [α]_D²⁰−16.52 (c 1.15, CHCl₃); H NMR (500

1

MHz, CDCl₃): δ 7.89 (d, J = 7.6 Hz, 2H, Ar-H), 7.84 (d, J = 7.6 Hz,

2H, Ar-H), 7.77 (d, J = 7.5 Hz, 2H, Ar-H), 7.71 (d, J = 7.6 Hz, 3H,

Ar-H), 7.60 (d, J = 7.0 Hz, 2H, Ar-H), 7.57−7.53 (m, 3H, Ar-H), 7.51

(d, J = 7.7 Hz, 2H, Ar-H), 7.47−7.37 (m, 7H, Ar-H), 7.33−7.26 (m,

20H, Ar-H), 7.25−7.20 (m, 16H, Ar-H), 7.20−7.11 (m, 20H, Ar-H),

7.11−7.05 (m, 5H, Ar-H), 6.92 (d, J = 8.0 Hz, 2H, Ar-H), 6.78 (d, J =

6.8 Hz, 1H, N−H), 6.40 (d, J = 8.2 Hz, 1H, N−H), 6.24 (d, J = 6.8

Hz, 1H, N−H), 5.61 (dd, J = 10.0, 8.1 Hz, 1H, H-2‴″), 5.35 (t, J =

8.4 Hz, 1H, H-2‴), 5.28−5.21 (m, 2H, H-1, H-2′), 5.09−5.00 (m,

2H, H-4), 4.92−4.85 (m, 2H, H-1″), 4.72 (d, J = 12.3 Hz, 1H), 4.67

(d, J = 8.0 Hz, 1H, H-1‴′), 4.65−4.59 (m, 3H, H-3), 4.59−4.53 (m,

3H, H-1‴″), 4.52−4.46 (m, 2H, H-1′), 4.45−4.41 (m, 3H), 4.40−

4.36 (m, 1H), 4.36−4.32 (m, 3H), 4.32−4.30 (m, 2H), 4.30−4.27

(m, 2H, H-1‴), 4.26−4.19 (m, 2H, H-3‴′), 4.15 (d, J = 12.0 Hz, 1H),

4.04 (dd, J = 9.8, 7.9 Hz, 1H, H-3″), 3.98−3.94 (m, 2H, H-4‴″), 3.90

(d, J = 2.5 Hz, 1H, H-4′), 3.83−3.72 (m, 4H, H-3′, H-3‴), 3.71−3.62

(m, 4H, H-5), 3.38 (dd, J = 10.3, 4.9 Hz, 1H), 3.55−3.50 (m, 2H),

3.50−3.46 (m, 3H, H-3‴″), 3.45−3.36 (m, 6H, H-4‴′), 3.36−3.29

(m, 2H, H-4″), 3.22 (td, J = 9.7, 6.6 Hz, 1H, H-2‴′), 3.11 (td, J = 9.8,

7.2 Hz, 1H, H-2), 3.04 (d, J = 9.0, 5.6 Hz, 1H), 2.81 (t, J = 8.2 Hz,

1H), 2.72 (td, J = 8.5, 7.0 Hz, 1H, H-2″), 2.27 (s, 3H, PhCH₃), 0.97

(s, 9H, TBDPS-t-Bu); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.8

(C), 165.0 (C), 164.9 (C), 164.8 (C), 161.7 (C), 161.6 (C), 161.1

(C), 139.3 (C), 138.8 (C), 138.6 (C), 138.4 (C), 138.1 (C), 137.9

(C), 137.8 (C), 135.7 (CH), 134.9 (C), 133.6 (CH), 133.3 (C),

133.2 (CH), 133.1 (CH), 132.7 (CH), 130.2 (CH), 130.1 (CH),

130.0 (CH), 129.9 (C), 129.7 (CH), 128.8 (CH), 128.7 (CH), 128.6

(CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.1

(CH), 128.0 (CH), 127.9 (CH), 127.7 (CH), 127.6 (CH), 127.4

(CH), 126.9 (CH), 126.3 (CH), 126.2 (CH), 126.0 (CH), 101.0

(CH), 100.2 (CH), 99.4 (CH), 98.8 (CH), 92.6 (C), 92.4 (C), 91.7

(C), 84.1 (CH), 80.0 (CH), 79.7 (CH), 79.5 (CH), 78.3 (CH), 77.4

(CH), 77.1 (CH), 76.6 (CH), 76.3 (CH), 75.9 (CH), 75.4 (CH),

75.2 (CH), 75.0 (CH₂), 74.9 (CH₂), 74.7 (CH₂), 74.0 (CH), 73.8

(CH), 73.7 (CH₂), 73.67 (CH₂), 73.5 (CH₂), 73.3 (CH, CH₂), 73.2

(CH), 72.3 (CH), 72.1 (CH), 72.05 (CH₂), 69.9 (CH₂), 69.6 (CH),

69.3 (CH₂), 69.1 (CH), 68.5 (CH₂), 67.7 (CH₂), 63.5 (CH₂), 59.3

(CH), 58.9 (CH), 58.4 (CH), 53.6 (C), 26.9 (CH₃), 21.4 (CH₃),

19.3 (C); HRMS (ESI-TOF) m/z: calcd for C₁₆₇H₁₆₆Cl₉N₃O₃₄SSi [M

+ 2H]²⁺, 1568.9013; found, 1568.9015.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-

benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-

benzyl-2-deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 →

3)-(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4-

O-benzoyl-6-O-tert-butyldiphenylsilyl-2-deoxy-2-trichloroacetami-

do-1-thio-β-^D-glucopyranoside (34a). A solution of 22 (55 mg,

0.026 mmol) and 16 (38 mg, 0.031 mmol) in dry CH₂Cl₂(516 μL)

was stirred with 3 Å pulverized molecular sieves (93 mg) at rt for 30

min under N₂. After cooling to −70 °C, NIS (5.8 mg, 0.026 mmol)

and TMSOTf (0.93 μL, 0.0052 mmol) were sequentially added to the

reaction mixture. After 1 h of stirring at −70 °C, the temperature was

raised to −60 °C and stirred for another 1 h. This was followed by

increase in temperature to −50 °C, and stirring was continued for 2 h

more at −50 °C. Then, the reaction was quenched by dropwise

addition of Et₃N at −50 °C. The reaction mixture was diluted with

CH₂Cl₂(5 mL), ﬁltered, and washed with saturated Na₂S₂O₃solution

(10 mL). The CH₂Cl₂layer was collected, dried over MgSO₄, ﬁltered,

and concentrated by evaporation to yield a viscous yellow crude that

was puriﬁed by column chromatography on silica gel with EtOAc/

= 1/4, v/v, run two times); [α]²_D⁰+25.75 (c 1.32, CHCl₃); H NMR

1

(500 MHz, CDCl₃): 7.96 (d, J = 7.7 Hz, 2H, Ar-H), 7.73 (d, J = 7.7

Hz, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 7.60−7.53 (m, 3H, Ar-H), 7.46−

7.36 (m, 6H, Ar-H), 7.34−7.24 (m, 14H, Ar-H), 7.21−7.15 (m, 5H,

Ar-H), 5.86 (d, J = 7.3 Hz, 1H, H-1), 5.66 (t, J = 9.0 Hz, 1H, H-2′),

5.05 (d, J = 11.6 Hz, 1H, CH₂Ph), 4.81 (d, J = 12.5 Hz, 1H, CH₂

group of Nap), 4.76−4.66 (m, 3H, H-1′, 2× CH₂Ph), 4.62 (d, J =

12.5 Hz, 1H, CH₂group of Nap), 4.49−4.42 (m, 3H, H-3, 2×

CH₂Ph), 4.42−4.36 (m, 3H, 3× CH₂Ph), 4.19 (d, J = 6.0 Hz, 1H, H-

2), 4.07 (d, J = 1.8 Hz, 1H, H-4′), 3.73 (d, J = 5.9 Hz, 1H, H-4), 3.69

(dd, J = 10.1, 2.3 Hz, 1H, H-3′), 3.66−3.50 (m, 6H, H-5, H-5′, H-6a,

H-6b, H-6a′, H-6b′); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.2

(C), 162.9 (C), 138.6 (C), 138.2 (C), 138.0 (C), 137.8 (C), 135.2

(C), 133.4 (CH), 133.36 (C), 133.2 (C), 130.1 (C), 129.9 (CH),

128.7 (CH), 128.5 (CH), 128.46 (CH), 128.4 (CH), 128.2 (CH),

128.1 (CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH),

126.8 (CH), 126.3 (CH), 126.1 (CH), 125.9 (CH), 104.8 (CH),

100.9 (CH), 86.5 (C), 79.8 (CH), 75.9 (CH), 74.9 (CH₂), 74.7

(CH), 74.1 (CH), 73.8 (CH₂), 73.4 (CH₂), 72.8 (CH), 72.0 (CH₂),

71.92 (CH), 71.90 (CH₂), 71.3 (CH), 69.6 (CH₂), 68.7 (CH₂), 66.6

(CH); HRMS (ESI-TOF) m/z: calcd for C₆₀H₅₇Cl₃NO₁₁[M + H]⁺,

1074.2981; found, 1074.2981.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-

benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-(6-O-ben-

zyl-2-deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-

O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4-O-

benzoyl-6-O-tert-butyldiphenylsilyl-2-deoxy-2-trichloroacetamido-

1-thio-β-^D-glucopyranoside (34). A solution of 23 (60 mg, 0.03

mmol) and 16 (43 mg, 0.035 mmol) in dry CH₂Cl₂(590 μL) was

stirred with 3 Å pulverized molecular sieves (103 mg) at rt for 30 min

under N₂. After cooling to −50 °C, NIS (6.6 mg, 0.03 mmol) and

TMSOTf (1.1 μL, 0.006 mmol) were sequentially added to the

reaction mixture. After 3 h, the reaction was quenched by dropwise

R

https://dx.doi.org/10.1021/acs.joc.0c02422

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

hexanes (1/5 to 1/3, v/v) to obtain the hexasaccharide 34a (44 mg,

52%) as a glassy solid, unreacted acceptor 16 (16 mg, 41% w.r.t the

initial amount of acceptor 16 taken) as a glassy solid and recovered

donor 22 (12 mg, 22%) as a glassy solid. R_f0.17 (EtOAc/hexanes =

1/3, v/v); [α]²_D⁰−21.88 (c 3.84, CHCl₃); ¹H NMR (500 MHz,

CDCl₃): δ 7.88 (dd, J = 16.6, 7.7 Hz, 4H, Ar-H), 7.76 (d, J = 7.6 Hz,

2H, Ar-H), 7.71 (d, J = 7.8 Hz, 1H, Ar-H), 7.67 (d, J = 7.7 Hz, 2H,

Ar-H), 7.59 (d, J = 7.4 Hz, 2H, Ar-H), 7.57−7.53 (m, 3H, Ar-H),

7.52−7.49 (m, 2H, Ar-H), 7.45−7.35 (m, 6H, Ar-H), 7.33−7.25 (m,

22H, Ar-H), 7.23−7.08 (m, 39H, Ar-H), 7.08−7.03 (m, 6H, Ar-H),

6.92 (d, J = 7.8 Hz, 2H, Ar-H), 6.85 (d, J = 6.4 Hz, 1H, N−H), 6.53

(d, J = 7.8 Hz, 1H, N−H), 6.48 (d, J = 7.6 Hz, 1H, N−H), 5.64−5.57

(m, 1H, H-2‴″), 4.46−5.39 (m, 1H, H-2‴), 5.30−5.21 (m, 2H, H-1,

H-2′), 5.08−4.99 (m, 2H, H-4, CH₂Ph), 4.89 (d, J = 10.1 Hz, 1H,

CH₂Ph), 4.81 (d, J = 10.3 Hz, 1H, CH₂Ph), 4.74−4.10 (m, 27H, H-

1′, H-1″, H-1‴, H-1‴′, H-1‴″, H-3, H-3″, H-3‴′, 17× CH₂Ph, 2×

CH₂group of Nap), 3.94 (s, 1H, H-4‴″), 3.86 (s, 1H, H-4‴), 3.84−

3.77 (m, 2H, H-3′, H-3‴), 3.73 (s, 1H, H-4′), 3.70−3.28 (m, 19H, H-

3‴″, H-4″, H-4‴′, H-5, H-5′, H-5″, H-5‴, H-5‴′, H-5‴″, H-6a, H-6b,

H-6a″, H-6b″, H-6a‴, H-6b‴, H-6a‴′, H-6b‴′, H-6a‴″, H-6b‴″),

3.24−3.17 (m, 1H, H-2‴′), 3.16−3.09 (m, 1H, H-2), 3.08−2.99 (m,

2H, H-2″, H-6a′), 2.81 (t, J = 8.1 Hz, 1H, H-6b′), 2.27 (s, 3H,

PhCH₃), 0.97 (s, 9H, TBDPS-t-Bu); ¹³C{¹H} NMR (125 MHz,

CDCl₃): δ 165.8 (C), 165.3 (C), 165.1 (C), 164.6 (C), 161.7 (C),

161.1 (C), 139.2 (C), 138.8 (C), 138.4 (C), 138.2 (C), 138.2 (C),

138.0 (C), 137.99 (C), 137.92 (C), 135.7 (CH), 134.95 (C), 133.5

(CH), 133.3 (C), 133.2 (CH), 133.1 (C), 132.7 (CH), 130.1 (C),

130.1 (CH), 129.99 (CH), 129.91 (CH), 129.85 (C), 129.7 (CH),

128.7 (CH), 128.64 (CH), 128.59 (CH), 128.51 (CH), 128.4 (CH),

128.3 (CH), 128.2 (CH), 128.1 (CH), 128.04 (CH), 127.9 (CH),

127.8 (CH), 127.6 (CH), 127.4 (CH), 127.3 (CH), 126.9 (CH),

126.3 (CH), 126.1 (CH), 125.97 (CH), 100.4 (CH), 100.2 (CH),

100.1 (CH), 99.3 (CH), 99.1 (CH), 92.6 (C), 92.4 (C), 84.2 (CH),

79.7 (CH), 79.5 (CH), 77.5 (CH), 77.3 (CH), 76.9 (CH), 76.4

(CH), 76.2 (CH), 76.1 (CH), 75.2 (CH), 75.2 (CH), 75.1 (CH₂),

74.95 (CH₂), 74.9 (CH₂), 74.7 (CH₂), 73.9 (CH), 73.8 (CH), 73.7

(CH₂), 73.5 (CH₂), 73.4 (CH), 73.37 (CH₂), 73.2 (CH), 72.8 (CH),

72.7 (CH), 72.1 (CH), 72.0 (CH₂), 69.1 (CH₂), 69.05 (CH), 69.03

(CH₂), 68.5 (CH₂), 68.46 (CH₂), 67.7 (CH₂), 63.4 (CH₂), 59.2

(CH), 59.1 (CH), 58.3 (CH), 26.9 (CH₃), 21.4 (CH₃), 19.3 (C);

HRMS (ESI-TOF) m/z: calcd for C₁₇₄H₁₇₀Cl₉N₃O₃₄SSiNa [M +

Na]⁺, 3248.8245; found, 3248.8296.

(C), 133.4 (CH), 130.1 (CH), 129.9 (C), 129.1 (CH), 128.7 (CH),

128.7 (CH), 128.6 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH),

126.4 (CH), 101.3 (CH), 99.5 (CH), 94.3 (CH), 92.4 (C), 80.0

(CH), 76.7 (CH), 75.6 (CH₂), 75.1 (CH), 74.5 (CH), 73.8 (CH₂),

73.6 (CH), 73.4 (CH), 68.8 (CH₂), 68.5 (CH₂), 66.4 (CH), 61.8

(CH), 25.8 (CH₃), 17.9 (C), −4.1 (CH₃), −5.0 (CH₃); HRMS (ESI-

TOF) m/z: calcd for C₄₈H₅₆Cl₃NO₁₂SiH [M + H]⁺, 994.2530; found,

994.2538.

tert-Butyldimethylsilyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-ben-

zyl-2-deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-

O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-(4-O-

acetyl-6-O-benzyl-2-deoxy-2-trichloroacetamido-β-^D-glucopyrano-

syl)-(1 → 3)-(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-

(1 → 3)-4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-β-^D-glu-

copyranoside (36). For reaction details, please see Scheme S1. A

solution of 25 (216 mg, 0.104 mmol) and 35 (121 mg, 0.124 mmol)

in dry CH₂Cl₂(2.1 mL) was stirred with 3 Å pulverized molecular

sieves (340 mg) at rt for 30 min under N₂. After cooling to −50 °C,

NIS (33 mg, 0.15 mmol) and TfOH (2.7 μL, 0.031 mmol) were

sequentially added to the reaction mixture. After 3 h, the reaction was

quenched by dropwise addition of Et₃N at −50 °C. The neutralized

reaction mixture was ﬁltered, diluted with CH₂Cl₂(5 mL), and

washed with saturated Na₂S₂O₃solution (10 mL, two times). The

CH₂Cl₂layer was collected, dried over MgSO₄, ﬁltered, and

concentrated by evaporation to yield viscous yellow crude that was

puriﬁed by column chromatography on silica gel with EtOAc/hexanes

(1/5 to 1/3, v/v) to obtain the hexasaccharide 36 (212 mg, 70%) as a

white amorphous foam. R_f0.31 (EtOAc/toluene = 1/8, v/v, run two

times); [α]²_D⁰−20.34 (c 1.77, CHCl₃); ¹H NMR (500 MHz, CDCl₃):

δ 7.95−7.88 (m, 4H, Ar-H), 7.86 (d, J = 7.6 Hz, 2H, Ar-H), 7.71 (d, J

= 7.9 Hz, 1H, Ar-H), 7.6−7.5 (m, 3H, Ar-H), 7.48−7.39 (m, 4H, Ar-

H), 7.38−7.34 (m, 3H, Ar-H), 7.33−7.25 (m, 19H, Ar-H), 7.24−7.14

(m, 28H, Ar-H), 7.14−7.1 (m, 6H, Ar-H), 7.09−7.03 (m, 2H, Ar-H),

6.81 (d, J = 6.7 Hz, 1H, N−H), 6.57−6.44 (m, 2H, N−H), 5.60 (dd, J

= 9.8, 8.2 Hz, 1H, H-2‴″), 5.47−5.36 (m, 2H, H-2′, PhCH

benzylidene), 5.24 (dd, J = 9.8, 7.9 Hz, 1H, H-2‴), 5.18 (d, J = 7.5

Hz, 1H, H-1), 5.02 (d, J = 11.4 Hz, 1H, CH₂Ph), 4.9−4.82 (m, 2H,

H-1‴′, CH₂Ph), 4.75−4.15 (m, 28H, H-1″, H-1′, H-1‴″, H-3, H-1‴,

H-3‴′, H-3″, 2× CH₂group of Nap, 16× CH₂Ph, H-6a), 3.60 (s, 1H,

H-4‴″), 3.9−3.83 (m, 3H, H-3′, H-4′, H-4‴), 3.78, (d, J = 10.0 Hz,

1H, H-3‴), 3.72−3.33 (m, 19H, H-4, H-3‴″, H-4″, H-4‴′, H-5, H-5′,

H-5″, H-5‴, H-5‴′, H-5‴″, H-6b′, H-6a″, H-6b″, H-6a‴, H-6b‴, H-

6a‴′, H-6b‴′, H-6a‴″, H-6b‴″), 3.17−3.06 (m, 2H, H-2, H-2″),

3.05−2.95 (m, 1H, H-2‴’), 1.62 (s, 3H, COCH₃), 0.8 (s, 9H, TBS-t-

Bu), 0.02 (s, 3H, TBS-CH₃), 0.008 (s, 3H, TBS-CH₃); ¹³C{¹H}

NMR (125 MHz, CDCl₃): δ 169.7 (C), 165.7 (C), 165.0 (C), 164.8

(C), 161.7 (C), 161.4 (C), 161.1 (C), 138.94 (C), 138.90 (C), 138.7

(C), 138.1 (C), 138.07 (C), 138.0 (C), 137.85 (C), 137.81 (C),

137.5 (C), 134.9 (C), 133.4 (CH), 133.3 (CH), 133.2 (CH), 133.1

(C), 133.0 (C), 130.07 (CH), 130.0 (CH), 129.8 (C), 128.8 (CH),

128.6 (CH), 128.5 (CH), 128.3 (CH), 128.26 (CH), 128.23 (CH),

128.2 (CH), 128.1 (CH), 128.08 (CH), 128.05 (CH), 128.0 (CH),

127.9 (CH), 127.87 (CH), 127.8 (CH), 127.7 (CH), 127.6 (CH),

127.57 (CH), 127.5 (CH), 127.4 (CH), 126.8 (CH), 126.3 (CH),

126.2 (CH), 126.1 (CH), 125.9 (CH), 100.8 (CH), 100.2 (CH),

100.0 (CH), 99.9 (CH), 99.2 (CH), 99.1 (CH), 94.0 (CH), 92.4

(C), 92.3 (C), 92.2 (C), 79.4 (CH), 79.2 (CH), 78.1 (CH), 77.6

(CH), 76.5 (CH), 76.2 (CH), 75.1 (CH), 74.9 (CH₂), 74.8 (CH),

74.76 (CH₂), 73.8 (CH), 73.7 (CH), 73.62 (CH₂), 73.6 (CH₂), 73.5

(CH₂), 73.4 (CH₂), 73.1 (CH), 72.7 (CH), 72.6 (CH), 72.0 (CH),

71.9 (CH₂), 69.5 (CH₂), 69.3 (CH), 69.1 (CH₂), 68.8 (CH₂), 68.6

(CH₂), 68.4 (CH₂), 68.3 (CH₂), 66.27 (CH), 62.3 (CH), 59.3 (CH),

59.1 (CH), 25.7 (CH₃), 20.6 (CH₃), 17.8 (C), −4.2 (CH₃), −5.1

(CH₃); HRMS (ESI-TOF) m/z: calcd for C₁₅₂H₁₅₇Cl₉N₃O₃₅Si [M +

H]⁺, 2932.7550; found, 2932.7600.

