Conformation-Controlled Hydrogen-Bond-Mediated Aglycone Delivery Method for α-Xylosylation

Delivery Method for α ‑Xylosylation

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Conformation-Controlled Hydrogen-Bond-Mediated Aglycone

∥

Deqin Cai, Ya Bian, Shengjie Wu, and Kan Ding*

Cite This: J. Org. Chem. 2021, 86, 9945 −9960

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sı Supporting Information

ABSTRACT: α-Xylosylated glycans and xylosyl derivatives are biomedi-

cally important molecules which show numerous bioactivities against

infection, cancer, inﬂammation, and so on. Lacking an eﬃcient α-

xylosylation method, the synthesis of α-xyloside-containing molecules was

full of challenges. Herein, a robust method is presented for selective α-

xylosylation via combination of a rare conformation-controlled strategy

and the hydrogen-bond-mediated aglycone delivery method. Various

native branched α-xyloside structures necessitate an orthogonally

protected xyloside, and a three-pot preparation method of the xylosyl

donor was developed for this novel α-xylosylation method, which was

further applied in the ﬁrst synthesis of the side chain N of xyloglucan. This

work provides an eﬃcient α-xylosylation method which would make

various α-xyloside structures achievable. The conformation-controlled

strategy also has important reference to the chemistry of ﬁve-carbon

pyranose.

INTRODUCTION

xyloglucan was reported to mediate the gut-liver circulating

■

bile acid metabolism to ameliorate liver damage. Many of

xyloglucans with simple structures were synthesized using a

Xylose is second only to glucose in natural abundance.

Interestingly, xylose is a minor sugar residue in mammalian

cells and so far, only found in two structures: xyloglucosyl

trisaccharide (D-Xyl-α1-3-D-Xyl-α1-3-D-Glc-β1-O-Ser) and

the tetrasaccharide linkage region (GlcA-β1-3-Gal-β1-3-Gal-

β1-4-Xyl-O-Ser) attached to core protein in proteoglycans.

The xyloglucosyl trisaccharide is an important modiﬁcation in

12,30−33

chemical or enzymatic method.

Due to the lack of

eﬃcient α-xylosylated methods, many complicated xyloglucan

structures had not been reported till date, which hinders their

related functional research and applications.

According to the published work, the most widely used

various proteins, such as bovine blood coagulation factors VII

building block for the construction of α-xylosides is tribenzyl-

and IX, notch receptor, and protein Z. The xylosyl structure

in the linkage region was regarded as the primer of biosynthesis

of glycosaminaglycans attached to proteoglycan, and a series of

34−37

protected 1 (Figure 1a).

However, the product usually

38−40

display no good stereoselectivity,

case was limited to speciﬁc acceptor. The undesired β-

byproduct may also present a great challenge for puriﬁcation.

and individual better

−9

xylosyl derivatives were synthesized as probes or inhibitors.

On the contrary, xylose is abundant in plants, such as xylan

arabinoxylan, glucuronoxylan, and glucuronoarabinoxylan),

xyloglucan, xylogalacturonan, and so forth.

mainly exist in various branches of xyloglucan.

Another frequently reported xylosyl building block for α-

xylosylation is 3-acetyl-2,4-dibenzyl-xyloside (2, Figure 1a).

The 3-OAc was supposed to favor α-product through remote

participation, but this method only displays good stereo-

(

0−12

α-Xylosides

3,14

Xyloglucan

is one of the major hemicelluloses in primary walls of

41−43

spermatophytes. Xyloglucan and its derivatives show multiple

selectivity in limited cases.

Hence, a novel method of α-

bioactivities against infection, cancer, inﬂammation, metabolic

xylosylation with high stereoselectivity and broad applicable

substrates is expectant.

15−21

diseases, and so forth.

drug delivery functional carrier.

oligosaccharides can also act as signaling molecules.

In addition, it is also an important

22−24

The xyloglucan-derived

5,26

Received: January 24, 2021

Published: July 22, 2021

Structurally, xyloglucan is an assembly of β-glucoside residues

with various side chains which were denoted by a special one-

letter code. Not limited to taxonomic signiﬁcance, the branch

pattern of xyloglucan also correlated with functional aspects,

certainly. For example, arabino-modiﬁed xyloglucan was

reported to have anti-infectious activity, and galacto-modiﬁed

2021 American Chemical Society

The Journal of Organic Chemistry

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Figure 1. (a) Two major protective group strategies of the xylosides for α-xylosylation, but both of them are pretty limited in the application of α-

xylosylation, (b) two xyloside models with diﬀerent chair conformations were designed for α-xylosylation via a HAD strategy in this work and a

possible mechanism. According to the anomeric eﬀect, α-xylosyl triﬂate was generated as the major triﬂate intermediate from donor 3, while β-

xylosyl triﬂate was generated for donor 4, which was supposed to explain the diﬀerent glycosylation results.

Recently, hydrogen-bond-mediated aglycone delivery

HAD) had been proved as a powerful method to construct

protecting group TBS (tert-butyldimethylsilyl) was employed

to lock the xyloside ring into an unusual chair conformation

favoring α-xylosylation, and only one hydroxyl was occupied

which avoids potential challenge in the regioselective reaction.

In the structure of both xyloglucoside trisaccharide (D-Xyl-

α1-3-D-Xyl-α1-3-D-Glc-β1-O-Ser) and xyloglucan with variable

branched chains, there were potential glycosyl substituted at 2-

OH, 3-OH, or 4-OH of α-xylosides, which necessitates an

orthogonally protected xyloside building block for α-

xylosylation. However, the three similar secondary hydroxyls

of xylopyranoside present a great challenge in regio-

(

a 1,2-cis glycosidic bond which was developed by Demchenko

4−48

and co-workers.

As the name implies, the hydroxyl of the

acceptor forms a hydrogen bond with the nitrogen atom of the

protective group, usually 2-O-picolinyl (Pic), 2-pyridinecar-

bonyl (Pico), or 2-quinolinecarbonyl (Quin), of the donor,

which facilitates nucleophilic attack of the acceptor from the

same face to the HAD protective group. For xylose, 4-OH and

-OH were direct to the α face, but only 4-OH can be

employed in the HAD glycosylation because the HAD

protective group in the position 2 will play a similar role to

the orthoparticipated protective group rather than the HAD

55,56

protection.

Many of the reported synthetic routes were

hindered by multiple synthetic steps, tedious process, and

57−60

9,50

challenge in the puriﬁcation of similar regio-isomers.

The

group.

reported regio-protection and migration of silyl groups in

Conformation-controlled glycosylation was proved as an

eﬃcient strategy for stereoselective glycosylation, which had

been successfully applied in the synthesis of β-arabinofurano-

61,62

xylosides inspired us to develop a new synthetic method.

Herein, we reported a robust method for various substituted

α-xylosides through conformation inversion and HAD

strategies.

sides, α-Kdo glycosides, α-sialic acid, β-manosides, and

so forth. The reported strategies mainly depend on cyclic

protecting groups to lock the conformation of the sugar ring.

Two hydroxyls were exposed after removing the cyclic

protecting group which may raise another challenge in the

regioselective reaction. In this work (Figure 1b), the bulky

RESULTS AND DISCUSSION

■

During the synthesis of orthogonally protected xyloside

building blocks, the similar three secondary hydroxyls of

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Scheme 1. Synthesis of Two Xylosyl Donor 11a and 12 and the Regio-Deprotection of Donor 12

TBSCl: t-butyldimethylsilyl chloride, 2-BMN: 2-(bromomethyl)naphthalene, TBAB: tetrabutylammonium bromide, PicoOH: 2-picolinic acid,

Nap: 2-naphthylmethyl, DDQ: 1,2-dichloro-4,5-dicyanobenzoquinone.

Scheme 2. Synthesis of Xylosyl Donors 11b, 11c, and 11e

xylosides present a great challenge. Recently, our laboratory

developed a novel protective strategy using a bulky TBS to

showed that the triisopropylsilyl (TIPS) group could be

migrated from 4-OH to 3-OH under excess NaH condition.

Based on this discovery, we developed an eﬃcient synthetic

route to these two xylosyl building blocks 11a (please check

protect the 4-OH of xyloside triol, directly. In 2013, Anuchit

et al. reported silyl migration phenomenon in xylosides. They

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Table 1. Comparative Investigation of Xylosyl Donors 11a and 11b-e in α-Xylosylation

entry

donor

product (yield)

stereoselectivity (α/β)

11a

11b

11c

11d

11e

16a (83%)

16b (78%)

16c (68%)

16d (75%)

α only

16.7/1

0.3/1

0.86/1

1.4/1

16e (91%)

Note: The ratio of the product was calculated by comparison of integrals of H NMR.

the analytic graph of H NMR, as shown in Figure S1) and 12

(

with a ratio of α/β = 16.7/1 (entry 2, Table 1). The diﬀerence

of the two glycosylation results was supposed to be related to

the two triﬂate intermediates (Figure 1b) generated from 11a

and 11b. To verify the function of the HAD group Pico in α-

xylosylation, we further replaced Pico of donor 11a by benzoyl

and generated a new donor named 11c. As shown in entry 3,

11c favored β product which was supposed to be induced by

better remote participation with an axial acyl protective group

at position 4. 11d and 11e were presented as negative xylosyl

building blocks which were used in α-xylosylation in the past

(entry 4 and 5, Table 1, entry 4 repeated three times). Finally,

xylosyl donor 11a was chosen as the best donor.

Scheme 1). The two xylosyl building blocks contained

diﬀerent protecting groups at C2: Bn for 11a and Nap for

2. TBS was ﬁrst used to protect 4-OH in good yield; then, a

key step is observed, in which 2-OH was selectively alkylated,

and TBS was followed migrating from 4-OH to 3-OH to aﬀord

and 10 in one-pot synthesis. The results of the product of

this key reaction suggested that the reaction rate of alkylation

was faster than silyl migration. For the reaction condition of

this key step, the reported NaH condition cannot aﬀord

product better than 24% yield after screening the factors of

equivalent of base and BnBr, reaction time, solvent, and

concentration (Table S1). Finally, we made such conversion

under NaOH/TBAB/BnBr conditions (Table S2). Solvent

plays an important role in the protection of 4-OH with Pico.

The reaction displays an excellent yield in pyridine while can

hardly react in dichloromethane (DCM). Then, we further

checked the orthogonality of the protecting group of xylosyl

building block 12 (Scheme 1). Pico, TBS, and Nap can be

removed by Cu(OAc) , TBAF/AcOH, and 1,2-dichloro-4,5-

dicyanobenzoquinone (DDQ), selectively and respectively.

We further synthesized xylosyl donors 11b, 11c, 11d, and

1e for comparative investigation (Scheme 2). 11b, 11d, and

1e were synthesized from known structures or according to

the reported procedure.

benzylated, and then, 4-methoxybenzyl (PMB) was removed

by DDQ to expose 4-OH, the remaining hydroxyl was

protected with picolinic acid to aﬀord 11b. The synthesis of

As shown in Table 2, the scope of substrates for donor 11a

was further examined. The structure of substrates ranges over

primary hydroxyl, secondary hydroxyl, and tertiary hydroxyl,

over phenolic hydroxyl and amino structures, monosaccharide,

disaccharide, and trisaccharide. The acceptors were obtained

from the commercial source (17a−17f and 17i) or a few

synthetic steps (17g, 17h, 17j, and 17k). These structures were

chosen by rational design. 17a−e and 17i were chosen as the

model of diﬀerent types of hydroxyl. The glycosylation with

tert-butanol 17c was concentration dependent. When the

reaction was performed with 0.07 M of the donor, the reaction

aﬀorded 18c with yield 84% (α/β = 24/1), while 0.02 M

resulted in 66% (α/β = 24/1). The alkyl primary alcohol, such

as methanol, was not chosen because there were already more

1,39,63

The known 11b-1 was

eﬃcient preparation methods. However, the alkyl primary

alcohol was employed as a solvent in the published method.

For the expensive alkyl primary alcohol substrate, 17i as an

example, this work is more preferable. The biosynthesis of

glycosaminoglycans originated from the β-xylosyl residue at the

1e was the initial step in the conversion of 5 to 11e-1 in three

steps. Then, 4-OH was selectively benzylated in low yield

which can be explained by low regio-selectivity of benzylation

and high reactivity of 11e-2. Acylation of 3-OH was carried out

to aﬀord 11e. 11c was synthesized from an intermediate by

esteriﬁcation. As shown in Table 1, various xylosyl donors were

compared. First, we performed the glycosylation, between

donor 11a and galactosyl acceptor 15, to obtain only the α

product in good yield (Entry 1, Table 1). Another Pico-

protected xylosyl building block 11b only aﬀorded products

L-Ser site of core protein. Many xyloside derivatives were

synthesized to unveil the function of this primer struc-

,66,67

ture.

Herein, 18d was synthesized as an epimer

derivative. Unexpectedly, the thiophenol donor did not work

well with 17f, but trichloroacetimide donor 11f did. 18f was

synthesized as a stereoisomer of the reported anti-tumor

68,69

activity β-naphthoxyloside.

The coupling between 17g,

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Table 2. Glycosylation of Xylosyl Donor 11a and Its Tricholoracetimidate Form 11f with Various Types of Substrates

The chloroacetimidate donor was employed, while the thiophenol donor did not work well. The reaction was carried out using the anomeric

reactivity-based thiophenol method.

7h, and xylosyl donor 11a was carried out using the anomeric

reactivity-based thiophenol method, which indicated that the

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Scheme 3. Synthesis of Target Xyloglucan Branch-Derived Pantesaccharide 26

xylosyl donor possessed relatively high reactivity. Acceptors 15,

7j, and 17k were chosen to investigate the eﬀect of the

acceptor size.

then treated with Cu(OAc) and aﬀorded pure trisaccharide

acceptor 24. For the design of galactosyl disaccharide donor

25, the position 4 of the reducing end residue was protected by

an armed protective group Bn to make the donor possesses

high reactivity. The coupling of disaccharide donor 25 and

trisaccharide 24 was catalyzed by 0.67 equiv TfOH in DCM

and aﬀorded the target pentasaccharide 26 which is derived

Unless otherwise speciﬁed, reactions were run with 1.5 equiv

of the donor and 1.0 equiv of the acceptor with the promoter

system of N-iodosuccinimide (N-iodosuccinimide (NIS), 2.0

equiv) and triﬂic acid (0.2 equiv) in the presence of 4 Å

molecular sieves at 0 °C to room temperature (RT) in DCM.

The structure of the xylosylated product was judged by the

coupling constant between H-1 and H-2 and together with the

coupling constant between H-2, H-3, and H-4 as corroborative

evidence. The α/β ratio of the product was calculated by

from the side chain N of xyloglucan.

CONCLUSIONS

■

In conclusion, we developed an eﬃcient method for α-

xylosylation via conformation-constraint HAD. Besides HAD,

bulky TBS was used to lock the conformation of the xylosyl

comparison of integrals in the corresponding H NMR

spectrum.

donor-favored S 2 attack from the α side of β-xylosyl triﬂate.

This method was further used in the synthesis of highly

branched xyloglucan-derived structure 26 (Scheme 3). The

xyloside residue in 26 was glycosylated at position 2 and 4.

Hence, the orthogonal-protected xylosyl donor 12 was

employed to couple with the glucosyl acceptor 19 and

aﬀorded disaccharide with α only stereoselectivity. Usually,

as the size of the acceptor become bigger, glycosylation

becomes more diﬃcult. To the best of our knowledge,

choosing hydroxyl with better reactivity in the latter

glycosylation favored the synthesis of complicated glycans.

Position 4 of the xyloside is less steric hindered than position

Pico at an axial direction may also favor α-product.

Additionally, a pot-economic and time-economic preparation

method of the orthogonally protected xylosyl building block

was developed which improves synthesis eﬃciency and makes

various substituted α-xylosides available. Finally, this novel α-

xylosylation method was employed in the synthesis of the side

chain N of xyloglucan. The conformation-controlled strategy

may further expand to other ﬁve-carbon pyranoses.

EXPERIMENTAL SECTION

General Experimental Procedures. Chemical reagents and

solvents were purchased from Sinopharm Chemical Reagent Co.

■

; hence, glycosylation at position 2 was performed

preferentially. The Nap at position 2 of disaccharide 20 was

then removed by DDQ and aﬀorded 21 in excellent yield. The

(

Shanghai, China) and used without further puriﬁcation. Reactions

were monitored by thin-layer chromatography (TLC) on glass Silica

Gel HSGF254 plates with UV 254 nm detection. TLC staining for

carbohydrate samples was performed by dipping the plates into 10%

H SO in methanol and drying with a heat gun. Anhydrous DCM was

L-arabinosyl donor 22 was employed to coupling with

disaccharide acceptor 21 and aﬀorded trisaccharide 23 with

good stereoselectivity (α/β = 16.7/1). Trisaccharide 23 was

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freshly distilled from calcium hydride under nitrogen prior to use.

Molecular sieves 4 Å powder was purchased from Sigma-Aldrich Co.

LLC (USA) and activated by heating at 200 °C under vacuum for 2 h.

H and C NMR spectra were recorded on a 400 MHz or 600 MHz

instrument. The chemical shifts were assigned in parts per million and

the coupling constants in Hertz. High-resolution mass spectra

Hz, aromatic), 7.14 (bd, 2H, J = 8.0 Hz, aromatic), 5.04 (d, 1H, J =

5.8 Hz, H-1), 4.91 (d, 1H, J = 11.4 Hz), 4.88 (d, 1H, J = 8.6 Hz), 4.84

(d, 1H, J = 11.4 Hz), 3.84 (dd, 1H, J = 4.9 Hz, J = 11.4 Hz, H-5a),

3.62 (t, 1H, J = 8.0 Hz, H-3), 3.39 (m, 1H, H-2), 3.23 (m, 2H, H-4

and H-5b), 2.28 (s, 3H), 0.86 (s, 9H), 0.08 (s, 3H), 0.00 (s, 3H).

C{ H} NMR (150 MHz, DMSO-d ): δ 136.7, 132.7, 132.4, 131.0,

(

HRMS) were measured on a Micromass Ultra Q-TOF spectrometer.

130.5, 129.8, 127.7, 127.6, 126.2, 125.9, 125.7, 125.6, 86.9, 80.6, 77.5,

Matrix-assisted laser desorption/ionization time-of-ﬂight (MALDI-

TOF) was measured on a Autoﬂex Max mass spectrometer (Bruker).

General Procedure for α-Xylosylation. Thiophenol Method.

The xylosyl donor (1.5 equiv) and acceptor (1.0 equiv) were

dissolved in DCM (0.03 M for the xylosyl donor), and the mixture

was stirred for another 15 min in the presence of molecular sieves 4 Å

powder. NIS (2.0 equiv) was added to the mixture which was further

cooled in ice bath. TfOH (0.2 equiv) was injected into the reaction

mixture dropwise, and the reaction mixture was continued stirring for

another 1 h at 0 °C to RT. The resulting mixture was quenched by

triethyl amine, ﬁltered, and concentrated. The residue was puriﬁed by

silica gel column chromatography and aﬀorded the xylosylation

product. The stereoselectivity of the product and conformation of the

xyloside ring were judged by coupling constant between H-1, H-2, H-

73.7, 69.6, 68.2, 26.0, 20.6, 18.0, −4.0, −4.6. HRMS (ESI) m/z: [M +

H] calcd for C H O SSi, 511.2338; found, 511.2327.

p-Tolyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldimethylsilyl-1-

thio-β-D-xylopyranoside (11a). Compound 9 (414 mg, 0.90

mmol), EDCI (516 mg, 2.69 mmol), DMAP (11 mg, 0.090 mmol),

and picolinic acid (224 mg, 1.82 mmol) were dissolved in pyridine (9

mL), and the mixture was stirred for another 12 h at RT. The

resulting mixture was quenched by methanol, concentrated, and co-

distilled with toluene. The residue was puriﬁed by silica gel column

chromatography with eluents EtOAc: PE = 1:3 and aﬀorded 11a (452

mg) as colorless syrup in 89% yield. [α]

NMR (600 MHz, CDCl

− 61.53 (c 0.5, DCM). H

): δ 8.75 (m, 1H, aromatic), 8.04 (d, 1H, J =

7.8 Hz, aromatic), 7.63 (td, 1H, J = 1.7 Hz, J = 7.7 Hz, aromatic), 7.42

(m, 3H), 7.30 (m, 2H, aromatic), 7.26 (m, 3H, aromatic), 7.12 (m,

2H, aromatic), 5.27 (d, 1H, J = 4.1 Hz, H-1), 4.99 (m, 1H, H-4), 4.74

(d, 1H, J = 11.0 Hz), 4.59 (m, 2H, H5a), 4.13 (t, 1H, J = 4.9 Hz, H-

3), 3.71 (dd, 1H, J = 4.6 Hz, J = 12.5 Hz, H5b), 3.57 (t, 1H, J = 4.4

Hz, H-4), 2.33 (s, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H).

, and H-4.

Anomeric Reactivity-Based Thiophenol Method. The xylosyl

donor (1.2 equiv) and acceptor (1.0 equiv) were dissolved in DCM

0.03 M for the xylosyl donor), and the mixture was stirred for

another 15 min in the presence of molecular sieves 4 Å powder. NIS

1.2 equiv) was added to the mixture which was further cooled in ice

(

C{ H} NMR (150 MHz, CDCl ): δ 164.5, 150.1, 147.9, 137.9,

(

137.3, 137.0, 132.6, 131.5, 129.8, 128.4, 128.0, 127.8, 127.0, 125.8,

bath. TfOH (0.1 equiv) was injected into the reaction mixture

dropwise, and the reaction mixture was continued stirring for another

86.9, 79.6, 73.5, 71.9, 69.2, 61.0, 25.9, 21.2, 18.1, 0.1, −4.7, −4.8.

HRMS (ESI) m/z: [M + H] calcd for C H NO SSi, 566.2396;

h at 0 °C to RT. The resulting mixture was quenched by triethyl

found, 566.2398.

amine, ﬁltered, and concentrated. The residue was puriﬁed by silica

gel column chromatography and aﬀorded the xylosylation product.

The stereoselectivity of the product and conformation of the xyloside

ring were judged by coupling constant between H-1, H-2, H-3, and H-

p-Tolyl 3-O-tert-butyldimethylsilyl-2-O-(2-naphthyl)-methyl-4-

O-picolinyl-1-thio-β-D-xylopyranoside (12). Compound 10 (115

mg, 0.22 mmol) synthesized from 5, EDCI (127 mg, 0.66 mmol),

DMAP (2.7 mg, 0.022 mmol), and picolinic acid (81 mg, 0.66 mmol)

were dissolved in pyridine (2.2 mL), and the mixture was stirred for

another 3 h at RT. The resulting mixture was quenched by methanol,

concentrated, and co-distilled with toluene. The residue was puriﬁed

by silica gel column chromatography with eluents EtOAc:PE = 1:3

p-Tolyl 2-O-benzyl-3-O-tert-butyldimethylsilyl-1-thio-β-D-xylo-

pyranoside (9). The known 6 (100 mg, 0.27 mmol), benzyl

bromide (38 μL, 0.32 mmol), and TBAB (8.7 mg, 0.027 mmol) were

dissolved in DCM (2.7 mL), and 5% sodium hydroxide aqueous

solution (2.7 mL) was added to the mixture subsequently. The

mixture was stirred at RT for another 48 h. The DCM layer of the

resulting mixture was collected and concentrated. The residue was

and aﬀorded 12 (126 mg) as a white solid in 91% yield. [α]

−

121.85 (c 0.8, DCM). H NMR (600 MHz, CDCl ): δ 8.70 (d, 1H, J

= 4.0 Hz, aromatic), 7.98 (d, 1H, J = 7.8 Hz, aromatic), 7.80 (m, 1H,

aromatic), 7.72 (m, 3H, aromatic), 7.43 (m, 6H, aromatic), 7.30

(ddd, 1H, J = 0.9 Hz, J = 4.7 Hz, J = 7.5 Hz, aromatic), 7.11 (d, 1H, J

= 8.0 Hz, aromatic), 5.34 (d, 1H, J = 3.9 Hz, H-1), 5.00 (m, 1H, H-4),

4.89 (d, 1H, J = 11.1 Hz), 4.71 (d,1H, J = 11.1 Hz), 4.65 (dd, 1H, J =

2.9 HZ, J = 12.6 Hz, H5a), 4.19 (t, 1H, J = 4.8 Hz), 3.74 (dd, 1H, J =

4.4 Hz, J = 12.5 Hz), 3.66 (t, 1H, J = 4.3 Hz), 2.33 (s, 3H), 0.91 (s,

puriﬁed by TLC with eluents EtOAc/PE = 1:10 and aﬀorded 9 (47

mg) in 38% yield. H NMR (400 MHz, Acetone-d ): δ 7.46−7.25 (m,

H), 7.15 (m, 2H), 5.05 (d, 1H, J = 5.9 Hz), 4.85 (d, 1H, J = 11.3

Hz), 4.75 (d, 1H, J = 11.2 Hz), 4.21 (dd, 1H, J = 3.5 Hz, J = 11.5 Hz),

.80 (t, 1H, J = 6.1 Hz), 3.48 (m, 2H), 3.37 (dd, 1H, J = 6.6 Hz, J =

1.5 Hz), 2.30 (s, 3H), 0.93 (s, 9H), 0.13 (s, 3H), 0.08 (s, 3H).

9H), 0.11 (s, 3H), 0.09 (s, 3H). C{ H} NMR (150 MHz, CDCl ):

C{ H} NMR (100 MHz, Acetone-d ): δ 138.3, 136.9, 132.3, 131.3,

δ 164.2, 149.5, 147.5, 137.3, 137.1, 135.2, 133.1, 131.4, 129.8, 128.1,

128.0, 127.7, 126.9, 126.8, 126.2, 126.1, 125.7, 86.9, 79.5, 73.5, 71.8₊,

68.8, 60.8, 25.8, 21.2, 18.1, −4.7, −4.8. HRMS (ESI) m/z: [M + H]

calcd for C H NO SSi, 616.2553; found, 616.2542.

29.5, 128.1, 127.6, 127.5, 87.1, 80.1, 74.0, 73.2, 69.8, 65.7, 25.4, 20.1,

7.8, −5.2, −5.4. HRMS (ESI) m/z: [M + H] calcd for

C H O SSi, 461.2182; found, 461.2168.

35 42

p-Tolyl 3-O-tert-butyldimethylsilyl-2-O-(2-naphthyl)methyl-1-

p-Tolyl 2-O-(2-naphthyl)methyl-4-O-picolinyl-1-thio-β-D-xylo-

pyranoside (13). 12 (50 mg, 0.081 mmol) was dissolved in pyridine

(0.8 mL), and TBAF (1 M in THF, 160 μL, 0.16 mmol) and acetic

acid (9.6 μL, 0.16 mmol) were added to the mixture. The mixture was

stirred at RT for another 16 h. The resulting mixture was

concentrated and puriﬁed by silica gel column chromatography with

eluents EtOAc/PE = 2.5:1 and aﬀorded 13 (26.7 mg) as a white solid

thio-β-D-xylopyranoside(10). Synthetic route A. 6 (740 mg, 2.0

mmol), 2-(bromomethyl)naphthalene (530 mg, 2.4 mmol), and

TBAB (64.4 mg, 0.2 mmol) were dissolved in DCM (20 mL), and 5%

sodium hydroxide aqueous solution (20 mL) was added to the

mixture subsequently. The mixture was stirred at RT for another 48 h.