tert-Butyldimethylsilyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galacto-

pyranosyl)-(1 → 3)-4,6-O-benzylidene-2-deoxy-2-trichloroacetami-

do-β-^D-glucopyranoside (35). For reaction details, please see Scheme

S4. To a solution of compound 50 (3.60 g, 3.23 mmol) in a 10:1 (v/

v) mixture of CH₂Cl₂(290 mL) and dd. H₂O (29 mL), DDQ (2.20 g,

9.69 mmol) was added under the argon atmosphere at 0 °C. After 6 h,

the reaction was completed as observed by TLC. To quench the

reaction, saturated NaHCO₃solution (20 mL) was slowly added to

the reaction mixture under the ice bath. Solvent extraction was then

done to wash the organic layer with saturated NaHCO₃solution (250

mL, three times). The organic layer was collected, dried over MgSO₄,

ﬁltered, and concentrated by evaporation. The resulting viscous crude

was puriﬁed by column chromatography on silica gel with EtOAc/

hexanes (1/6 to 1/4, v/v) to yield the desired pure product 35 (2.42

g, 77%) as a white amorphous foam. R_f0.32 (EtOAc/hexanes = 1/3,

v/v); [α]²_D⁵−57.1 (c 1.1, CHCl₃); H NMR (500 MHz, CDCl₃): δ

1

7.98 (d, J = 8.0 Hz, 2H, Ar-H), 7.50−7.41 (m, 3H, Ar-H), 7.37−7.23

(m, 15H, Ar-H), 6.88 (d, J = 7.2 Hz, 1H, N−H), 5.46 (s, 1H, CHPh),

5.21 (m, 2H, H-1, H-2′), 4.80 (d, J = 7.9 Hz, 1H, H-1′), 4.70 (d, J =

11.7 Hz, 1H, CH₂Ph), 4.65 (d, J = 11.8 Hz, 1H, CH₂Ph), 4.54 (t, J =

9.4 Hz, 1H, H-3), 4.42 (d, J = 11.7 Hz, 1H, CH₂Ph), 4.33 (d, J = 11.7

Hz, 1H, CH₂Ph), 4.22 (dd, J = 10.4, 4.8 Hz, 1H, H-6a), 3.78 (d, J =

3.4 Hz, 1H, H-4′), 3.75 (t, J = 9.1 Hz, 1H, H-4), 3.69 (t, J = 10.3 Hz,

1H, H-6b), 3.66−3.58 (m, 2H, H-3′, H-6a′), 3.57−3.50 (m, 2H, H-

5′, H-6b′), 3.46 (td, J = 9.7, 4.8 Hz, 1H, H-5), 3.33 (dt, J = 9.7, 7.5

Hz, 1H, H-2), 2.48 (d, J = 9.5 Hz, 1H, OH), 0.84 (s, 9H, TBS-t-Bu),

0.07 (s, 3H, TBS-CH₃), 0.04 (s, 3H, TBS-CH₃); ¹³C{¹H} NMR (125

MHz, CDCl₃): δ 166.9 (C), 161.8 (C), 138.2 (C), 137.8 (C), 137.6

tert-Butyldimethylsilyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galacto-

pyranosyl)-(1 → 3)-(4,6-O-benzylidene-2-deoxy-2-trichloroaceta-

mido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-benzoyl-4,6-di-O-benzyl-

β-^D-galactopyranosyl)-(1 → 3)-4,6-O-benzylidene-2-deoxy-2-tri-

chloroacetamido-β-^D-glucopyranoside (37). For reaction details,

S

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Article

please see Scheme S9. To a solution of compound 53 (964.4 mg, 0.49

mmol) in a 10:1 (v/v) mixture of CH₂Cl₂(45 mL) and dd. H₂O (4.5

mL), DDQ (336 mg, 1.48 mmol) was added under the argon

atmosphere at 0 °C. After 5 h, the reaction was completed as observed

by TLC. Saturated NaHCO₃solution (5 mL) was then slowly added

to the reaction mixture under the ice bath to quench the reaction.

Solvent extraction was done to wash the CH₂Cl₂layer with saturated

NaHCO₃solution (40 mL, two times). The CH₂Cl₂layer was

collected, dried over MgSO₄, ﬁltered, and concentrated by

evaporation to yield a viscous yellow crude that was puriﬁed by

column chromatography on silica gel with EtOAc/hexanes (1/4, v/v)

to yield the desired pure product 37 (582 mg, 65%) as a white

amorphous foam. R_f0.31 (EtOAc/hexanes = 1/2, v/v); [α]²_D⁰−21.1

(c 1.09, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.97−7.88 (m, 4H,

Ar-H), 7.49−7.41 (m, 4H, Ar-H), 7.38 (d, J = 7.1 Hz, 2H, Ar-H),

7.35−7.26 (m, 20H, Ar-H), 7.25−7.23 (m, 3H, Ar-H), 7.23−7.21 (m,

5H, Ar-H), 7.20−7.16 (m, 2H, Ar-H), 6.82 (d, J = 6.9 Hz, 1H, N−H),

6.63 (d, J = 7.4 Hz, 1H, N−H), 5.48−5.42 (m, 2H, H-2′, PhCH

benzylidene), 5.41 (s, 1H, PhCH benzylidene), 5.17 (d, J = 7.7 Hz,

1H, H-1), 5.13 (dd, J = 9.9, 8.0 Hz, 1H, H-2‴), 5.0 (d, J = 8.1 Hz, 1H,

H-1″), 4.79 (d, J = 11.9 Hz, 1H), 4.70−4.60 (m, 4H, H-1′, H-1‴),

4.55−4.47 (m, 2H, H-3), 4.40 (d, J = 11.6 Hz, 1H), 4.37−4.32 (m,

2H, H-3″), 4.31−4.23 (m, 3H), 4.17 (dd, J = 10.3, 4.8 Hz, 1H), 3.90

(dd, J = 10.1, 2.7 Hz, 1H, H-3′), 3.86 (d, J = 2.6 Hz, 1H, H-4′), 3.76

(d, J = 3.3 Hz, 1H, H-4‴), 3.72−3.60 (m, 4H, H-4, H-4″), 3.59−3.49

(m, 5H, H-3‴), 3.49−3.34 (m, 4H), 3.25 (td, J = 9.7, 8.0 Hz, 1H, H-

2″), 3.09 (td, J = 8.5, 6.8 Hz, 1H, H-2), 2.40 (d, J = 9.15 Hz, 1H, O−

H), 0.8 (s, 9H, TBS-t-Bu), 0.016 (s, 3H, TBS-CH₃), −0.017 (s, 3H,

TBS-CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 166.78 (C), 165.0

(C), 161.7 (C), 161.6 (C), 138.9 (C), 138.2 (C), 137.9 (C), 137.7

(C), 137.5 (C), 137.3 (C), 133.4 (CH), 130.0 (CH), 129.9 (C),

129.7 (C), 129.1 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH),

128.58 (CH), 128.5 (CH), 128.3 (CH), 128.2 (CH), 128.19 (CH),

128.11 (CH), 128.1 (CH), 128.0 (CH), 127.99 (CH), 127.9 (CH),

127.6 (CH), 126.3 (CH), 126.2 (CH), 101.1 (CH), 100.9 (CH),

100.2 (CH), 99.5 (CH), 99.4 (CH), 93.9 (CH), 92.4 (C), 91.9 (C),

79.6 (CH), 79.4 (CH), 77.9 (CH), 76.5 (CH), 76.47 (CH), 75.5

(CH₂), 75.0 (CH), 74.9 (CH₂), 74.6 (CH), 74.4 (CH), 73.6 (CH₂),

73.5 (CH), 73.4 (CH), 73.3 (CH), 72.8 (CH), 68.6 (CH₂), 68.58

(CH₂), 68.5 (CH₂), 68.4 (CH₂), 66.3 (CH), 66.2 (CH), 62.4 (CH),

59.5 (CH), 25.7 (CH₃), 17.8 (C), −4.2 (CH₃), −5.1 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₉₀H₉₇Cl₆N₂O₂₃Si [M + H]⁺, 1815.4360;

found, 1815.4403.

tert-Butyldimethylsilyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-ben-

zyl-2-deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-

O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-(4,6-O-

benzylidene-2-deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1

→ 3)-(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-

4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-β-^D-glucopyra-

noside (38). For reaction details, please see Scheme 2. A solution of 8

(225 mg, 0.19 mmol) and 37 (200 mg, 0.11 mmol) in anhydrous

CH₂Cl₂(5 mL) was stirred with 3 Å pulverized molecular sieves (900

mg) at rt for 30 min under the N₂atmosphere. After cooling to −50

°C, NIS (50 mg, 0.22 mmol) was added to the reaction mixture,

followed by the addition of TfOH (2.91 μL, 0.033 mmol). After 4 h,

the reaction was quenched by dropwise addition of Et₃N, diluted with

CH₂Cl₂(12 mL), and ﬁltered. The ﬁltrate was washed with saturated

Na₂S₂O₃solution (15 mL), dried over MgSO₄, ﬁltered, and

concentrated by evaporation to yield a viscous yellow crude that

was puriﬁed by column chromatography on silica gel with EtOAc/

hexanes (1/6, v/v) to yield the pure hexasaccharide 38 (263 mg,

82%) as a white amorphous foam. R_f0.41 (EtOAc/toluene = 1/7, v/

v); [α]²_D⁰−21.11 (c 0.9, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.9

(d, J = 8.1 Hz, 4H, Ar-H), 7.81 (d, J = 7.3 Hz, 2H, Ar-H), 7.71 (d, J =

7.8 Hz, 1H, Ar-H), 7.54 (d, J = 7.6 Hz, 1H, Ar-H), 7.53−7.49 (m, 2H,

Ar-H), 7.48−7.42 (m, 3H, Ar-H), 7.41−7.37 (m, 6H, Ar-H), 7.36−

7.24 (m, 24H, Ar-H), 7.24−7.23 (m, 6H, Ar-H), 7.22−7.17 (m, 11H,

Ar-H), 7.17−7.10 (m, 10H, Ar-H), 7.08−7.03 (m, 2H, Ar-H), 6.80

(d, J = 6.85 Hz, 1H, N−H), 6.62 (d, J = 7.15 Hz, 1H, N−H), 6.52 (d,

J = 8.0 Hz, 1H, N−H), 5.61 (dd, J = 10.0, 8.0 Hz, 1H, H-2‴″), 5.47−

5.39 (m, 3H, H-2‴, 2× PhCH benzylidene), 5.33 (dd, J = 9.1, 8.2 Hz,

1H, H-2′), 5.17 (d, J = 7.7 Hz, 1H, H-1), 5.07−4.96 (m, 2H, H-1″,

CH₂Ph), 4.87 (d, J = 10.3 Hz, 1H, CH₂Ph), 4.75 (d, J = 11.9 Hz, 1H,

CH₂Ph), 4.72 (d, J = 12.4 Hz, 1H, CH₂group of Nap), 4.69−4.61

(m, 3H, H-1‴, H-1‴′, CH₂Ph), 4.60−4.16 (m, 21H, H-1‴″, H-1′, H-

3, H-3″, CH₂group of Nap, 12× CH₂Ph, H-6a, H-6a″, H-3‴′), 3.95

(d, J = 1.7 Hz, 1H, H-4‴″), 3.87 (dd, J = 10.1, 2.7 Hz, 1H, H-3‴),

3.85−3.79 (m, 3H, H-3′, H-4′, H-4‴), 3.70−3.30 (m, 19H, H-4, H-

4″, H-3‴″, H-4‴′, H-5, H-5′, H-5″, H-5‴, H-5‴′, H-5‴″, H-6b, H-

6b″, H-6a′, H-6b′, H-6a‴, H-6b‴, H-6a‴′, H-6b‴′, H-6b‴″), 3.26−

3.17 (m, 1H, H-2‴′), 3.16−3.04 (m, 2H, H-2, H-2″), 0.79 (s, 9H,

TBS-t-Bu), 0.02 (s, 3H, TBS-CH₃), −0.012 (s, 3H, TBS-CH₃);

¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.7 (C), 165.0 (C), 161.7

(C), 161.1 (C), 139.0 (C), 138.9 (C), 138.8 (C), 138.2 (C), 138.1

(C), 138.0 (C), 137.9 (C), 137.6 (C), 137.4 (C), 134.9 (C), 133.4

(CH), 133.2 (CH), 133.16 (C), 133.1 (C), 130.0 (CH), 129.9 (C),

129.8 (C), 128.9 (CH), 128.87 (CH), 128.7 (CH), 128.6 (CH),

128.5 (CH), 128.49 (CH), 128.4 (CH), 128.37 (CH), 128.3 (CH),

128.26 (CH), 128.2 (CH), 128.16 (CH), 128.1 (CH), 128.06 (CH),

128.0 (CH), 127.9 (CH), 127.8 (CH), 127.76 (CH), 127.7 (CH),

127.4 (CH), 126.9 (CH), 126.3 (CH), 126.28 (CH), 126.1 (CH),

125.9 (CH), 100.9 (CH), 100.3 (CH), 100.1 (CH), 100.0 (CH),

99.5 (CH), 99.2 (CH), 94.0 (CH), 92.4 (C), 91.9 (C), 79.5 (CH),

79.4 (CH), 79.1 (CH), 78.0 (CH), 77.5 (CH), 76.4 (CH), 76.39

(CH), 76.23 (CH), 75.2 (CH), 74.9 (CH₂), 74.87 (CH₂), 74.84

(CH₂), 74.5 (CH), 73.8 (CH), 73.7 (CH₂), 73.66 (CH₂), 73.61

(CH₂), 73.6 (CH), 73.5 (CH₂), 73.1 (CH), 73.0 (CH), 72.8 (CH),

72.1 (CH), 72.0 (CH₂), 69.2 (CH₂), 68.9 (CH₂), 68.7 (CH₂), 68.6

(CH₂), 68.56 (CH₂), 68.4 (CH₂), 66.3 (CH), 62.4 (CH), 60.0 (CH),

59.0 (CH), 25.7 (CH₃), 17.9 (C), −4.2 (CH₃), −5.1 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₁₅₀H₁₅₂Cl₉N₃O₃₄SiNa₂[M + 2Na]²⁺,

1466.8499; found, 1466.8500.

tert-Butyldimethylsilyl(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galacto-

pyranosyl)-(1 → 3)-(4,6-di-O-benzyl-2-deoxy-2-trichloroacetami-

do-β-^D-glucopyranosyl)-(1 → 3)-(2-O-benzoyl-4,6-di-O-benzyl-β-D-

galactopyranosyl)-(1 → 3)-(4,6-O-benzylidene-2-deoxy-2-trichlor-

oacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-O-benzoyl-4,6-di-O-

benzyl-β-^D-galactopyranosyl)-(1 → 3)-4,6-O-benzylidene-2-deoxy-

2-trichloroacetamido-β-^D-glucopyranoside (39). For reaction de-

tails, please see Scheme 2. To a solution of compound 38 (263 mg,

0.091 mmol) in a 10:1 (v/v) mixture of CH₂Cl₂(8.27 mL) and dd.

H₂O (0.83 mL), DDQ (62 mg, 0.27 mmol) was added under the

argon atmosphere at 0 °C. After 6 h, the reaction was completed as

observed by TLC. Saturated NaHCO₃solution (2 mL) was then

slowly added to the reaction mixture under the ice bath to quench the

reaction. Solvent extraction was done to wash the CH₂Cl₂layer with

saturated NaHCO₃solution (7 mL, two times). The CH₂Cl₂layer

was collected, dried over MgSO₄, ﬁltered, and concentrated by

evaporation to yield a viscous yellow crude that was puriﬁed by

column chromatography on silica gel with EtOAc/hexanes (1/4, v/v)

to yield the desired pure product 39 (155 mg, 62%) as a white

amorphous foam. R_f0.28 (EtOAc/hexanes = 1/2, v/v); [α]²_D⁰−25.39

(c 3.19, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 8.01 (d, J = 7.6 Hz,

2H, Ar-H), 7.91 (d, J = 7.6 Hz, 2H, Ar-H), 7.85 (d, J = 7.6 Hz, 2H,

Ar-H), 7.51−7.42 (m, 3H, Ar-H), 7.42−7.37 (m, 5H, Ar-H), 7.37−

7.31 (m, 7H, Ar-H), 7.31−7.30 (m, 2H, Ar-H), 7.30−7.26 (m, 9H,

Ar-H), 7.25−7.24 (m, 3H, Ar-H), 7.24−7.23 (m, 6H, Ar-H), 7.23−

7.18 (m, 14H, Ar-H), 7.18−7.15 (m, 6H, Ar-H), 7.14−7.09 (m, 4H,

Ar-H), 6.80 (d, J = 6.8 Hz, 1H, N−H), 6.68 (d, J = 8.15 Hz, 1H, N−

H), 6.63 (d, J = 7.1 Hz, 1H, N−H), 5.47−5.36 (m, 4H, H-2′, H-2‴,

2× PhCH benzylidene), 5.23−5.15 (m, 2H, H-1, H-2‴″), 5.01 (d, J =

7.95 Hz, 1H, H-1″), 4.86 (d, J = 10.35 Hz, 1H), 4.78−4.15 (m, 25H,

H-1‴″, H-1‴′, H-1, H-1‴, H-3, H-3″, H-3‴′, 15× CH₂Ph, H-6a, H-

6a″), 3.93−3.86 (m, 3H, H-3′, H-3‴, H-4‴″), 3.85−3.82 (m, 2H, H-

4′, H-4‴), 3.70−3.29 (m, 20H, H-4, H-4″, H-4‴′, H-3‴″, H-2‴′, H-5,

H-5′, H-5″, H-5‴, H-5‴′, H-5‴″, H-6b, H-6a′, H-6b′, H-6a‴, H-6b‴,

H-6a‴′, H-6b‴′, H-6a‴″, H-6b‴″), 3.18−3.03 (m, 2H, H-2, H-2″),

2.49 (d, J = 4.95 Hz, 1H, O−H), 0.8 (s, 9H, TBS-t-Bu), 0.024 (s, 3H,

TBS-CH₃), −0.01 (s, 3H, TBS-CH₃); ¹³C{¹H} NMR (125 MHz,

T

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J. Org. Chem. XXXX, XXX, XXX−XXX

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CDCl₃): δ 167.3 (C), 165.0 (C), 161.7 (C), 161.4 (C), 139.0 (C),

138.87 (C), 138.2 (C), 138.1 (C), 137.9 (C), 137.7 (C), 137.6 (C),

137.4 (C), 133.5 (CH), 133.4 (CH), 130.2 (CH), 130.0 (CH), 129.9

(C), 129.8 (C), 129.6 (C), 128.9 (CH), 128.86 (CH), 128.7 (CH),

128.63 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH),

128.2 (CH), 128.1 (CH), 128.09 (CH), 128.06 (CH), 128.0 (CH),

127.96 (CH), 127.8 (CH), 127.7 (CH), 127.66 (CH), 127.4 (CH),

126.3 (CH), 100.9 (CH), 100.3 (CH), 100.0 (CH), 99.6 (CH), 99.4

(CH), 99.3 (CH), 93.9 (CH), 92.5 (C), 92.4 (C), 91.9 (C), 79.3

(CH), 79.1 (CH), 78.0 (CH), 77.6 (CH), 76.8 (CH), 76.5 (CH),

76.4 (CH), 76.2 (CH), 75.7 (CH₂), 75.2 (CH), 74.9 (CH), 74.86

(CH₂), 74.8 (CH₂), 74.5 (CH), 73.7 (CH₂), 73.6 (CH₂), 73.5 (CH),

73.4 (CH₂), 73.1 (CH), 72.8 (CH), 69.1 (CH₂), 68.9 (CH₂), 68.7

(CH₂), 68.6 (CH₂), 68.55 (CH₂), 68.2 (CH₂), 66.3 (CH), 62.4

(CH), 60.0 (CH), 58.8 (CH), 25.7 (CH₃), 17.9 (C), −4.2 (CH₃),

−5 . 1 (C H ₃) ; H R M S ( E S I - T O F) m/z : ca lc d fo r

C₁₃₉H₁₄₄Cl₉N₃O₃₄SiNa [M + Na]⁺, 2770.6475; found, 2770.6435.

tert-Butyldimethylsilyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-O-ben-

zyl-2-deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-(2-

O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-(4,6-di-

O-benzyl-2-deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 →

3)-(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-

(4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-β-^D-glucopyra-

nosyl)-(1 → 3)-(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyrano-

syl)-(1 → 3)-4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-β-^D-

glucopyranoside (40). For reaction details, please see Scheme 2. A

solution of 8 (80 mg, 0.066 mmol) and 39 (91 mg, 0.033 mmol) in

anhydrous CH₂Cl₂(1.6 mL) was stirred with 3 Å pulverized

molecular sieves (340 mg) at rt for 30 min under the N₂atmosphere

and then cooled down to −50 °C. NIS (17.2 mg, 0.076 mmol) was

added to the reaction mixture, followed by addition of TfOH (0.9 μL,

0.009 mmol). After 3 h, the reaction was quenched by dropwise

addition of Et₃N, diluted with CH₂Cl₂(5 mL), and ﬁltered. The

ﬁltrate was washed with saturated Na₂S₂O₃solution (10 mL), dried

over MgSO₄, ﬁltered, and concentrated by evaporation to yield a

viscous yellow crude that was puriﬁed by column chromatography on

silica gel with EtOAc/hexanes (1/5 to 1/3, v/v) to aﬀord

octasaccharide 40 (77 mg, 61%) as a glassy solid. R_f0.27 (EtOAc/

toluene = 1/8, v/v, run two times); [α]²_D⁰−26.82 (c 2.13, CHCl₃); ¹H

NMR (500 MHz, CDCl₃): δ 7.93−7.86 (m, 6H, Ar-H), 7.81 (d, J =

7.5 Hz, 2H, Ar-H), 7.71 (d, J = 7.7 Hz, 1H, Ar-H), 7.56−7.50 (m, 3H,

Ar-H), 7.48−7.36 (m, 9H, Ar-H), 7.35−7.25 (m, 28H, Ar-H), 7.23−

7.19 (m, 18H, Ar-H), 7.18−7.12 (m, 20H, Ar-H), 7.12−7.08 (m, 6H,

Ar-H), 7.07−7.02 (m, 4H, Ar-H), 6.78 (d, J = 6.6 Hz, 1H, N−H),

6.59 (d, J = 6.85 Hz, 1H, N−H), 6.55−6.45 (m, 2H, 2× N−H), 5.60

(dd, J = 9.7, 8.3 Hz, 1H, H-2‴‴′), 5.46−5.38 (m, 4H, H-2′, H-2‴″,

2× PhCH benzylidene), 5.32 (t, J = 8.8 Hz, 1H, H-2‴), 5.17 (d, J =

7.7 Hz, 1H, H-1), 5.05−4.97 (m, 2H, H-1″, CH₂Ph), 4.88 (d, J = 10.3

Hz, 1H, CH₂Ph), 4.79 (d, J = 10.4 Hz, 1H, CH₂Ph), 4.76−4.65 (m,

4H, H-1‴‴, CH₂Ph, CH₂group of Nap), 4.64−4.12 (m, 31H, H-1‴″,

H-1‴, H-1′, H-3, CH₂group of Nap, H-3″, H-3‴‴, H-3‴′, 19×

CH₂Ph, H-1‴′, H-1‴‴′, H-6a, H-6a″), 3.94 (s, 1H, H-4‴‴′), 3.89−

3.77 (m, 6H, H-3′, H-4′, H-3‴, H-4‴, H-3‴″, H-4‴″), 3.70−3.30 (m,

27H, H-4, H-4″, H-4‴‴, H-4‴′, H-3‴‴′, H-5, H-5′, H-5″, H-5‴, H-

5‴′, H-5‴″, H-5‴‴, H-5‴‴′, H-6b, H-6a′, H-6b′, H-6b″, H-6a‴, H-

6b‴, H-6a‴′, H-6b‴′, H-6a‴″, H-6b‴″, H-6a‴‴, H-6b‴‴, H-6a‴‴′,

H-6b‴‴′), 3.24−3.03 (m, 4H, H-2, H-2″, H-2‴′, H-2‴‴), 0.79 (s,

9H, TBS-t-Bu), 0.019 (s, 3H, TBS-CH₃), −0.014 (s, 3H, TBS-CH₃);

¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.7 (C), 165.3 (C), 165.0

(CH), 77.5 (CH), 77.4 (CH), 76.8 (CH), 76.4 (CH), 76.36 (CH),

76.3 (CH), 76.2 (CH), 75.3 (CH), 75.2 (CH), 75.1 (CH₂), 74.9

(CH₂), 74.89 (CH₂), 74.8 (CH₂), 74.5 (CH), 73.9 (CH), 73.8 (CH),

73.7 (CH₂), 73.6 (CH₂), 73.57 (CH), 73.52 (CH₂), 73.5 (CH₂), 73.2

(CH), 73.1 (CH), 72.8 (CH), 72.7 (CH), 72.1 (CH), 72.0 (CH₂),

69.1 (CH₂), 69.0 (CH₂), 68.9 (CH₂), 68.7 (CH₂), 68.6 (CH₂), 68.5

(CH₂), 68.4 (CH₂), 66.3 (CH), 62.5 (CH), 60.0 (CH), 59.1 (CH),

59.0 (CH), 25.7 (CH₃), 17.9 (C), −4.1 (CH₃), −5.1 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₁₉₉H₂₀₀Cl₁₂N₄O₄₅SiNa₂[M + 2Na]²⁺,

1933.4646; found, 1933.4641.

From Compounds 42 to 45, Please See Scheme S2 for

Reaction Details. 4-Methylphenyl 4,6-O-Benzylidene-3-O-(naph-

thalene-2-ylmethyl)-1-thio-β-^D-galactopyranoside (42). To a sol-

ution of compound 41^33,34(18.80 g, 50.2 mmol) in benzene (166

mL) was added Bu₂SnO (16.25 g, 65.0 mmol), and the resulting

mixture was heated with a silicone oil bath under reﬂuxing condition

with stirring overnight. At the same time, the reaction vessel was

connected with Dean−Stark apparatus to remove water. Most of the

benzene was removed by distillation at 100 °C and the rest was kept

under high vacuum for 2 h prior to the next step. To a solution of the

resulting dried residue in DMF (166 mL) were sequentially added

2NapMeBr (16.66 g, 75.4 mmol) and CsF (12.21 g, 80.4 mmol) with

stirring at room temperature (rt) for 6 h under the N₂atmosphere.

After the completion of the reaction, the solvent was removed by

evaporation and the concentrated residue was partitioned by EtOAc

(350 mL)/ice H₂O (350 mL). The organic layer was further washed

with brine (200 mL, ﬁve times), dried over MgSO₄, ﬁltered, and

concentrated in vacuo to aﬀord the crude as a white solid. The crude

was puriﬁed by recrystallization in a mixture of CH₂Cl₂/hexanes (1/

20, v/v) to provide the desired product 42 (23.77 g, 92%) as a white

solid. R_f0.70 (EtOAc/hexanes = 2/1, v/v); [α]²_D⁵10.8 (c 1.2, CHCl₃);

¹H NMR (400 MHz, CDCl₃): δ 7.84−7.77 (m, 3H, Ar-H), 7.74 (m,

1H, Ar-H), 7.57 (d, J = 8.1 Hz, 2H, Ar-H), 7.47 (m, 3H, Ar-H), 7.40

(dd, J = 7.1, 2.5 Hz, 2H, Ar-H), 7.37−7.31 (m, 3H, Ar-H), 7.05 (d, J

= 8 Hz, 2H, Ar-H), 5.38 (s, 1H, PhCH benzylidene), 4.88 (s, 2H,

CH₂group of Nap), 4.44 (d, J = 9.4 Hz, 1H, H-1), 4.31 (d, J = 12.3

Hz, 1H, H-6a), 4.12 (d, J = 3.2 Hz, 1H, H-4), 3.90 (m, 2H, H-2, H-

6b), 3.53 (dd, J = 9.3, 3.3 Hz, 1H, H-3), 3.38 (s, 1H, H-5), 2.50 (d, J

= 1.8 Hz, 1H, O−H), 2.33 (s, 3H, PhCH₃); ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 138.6 (C), 138.1 (C), 135.7 (C), 134.6 (CH), 133.4

(C), 133.3 (C), 129.9 (CH), 129.2 (CH), 128.5 (CH), 128.3 (CH),

128.1 (CH), 127.9 (CH), 126.9 (CH), 126.8 (CH), 126.8 (C), 126.4

(CH), 126.2 (CH), 126.0 (CH), 101.4 (CH), 87.4 (CH), 80.4 (CH),

73.6 (CH), 72.1 (CH₂), 70.2 (CH), 69.6 (CH₂), 67.4 (CH), 21.4

(CH₃); HRMS (ESI-TOF) m/z: calcd for C₃₁H₃₁O₅S [M + H]⁺,

515.1887; found, 515.1891.

4-Methylphenyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(naphtha-

lene-2-ylmethyl)-1-thio-β-^D-galactopyranoside (43). 4-DMAP

(1.50 g, 12.3 mmol) and Bz₂O (18.55 g, 82.0 mmol) were sequentially

added to a solution of compound 42 (21.11 g, 41.0 mmol) in

anhydrous pyridine (205 mL) at rt. After 3 h, the reaction mixture was

quenched under the ice bath by adding MeOH (15 mL) and

concentrated by evaporation. The resulting residue was redissolved in

CH₂Cl₂(200 mL), washed with 1 N HCl (200 mL, three times) to

completely remove the pyridine, dried over MgSO₄, ﬁltered, and

concentrated in vacuo to yield the crude product as a pale-yellow-

white solid. The crude was puriﬁed by recrystallization in a mixture of

CH₂Cl₂/hexanes (1/20, v/v) to provide the desired product 43

(22.71 g, 89%) as a white solid. R_f0.38 (EtOAc/hexanes = 1/2, v/v);

[α]²_D⁵−36.3 (c 1.2, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ 8.03 (d,

J = 7.8 Hz, 2H, Ar-H), 7.73 (d, J = 7.7 Hz, 1H, Ar-H), 7.59 (dd, J =

17.7, 7.5 Hz, 4H, Ar-H), 7.45 (m, 8H, Ar-H), 7.37 (s, 3H, Ar-H), 7.26

(d, J = 5.6 Hz, 1H, Ar-H), 7.04 (d, J = 7.6 Hz, 2H, Ar-H), 5.53 (t, J =

9.6 Hz, 1H, H-2), 5.47 (s, 1H, PhCH benzylidene), 4.81−4.66 (m,

3H, H-1, CH₂group of Nap), 4.37 (d, J = 12.2 Hz, 1H, H-6a), 4.25

(s, 1H, H-4), 4.00 (d, J = 12.3 Hz, 1H, H-6b), 3.80 (d, J = 9.6 Hz, 1H,

H-4), 3.46 (s, 1H, H-5), 2.32 (s, 3H, PhCH₃); ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 165.2 (C), 138.4 (C), 137.9 (C), 135.4 (C), 134.6

(CH), 133.3 (C), 133.2 (CH), 130.5 (C), 130.1 (CH), 129.7 (CH),

129.3 (CH), 128.6 (CH), 128.4 (CH), 128.3 (CH), 128.0 (CH),

(C), 161.7 (C), 161.1 (C), 139.2 (C), 139.0 (C), 138.9 (C), 138.8

(C), 138.2 (C), 138.1 (C), 138.0 (C), 137.6 (C), 137.4 (C), 134.9

(C), 133.4 (CH), 133.2 (CH), 133.1 (C), 130.0 (CH), 129.9 (C),

129.8 (C), 128.9 (CH), 128.7 (CH), 128.6 (CH), 128.57 (CH),

128.5 (CH), 128.4 (CH), 128.3 (CH), 128.22 (CH), 128.2 (CH),

128.17 (CH), 128.12 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH),

127.8 (CH), 127.78 (CH), 127.7 (CH), 127.6 (CH), 127.4 (CH),

127.39 (CH), 126.9 (CH), 126.3 (CH), 126.29 (CH), 126.2 (CH),

126.1 (CH), 126.0 (CH), 100.9 (CH), 100.3 (CH), 100.2 (CH),

100.1 (CH), 99.5 (CH), 99.3 (CH), 99.1 (CH), 94.0 (CH), 92.5

(C), 92.4 (C), 91.9 (C), 79.5 (CH), 79.4 (CH), 79.2 (CH), 78.0

U

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127.9 (CH), 127.7 (C), 126.9 (CH), 126.7 (CH), 126.3 (CH), 126.1

(CH), 125.9 (CH), 101.5 (CH), 85.7 (CH), 78.4 (CH), 73.4 (CH),

71.3 (CH₂), 70.2 (CH), 69.5 (CH₂), 69.4 (CH), 21.5 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₃₈H₃₄O₆SNa [M + Na]⁺, 641.1968;

found, 641.1979.

acetate (2.14 g, 23.2 mmol) was added to the ice-cold solution of the

starting material 46^32,35(10.42 g, 21.2 mmol) in anhydrous DMF (85

mL). After 1 h, the reaction was quenched by adding MeOH (15 mL)

and concentrated by evaporation. The residue was redissolved in

CH₂Cl₂(100 mL), washed with saturated NaHCO₃solution (100

mL, two times), dried over MgSO₄, ﬁltered, and concentrated in

vacuo.

4-Methylphenyl 2-O-benzoyl-4-O-benzyl-3-O-(naphthalene-2-

ylmethyl)-1-thio-β-^D-galactopyranoside (44). To a solution of

compound 43 (22.71 g, 36.7 mmol) in anhydrous CH₂Cl₂(184

mL) at 0 °C under N₂, 1 M solution of BH₃.THF complex (147 mL,

147.0 mmol) was added, followed by the addition of TMSOTf (3.32

mL, 18.4 mmol). After 2 h, the reaction was quenched by dropwise

addition of Et₃N to neutralize the pH, followed by the slow addition

of MeOH (20 mL) under the ice bath. After concentrating the

neutralized reaction mixture by evaporation, the resulting residue was

redissolved in CH₂Cl₂(200 mL), washed with saturated NaHCO₃

solution (200 mL, two times), dried over MgSO₄, ﬁltered, and

concentrated in vacuo. Recrystallization was done with CH₂Cl₂/

hexanes (1/20, v/v) to aﬀord the pure product 44 (18.22 g, 80%) as a

white solid. R_f0.45 (EtOAc/hexanes = 1/1, v/v); [α]²_D⁵+16.3 (c 1.2,

CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d, J = 7.2 Hz, 2H, Ar-

H), 7.73 (d, J = 7.2 Hz, 1H, Ar-H), 7.58 (dd, J = 12.9, 8.9 Hz, 4H, Ar-

H), 7.47−7.38 (m, 4H, Ar-H), 7.36−7.23 (m, 8H, Ar-H), 7.02 (d, J =

7.9 Hz, 2H, Ar-H), 5.70 (t, J = 9.7 Hz, 1H, H-2), 5.03 (d, J = 11.8 Hz,

1H, CH₂Ph), 4.82 (d, J = 12.4 Hz, 1H, CH₂group of Nap), 4.72−

4.64 (m, 3H, H-1, CH₂Ph, CH₂group of Nap), 3.96 (d, J = 2.1 Hz,

1H, H-4), 3.87 (dd, J = 11.3, 6.9 Hz, 1H, H-6a), 3.74 (dd, J = 9.7, 2.5

Hz, 1H, H-3), 3.56 (dd, J = 11.3, 5.2 Hz, 1H, H-6b), 3.53−3.46 (m,

1H, H-5), 2.28 (s, 3H, PhCH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃):

δ 165.5 (C), 138.3 (C), 138.1 (C), 135.1 (C), 133.3 (CH), 133.2

(C), 132.9 (CH), 130.3 (C), 130.1 (CH), 129.8 (CH), 129.7 (C),

128.7 (CH), 128.6 (CH), 128.57 (CH), 128.5 (CH), 128.1 (CH),

128.0 (CH), 127.9 (CH), 126.9 (CH), 126.4 (CH), 126.2 (CH),

126.0 (CH), 87.5 (CH), 81.4 (CH), 79.2 (CH), 74.3 (CH₂), 72.4

(CH₂), 72.4 (CH), 70.7 (CH), 62.4 (CH₂), 21.3 (CH₃); HRMS

(ESI-TOF) m/z: calcd for C₃₈H₃₆O₆SNa [M + Na]⁺, 643.2125;

found, 643.2132.

To the resulting solid residue solution in DMF (42 mL), imidazole

(4.32 g, 63.4 mmol) and tert-butylchlorodimethylsilane (6.38 g, 42.3

mmol) were sequentially added at rt. After 2 h, the reaction was

quenched by adding MeOH (10 mL) and concentrated in vacuo to

dryness. The resulting crude was redissolved in CH₂Cl₂(100 mL) and

washed sequentially with dd. H₂O (100 mL, two times) and saturated

NaHCO₃solution (100 mL, two times). The CH₂Cl₂layer was

collected, dried over MgSO₄, ﬁltered, and concentrated in vacuo. The

crude product was puriﬁed by column chromatography on silica gel

with EtOAc/hexanes (1/3, v/v) to aﬀord the desired pure product 47

(9.43 g, 79% in two steps) as an amorphous white foam. R_f0.58

1

(EtOAc/hexanes = 1/1, v/v); [α]²_D⁵−9.6 (c 1.0, CHCl₃); H NMR

(500 MHz, CDCl₃): δ 6.99 (d, J = 9.2 Hz, 1H, N−H), 5.36 (t, J = 9.4

Hz, 1H, H-3), 5.09 (t, J = 9.7 Hz, 1H, H-4), 4.89 (d, J = 7.9 Hz, 1H,

H-1), 4.23 (dd, J = 12.1, 6.2 Hz, 1H, H-6a), 4.16 (dd, J = 12.1, 2.5 Hz,

1H, H-6b), 3.99 (ddd, J = 10.8, 9.1, 8.0 Hz, 1H, H-2), 3.76 (ddd, J =

9.8, 6.1, 2.5 Hz, 1H, H-5), 2.08 (s, 3H, COCH₃), 2.04 (s, 3H,

COCH₃), 2.03 (s, 3H, COCH₃), 0.88 (s, 9H, TBS-t-Bu), 0.12 (s, 3H,

TBS-CH₃), 0.10 (s, 3H, TBS-CH₃); ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 171.3 (C), 170.8 (C), 169.5 (C), 162.04 (C), 96.0 (CH),

92.6 (C), 72.2 (CH), 71.9 (CH), 69.1 (CH), 62.7 (CH₂), 58.1 (CH),

25.7 (CH₃), 20.9 (CH₃), 20.8 (2xCH₃), 18.0 (C), −4.1 (CH₃), −5.1

(CH₃); HRMS (ESI-TOF) m/z: calcd for C₂₀H₃₂Cl₃NO₉SiNa [M +

Na]⁺, 586.0804; found, 586.0821.

tert-Butyldimethylsilyl 4,6-O-Benzylidene-2-deoxy-2-trichloroa-

cetamido-β-^D-glucopyranoside (48). A catalytic amount of

NaOMe (356 μL, 1.6 mmol) was added to a solution of starting

material 47 (9.04 g, 16.0 mmol) in a 4:1 v/v mixture of MeOH (36

mL) and CH₂Cl₂(9 mL) at rt. After 1 h, the reaction was quenched

by neutralizing the pH by slowly adding IR-120H + Amberlite resin.

The reaction solution was ﬁltered, concentrated by evaporation, and

dried under high vacuum. The resulting white solid was dissolved in

CH₃CN (64 mL). Then, camphor sulfonic acid (1.86 g, 8.0 mmol)

and benzaldenhyde dimethyl acetal (7.23 mL, 48.0 mmol) were added

with stirring at 0 °C under the N₂atmosphere. After 3 h, the reaction

was quenched by dropwise addition of Et₃N to neutralize the pH.

After concentrating in vacuo, the resulting white residue was

redissolved in CH₂Cl₂(70 mL), washed with saturated NaHCO₃

solution (70 mL, two times), dried over MgSO₄, ﬁltered, and

concentrated by evaporation. The crude product was recrystallized

with CH₂Cl₂/hexanes (1/20, v/v) to aﬀord the pure product 48 (7.08

g, 84% yield in two steps) as a white amorphous foam. R_f0.44

4-Methylphenyl 2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalene-

2-ylmethyl)-1-thio-β-^D-galactopyranoside (45). BnBr (8.70 mL,

72.5 mmol) and NaH (60% in mineral oil, 1.93 g, 48.3 mmol)

were added to the ice-cold solution of the starting material 44 (15.0 g,

24.2 mmol) in DMF (120.8 mL) under the N₂atmosphere. After 3 h,

the reaction was quenched by pouring dd. H₂O (15 mL) under the ice

bath. Solvent extraction was then done by using CH₂Cl₂(150 mL)

and brine (150 mL, ﬁve times) to remove most of the DMF. This was

followed by washing the CH₂Cl₂layer with saturated NaHCO₃

solution (150 mL, two times). The CH₂Cl₂layer was collected,

dried over MgSO₄, ﬁltered, and concentrated by evaporation. The

crude residue was recrystallized with CH₂Cl₂/hexanes (1/20, v/v) to

yield the desired monosaccharide donor 45 (14.94 g, 87%) as a white

solid. R_f0.65 (EtOAc/hexanes = 1/2, v/v); [α]²_D⁵+43.1 (c 1.1,

(EtOAc/hexanes = 1/2, v/v); [α]²_D⁵−38.0 (c 1.0, CHCl₃); H NMR

1

CHCl₃); H NMR (400 MHz, CDCl₃): δ 7.99−7.96 (m, 2H, Ar-H),

(400 MHz, CDCl₃): δ 7.50−7.45 (m, 2H, Ar-H), 7.40−7.34 (m, 3H,

Ar-H), 6.94 (d, J = 7.4 Hz, 1H, NH), 5.52 (s, 1H, PhCH

benzylidene), 5.08 (d, J = 7.9 Hz, 1H, H-1), 4.31−4.20 (m, 2H, H-

3, H-6a), 3.76 (t, J = 10.0 Hz, 1H, H-6b), 3.57−3.45 (m, 3H, H-2, H-

4, H-5), 3.06 (d, J = 3.2 Hz, 1H, O−H), 0.89 (s, 9H, TBS-t-Bu), 0.12

(s, 1H, TBS-CH₃), 0.11 (s, 3H, TBS-CH₃); ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 162.4 (C), 137.2 (C), 129.5 (CH), 128.5 (CH),

126.5 (CH), 102.1 (CH), 95.4 (CH), 92.7 (C), 81.8 (CH), 69.9

(CH), 68.8 (CH₂), 66.4 (CH), 61.8 (CH), 25.8 (CH₃), 18.0 (C),

−4.0 (CH₃), −4.9 (CH₃); HRMS (ESI-TOF) m/z: calcd for

C₂₁H₃₀Cl₃NO₆SiNa [M + Na]⁺, 548.0800; found, 548.0802.

7.71 (d, J = 7.3 Hz, 1H, Ar-H), 7.58−7.52 (m, 4H, Ar-H), 7.44−7.38

(m, 4H, Ar-H), 7.36−7.22 (m, 13H, Ar-H), 6.97 (d, J = 8.2 Hz, 2H,

Ar-H), 5.67 (t, J = 9.8 Hz, 1H, H-2), 5.01 (d, J = 11.7 Hz, 1H,

CH₂Ph), 4.78 (d, J = 12.4 Hz, 1H, CH₂group of Nap), 4.68 (d, J =

9.9 Hz, 1H, H-1), 4.63 (dd, J = 12.0, 8.7 Hz, 2H, CH₂Ph, CH₂group

of Nap), 4.47 (d, J = 11.6 Hz, 1H, CH₂Ph), 4.43 (d, J = 11.6 Hz, 1H,

CH₂Ph), 4.07 (d, J = 2.6 Hz, 1H, H-4), 3.73−3.63 (m, 4H, H-3, H-5,

H-6a, H-6b), 2.26 (s, 3H, PhCH₃); ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 165.5 (C), 138.7 (C), 138.1 (C), 137.8 (C), 135.3 (C),

133.3 (C), 133.2 (CH), 133.0 (CH), 130.4 (C), 130.1 (CH), 129.9

(C), 129.7 (CH), 128.7 (CH), 128.5 (CH), 128.4 (CH), 128.2

(CH), 128.2 (CH), 128.0 (CH), 127.8 (CH), 127.7 (CH), 126.7

(CH), 126.3 (CH), 126.1 (CH), 125.9 (CH), 87.5 (CH), 81.3 (CH),

77.9 (CH), 74.6 (CH₂), 73.8 (CH₂), 73.0 (CH), 72.0 (CH₂), 70.7

(CH), 69.1 (CH₂), 21.3 (CH₃); HRMS (ESI-TOF) m/z: calcd for

C₃₈H₃₄O₆SNa [M + Na]⁺, 733.2594; found, 733.2626.