The DCM layer of the resulting mixture was collected and

concentrated. The residue was puriﬁed by TLC with eluents

EtOAc:PE = 1:10 and aﬀorded 10 (327 mg) in 32% yield.

in 67% yield. [α] − 25.71 (c 0.14, DCM). H NMR (600 MHz,

CDCl ): δ 8.68 (dd, 1H, J = 0.7 Hz, J = 4.7 Hz, aromatic), 8.04 (d,

Synthetic route B. 12 (10 mg, 0.016 mmol) was dissolved in

MeOH/DCM (1/10, 1.1 mL), and copper(II) acetate (5.8 mg, 0.032

mmol) was added to the mixture. The mixture was stirred at RT for

another 5 h. The resulting mixture was quenched by three drops of

sodium bicarbonate, concentrated, and puriﬁed by silica gel column

chromatography with eluents EtOAc/PE = 1:4 and aﬀorded 10 (7.2

1H, J = 7.9 Hz, aromatic), 7.80 (m, 4H, aromatic), 7.72 (td, 1H, J =

6.0 Hz, J = 7.7 Hz, aromatic), 7.55 (dd, 1H, J = 1.6 Hz, J = 8.4 Hz,

aromatic), 7.46 (m, 4H, aromatic), 7.37 (ddd, 1H, J = 1.1 Hz, J = 4.7

Hz, J = 5.9 Hz, aromatic), 7.13 (d, 1H, J = 7.9 Hz, aromatic), 5.10 (m,

2H), 4.93 (d, 1H, J = 11.2 Hz), 4.68 (d, 1H, J = 9.1 Hz, H-1), 4.33

(dd, 1H, J = 5.3 Hz, J = 11.5 Hz, H5a), 4.12 (t, 1H, J = 8.7 Hz, H-3),

3.51 (t, 1H, J = 8.8 Hz, H-2), 3.44 (dd, 1H, J = 9.7 Hz, J = 11.4 Hz,

mg) in 87% yield.

H NMR (600 MHz, DMSO-d ): δ 7.88 (m, 3H, aromatic), 7.82

H5b), 2.35 (s, 3H). C{ H} NMR (150 MHz, CDCl ): δ 164.7,

(s, 1H, aromatic), 7.56−7.46 (m, 3H, aromatic), 7.35 (bd, 2H, J = 8.1

149.9, 147.5, 137.2, 132.9, 129.9, 128.4, 128.1, 127.8, 127.3, 127.1,

951

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The Journal of Organic Chemistry

Article

26.2, 126.1, 125.7, 88.3, 80.4, 75.3, 73.0, 66.0, 21.3. HRMS (ESI) m/

11c (1.10 g) in 94% yield. H NMR (600 MHz, CDCl ): δ 8.04 (m,

z: [M + H] calcd for C H NO S, 502.1688; found, 502.1669.

1H, aromatic), 7.51 (t, 1H, J = 7.9 Hz, aromatic), 7.42 (d, 2H, J = 8.1

Hz, aromatic), 7.38−7.22 (m, 7H, aromatic), 7.11 (d, 2H, J = 8.0 Hz,

aromatic), 5.32 (d, 1H, J = 3.7 Hz, H-1), 4.93 (m, 1H, H-4), 4.75 (d,

1H, J = 11.2 Hz), 4.62 (dd, 1H, J = 2.9 Hz, J = 12.6 Hz), 4.58 (d, 1H,

J = 11.2 Hz), 4.08 (t, 1H, J = 4.7 Hz), 3.67 (dd, 1H, J = 4.1 Hz, J =

12.5 Hz), 3.59 (t, 1H, J = 4.2 Hz), 2.32 (s, 3H), 0.92 (s, 9H), 0.10 (s,

3H), 0.08 (s, 3H). C{ H} NMR (150 MHz, CDCl ): δ 166.1,

137.8, 137.2, 133.2, 132.8, 131.3, 130.0, 129.8, 128.4, 128.0, 127.8,

86.8, 79.3, 73.3, 71.0, 69.0, 60.9, 25.8, 21.2, 18.1, −4.7, −4.8. HRMS

(ESI) m/z: [M + Na] calcd for C H O SSiNa, 587.2263; found,

p-Tolyl 3-O-tert-butyldimethylsilyl-4-O-picolinyl-1-thio-β-D-xylo-

pyranoside (14). 12 (163 mg, 0.26 mmol) was dissolved in DCM/

H O (5/1, 6 mL), and DDQ (90 mg, 0.40 mmol) was then added.

The mixture was stirred for another 20 h at RT. The resulting mixture

was diluted, and the organic phase was concentrated and puriﬁed by

silica gel column chromatography with eluents EtOAc/PE = 1:2 and

aﬀorded 14 (134 mg) as a white solid in 87% yield. [α] − 124.45 (c

Hz, J = 1.6 Hz, J = 2.6 Hz, aromatic), 8.11 (dt, 1H, J = 1.0 Hz, J = 7.8

Hz, aromatic), 7.84 (td, 1H, J = 1.8 Hz, J = 7.7 Hz, aromatic), 7.48

.3, DCM). H NMR (600 MHz, CDCl ): δ 8.72 (ddd, 1H, J = 0.8

587.2258.

(

ddd, 1H, J = 1.2 Hz, J = 4.8 Hz, J = 6.0 Hz, aromatic), 7.41 (m, 2H),

.10 (m, 2H), 5.03 (m, 2H), 4.58 (dd, 1H, J = 3.0 Hz, J = 12.3 Hz),

.02 (t, 1H, J = 5.1 Hz), 3.68 (m, 2H), 2.32 (s, 3H), 0.88 (s, 9H),

.17 (s, 3H), 0.10 (s, 3H). C{ H} NMR (150 MHz, CDCl ): δ

p-Tolyl 2-O-benzyl-1-thio-β-D-xylopyranoside (11e-1). The

known xylosyl start material 5 (5 g, 19.5 mmol), 2,3-butanedione

(2.1 mL, 23.4 mmol), and trimethoxymethane (6.4 mL, 58.5 mmol)

were dissolved in methanol (200 mL), and then, boron triﬂuoride

etherate (5 mL, 39 mmol) was added to the mixture dropwise. The

resulting mixture was stirred for another 5 h and then neutralized with

triethylamine and concentrated. The residue was puriﬁed by silica gel

column chromatography with eluents EtOAc/PE = 1:4 and aﬀorded

the intermediate p-tolyl 3,4-O-(2′,3′-dimethoxybutane-2′3′-diyl)-1-

63.9, 150.0, 147.6, 137.6, 137.0, 132.1, 129.7, 127.2, 125.1, 89.1,

2.4, 70.9, 61.3, 25.7, 21.1, 18.1, −4.7, −5.0. HRMS (ESI) m/z: [M +

H] calcd for C H NO SSi, 476.1927; found, 476.1934.

p-Tolyl 2,3-di-O-benzyl-1-thio-β-D-xylopyranoside (11b-2). The

known 11b-1 (1.34 g, 3.56 mmol) was dissolved in DMF (35 mL),

and sodium hydride (60% in kerosene, 342 mg, 8.54 mmol) was

added to the mixture. Benzyl bromide (1.043 mL, 8.54 mmol) was

added to the stirring mixture after 5 min. The mixture was stirred for

another 12 h at RT. The resulting mixture was quenched by acetic

acid and concentrated. The residue was taken up with DCM and

washed with sodium bicarbonate solution and water. The organic

phase was concentrated, and the residue was employed in the next

thio-β-D-xylopyranoside (4.52 g) as a white solid in 62% yield. [α]

86.98 (c 0.27, DCM). H NMR (600 MHz, CDCl ): δ 7.44 (m, 2H),

7.12 (m, 2H), 4.40 (d, 1H, J = 9.2 Hz, H-1), 3.96 (dd, 1H, J = 4.4 Hz,

J = 10.7 Hz), 3.69 (m, 2H), 3.43 (m, 2H), 3.31 (s, 3H), 3.24 (s, 3H),

2.34 (s, 3H), 1.33 (s, 3H), 1.28 (s, 3H). C{ H} NMR (150 MHz,

CDCl ): δ 138.9, 134.2, 130.0, 127.0, 100.0, 99.6, 89.5, 74.0, 69.1,

68.1, 65.6, 48.2, 48.1, 21.3, 17.8, 17.7. HRMS (ESI) m/z: [M + Na]

step directly. The residue from above was dissolved in DCM/H O

calcd for C H O SNa, 393.1348; found, 393.1335. The pre-

18 26

(

5/1, 36 mL), and DDQ (1.3 g, 5.7 mmol) was added to the mixture.

benzylated start material p-tolyl 3,4-O-(2′,3′-dimethoxybutane-2′3′-

diyl)-1-thio-β-D-xylopyranoside (10 g, 0.270 mol) was dissolved in

DMF (270 mL), and sodium hydride (60% in kerosene, 1.3 g, 0.324

mol) was added. Benzyl bromide (4 mL, 0.324 mol) was injected into

the reaction mixture after 5 min. The reaction mixture was further

stirred for another 3 h and then concentrated under vacuum to

remove most DMF. The residue was taken up with ethyl ether and

then washed with water for three times. The organic layer was

concentrated and aﬀorded the crude-benzylated intermediate. The

The mixture was stirred for another 5 h at RT. The resulting mixture

was ﬁltered through celite. The organic phase was washed with

sodium thiosulfate solution and sodium bicarbonate solution. The

organic phase was concentrated and puriﬁed by silica gel column

chromatography with eluents EtOAc/PE = 1:4 and aﬀorded 11b-2

(940 mg) in 60% yield. H NMR (600 MHz, CDCl ): δ 7.45 (d, 2H, J

8.1 Hz, aromatic), 7.43−7.28 (m, 10H, aromatic), 7.15 (d, 2H, J =

(

.9 Hz, aromatic), 5.13 (d, 1H, J = 4.8 Hz, H-1), 4.82 (dd, 2H, J =

0.1 Hz, J = 9.5 Hz), 4.66 (dd, 2H, J = 4.9 Hz, J = 4.8 Hz), 4.41 (dd,

H, J = 3.0 Hz, J = 3.0 Hz), 3.73 (m, 2H), 3.65 (t, 1H, J = 5.5 Hz),

intermediate was then dissolved in DCM/TFA/H O (10/1/0.1, 91.5

mL). The reaction mixture was stirred for another 2 h and neutralized

with triethyl amine and concentrated. The residue was puriﬁed by

silica gel column chromatography with eluents MeOH/DCM = 1:20

.51 (dd, 1H, J = 5.5 Hz, J = 11.8 Hz), 2.37 (s, 3H). C{ H} NMR

150 MHz, CDCl ): δ 137.9, 137.5, 137.3, 131.8, 129.8, 128.6, 128.1,

28.0, 127.8, 87.3, 78.7, 78.0, 73.6, 73.5, 68.2, 65.0, 21.1. HRMS

and aﬀorded 11e-1 (9.0 g) as a light yellow solid in 96% yield. [α] −

ESI) m/z: [M + H]⁺calcd for C H O S, 437.1787; found,

(

26.41 (c 0.13, DCM). H NMR (600 MHz, CDCl ): δ 7.43 (m, 2H),

37.1775.

p-Tolyl 2,3-di-O-benzyl-4-O-picolinyl-1-thio-β-D-xylopyranoside

11b). 11b-2 (940 mg, 2.15 mmol), DMAP (210 mg, 1.72 mmol),

7.38 (m, 4H), 7.33 (m, 1H), 7.14 (m, 2H), 4.96 (d, 1H, J = 11. 1 Hz),

4.72 (d, 1H, J = 8. 1 Hz, H-1), 4.64 (d, 1H, J = 11. 2 Hz), 4.13 (dd,

1H, J = 4.7 Hz, J = 11.6 Hz, H5a), 3.66 (m, 1H), 3.60 (t, 1H, J = 7.7

Hz), 3.36 (t, 1H, J = 7.9 Hz), 3.30 (dd, 1H, J = 8.7 Hz, J = 11.6 Hz),

(

EDCI (1.24 g, 6.45 mmol), and picolinic acid (793 mg, 6.45 mmol)

were dissolved in DCM (12 mL), and the resulting mixture was

stirred at RT for another 14 h. The reaction mixture was concentrated

and puriﬁed by silica gel column chromatography with eluents

2.35 (s, 3H). C{ H} NMR (150 MHz, CDCl ): δ 138.1, 137.9,

132.5, 130.1, 130.0, 128.8, 128.4, 88.1, 80.0, 76.7, 74.8, 69.5, 67.9,

−

21.3. HRMS (ESI) m/z: [M − H] calcd for C H O S, 345.1163;

EtOAc/PE = 1:2 and aﬀorded 11b (1.10 g) in 94% yield. H NMR

found, 345.1161.

(

600 MHz, CDCl ): δ 8.75 (m, 1H, aromatic), 8.01 (d, 1H, J = 7.9

p-Tolyl 2,4-di-O-benzyl-1-thio-β-D-xylopyranoside (11e-2). 11e-1

(350 mg, 0.78 mmol) was dissolved in DMF (7.8 mL), and sodium

hydride (60% in kerosene, 32 mg, 0.86 mmol) was added to the

mixture. Benzyl bromide (95 μL, 0.78 mmol) was added to the

stirring mixture after 5 min. The mixture was stirred for another 20 h

at RT. The resulting mixture was quenched by acetic acid and

concentrated. The residue was taken up with DCM and washed with

sodium bicarbonate solution and water. The organic phase was

concentrated, and the residue was puriﬁed by silica gel column

Hz, aromatic), 7.75 (td, 1H, J = 1.7 Hz, J = 7.8 Hz, aromatic), 7.46

m, 3H, aromatic), 7.37 (m, 2H, aromatic), 7.31 (m, 3H, aromatic),

.22 (m, 2H, aromatic), 7.18 (m, 3H, aromatic), 7.13 (m, 2H,

aromatic), 5.26 (m, 1H, H-4), 4.81 (m, 4H), 4.69 (d, 1H, J = 10.5),

(

.38 (dd, 1H, J = 4.7 Hz, J = 11.7 Hz, H5a), 3.94 (t, 1H, J = 7.8 Hz),

.60 (t, 1H, J = 7.7 Hz), 3.54 (dd, 1H, J = 8.5 Hz, J = 11.8 Hz, H5b),

.34 (s, 3H). ¹³C{ H} NMR (150 MHz, CDCl ): δ 164.4, 150.1,

47.6, 138.1, 137.1, 132.7, 129.9, 128.5, 128.3, 128.0, 127.8, 127.2,

5.7, 88.1, 81.2, 79.6, 77.4, 75.0, 71.8, 65.1, 21.3. HRMS (ESI) m/z:

chromatography with eluents EtOAc/PE = 1:6 and aﬀorded 11e-2

[

M + H] calcd for C H NO S, 542.2001; found, 542.1995.

(89 mg) in 21% yield. H NMR (600 MHz, CDCl

): δ 7.43 (m, 4H,

p-Tolyl 4-O-benzoyl-2-O-benzyl-3-O-tert-butyldimethylsilyl-1-

aromatic), 7.39−7.27 (m, 8H, aromatic), 7.12 (m, 2H, aromatic),

4.93 (d, 1H, J = 10.9 Hz), 4.75 (d, 1H, J = 10.9 Hz), 4.69 (d, 1H, J =

11.8 Hz), 4.63 (d, 1H, J = 11.8 Hz), 4.56 (d, 1H, J = 9.6 Hz, H-1),

4.03 (dd, 1H, J = 5.2 Hz, H5a), 3.72 (t, 1H, J = 8.8 Hz), 3.50 (m, 1H,

H-4), 3.31 (t, 1H, J = 9.3 Hz), 3.18 (dd, 1H, J = 10.4 Hz, J = 11.4 Hz,

thio-β-D-xylopyranoside (11c). 9 (100 mg, 0.22 mmol) and benzoyl

chloride (60 μL, 0.51 mmol) were dissolved in pyridine (2 mL). The

mixture was stirred overnight at RT. The mixture was diluted with

DCM and extracted with 1 M HCl₍_a_q₎and sodium bicarbonate

solution. The DCM layer was concentrated and puriﬁed by silica gel

column chromatography with eluents EtOAc/PE = 1:15 and aﬀorded

H5b), 2.34 (s, 3H). C{ H} NMR (150 MHz, CDCl ): δ 137.7,

137.6, 137.5, 132.2, 129.3, 129.1, 128.1, 127.7, 127.5, 127.4, 87.9,

952

J. Org. Chem. 2021, 86, 9945−9960

The Journal of Organic Chemistry

Article

0.0, 77.4, 74.7, 72.6, 67.0, 20.7. HRMS (ESI) m/z: [M + H] calcd

Benzyl 2,3-di-O-benzyl-4-O-picolinyl-α/β-D-xylopyranosyl-(1 →

6)-2,3,4-tri-O-benzoyl-β-D-galactopyranoside (16b). 11b (56 mg,

0.104 mmol) and 15 (40 mg, 0.069 mmol) were reacted to aﬀord 16b

(53.4 mg, α/β = 16.7/1, 78%) as a white solid according to the

thiophenol method of general procedure (eluents: EtOAc/PE = 1:1)

for C H O S, 437.1787; found, 437.1778.

p-Tolyl 3-O-acetyl-2,4-di-O-benzyl-1-thio-β-D-xylopyranoside

11e). 11e-2 (89 mg, 0.17 mmol) was dissolved in pyridine (1 mL)

and acetic acid (1 mL). The mixture was stirred for another 16 h at

RT. The resulting mixture was concentrated and co-distilled with

toluene. The residue was puriﬁed by silica gel column chromatog-

(

for α-xylosylation. [α] ± 62.60 (c 0.11, DCM). NMR of α product:

H NMR (600 MHz, CDCl ): δ 8.64 (m, 1H, aromatic),8.11 (m, 2H,

raphy with eluents EtOAc/PE = 1:6 and aﬀorded 11e (92 mg) in 96%

aromatic), 7.93 (m, 3H, aromatic), 7.78 (m, 2H, aromatic), 7.69 (td,

1H, J = 1.7 Hz, J = 7.8 Hz, aromatic), 7.61 (t, 1H, J = 7.4 Hz,

aromatic), 7.57−7.15 (m, 25H, aromatic), 5.91 (d, 1H, J = 3.0 Hz, H-

yield. H NMR (600 MHz, CDCl ): δ 7.42 (m, 2H, aromatic), 7.36−

7.23 (m, 10H, aromatic), 7.12 (m, 2H, aromatic), 5.21 (t, 1H, J = 8.8

Gal

Hz, H-3), 4.86 (d, 1H, J = 11.1 Hz), 4.67 (d, 1H, J = 9.1 Hz, H-1),

4 ), 5.84 (dd, 1H, J = 8.0 Hz, J = 10.3 Hz, H-2 ), 5.52 (dd, 1H, J =

Gal

Xyl

.56 (m, 3H), 4.07 (dd, 1H, J = 5.1 Hz, J = 1.6 Hz, H-5a), 3.53 (m,

3.4 Hz, J = 10.4 Hz, H-3 ), 5.24 (m, 1H, H-4 ), 4.90 (d, 2H, J =

Gal

Xyl

H, H-5), 3.40 (t, 1H, J = 8.9 Hz, H-2), 3.30 (dd, 1H, J = 9.8 Hz, J =

11.8 Hz), 4.84−4.65 (m, 6H, H-1 , H-1 ), 4.20 (m, 2H, H-3 ),

1.6 Hz, H-5b), 2.35 (s, 3H), 1.94 (s, 3H). C{ H} NMR (150

3.92 (m, 3H), 3.69 (dd, 1H, J = 5.0 Hz, J = 10.3 Hz), 3.60 (dd, 1H, J

Xyl 13

MHz, CDCl ): δ 170.0, 138.2, 138.0, 137.9, 132.8, 129.9, 129.7,

= 4.4 Hz, J = 9.2 Hz, H-2 ). C{ H} NMR (150 MHz, CDCl ): δ

28.6, 128.5, 128.2, 128.1, 127.9, 127.8, 88.8, 78.8, 76.0, 75.3, 74.8,

165.8, 165.6, 165.4, 164.4, 150.1, 150.0, 147.7, 136.9, 133.3, 130.2,

130.0, 129.9, 128.8, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.6,

127.0, 125.4, 99.5, 97.5, 79.5, 78.7, 75.5, 73.6, 73.0, 72.5, 72.0, 70.5,

70.0, 68.9, 66.6, 59.2. HRMS (ESI) m/z: [M + H]⁺calcd for

C H NO , 1000.3539; found, 1000.3527.

72.8, 67.3, 21.3, 21.1. HRMS (ESI) m/z: [M + H] calcd for

C H O S, 479.1892; found, 479.1890.

p-Tolyl 2,3,4-tri-O-benzoyl-1-thio-β-D-galactopyranoside (15).

The known donor p-tolyl 2,3,4-tri-O-benzoyl-6-O-t-butyldimethylsil-

yl-1-thio-β-D-galactopyranoside (4.27 g, 6.0 mmol) and commer-

cially available BnOH (740 μL, 7.2 mmol) were dissolved in DCM

Benzyl 4-O-benzoyl-2-O-benzyl-3-O-tert-butyldimethylsilyl-α/β-

D-xylopyranosyl-(1 → 6)-2,3,4-tri-O-benzoyl-β-D-galactopyrano-

side (16c). 11c (36.4 mg, 0.064 mmol) and 15 (25 mg, 0.043

mmol) were reacted to aﬀord 16c (30 mg, α/β ≈ 0.3/1, 68%)

according to the thiophenol method of general procedure (eluents:

(

60 mL), and the mixture was stirred for another 15 min in the

presence of molecular sieves 4 Å powder. NIS (1.7 g, 7.8 mmol) was

added to the mixture which was further cooled in ice bath. TMSOTf

(

327 μL, 1.8 mmol) was injected into the reaction mixture dropwise,

and the reaction mixture was continued stirring for another 1 h at 0

C to RT. The resulting mixture was quenched by triethyl amine,

EtOAc/PE = 1:4) for α-xylosylation. NMR of α/β products: H NMR

(600 MHz, CDCl

5.81 (m, 2.6H, H-2 and H-4 of β product), 5.47 (m, 1.3H, H-3

of β product), 5.07 (m, 1.3H, H-4 of β product), 4.94 (m, 1.3H),

4.89 (d, 0.3H, J = 12.7 Hz), 4.84 (d, 1H, J = 12.7 Hz), 4.76 (m, 2H),

): δ 8.12−7.07 (m, 43.5H, aromatic and CHCl ),

Gal

Xyl

ﬁltered, and washed with sodium bicarbonate solution and sodium

thiosulfate solution. The organic layer was concentrated, the residue

was taken up with THF (60 mL), and TBAF (1 M in THF, 7.2 mL,

Gal

4.70 (d, 1H, J = 7.9 Hz, H-1 of β product), 4.64−4.44 (m, 2.9H, H-

Xyl

.2 mmol) and acetic acid (410 μL, 7.2 mmol) were also added to the

of β product), 4.24 (t, 0.3H, J = 8.4 Hz), 4.19 (m, 0.3H), 4.03−

Xyl Xyl

mixture. The mixture was stirred for another 16 h at RT. The

resulting mixture was concentrated and puriﬁed by silica gel column

chromatography with eluents EtOAc/PE/DCM = 1:4:2.5 to 1:3:2

3.86 (m, 4.5H, H-3 and H-5a of β product), 3.80 (m, 1.6H), 3.55

Xyl

(m, 0.2H), 3.39 (m, 1.3H, H-2 of β product), 3.23 (m, 1H, H-5b

of β product), 0.77 (m, 12.2H), 0.10 (s, 0.8H), 0.00 (m, 3.6H), −0.06

and aﬀorded 15 (1.72 g, 50% in two steps). H NMR (600 MHz,

(m, 3H). C{ H} NMR (150 MHz, CDCl ): δ 165.8, 165.7, 165.4,

CDCl ): δ 8.15 (d, 2H, J = 7.9 Hz, aromatic), 7.96 (d, 2H, J = 7.9 Hz,

aromatic), 7.84 (m, 2H, J = 8.0 Hz, aromatic), 7.65 (t, 1H, aromatic),

138.8, 138.3, 136.9, 136.5, 133.6, 133.3, 130.2, 130.1, 130.0, 129.9,

129.8, 129.6, 129.4, 129.0, 128.7, 128.6, 128.4, 128.2, 128.0, 127.9,

127.8, 127.7, 103.8, 99.9, 99.2, 97.5, 81.6, 79.9, 74.5, 74.0, 73.4, 73.3,

73.0, 72.0, 71.9, 71.3, 70.7, 70.3, 69.9, 69.4, 69.0, 68.8, 67.7, 66.9,

7.61−7.39 (m, 6H), 7.31−7.19 (m, 7H, aromatic), 5.96 (dd, 1H, J =

8.1 Hz, J = 10.3 Hz, H-2), 5.87 (d, 1H, J = 3.3 Hz, H-4), 5.59 (dd,

1H, J = 3.3 Hz, J = 10.4 Hz, H-3), 4.98 (d, 1H, J = 12.6 Hz), 4.88 (d,

1H, J = 7.9 Hz, H-1), 4.78 (d, 1H, J = 12.6 Hz), 4.04 (t, 1H, J = 6.7

62.2, 59.3, 25.8, 18.1, 0.1, −4.0, −4.1, −4.6. HRMS (ESI) m/z: [M +

] calcd for C59

66NO14Si, 1040.4247; found, 1040.4256.