tert-Butyldimethylsilyl (2-O-Benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-4,6-O-benzyli-

dene-2-deoxy-2-trichloroacetamido-β-^D-glucopyranoside (50). For

reaction details, please see Scheme S4. A solution of 45 (3.23 g, 4.54

mmol) and 48 (2.0 g, 3.80 mmol) in anhydrous CH₂Cl₂(63 mL) was

stirred with 3 Å pulverized molecular sieves (10.50 g) at rt for 30 min

under the N₂atmosphere. After cooling to −60 °C, NIS (1.11 g, 4.93

mmol) was added to the reaction mixture, followed by the addition of

TMSOTf (137.0 μL, 0.76 mmol). After 4 h, the reaction was

From Compounds 47 and 48, Please See Scheme S3 for

Reaction Details. tert-Butyldimethylsilyl 3,4,6-Tri-O-acetyl-2-

deoxy-2-trichloroacetamido-β-^D-glucopyranoside (47). Hydrazine

V

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quenched by dropwise addition of Et₃N to neutralize the reaction

mixture and ﬁltered through a pad of Celite. The ﬁltrate was washed

with saturated Na₂S₂O₃solution (65 mL, two times), dried over

MgSO₄, ﬁltered, and concentrated by evaporation to yield the thick

yellow residue. The residue was puriﬁed by column chromatography

on silica gel with EtOAc/hexanes (1/4, v/v) to yield the pure

disaccharide 50 (3.60 g, 85%) as a white amorphous foam. R_f0.43

(EtOAc/hexanes = 1/5, v/v, run two times); [α]²_D⁵+9.2 (c 1.2,

(CH), 73.7 (CH₂), 73.1 (CH), 72.1 (CH), 72.0 (CH₂), 68.6 (CH₂),

62.5 (CH₂), 57.4 (CH), 21.2 (CH₃); HRMS (ESI-TOF) m/z: calcd

for C₆₀H₅₈Cl₃NO₁₁SNa [M + Na]⁺, 1130.2677; found, 1130.2677.

4-Methylphenyl (2-O-Benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-2-deoxy-2-trichloroace-

tamido-1-thio-β-^D-glucopyranoside (52). For reaction details, please

see Scheme S5. A solution of compound 2 (1.50 g, 1.35 mmol) in

80% aq AcOH (64 mL) was stirred and heated at 54 °C with a

silicone oil bath for 3.5 h. After completing the reaction, the reaction

mixture was concentrated by evaporation to yield the viscous crude.

Crude was redissolved in EtOAc (20 mL) and washed with dd. H₂O

(20 mL, two times), followed by washing with saturated NaHCO₃

solution (20 mL, four times). The organic layer was collected, dried

over MgSO₄, ﬁltered, and concentrated by evaporation to yield a

viscous crude. Pure product (52) was isolated after puriﬁcation of the

crude by column chromatography on silica gel with EtOAc/hexanes

(1/2, v/v) in 70% yield (0.96 g) as a white amorphous solid. R_f0.14

(EtOAc/hexanes = 1/2, v/v); [α]²_D⁰+9.62 (c 1.04, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): δ 7.90 (d, J = 7.6 Hz, 2H, Ar-H), 7.74 (d, J = 7.6

Hz, 1H, Ar-H), 7.62−7.51 (m, 4H, Ar-H), 7.48−7.40 (m, 2H, Ar-H),

7.39−7.30 (m, 5H, Ar-H), 7.30−7.25 (m, 9H, Ar-H), 7.19 (d, J = 8.4

Hz, 1H, Ar-H), 7.03 (d, J = 7.8 Hz, 2H, Ar-H), 6.81 (d, J = 6.9 Hz,

1H, N−H), 5.68−5.58 (m, 1H, H-2′), 5.25 (d, J = 10.4 Hz, 1H, H-1),

4.95 (d, J = 11.7 Hz, 1H, CH₂Ph), 4.74 (d, J = 12.1 Hz, 1H, CH₂

group of Nap), 4.64−4.55 (m, 3H, H-1′, CH₂Ph, CH₂group of Nap),

4.44 (dd, J = 21.1, 11.7 Hz, 2H, 2× CH₂Ph), 4.38−4.21 (m, 2H, H-3,

O−H), 3.99−3.90 (m, 1H, H-4′), 3.83 (dd, J = 11.5, 2.6 Hz, 1H, H-

6a), 3.73−3.61 (m, 4H, H-3′, H-5′, H-6a′, H-6b), 3.55−3.44 (m, 2H,

H-4, H-6b′), 3.43−3.33 (m, 1H, H-5), 3.22−3.05 (m, 1H, H-2),

2.35−2.10 (m, 4H, PhCH₃, OH); ¹³C{¹H} NMR (125 MHz,

CDCl₃): δ 165.6 (C), 161.7 (C), 138.9 (C), 138.3 (C), 137.7 (C),

134.8 (C), 133.6 (CH), 133.4 (CH), 133.3 (C), 133.2 (C), 130.2

(CH), 130.1 (CH), 128.7 (CH), 128.6 (CH), 128.5 (CH), 128.46

(CH), 128.2 (CH), 128.0 (CH), 127.8 (CH), 126.9 (CH), 126.4

(CH), 126.3 (CH), 125.9 (CH), 101.2 (CH), 92.2 (C), 83.9 (CH),

81.8 (CH), 80.2 (CH), 79.8 (CH), 74.8 (CH₂), 74.3 (CH), 73.9

(CH₂), 72.7 (CH₂), 72.2 (CH), 70.6 (CH), 68.9 (CH₂), 63.4 (CH₂),

57.4 (CH), 21.3 (CH₃); HRMS (ESI-TOF) m/z: calcd for

C₅₃H₅₂Cl₃NO₁₁SNa [M + Na]⁺, 1040.2204; found, 1040.2220.

tert-Butyldimethylsilyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naph-

thalen-2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-(4,6-O-benzyli-

dene-2-deoxy-2-trichloroacetamido-β-^D-glucopyranosyl)-(1 → 3)-

(2-O-benzoyl-4,6-di-O-benzyl-β-^D-galactopyranosyl)-(1 → 3)-4,6-

O-benzylidene-2-deoxy-2-trichloroacetamido-β-^D-glucopyranoside

(53). For reaction details, please see Scheme S9. A mixture of

thiogalactoside 45 (164.4 mg, 0.23 mmol), compound 49 (100 mg,

0.19 mmol), and AW-300 molecular sieves (200 mg) in anhydrous

CH₂Cl₂(0.64 mL) was stirred at rt for 30 min under the N₂

atmosphere and then cooled down to −60 °C. NIS (52 mg, 0.23

mmol) and TfOH (3.4 μL, 0.04 mmol) were sequentially added to

the resulting mixture and stirred at −60 °C for 2 h. The reaction was

then warmed to −40 °C, followed by the addition of 35 (75 mg, 0.08

mmol). Then, NIS (34.6 mg, 0.154 mmol) and TfOH (1.36 μL, 0.02

mmol) were added to the reaction mixture. After stirring for 12 h at

−40 °C, the reaction was quenched by dropwise addition of Et₃N,

diluted with CH₂Cl₂(5 mL), and ﬁltered. The ﬁltrate was washed

with saturated Na₂S₂O₃solution (10 mL, two times), dried over

MgSO₄, ﬁltered, and concentrated by evaporation to aﬀord a thick

yellow crude that was puriﬁed by column chromatography on silica

gel with EtOAc/hexanes (1/4, v/v) to obtain tetrasaccharide 53 (93.6

mg, 0.048 mmol, 60% w.r.t compound 35) as a white amorphous

foam. R_f0.47 (EtOAc/toluene = 1/7, v/v); [α]²_D⁵+4.7 (c 1.1, CHCl₃);

¹H NMR (500 MHz, CDCl₃): δ 7.90 (dd, J = 7.7, 1.3 Hz, 2H, Ar-H),

1

CHCl₃); H NMR (500 MHz, CDCl₃): δ 7.90 (dd, J = 8.1, 1.1 Hz,

2H, Ar-H), 7.72 (d, J = 7.6 Hz, 1H, Ar-H), 7.56−7.46 (m, 4H, Ar-H),

7.46−7.38 (m, 4H, Ar-H), 7.36−7.22 (m, 15H, Ar-H), 7.17 (dd, J =

8.5, 1.4 Hz, 1H, Ar-H), 6.90 (d, J = 6.9 Hz, 1H, NH), 5.61 (dd, J =

10.0, 8.0 Hz, 1H, H-2′), 5.45 (s, 1H, PhCH benzylidene), 5.25 (d, J =

7.8 Hz, 1H, H-1), 4.98 (d, J = 11.7 Hz, 1H, CH₂Ph), 4.75−4.69 (m,

2H, H-1′, CH₂group of Nap), 4.62 (d, J = 11.7 Hz, 1H, CH₂Ph),

4.58−4.49 (m, 2H, H-3, CH₂group of Nap), 4.39 (d, J = 11.6 Hz,

1H, CH₂Ph), 4.31 (d, J = 11.6 Hz, 1H, CH₂Ph), 4.21 (dd, J = 10.4,

4.9 Hz, 1H, H-5), 3.97 (d, J = 2.3 Hz, 1H, H-4′), 3.74 (t, J = 9.1 Hz,

1H, H-4), 3.68 (t, J = 10.2 Hz, 1H, H-6a), 3.62 (dd, J = 8.8, 7.5 Hz,

1H, H-6a′), 3.56 (dd, J = 10.1, 2.7 Hz, 1H, H-3′), 3.51 (dd, J = 9.0,

5.7 Hz, 1H, H-5), 3.49−3.40 (m, 2H, H-6b, H-6b′), 3.20 (td, J = 9.8,

7.4 Hz, 1H, H-2), 0.81 (s, 9H, TBS-t-Bu), 0.04 (s, 3H, TBS-CH₃),

0.01 (s, 3H, TBS-CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 165.4

(C), 161.7 (C), 138.6 (C), 137.8 (C), 137.5 (C), 135.0 (C), 133.09

(C), 133.07 (CH), 133.0 (C), 130.1 (C), 130.0 (CH), 128.9 (CH),

128.6 (CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.2 (CH),

128.0 (CH), 127.9 (CH), 127.7 (CH), 127.6 (CH), 126.7 (CH),

126.3 (CH), 126.1 (CH), 126.0 (CH), 125.8 (CH), 101.0 (CH),

99.9 (CH), 93.9 (CH), 92.2 (C), 79.9 (CH), 79.7 (CH), 77.4 (C),

75.1 (CH), 74.5 (2× CH₂), 73.7 (CH₂), 73.5 (CH), 72.5 (CH), 72.2

(CH), 71.8 (CH₂), 68.7 (CH₂), 66.3 (CH), 62.0 (CH), 25.7 (CH₃),

17.8 (C), −4.2 (CH₃), −5.1 (CH₃); HRMS (ESI-TOF) m/z: calcd

for C₅₉H₆₄Cl₃NO₁₂SiH [M + H]⁺, 1112.3336; found, 1112.3356.