Hz, H-5), 3.90 (dd, 1H, J = 6.6 Hz, J = 11.8 Hz, H6a), 3.72 (dd, 1H, J

Benzyl 2,3,4-tri-O-benzyl-α/β-D-xylopyranosyl-(1 → 6)-2,3,4-tri-

O-benzoyl-β-D-galacto-pyranoside (16d). 11d (26.8 mg, 0.051

mmol) and 15 (20 mg, 0.034 mmol) were reacted to aﬀord 16d

(25 mg, α/β = 0.86/1, 75%) as a white solid according to the

thiophenol method of general procedure (eluents: EtOAc/PE = 1:4)

6.8 Hz, J = 11.7 Hz, H6b). C{ H} NMR (150 MHz, CDCl ): δ

167.0, 165.6, 165.5, 136.7, 134.0, 133.5, 133.4, 130.3, 130.0 129.9,

29.4, 128.8, 128.5, 128.1, 128.0, 100.0, 74.1, 71.9, 71.0, 70.0, 69.1,

found, 583.1968.

for α-xylosylation. [α]

products: H NMR (600 MHz, CDCl

+ 67.47 (c 0.6, DCM). NMR of α/β

Benzyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldimethylsilyl-α-D-

): δ 8.12−7.07 (m, 78.7H,

xylopyranosyl-(1 → 6)-2,3,4-tri-O-benzoyl-β-D-galactopyranoside

aromatic and CHCl ), 5.87 (m, 3.2H), 5.81 (dd, 1.1H, J = 7.9 Hz, J =

(16a). 11a (34.7 mg, 0.062 mmol) and 15 (24 mg, 0.041 mmol) were

10.3 Hz), 5.51 (dd, 1H, J = 3.5 Hz, J = 10.3 Hz), 5.47 (dd, 1.2H, J =

3.5 Hz, J = 10.4 Hz), 4.98−4.84 (m, 6.7H), 4.83 (d, 1.2H, J = 11.0

Hz), 4.80−4.75 (m, 3.7H), 4.75−4.70 (m, 2.8H), 4.70−4.63 (m,

reacted to aﬀord 16a (35 mg, α only, 83%) as a white solid according

to the thiophenol method of general procedure (eluents: EtOAc/PE =

Xyl

:2) for α-xylosylation. [α]_D+ 66.40 (c 0.14, DCM). H NMR (600

4.5H), 4.62 (d, 1H, J = 3.3 Hz, H-1 of α product), 4.58 (d, 1.2H, J

Xyl

MHz, CDCl ): δ 8.65 (d, 1H, J = 4.1 Hz, aromatic), 8.09 (m,3H,

= 11.6 Hz), 4.41 (d, 1H, J = 7.5 Hz, H-1 of β product), 4.20 (m,

aromatic), 7.92 (m, 2H, aromatic), 7.77 (m, 3H, aromatic), 7.61 (m,

1H), 4.08 (m, 1.2H), 4.01 (dd, 1.2H, J = 4.6 Hz, J = 10.8 Hz), 3.96 (t,

1H, J = 9.2 Hz), 3.89 (m, 2.2H), 3.77 (m, 2.2H), 3.65 (m, 2H), 3.61−

H, aromatic), 7.54 (m, 1H, aromatic), 7.50−7.14 (m, 19H,

Gal

Xyl

aromatic), 5.86 (d, 1H, J = 3.3 Hz, H-4 ), 5.82 (dd, 1H, J = 8.0

3.51 (m, 3.4H), 3.46 (dd, 1H, J = 3.4 Hz, J = 9.5 Hz, H-2 of α

Gal

Xyl

Hz, J = 10.3 Hz, H-2 ), 5.51 (dd, 1H, J = 3.5 Hz, J = 10.4 Hz, H-

product), 3.38 (t, 1H, J = 7.9 Hz, H-2 of β product), 3.12 (dd, 1H, J

Gal

Xyl

), 5.12 (m, 1H, H-4 ), 4.92 (d, 1H, J = 12.8 Hz), 4.79 (m, 2H,

= 9.6 Hz, J = 11.7 Hz), 1.59 (s, 7.8H). C{ H} NMR (150 MHz,

Gal

Xyl

H-1 ), 4.71 (d, 1H, J = 12.0 Hz), 4.58 (m, 2H, H-1 ), 4.31 (t, 1 H,

J = 8.3 Hz, H-3 ), 4.18 (m, 1H,, H-5 ), 3.91 (m, 2H, H-6a and

H-5a ), 3.85 (dd, 1H, J = 5.6 Hz, J = 11.1 Hz, H-5b ), 3.57 (dd,

CDCl ): δ 165.9, 165.7, 165.6, 165.5, 165.4, 139.1, 138.8, 138.7,

Xyl

Gal

138.5, 138.3, 136.9, 136.7, 133.7, 133.6, 133.3, 130.2, 130.1, 129.9,

129.6, 129.4, 129.2, 129.1, 129.0, 128.7, 128.6, 128.5, 128.4, 128.3,

128.2, 128.0, 127.8, 127.7, 104.2, 99.9, 99.4, 97.1, 83.8, 82.0, 81.5,

79.7, 78.1, 78.0, 75.9, 75.7, 75.1, 73.6, 73.4, 73.1, 72.0, 70.7, 70.4,

70.1, 69.9, 69.1, 68.8, 67.9, 66.4, 63.9, 60.4. HRMS (ESI) m/z: [M +

Xyl

Gal

1H, J = 4.7 Hz, J = 10.3 Hz, H-6b ), 3.41 (dd, 1H, J = 3.1 Hz, J = 8.4

Xyl

Hz, H-2 ), 0.77 (s, 9H), 0.11 (s,3H), 0.03 (s, 3H). C{ H} NMR

150 MHz, CDCl ): δ 165.8, 165.7, 165.4, 163.9, 149.3, 147.1, 133.3,

(

30.2, 130.0, 129.9, 128.7, 128.6, 128.5, 128.4, 128.2, 99.4, 97.6, 79.7,

Na] calcd for C H O Na, 1007.3619; found, 1007.3620.

56 13

4.0, 73.6, 73.0, 72.1, 71.0, 70.5, 70.0, 68.9, 66.7, 59.4, 25.8, 18.1,

Benzyl 3-O-acetyl-2,4-tri-O-benzyl-α/β-D-xylopyranosyl-(1 → 6)-

2,3,4-tri-O-benzoyl-β-D-galactopyranoside (16e). 11e (59.8 mg,

0.104 mmol) and 15 (40 mg, 0.069 mmol) were reacted to aﬀord 16e

−

4.1, −4.6. HRMS (ESI) m/z: [M + H] calcd for C H NO Si,

024.3940; found, 1024.3954.

953

J. Org. Chem. 2021, 86, 9945−9960

The Journal of Organic Chemistry

Article

(

65 mg, α/β = 1.4/1, 91%) as a white solid according to the

DCM, washed with water, and concentrated. The residue was puriﬁed

thiophenol method of general procedure (eluents: EtOAc/PE = 1:3)

for α-xylosylation. [α] + 82.31 (c 0.6, DCM). NMR of α/β

products: H NMR (600 MHz, CDCl ): δ 8.14−7.10 (m, 82.1H,

aromatic and CHCl ), 5.83 (m, 4.8H), 5.54 (t, 1.4H, J = 9.6 Hz, H-

by silica gel column chromatography with eluents EtOAc: PE = 1:4

and aﬀorded 17g (144 mg, 48% in three steps). H NMR (600 MHz,

CDCl ): δ 8.08 (d, 2H, J = 7.2 Hz, aromatic), 7.92 (m, 2H, J = 7.2

Hz, aromatic), 7.66 (m, 2H), 7.61 (m, 2H), 7.55−7.28 (m, 13H),

7.15 (t, 1H, J = 7.6 Hz), 7.08 (d, 1H, J = 8.0 Hz), 5.81 (d, 1H, J = 3.2

Hz, H-4), 5.15 (t, 1H, J = 9.7 Hz, H-2), 4.81 (D, 1H, J = 9.8 Hz, H-

1), 4.14 (dd, 1H, J = 2.9 Hz, J = 9.5 Hz), 3.92 (t, 1H, J = 6.8 Hz), 3.84

(dd, 1H, J = 6.1 Hz, J = 10.3 Hz), 3.76 (m, 1H), 2.33 (s, 3H), 1.00 (s,

Xyl

of α product), 5.47 (m, 2.4H), 5.11 (t, 1H, J = 9.2 Hz, H-3 of β

product), 4.92 (d, 2.4H, J = 12.7 Hz), 4.86 (d, 1H, J = 12.0 Hz), 4.78

Xyl

(

m, 2.9H), 4.74 (d, 1H, J = 8.0 Hz), 4.71 (d, 1.4H, J = 3.3 Hz, H-1

of α product), 4.66 (m, 2.5H), 4.62−4.49 (m, 6.9H), 4.47 (m, 2H, H-

Xyl

of β product), 4.20 (dd, 1.4H, J = 3.2 Hz, J = 7.6 Hz), 4.07 (t, 1H,

9H). C{ H} NMR (150 MHz, CDCl ): δ 166.8, 166.4, 138.6, 135.7,

J = 5.8 H), 4.02 (dd, 1H, J = 5.2 Hz, J = 10.6 Hz), 3.94−3.83 (m, 4H,

135.6, 134.5, 133.6, 133.5, 133.1, 132.9, 130.2, 129.9, 129.8, 129.7,

129.5, 128.6, 128.5, 127.9, 127.8, 127.4, 85.6, 77.9, 73.6, 71.9, 70.6,

61.8, 26.8, 21.4, 19.2. HRMS (ESI) m/z: [M + NH₄]⁺calcd for

C H NO SSi, 750.2921; found, 750.2899.

Xyl

H-5a of α product), 3.76−3.65 (m, 2.5H, H-5b of α product and,

Xyl

H-5a of β product), 3.59 (dd, 1H, J = 3.6 Hz, J = 10.3 Hz), 3.53 (m,

Xyl

.5H, H-4 of α product), 3.47−3.38 (m, 2.5H, H-2 of α product

and, H-4 of β product), 3.27 (dd, 1H, J = 7.4 Hz, J = 9.3 Hz, H-2

p-Tolyl 2,3,4-tri-O-benzoyl-β-D-galactopyranosyl-(1 → 6)-2,3,4-

Xyl

of β product), 3.16 (dd, 1H, J = 10.0 Hz, J = 11.7 Hz, H-5b of β

product). 2.05 (s, 4.1H), 1.93 (m, 3H). C{ H} NMR (150 MHz,

tri-O-benzoyl-1-thio-β-D-galacto-pyranoside (17j). The known

donor p-tolyl 2,3,4-tri-O-benzoyl-6-O-t-butyldimethylsilyl-1-thio-β-D-

galactopyranoside (1.35 g, 1.9 mmol) and 15 (1.0 μL, 1.7 mmol) was

dissolved in DCM (17 mL), and the mixture was stirred for another

15 min in the presence of molecular sieves 4 Å powder. NIS (497 mg,

2.2 mmol) was added to the mixture which was further cooled in ice

bath. TMSOTf (93 μL, 0.51 mmol) was injected into the reaction

mixture dropwise, and the reaction mixture was continued stirring for

another 1 h at 0 °C to RT. The resulting mixture was quenched by

triethyl amine, ﬁltered, and washed with sodium bicarbonate solution

and sodium thiosulfate solution. The organic layer was concentrated,

and the residue was taken up with THF (17 mL), and TBAF (1 M in

THF, 2.0 mL, 2.0 mmol) and acetic acid (116 μL, 2.0 mmol) were

also added to the mixture. The mixture was stirred for another 16 h at

RT. The resulting mixture was concentrated and puriﬁed by silica gel

CDCl ): δ 170.0, 169.9, 165.8, 165.6, 165.4, 165.2, 133.6, 133.2,

30.1, 130.0, 129.9, 129.8, 129.5, 128.6, 128.5, 128.4, 128.3, 128.0,

27.9, 127.7, 127.6, 127.5, 103.7, 99.8, 99.2, 96.3, 79.1, 75.8, 75.4,

4.3, 73.0, 72.9, 72.8, 72.7, 71.9, 70.5, 69.9, 69.1, 66.4, 63.4, 59.9,

1.1, 21.0. HRMS (ESI) m/z: [M + NH ] calcd for C H NO ,

55 56

54.3701; found, 954.3635.

-O-Benzyl-4-O-picolinyl-3-O-tert-butyldimethylsilyl-α/β-D-xylo-

pyranosyl trichloroacetimidate (11f). To a solution of compound

1a (67.8 mg, 0.12 mmol) in DCM (1.2 mL), NIS (40 mg, 0.18

mmol) and triﬂuoroacetyl (TFA) (9 μL, 0.12 mmol) were added at 0

C. About 25 min later, TLC indicated the end of the reaction. The

mixture was diluted with DCM and washed with sodium thiosulfate

and sodium bicarbonate solution; DCM was re-extracted once. The

organic layer was concentrated and dried under vacuum. The residue

column chromatography with eluents EtOAc/PE = 1:1.5 to 1:1 and

was redissolved in DCM, and CCl CN (60 μL, 0.60 mmol) and DBU

aﬀorded 17j (1.0 g, 77% in two steps). H NMR (600 MHz, CDCl ):

(

9 μL, 0.06 mmol) were added subsequently. About 30 min later,

δ 8.16−7.04 (m, 35H, aromatic), 5.91 (d, 1H, J = 3.2 Hz), 5.84 (dd,

1H, J = 7.9 Hz, J = 10.3 Hz), 5.81−5.73 (m, 2H), 5.55 (dd, 1H, J =

3.3 Hz, J = 10.4 Hz), 5.45 (dd, 1H, J = 3.4 Hz, J = 10.3 Hz), 4.85 (d,

1H, J = 7.9 Hz), 4.70−4.61 (m, 2H), 4.45 (d, 1H, J = 12.6 Hz), 4.17−

4.08 (m, 2H), 3.95 (t, 1H, J = 6.5 Hz), 3.90 (m, 1H), 3.68 (dd, 1H, J

= 6.35 Hz, J = 11.98 Hz), 3.50 (dd, 1H, J = 6.47 Hz, J = 11.99 Hz).