4-Methylphenyl(2-O-benzoyl-4,6-di-O-benzyl-3-O-(naphthalen-

2-ylmethyl)-β-^D-galactopyranosyl)-(1 → 3)-4-O-benzyl-2-deoxy-2-

trichloroacetamido-1-thio-β-^D-glucopyranoside (51). For reaction

details, please see Scheme S5. To a solution of compound 2 (2.60 g,

2.35 mmol) in CH₂Cl₂(12 mL) at 0 °C was added (1 M) BH₃.THF

(9.40 mL, 9.40 mmol) solution. After 10 min, TMSOTf (213.0 μL,

1.18 mmol) was slowly added with continuous stirring. After 2 h, the

reaction was quenched by dropwise addition of Et₃N to neutralize the

pH. The neutralized reaction mixture was then extracted with

saturated NaHCO₃solution (30 mL, two times). The organic layer

was collected, dried over MgSO₄, ﬁltered, and concentrated by

evaporation to aﬀord the viscous crude. Column chromatography on

silica gel with EtOAc/hexanes (1/4, v/v) was done to purify the crude

to furnish the pure product 51 (2.42 g, 93%) as a white amorphous

foam. R_f0.30 (EtOAc/hexanes = 1/2, v/v); [α]²_D⁰−6.66 (c 0.9,

CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 7.94 (d, J = 7.6 Hz, 2H, Ar-

H), 7.75 (d, J = 7.4 Hz, 1H, Ar-H), 7.64−7.53 (m, 4H, Ar-H), 7.48−

7.42 (m, 2H, Ar-H), 7.42−7.37 (m, 2H, Ar-H), 7.36−7.32 (m, 2H,

Ar-H), 7.32−7.26 (m, 7H, Ar-H), 7.25−7.22 (m, 4H, Ar-H), 7.20−

7.16 (m, 3H, Ar-H), 7.15−7.1 (m, 2H, Ar-H), 6.95 (d, J = 7.95 Hz,

2H, Ar-H), 6.87 (d, J = 7.9 Hz, 1H, N−H), 5.67 (dd, J = 9.9, 8.0 Hz,

1H, H-2′), 5.05 (d, J = 11.5 Hz, 1H, CH₂Ph), 4.97 (d, J = 10.3 Hz,

1H, CH₂Ph), 4.9 (d, J = 9.9 Hz, 1H, H-1), 4.78 (d, J = 12.3 Hz, 1H,

CH₂group of Nap), 4.69 (d, J = 7.9 Hz, 1H, H-1′), 4.61 (d, J = 11.5

Hz, 1H, CH₂Ph), 4.58 (d, J = 12.4 Hz, 1H, CH₂group of Nap),

4.50−4.37 (m, 3H, H-3, 2× CH₂Ph), 4.32 (d, J = 11.8 Hz, 1H,

CH₂Ph), 4.02 (d, J = 2.3 Hz, 1H, H-4′), 3.83 (d, J = 11.5 Hz, 1H, H-

6a), 3.68 (d, J = 11.0 Hz, 1H, H-6b), 3.62−3.48 (m, 4H, H-3′, H-5′,

H-6a′, H-6b′), 3.45−3.36 (m, 2H, H-4, H-5), 3.30 (m, 1H, H-2), 2.24

(s, 3H, PhCH₃), 2.03 (s, 1H, O−H); ¹³C{¹H} NMR (125 MHz,

CDCl₃): δ 165.6 (C), 161.2 (C), 138.7 (C), 138.6 (C), 138.1 (C),

138.0 (C), 134.9 (C), 133.3 (CH), 133.2 (C), 133.1 (CH), 130.1

(CH), 129.9 (CH), 128.7 (CH), 128.6 (CH), 128.5 (CH), 128.4

(CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 128.04 (CH), 128.0

(CH), 127.8 (CH), 127.7 (CH), 127.0 (CH), 126.3 (CH), 126.1

(CH), 126.0 (CH), 100.5 (CH), 92.7 (C), 84.8 (CH), 79.4 (CH),

79.3 (CH), 77.5 (CH), 76.1 (CH), 75.0 (CH₂), 74.9 (CH₂), 74.2

7.85 (dd, J = 8.2, 1.2 Hz, 2H, Ar-H), 7.70 (d, J = 7.8 Hz, 1H, Ar-H),

7.51−7.44 (m, 5H, Ar-H), 7.43−7.38 (m, 6H, Ar-H), 7.35−7.17 (m,

32H, Ar-H), 7.13 (dd, J = 8.4, 1.43 Hz, 1H, Ar-H), 6.78 (d, J = 6.85

Hz, 1H, NH), 6.62 (d, J = 5.4 Hz, 1H, NH″), 5.55 (dd, J = 10.05, 8.0

Hz, 1H, H-2‴), 5.45 (s, 1H, PhCH benzylidene), 5.43 (m, 2H, PhCH

benzylidene, H-2′), 5.18 (d, J = 7.75 Hz, 1H, H-1), 5.06 (d, J = 8.05

Hz, 1H, H-1″), 4.95 (d, J = 11.7 Hz, 1H, CH₂Ph), 4.76 (d, J = 11.95

W

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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Hz, 1H, CH₂Ph), 4.68 (d, J = 12.3 Hz, 1H, CH₂group of Nap), 4.64

(d, J = 7.8 Hz, 1H, H-1′), 4.60 (t, J = 10.3 Hz, 2H, H-1‴, CH₂Ph),

4.53−4.46 (m, 3H, H-3, CH₂Ph, CH₂group of Nap), 4.40 (d, J =

11.65 Hz, 1H, CH₂Ph), 4.37−4.22 (m, 6H, H-3, H-6a″, CH₂Ph), 4.19

(dd, J = 10.3, 4.8 Hz, 1H, H-6a), 3.93 (d, J = 2.1 Hz, 1H, H-4‴),

3.90−3.85 (m, 2H, H-3′, H-4′), 3.71−3.59 (m, 4H, H-4, H-4″, H-6b,

H-6b″), 3.59−3.56 (m, 1H, H-3‴), 3.55−3.46 (m, 4H, H-5″, H-5′,

H-5‴, H-6a′), 3.46−3.40 (m, 2H, H-5, H-6a‴), 3.42−3.33 (m, 2H,

H-6b′, H-6b‴), 3.16−3.03 (m, 2H, H-2, H-2″), 0.79 (s, 9H, TBS-t-

Bu), 0.02 (s, 3H, TBS-CH₃), −0.01 (s, 3H, TBS-CH₃); ¹³C{¹H}

NMR (125 MHz, CDCl₃): δ 165.5 (C), 165.1 (C), 161.8 (C), 161.7

(C), 139.0 (C), 138.7 (C), 138.0 (C), 137.9 (C), 137.6 (C), 137.4

(C), 135.0 (C), 133.4 (CH), 133.2 (CH), 133.18 (C), 133.1 (C),

130.1 (CH), 130.06 (CH), 130.0 (C), 129.1 (CH), 128.9 (CH),

128.7 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH),

128.3 (CH), 128.2 (CH), 128.19 (CH), 128.15 (CH), 128.1 (CH),

128.0 (CH), 127.8 (CH), 127.7 (CH), 126.7 (CH), 126.4 (CH),

126.3 (CH), 126.2 (CH), 126.1 (CH), 125.9 (CH), 101.1 (CH),

101.0 (CH), 100.3 (CH), 100.1 (CH), 99.3 (CH), 94.0 (CH), 92.4

(C), 91.8 (C), 80.1 (CH), 79.6 (CH), 79.4 (CH), 78.0 (CH), 76.6

(CH), 75.0 (CH₂), 75.0 (CH), 74.7 (CH), 74.7 (CH₂), 73.8 (CH₂),

73.7 (CH₂), 73.6 (CH), 73.5 (CH), 72.8 (CH), 72.6 (CH), 72.2

(CH), 72.0 (CH₂), 68.7 (CH₂), 68.6 (CH₂), 66.3 (CH), 66.28 (CH),

62.5 (CH), 59.9 (CH), 25.8 (CH₃), 17.9 (C), −4.1 (CH₃), −5.1

(CH₃); HRMS (ESI-TOF) m/z: calcd for C₁₀₁H₁₀₄Cl₆N₂O₂₃SiNa [M

+ Na]⁺, 1976.4827; found, 1976.4893.

Zhijay Tu − Institute of Biological Chemistry, Academia

Sinica, Taipei 11529, Taiwan

Ming-Shiuan Lu − Department of Chemistry, National

Taiwan University, Taipei 10617, Taiwan

Shih-Hao Liu − Institute of Biological Chemistry, Academia

Sinica, Taipei 11529, Taiwan

Septila Renata − Institute of Biological Chemistry and

Chemical Biology and Molecular Biophysics, Taiwan

International Graduate Program, Institute of Biological

Chemistry, Academia Sinica, Taipei 11529, Taiwan; Institute

of Bioinformatics and Structural Biology, College of Life

Science, National Tsing Hua University, Hsinchu 300044,

Taiwan

Riping Phang − Department of Chemistry, National Taiwan

University, Taipei 10617, Taiwan

Peng-Kai Liu − Institute of Biochemical Sciences, College of

Life Science, National Taiwan University, Taipei 10617,

Taiwan

Bhaswati Ghosh − Institute of Biological Chemistry, Academia

Sinica, Taipei 11529, Taiwan

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02422

Notes

The authors declare no competing ﬁnancial interest.

ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02422.

ACKNOWLEDGMENTS

■

This research work was supported by the Ministry of Science

and Technology of Taiwan (108-2113-M-001-001-), Academia

Sinica (AS-105-TP-B05), and ([AS-SUMMIT-109], [MOST-

108-3114-Y-001-002], and [AS-KPQ-109-BioMed]). NMR

spectra were acquired at the NMR facility of the Institute of

Biological Chemistry at Academia Sinica.

Synthesis of type I LacNAc hexasaccharide 36, donor

45, GlcNTCA building block 48, disaccharide building

blocks 2 and 35, type I LacNAc disaccharide donors (4,

6, 7, and 8) and (1, 3, and 5) and acceptors (10−13 and

15) and (14 and 16), type I LacNAc disaccharide donor

9, type I LacNAc tetrasaccharide acceptor 37, and [2 +

2] chemoselective glycosylation; reference donors and

linear correlation; reactivity ratio and RRV of

disaccharides 1−9 and 10−16; listed estimated ln-

(RRV_D); and copies of NMR spectra of new compounds

(PDF)

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AUTHOR INFORMATION

■

Corresponding Author

Chun-Hung Lin − Institute of Biological Chemistry and

Chemical Biology and Molecular Biophysics, Taiwan

International Graduate Program, Institute of Biological

Chemistry, Academia Sinica, Taipei 11529, Taiwan;

Department of Chemistry, National Taiwan University,

Taipei 10617, Taiwan; Institute of Biochemical Sciences,

College of Life Science, National Taiwan University, Taipei

10617, Taiwan; orcid.org/0000-0002-6795-8825;

Phone: (886-2) 2789-0110; Email: chunhung@

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Authors

Nitish Verma − Institute of Biological Chemistry and

Chemical Biology and Molecular Biophysics, Taiwan

International Graduate Program, Institute of Biological

Chemistry, Academia Sinica, Taipei 11529, Taiwan;

Department of Chemistry, National Tsing Hua University,

Hsinchu 300044, Taiwan; orcid.org/0000-0002-4080-

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https://dx.doi.org/10.1021/acs.joc.0c02422

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Threshold of Thioglycoside Reactivity Difference Is Critical for Efficient Synthesis of Type i Oligosaccharides by Chemoselective Glycosylation

DOI: 10.1021/acs.joc.0c02422

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Article abstract of DOI:10.1021/acs.joc.0c02422

Full text of DOI:10.1021/acs.joc.0c02422

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