TLC indicated the end of the reaction. The reaction mixture was

concentrated and puriﬁed by silica gel column chromatography with

eluents EtOAc/PE/DCM = 1:4:2.5, containing 0.5% Et N, to aﬀord

1a (47 mg, 65%).

p-Tolyl 2,3-di-O-benzoyl-6-O-tert-butyldiphenylsilyl-1-thio-β-D-

galactopyranoside (17g). p-Tolyl 3-O-levulinoyl-4,6-O-benzylidene-

C{ H} NMR (150 MHz, CDCl ): δ 166.9, 165.8, 165.6, 165.5,

-thio-β-D-galactopyranoside (2.0 g, 3.47 mmol) was dissolved in

65.4, 136.7, 133.9, 133.8, 133.5, 133.3, 130.3, 130.2, 130.0, 129.9,

DCM/H O/TFA (10/1/0.1, 11.1 mL), and the mixture was stirred

129.5, 129.4, 129.2, 129.0, 128.9, 128.8, 128.6, 128.4, 128.1, 128.0,

01.5, 99.5, 74.3, 73.2, 71.9, 70.4, 70.1, 69.9, 69.0, 68.8, 68.5, 60.7.

for another 1 h. The resulting mixture was diluted with DCM and

washed with sodium bicarbonate solution. The organic layer was

concentrated and puriﬁed by silica gel column chromatography with

eluents MeOH/DCM = 1:20 and aﬀorded p-tolyl 2-O-benzoyl-3-O-

levulinoyl-1-thio-β-D-galactopyranoside (1.43 g, 85%). H NMR (600

MHz, CDCl ): δ 8.03 (m, 2H, J = 7.7 Hz, aromatic), 7.59 (t, 1H, J =

HRMS (ESI) m/z: [M + NH ] calcd for C H NO , 1074.3548;

61 56

found, 1074.3523.

p-Tolyl 2,3,4-tri-O-benzoyl-β-D-galactopyranosyl-(1 → 6)-2,3,4-

tri-O-benzoyl-β-D-galactopyranosyl-(1 → 6)-2,3,4-tri-O-benzoyl-1-

thio-β-D-galactopyranoside (17k). The known donor p-tolyl 2,3,4-

tri-O-benzoyl-6-O-t-butyldimethylsilyl-1-thio-β-D-galactopyranoside

(133 mg, 0.188 mmol) and 17j (180 mg, 0.17 mmol) were dissolved

in DCM (17 mL), and the mixture was stirred for another 15 min in

the presence of molecular sieves 4 Å powder. NIS (49.5 mg, 0.22

mmol) was added to the mixture which was further cooled in ice bath.

TfOH (3.0 μL, 0.034 mmol) was injected into the reaction mixture

dropwise, and the reaction mixture was continued stirring for another

1 h at 0 °C to RT. The resulting mixture was quenched by triethyl

amine, ﬁltered, and washed with sodium bicarbonate solution and

sodium thiosulfate solution. The organic layer was concentrated, and

.2 Hz, aromatic), 7.46 (t, 1H, J = 7.8 Hz, aromatic), 7.35 (d, 2H, J =

.0 Hz, aromatic), 7.08 (d, 2H, J = 7.9 Hz, aromatic), 5.59 (t, 1H, J =

.9 Hz), 5.04 (dd, 1H, J = 3.0 Hz, J = 9.8 Hz), 4.81 (d, 1H, J = 10

Hz), 4.28 (bs, 1H), 4.02 (dd, 1H, J = 6.2 Hz, J = 11.9 Hz), 3.86 (dd,

H, J = 4.1 Hz, J = 12.0 Hz), 3.70 (t, 1H, J = 5.2 Hz), 2.69 (m, 1H),

.51 (m, 1H), 2.45−2.75 (m, 5H), 2.11 (s, 3H). C{ H} NMR (150

MHz, CDCl ): δ 208.2, 172.0, 165.3, 138.4, 133.4, 133.1, 130.0,

29.8, 129.6, 128.8, 128.5, 87.0, 78.2, 75.4, 68.1, 67.8, 62.8, 38.3, 29.8,

8.3, 21.2. HRMS (ESI) m/z: [M + NH ] calcd for C H NO S,

25 32

06.1843; found, 506.1835. p-Tolyl 2-O-benzoyl-3-O-levulinoyl-1-

thio-β-D-galactopyranoside (200 mg, 0.40 mmol), BPSCl (156 μL,

.60 mmol), and imidazole (40.8 mg, 0.60 mmol) were dissolved in

the residue was taken up with DCM/TFA/H O (10/1/0.1, 2.22 mL).

The mixture was stirred for another 1 h at RT. The resulting mixture

was diluted with DCM and washed with sodium bicarbonate solution.

The organic layer was concentrated and puriﬁed by silica gel column

chromatography with eluents EtOAc/PE/DCM = 1:10:5.5 to 1:2:1.5

DCM (4 mL). The reaction mixture was stirred for another 12 h at

RT. The reaction mixture was quenched by methanol and

concentrated. The residue was taken up with pyridine (3 mL) and

benzoyl chloride (450 μL, 3.85 mmol). The reaction mixture was

stirred for another 3 h at RT. The reaction mixture was quenched by

methanol and concentrated. The residue was taken up with DCM and

washed with 1 M HCl₍_a_q₎, sodium bicarbonate solution. The DCM

layer was concentrated, and the residue was taken up with MeOH/

DCM (1/1, 4.6 mL). Acetic acid (598 μL, 10.5 mmol) and hydrazine

monohydrate (298 μL, 6.1 mmol) were added to the mixture. The

mixture was stirred overnight. The resulting mixture was diluted with

and aﬀorded 17k (161 mg, 62% in two steps). H NMR (600 MHz,

CDCl ): δ 8.10 (m, 2H, aromatic), 8.02 (m, 4H, aromatic), 7.94 (m,

4H, aromatic), 7.88 (m, 2H, aromatic), 7.78 (m, 6H), 7.65−7.05 (m,

32H), 5.98 (d, 1H, J = 3.2 Hz), 5.84 (d, 1H, J = 3.4 Hz), 5.74 (m,

4H), 5.53 (dd, 1H, J = 3.4 Hz, J = 10.4 Hz), 5.49 (dd, 1H, J = 3.3 Hz,

J = 10.4 Hz), 5.43 (dd, 1H, J = 3.4 Hz, J = 10.4 Hz), 4.77 (d, 1H, J =

7.9 Hz), 4.63 (m, 3H), 4.41 (d, 1H, J = 12.8 Hz), 4.10 (m, 3H),

3.95−3.75 (m, 3H), 3.65 (dd, 1H, J = 5.0 Hz, J = 9.8 Hz), 3.47 (dd,

954

J. Org. Chem. 2021, 86, 9945−9960

The Journal of Organic Chemistry

Article

H, J = 6.8 Hz, J = 12.2 Hz), 3.32 (dd, 1H, J = 6.0 Hz, J = 12.2 Hz).

74.0, 73.8, 61.9, 28.9, 25.7, 18.0, −4.1, −4.6. HRMS (ESI) m/z: [M +

C{ H} NMR (150 MHz, CDCl ): δ 166.7, 165.7, 165.6, 165.5,

H] calcd for C H NO Si, 516.2776; found, 516.2767.

28 43

65.4, 165.3, 136.7, 133.8, 133.6, 133.5, 133.4, 133.3, 130.3, 130.2,

29.9, 129.5, 129.4, 129.1, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4,

28.3, 128.1, 127.9, 101.2, 101.1, 99.4, 74.3, 73.1, 72.5, 71.9, 71.8,

N-tert-Butoxycarbonyl-O-(2-O-Benzyl-4-O-picolinyl-3-O-tert-bu-

tyldimethylsilyl-α-D-xylopyranosyl)-L-serine benzyl ester (18d). 11a

(

35 mg, 0.062 mmol) and commercially available 17d (12 mg, 0.041

mmol) were reacted to aﬀord 18d (25 mg, α only, 84%) as a white

0.3, 70.1, 69.9, 68.9, 68.8, 68.1, 68.0, 66.9, 60.8, 60.5. HRMS (ESI)

solid according to the thiophenol method of general procedure

m/z: [M + NH₄] calcd for C H NO , 1548.4863; found,

(

eluents: EtOAc/PE = 1:4) for α-xylosylation. [α] + 5.41 (c 0.11,

1548.4850.

DCM). H NMR (600 MHz, CDCl ): δ 8.76 (d, 1H, J = 4.2 Hz,

Iso-Propyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldimethylsilyl-

aromatic), 8.11 (d, 1H, J = 7.8 Hz),7.80 (m, 1H, aromatic), 7.46 (m,

α-D-xylopyranoside (18a). 11a (50 mg, 0.088 mmol) and 17a (4.5

μL, 0.059 mmol) were reacted to aﬀord 18a (25 mg, α only, 85%)

according to the thiophenol method of general procedure (eluents:

H, aromatic), 7.36−7.23 (m, 10H), 5.56 (d, 1H, J = 8.5 Hz, NH),

.18−5.06 (m, 3H, H-4), 4.65−4.47 (m, 4H, H-1), 4.19 (t, 1H, J =

8.5 Hz, H-3), 3.90 (m, 2H), 3.79 (dd, 1H, J = 5.5 Hz, J = 11.1 Hz, H-

EtOAc/PE = 1:4) for α-xylosylation. H NMR (600 MHz, CDCl ): δ

a), 3.69 (t, 1H, J = 10.6 Hz, H-5b), 3.37 (dd, 1H, J = 3.2 Hz, J = 8.5

.75 (d, 1H, J = 4.2 Hz, aromatic), 8.13 (d, 1H, J = 7.8 Hz),7.82 (m,

H, aromatic), 7.47 (m, 1H, aromatic), 7.41−7.22 (m, 5H, aromatic),

.13 (m, 1H), 4.75 (d, 1H, J = 3.5 Hz), 4.71 (d, 1H, J = 12.0 Hz),

.57 (d, 1H, J = 12.0 Hz), 4.26 (t, 1H, J = 8.7 Hz), 3.78 (m, 3H), 3.38

Hz, H-2), 1.43 (s, 9H), 0.74 (s, 9H), 0.04 (s, 3H), −0.02 (s, 3H).

C{ H} NMR (150 MHz, CDCl ): δ 170.4, 164.5, 155.6, 149.9,

47.8, 138.2, 137.0, 135.4, 128.7, 128.5, 128.4, 128.2, 128.1, 127.9,

27.1, 125.6, 98.4, 80.2, 79.8, 73.4, 73.1, 70.9, 69.4, 67.4, 59.5, 54.3,

(dd, 1H, J = 3.5 Hz, J = 8.9 Hz), 1.23 (d, 3H, J = 6.3 Hz), 1.13 (d,

8.4, 25.8, 18.0, −4.2, −4.7. HRMS (ESI) m/z: [M + H] calcd for

H, J = 6.1 Hz), 0.73 (s, 9H), 0.06 (s, 3H), −0.03 (s, 3H). C{ H}

C H N O Si, 737.3469; found, 737.3484.

NMR (150 MHz, CDCl ): δ 164.7, 149.9,147.9, 138.5, 137.1, 128.4,

39 53

p-Methoxylbenzyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldime-

thylsilyl-α-D-xylopyranoside (18e). 11a (40 mg, 0.071 mmol) and

commercially available 17e (6.5 mg, 0.047 mmol) were reacted to

aﬀord 18e (22 mg, α only, 81%) as a white solid according to the

thiophenol method of general procedure (eluents: EtOAc/PE/DCM

28.3, 127.9, 127.1, 125.6, 95.3, 80.2, 74.0, 73.5,71.3, 69.7, 58.7, 25.8,

3.4, 21.4, 18.1, −4.0, −4.7. HRMS (ESI) m/z: [M + H] calcd for

C H NO Si, 502.2625; found, 502.2629.

-Adamantyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldimethyl-

silyl-α-D-xylopyranoside (18b). 11a (50 mg, 0.088 mmol) and

commercially available 17b (9 mg, 0.059 mmol) were reacted to

aﬀord 18b (33 mg, α only, 93%) as light yellow syrup according to the

thiophenol method of general procedure (eluents: EtOAc/PE = 1:2)

for α-xylosylation. [α]_D+ 25.13 (c 0.5, DCM). H NMR (600 MHz,

CDCl ): δ 8.75 (d, 1H, J = 4.0 Hz, aromatic), 8.14 (d, 1H, J = 7.8 Hz,

aromatic), 7.81 (m, 1H, aromatic), 7.46 (m, 1H, aromatic), 7.39−

1:4:2.5) for α-xylosylation. [α] + 21.20 (c 0.5, DCM). H NMR

(600 MHz, CDCl ): δ 8.74 (m, 1H, aromatic), 8.10 (d, 1H, J = 7.9

Hz, aromatic), 7.81 (m, 1H, aromatic), 7.81 (m, 1H, aromatic), 7.46

(m, 1H, aromatic), 7.29 (m, 7H, aromatic), 6.85 (d, 2H, J = 8.6 Hz,

aromatic), 5.13 (m, 1H), 4.70 (d, 1H, J = 3.4 Hz), 4.61 (m, 2H), 4.42

(

m, 2H), 4.28 (t, 1H, J = 8.8 Hz), 3.76 (m, 5H), 3.37 (dd, 1H, J = 3.4

Hz, J = 8.8 Hz), 0.71 (s, 9H), 0.04 (s, 3H), −0.05 (s, 3H). C{ H}

NMR (150 MHz, CDCl ): δ 164.6, 159.4, 150.0, 147.9, 138.3, 137.0,

.23 (m, 5H, aromatic), 5.20 (d, 1H, J = 3.4 Hz, H-1), 5.12 (m, 1H),

.62 (m, 2H), 4.28 (t, 1H, J = 8.6 Hz), 3.93 (t, 1H, J = 10.6 Hz), 3.73

30.1, 129.2, 128.4, 128.1, 127.8, 127.1, 125.5, 113.9, 95.5, 80.0, 73.7,

(m, 1H), 3.35 (dd, 1H, J = 3.4 Hz, J = 8.7 Hz), 2.12 (s, 3H), 1.80 (m,

73.3, 71.3, 58.9, 55.4, 25.8, 18.1, −4.1, −4.7. HRMS (ESI) m/z: [M +

H), 1.60 (m, 6H), 0.71 (s, 9H), 0.00 (s, 3H), −0.04 (s, 3H).

H] calcd for C H NO Si, 580.2731; found, 580.2718.

C{ H} NMR (150 MHz, CDCl ): δ 164.7, 149.9, 148.0, 138.4,

-Naphthyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldimethylsil-

37.0, 128.3, 128.2, 127.7, 127.0, 125.6, 90.2, 80.2, 74.6, 74.0, 73.1,

yl-α-D-xylopyranoside (18f). Xylosyl donor 11f (40 mg, 0.067

mmol) and 2-naphthol (8 mg, 0.10 mmol) were dissolved in DCM (2

mL), and the mixture was stirred for another 15 min in the presence

of molecular sieves 4 Å powder. NIS (0.20 mmol) was added to the

mixture which was further cooled in ice bath. TfOH (0.02 mmol) was

injected into the reaction mixture dropwise, and the reaction mixture

was continued stirring for another 1 h at 0 °C to RT. The resulting

mixture was quenched by triethyl amine, ﬁltered, and concentrated.

The residue was puriﬁed by silica gel column chromatography with

eluents EtOAc/PE/DCM = 1:6:3.5 and aﬀorded 18f (30 mg, 92%) as

1.1, 58.8, 42.6, 36.4, 30.7, 25.8, 18.1, −4.1, −4.7. HRMS (ESI) m/z:

[

M + H] calcd for C H NO Si, 594.3251; found, 594.3260.

tert-Butyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldimethylsilyl-

α-D-xylopyranoside (18c). Procedure A: 11a (70 mg, 0.123 mmol)

and commercially available 17c (7.7 μL, 0.107 mmol) were reacted to

aﬀord 18c (41 mg, 66%, α/β = 24/1) as a white solid according to the

thiophenol method of general procedure (eluents: EtOAc/PE = 1:4)

for α-xylosylation while the concentration of 11a is 0.02 M. Procedure

B: 11a (50 mg, 0.088 mmol) and commercially available 17c (5.5 μL,

0.059 mmol) were reacted to aﬀord 18c as a white solid (38 mg, 84%,

a white solid. [α]_D+ 35.17 (c 0.1, DCM). H NMR (600 MHz,

α/β = 24/1) according to the thiophenol method of general

procedure for α-xylosylation while the concentration of 11a is 0.07

CDCl ): δ 8.76 (d, 1H, J = 4.5 Hz, aromatic), 8.14 (d, 1H, J = 7.8 Hz,

aromatic),7.86−7.65 (m, 4H, aromatic), 7.50−7.19 (m, 10H,

aromatic), 5.46 (d, 1H, J = 3.3 Hz, H-1), 5.29 (m, 1H, H-4), 4.80

M. [α]²+ 5.37 (c 0.8, DCM). H NMR of α product (600 MHz,

CDCl ): δ 8.76 (d, 1H, J = 4.1 Hz, aromatic), 8.14 (d, 1H, J = 7.8 Hz,

aromatic), 7.80 (m, 1H, aromatic), 7.46 (m, 1H, aromatic), 7.38−

(d, 1H, J = 12.0 Hz), 4.60 (d, 1H, J = 12.1 Hz), 4.54 (t, 1H, J = 7.8

Hz, H-3), 3.88 (d, 2H, J = 8.2 Hz), 3.61 (dd, 1H, J = 3.3 Hz, J = 8.9

.24 (m, 5H), 5.13 (m, 1H, H-4), 5.05 (d, 1H, J = 3.3 Hz, H-1), 4.63

Hz, H-2), 0.79 (s, 9H), 0.15 (s, 3H), 0.05 (s, 3H). C{ H} NMR

150 MHz, CDCl ): δ 164.6, 154.5, 149.9, 147.8, 138.1, 137.1, 134.4,

(s, 2H), 4.27 (t, 1H, J = 8.6 Hz, H-3), 3.90 (t, 1H, J = 10.4 Hz, H-5a),

(

3.73 (dd, 1H, J = 5.4 Hz, J = 10.9 Hz, H-5b), 3.35 (t, 1H, J = 3.4 Hz, J

29.5, 128.5, 128.3, 128.0, 127.7, 127.2, 126.5, 125.6, 124.4, 119.2,

11.0, 95.9, 80.1, 73.9, 73.4, 71.3, 59.4, 25.8, 18.1, −4.0, −4.7. HRMS

8.7 Hz, H-2), 1.23 (s, 9H), 0.72 (s, 9H), 0.00 (s, 3H), −0.04 (s,

H). ¹³C{ H} NMR (150 MHz, CDCl ): δ 164.7, 149.9, 148.1, 138.6,

(

ESI) m/z: [M + H] calcd for C H NO Si, 586.2625; found,

37.0, 128.3, 128.0, 127.7, 127.0, 125.6, 91.8, 80.3, 75.3, 74.0, 73.2,

86.2612.

1.1, 58.8, 28.8, 25.8, 18.1, −4.2, −4.7. HRMS (ESI) m/z: [M + H]

p-Tolyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldimethylsilyl-α-D-

calcd for C H NO Si, 516.2776; found, 516.2779. H NMR of β

product (600 MHz, CDCl ): δ 8.75 (d, 1H, J = 4.1 Hz, aromatic),

xylopyranosyl-(1 → 6)-2,4-di-O-benzoyl-6-O-tert-butyldiphenylsil-

yl-1-thio-β-D-galactopyranoside (18g). 11a (48 mg, 0.071 mmol)

and 17g (52 mg, 0.071 mmol) were reacted to aﬀord 18g (58 mg, α

only, 71%) as a white solid according to the anomeric reactivity-based

thiophenol method of general procedure (eluents: EtOAc/PE = 1:2)

8.10 (d, 1H, J = 7.8 Hz, aromatic), 7.83 (m, 1H, aromatic), 7.47 (m,

H, aromatic), 7.35−7.26 (m, 5H, aromatic), 5.16 (m, 1H, H-4), 5.02

(d, 1H, J = 11.3 Hz), 4.65 (d, 1H, J = 11.3 Hz), 4.62 (d, 1H, J = 7.4

Hz, H-1), 4.09 (dd, 1H, J = 5.3 Hz, J = 11.5 Hz, H-5a), 4.00 (t, 1H, J

8.6 Hz, H-3), 3.40 (dd, 1H, J = 9.9 Hz, J = 11.4 Hz, H-5b), 3.30 (t,

H, J = 7.8 Hz, H-2), 1.25 (s, 9H), 0.71 (s, 9H), −0.07 (s, 3H), −0.03

for α-xylosylation. [α] + 33.22 (c 0.3, DCM). H NMR (600 MHz,

CDCl ): δ 8.70 (m, 1H, aromatic), 8.05 (m, 2H, aromatic), 7.87 (m,

(

2H, aromatic), 7.66 (m, 2H, aromatic), 7.55 (m, 3H, aromatic), 7.50

(m, 1H, aromatic), 7.44−7.28 (m, 14H, aromatic), 7.18 (t, 2H, J = 7.5

Hz, aromatic), 7.22−7.14 (m, 7H, aromatic), 5.95 (d, 1H, J = 2.9 Hz,

s, 3H). ¹³C{ H} NMR (150 MHz, CDCl ): δ 164.6, 149.9, 148.1,

38.6, 137.0, 128.3, 127.4, 127.2, 127.0, 125.4, 98.4, 82.0, 76.0, 74.4,

955

J. Org. Chem. 2021, 86, 9945−9960

The Journal of Organic Chemistry

Article

H-4^G^a^l), 5.57 (m, 1H, H-2^G^a^l), 5.10 (d, 1H, J = 2.2 Hz, H-1^X^y^l), 4.83

165.6, 165.5, 165.4, 150.1, 147.9, 138.3, 137.1, 136.7, 133.6, 133.6,

133.3, 133.3, 130.2, 130.1, 129.9, 129.9, 129.5, 129.4, 129.3, 129.1,

129.0, 128.8, 128.7, 128.5, 128.4, 128.3, 128.1, 127.9, 127.0, 125.6,

101.3, 99.4, 98.2, 79.3, 73.5, 73.1, 73.0, 72.6, 71.9, 70.8, 70.2, 70.1,

69.9, 68.8, 68.4, 68.1, 66.3, 59.7, 29.8, 25.8, 18.0, −4.2, −4.7. HRMS

Xyl

Gal

(

m, 2H, H-4 and H-1 ), 4.47 (d, 1H, J = 11.9 Hz), 4.29 (d, 1H, J

11.8 Hz), 4.11 (m, 1H, H-3 ), 3.89 (m, 2H, H-3 ), 3.82 (dd, 1H,

Gal

Xyl

J = 6.1 Hz, J = 10.3 Hz), 3.75 (dd, 1H, J = 7.0 Hz, J = 10.3 Hz), 3.69

(

m, 1H), 3.58 (m, 1H), 3.26 (dd, 1H, J = 2.8 Hz, J = 7.8 Hz, H-2^X^y^l),

.34 (s, 3H), 1.04 (s,9H), 0.67 (s, 9H), −0.14 (s, 3H), −0.20 (s, 3H).

(ESI) m/z: [M + H] calcd for C H NO Si, 1498.5254; found,

C{ H} NMR (150 MHz, CDCl ): δ 165.5, 165.2, 163.9, 150.0

1498.5259.

47.5, 138.4, 138.3, 136.7, 135.7, 135.7, 134.0, 133.1, 133.1, 133.0,

32.9, 130.3, 130.2, 129.9, 129.8, 129.7, 128.4, 128.1, 128.0, 127.9,

27.8, 127.3, 126.7, 125.4, 95.5, 86.6, 78.3, 78.3, 76.0, 73.1, 72.5, 70.2,

p-Tolyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldimethylsilyl-α-D-

xylopyranosyl-(1 → 6)-2,3,4-tri-O-benzoyl-β-D-galactopyranosyl-(1

→

6)-2,3,4-tri-O-benzoyl-β-D-galactopyranosyl-(1 → 6)-2,3,4-tri-O-

benzoyl-1-thio-β-D-galactopyranoside (18k). 11a (11.8 mg, 0.021

mmol) and 17k (21 mg, 0.014 mmol) were reacted to aﬀord 18k (22

mg, α only, 81%) as a white solid according to the thiophenol method

of general procedure (eluents: EtOAc/PE = 1:1.5) for α-xylosylation.

6.8, 62.1, 60.3, 26.9, 25.8, 21.4, 19.2, 18.0, −4.5, −5.1. HRMS (ESI)

m/z: [M + H] calcd for C H NO SSi , 1174.4627; found,

174.4640.

p-Tolyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldimethylsilyl-α-D-

xylopyranosyl-(1 → 6)-2,3,4-tri-O-benzoyl-1-thio-β-D-galactopyra-

[

(

α] + 147.30 (c 0.1, DCM). H NMR (600 MHz, CDCl ): δ 8.77

[

d, 1H, J = 4.0 Hz, aromatic), 8.11 (m, 3H, aromatic), 8.01 (m, 4H,

noside (18h). 11a (15 mg, 0.026 mmol) and 17h (13.2 mg, 0.022

mmol) were reacted to aﬀord 18h (18.3 mg, α only, 80%) according

to the anomeric reactivity-based thiophenol method of general

aromatic), 7.93 (m, 4H, aromatic), 7.87 (m, 2H, aromatic), 7.77 (m,

7H, aromatic), 7.60−7.05 (m, 41H, aromatic and CHCl ), 5.92 (d,

1H, J = 3.2 Hz), 5.88 (d, 1H, J = 3.0 Hz), 5.80 (d, 1H, J = 3.5 Hz),

procedure (eluents: EtOAc/PE/DCM = 1:4:2.5) for α-xylosylation.

.71 (m, 2H), 5.64 (dd, 1H, J = 7.9 Hz, J = 10.3 Hz), 5.52 (m, 2H),

.41 (dd, 1H, J = 3.5 Hz, J = 10.4 Hz), 4.99 (m, 1H), 4.76 (d, 1H, J =

.9 Hz), 4.68−4.54 (m, 4H), 4.50 (d, 1H, J = 12.0 Hz), 4.40 (m, 2H),

H NMR (600 MHz, CDCl ): δ 8.75 (m, 1H, aromatic), 8.06 (m, 1H,

aromatic), 7.98 (m, 2H, aromatic), 7.87 (m, 2H, aromatic),7.75 (m,

H, aromatic), 7.60 (m, 1H, aromatic), 7.56−7.16 (m, 18H), 5.89 (d,

H, J = 2.8 Hz, H-4 ), 5.68 (t, 1H, J = 9.8 Hz, H-2 ), 5.56 (dd, 1H,

Gal Gal

4.15−3.95 (m, 6H), 3.80 (m, 1H), 3.70−3.55 (m, 3H), 3.40 (dd, 1H,

Gal

Xyl

J = 4.8 Hz, J = 10.1 Hz), 3.26 (dd, 1H, J = 3.0 Hz, J = 8.0 Hz), 3.19

J = 3.2 Hz, J = 9.9 Hz, H-3 ), 5.12 (m, 1H, H-4 ), 4.95 (d, 1H, J =

Gal

Xyl

(m, 1H), 0.72 (s, 9H), −0.01 (s. 3H), −0.04 (s, 3H). C{ H} NMR

.9 Hz, H-1 ), 4.68 (dd, 1H, J = 12 Hz), 4.57 (m, 2H, H-1 ), 4.24

Xyl

(150 MHz, CDCl ): δ 165.6, 165.5, 165.4, 165.3, 165.2, 164.4, 150.1,

(m, 2H, H-3 ), 3.84 (m, 3H), 3.49 (dd,1H, J = 5.2 Hz, J = 10.5 Hz),

Xyl

147.9, 138.3, 137.1, 136.8, 133.5, 133.4, 133.3, 133.2, 130.3, 130.2,

130.1, 129.9, 129.6, 129.5, 129.4, 129.2, 129.1, 128.8, 128.7, 128.6,

.39 (dd, 1H, J = 3.3 Hz, J = 8.5 Hz, H-2 ) 2.38 (s, 3H), 0.76 (s,

H), 0.09 (s, 3H), 0.01 (s, 3H). C{ H} NMR (150 MHz, CDCl ):

28.5, 128.4, 128.3, 128.1, 127.9, 127.8, 127.1, 125.7, 101.3, 100.9,

9.4, 98.2, 78.9, 73.4, 73.1, 73.0, 72.5, 72.3, 72.0, 71.9, 71.8, 70.7,

0.2, 70.1, 69.9, 68.8, 68.1, 67.9, 66.2, 65.7, 60.5, 59.8, 25.8, 21.2,

δ 165.6, 165.5, 165.3, 164.5, 150.0, 147.9, 138.7, 138.3, 137.0, 134.7,

33.6, 133.4, 133.3, 130.1, 130.0, 129.9, 129.8, 129.6, 129.2, 129.1,

28.6, 128.5, 128.4, 128.0, 127.6, 127.0, 125.6, 98.0, 86.1, 79.8, 76.5,

3.8, 73.4, 71.1, 69.0, 68.2, 67.2, 59.4, 31.8, 29.8, 25.8, 21.5, 18.1,

8.0, −4.2, −4.8. HRMS (MALDI-TOF) m/z: [M + Na] calcd for

H NNaO 0Si, 1994.6388; found, 1994.6199.

-Azidohexan-1-yl 2,3,4-tri-O-benzoyl-β-D-glucopyranoside (19).

−

4.0, −4.6. HRMS (ESI) m/z: [M + H] calcd for C H NO SSi,

112 105 3

040.3711; found, 1040.3708.

The trichloroimidate donor 2,3,4-tri-O-benzoyl-6-O-tert-butyldiphe-

nylsilyl-α-D-glucopyranosyl trichloroacetimidate (478 mg, 0.55 mmol)

and 6-azido-1-hexanol^[(157 mg, 1.10 mmol) were dissolved in

DCM (5.5 mL), and freshly activated molecular sieves (500 mg) were

added to the solution. The solution was stirred for another 15 min

under nitrogen at RT. The reaction ﬂask was put in ice bath, and

triﬂuoromethanesulfonic acid (TfOH, 9.7 μL, 0.11 mmol) was

injected into the reaction mixture dropwise 5 min later. The reaction

mixture was kept stirring for another 2 h, and the temperature was

allowed to gradually warm to RT. The resulting mixture was

neutralized with triethylamine, ﬁltered through celite, and concen-

trated to aﬀord crude 6-azido-1-hexanol 2,3,4-tri-O-benzoyl-6-O-tert-

butyldiphenylsilyl-β-D-glucopyranoside which was employed in the

next step directly. The residue from above was dissolved in THF (20

mL). TBAF (1 M in THF, 2 mL, 2 mmol) and acetic acid (120 μL, 2

mmol) were added into the reaction mixture. The resulting mixture

was stirred overnight and puriﬁed by silica gel column chromatog-

-Azidohexan-1-yl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldime-

thylsilyl-1-thio-α-D-xylopyranoside (18i). 11a (20 mg, 0.035 mmol)

and 6-azido-1-hexanol (17i) (10 μL, 0.029 mmol) were reacted to

aﬀord 18i (13 mg, α only, 76%) as colorless liquid according to the

thiophenol method of general procedure (eluents: EtOAc/PE = 1:4)

for α-xylosylation. H NMR (600 MHz, CDCl ): δ 8.77 (m, 1H,

aromatic), 8.12 (d, 1H, J = 7.9 Hz, aromatic),7.83 (m, 1H, aromatic),

.48 (m, 1H, aromatic), 7.39−7.27 (m, 5H, aromatic), 5.13 (m, 1H,

H-4), 4.74 (d, 1H, J = 12.1 Hz), 4.60 (d, 1H, J = 3.4 Hz, H-1), 4.55

d, 1H, J = 12.1 Hz), 4.26 (t, 1H, J = 8.8 Hz, H-3), 3.73 (m, 2H, H-

(

), 3.61 (m, 1H), 3.38 (dd, 1H, J = 3.6 Hz, J = 9.1 Hz, H-2), 3.32 (m,

H), 3.26 (m, 2H), 1.39 (m, 4H), 0.74 (s, 9H), 0.07 (s, 3H), −0.02

s, 3H). ¹³C{ H} NMR (150 MHz, CDCl ): δ 164.7, 150.0, 147.9,

38.5, 137.1, 128.5, 128.2, 127.9, 127.1, 125.6, 97.4, 80.3, 73.7, 73.6,

1.2, 68.4, 58.8, 51.5, 29.4, 28.9, 26.7, 25.9, 25.8, 18.1, −4.1, −4.7.

HRMS (MALDI-TOF) m/z: [M + Na] calcd for C H N NaO Si,

07.2928; found, 607.2865.

p-Tolyl 2-O-benzyl-4-O-picolinyl-3-O-tert-butyldimethylsilyl-α-D-

xylopyranosyl-(1 → 6)-2,3,4-tri-O-benzoyl-β-D-galactopyranosyl-(1

6)-2,3,4-tri-O-benzoyl-1-thio-β-D-galactopyranoside (18j). 11a

30 mg, 0.053 mmol) and 17j (37 mg, 0.035 mmol) were reacted to

aﬀord 18j (40 mg, α only, 77%) as a white solid according to the

thiophenol method of general procedure (eluents: EtOAc/PE = 1:2)

^f^o^r^α^-^x^y^l^o^s^y^l^a^tⁱ^oⁿ^.^[^α^]D + 77.50 (c 0.1, DCM). H NMR (600 MHz,

CDCl ): δ 8.76 (d, 1H, J = 4.0 Hz, aromatic), 8.11 (m, 3H, aromatic),

.03 (m, 2H), 7.96 (m, 2H), 7.86 (m, 2H), 7.76 (m, 5H), 7.62 (t, 1H,

J = 7.5 Hz, aromatic), 7.56 (t, 1H, J = 7.5 Hz, aromatic), 7.54−7.04

m, 27H, aromatic and CHCl ), 5.93 (d, 1H, J = 3.1 Hz), 5.84 (d, 1H,

J = 3.3 Hz), 5.76 (m, 2H), 5.60 (dd, 1H, J = 3.4 Hz, J = 10.4 Hz),

.42 (dd, 1H, J = 3.5 Hz, J = 10.4 Hz), 5.03 (m, 1H, H-4 ), 4.86 (d,

H, J = 7.9 Hz), 4.65 (d, 1H, J = 8.0 Hz), 4.58 (m, 3H), 4.50 (d, 1H, J

3.1 Hz, H-1 ), 4.40 (d, 1H, J = 12.7 Hz), 4.14 (m, 4H, H-3 ),

.88 (dd, 1H, J = 7.4 Hz, J = 10.3 Hz), 3.74 (dd, 1H, J = 5.4 Hz, J =

1.2 Hz, H-5a ), 3.67 (m, 2H, H-5b ), 3.45 (dd, 1H, J = 7.3 Hz, J =

0.4 Hz), 3.29 (dd, 1H, J = 3.1 Hz, J = 8.3 Hz, H-2 ), 0.72 (s, 9H),

raphy with eluents EtOAc/PE = 1:2 and aﬀorded 19 (186 mg, 52%)

as a syrup. H NMR (600 MHz, CDCl ): δ 7.95 (ddd, 4H, J = 1.1 Hz,

→

(

J = 8.2 Hz, J = 9.5 Hz, Aromatic), 7.84 (dd, 2H, J = 1.1 Hz, J = 8.2 Hz,

Aromatic), 7.52 (td, 2H, J = 0.7 Hz, J = 7.5 Hz, Aromatic), 7.44−7.35

(

m, 5H, Aromatic), 7.28 (dd, 2H, J = 7.7 Hz, J = 8.1 Hz, Aromatic),

.94 (t, 1H, J = 9.7 Hz), 5.49 (m, 2H), 4.82 (d, 1H, J = 7.9 Hz, H1),

3.96 (m, 1H), 3.87 (dd, 1H, J = 2.1 Hz, J = 12.6 Hz), 3.80 (m, 1H),

3.75 (dd, 1H, J = 4.5 Hz, J = 12.3 Hz), 3.54 (m, 1H), 3.06 (m, 2H),

.53 (m, 2H), 1.33 (m, 2H), 1.21 (m, 4H). C{ H} NMR (150

MHz, CDCl ): δ 166.2, 166.0, 165.1, 133.8, 133.4, 130.0, 129.8,

(

129.4, 129.0, 128.7, 128.6, 128.5, 128.4, 101.4, 74.7, 72.9, 72.0, 69.7,

1.5, 51.3, 29.3, 28.7, 26.4, 25.5. HRMS (ESI) m/z: [M + NH₄]⁺

Xyl

calcd for C H N O , 635.2712; found, 635.2715.

-Azidohexan-1-yl 3-O-tert-butyldimethylsilyl-2-O-(2-naphthyl)-

Xyl

methyl-4-O-picolinyl-α-D-xylopyranosyl-(1 → 6)-2,3,4-tri-O-benzo-

yl-β-D-glucopyranoside (20). Xylosyl donor 18 (79 mg, 0.13 mmol)

and glucosyl acceptor 19 (70 mg, 0.11 mmol) were dissolved in DCM

(3 mL). The reaction mixture was stirred at RT for another 15 min

after adding 200 mg of freshly activated molecular sieves. NIS (36 mg,

Xyl

.02 (s, 3H), −0.04 (s, 3H). C{ H} NMR (150 MHz, CDCl ): δ

956

J. Org. Chem. 2021, 86, 9945−9960

The Journal of Organic Chemistry

Article

.16 mmol) was added to the mixture, and the reaction mixture was

H⁴^X^y^l), 4.85 (d, 1H, J = 11.3 Hz), 4.67 (m, 2H), 4.60 (d, 1H, J = 11.1

Glc

5aXyl

2Xyl

cooled in ice bath. TMSOTf (3.9 μL, 0.02 mmol) was injected into

the mixture dropwise after 5 min, and the mixture was stirred for

another 1 h. The resulting mixture was neutralized with triethylamine,

ﬁltered through celite, and concentrated. The resulting residue was

puriﬁed by silica gel column chromatography with eluents EtOAc/

PE/DCM = 1:4:2.5 and aﬀorded 20 (96.2 mg) as a syrup in 81%

Hz), 4.51 (m, 3H, H ), 4.33 (m, 1H, H ), 4.00 (m, 2H, H

Ara

3Xyl

4Ara

5bXyl

and H ), 3.93−3.76 (m, 5H, H and H ), 3.68 (m, 5H, H

Ara

and H ), 3.43 (m, 1H), 3.02 (m, 2H), 1.42 (m, 2H), 1.25 (m, 2H),

1.14 (m, 4H), 0.76 (s, 9H), 0.08 (bd, 6H). C{ H} NMR (150 MHz,

CDCl ): δ 164.6, 164.1, 163.7, 163.2, 148.4, 146.4, 137.9, 137.7,

137.2, 135.9, 132.3, 132.0, 128.6, 128.5, 128.3, 127.7, 127.6, 127.3,

127.2, 127.1, 126.7, 126.4, 126.2, 125.8, 124.6, 99.9, 74.9, 72.7, 72.1,

71.8, 71.3, 70.8, 70.6, 70.4, 68.9, 68.6, 59.4, 50.0, 28.0, 27.4, 25.1₊,

24.5, 24.3, 16.8, 5.2, 5.9. HRMS (MALDI-TOF) m/z: [M + Na]

calcd for C H N NaO Si, 1393.5604; found, 1393.4897.

yield. [α]²+ 12.30 (c 0.1, DCM). H NMR (600 MHz, CDCl ): δ

.72 (m, 1H, aromatic), 8.07 (d, 1H, J = 7.8 Hz, aromatic), 7.99−7.92

(

m, 4H, aromatic), 7.84−7.71 (m, 7H, aromatic), 7.55−7.49 (m, 3H,

aromatic), 7.48−7.34 (m, 8H, aromatic), 7.27 (m, 2H, aromatic),

Glc

.88 (t, 1H, J = 9.6 Hz, H-3 ), 5.47 (m, 2H, H-2 , H-4 ), 5.09 (m,

6-Azidohexan-1-yl 2,3,4-tri-O-benzyl-α-L-arabinosyl-(1 → 2)-3-

O-tert-butyldimethylsilyl-α-D-xylopyranosyl-(1 → 6)-2,3,4-tri-O-

benzoyl-β-D-glucopyranoside (24). The pre-deprotected trisacchar-

ide 23 (29 mg, 0.023 mmol) and copper(II) acetate (8.4 mg, 0.046

mmol) were dissolved in a mixture of MeOH/DCM (1/10, 2.2 mL),

and the reaction was stirred overnight. The resulting mixture was

quenched by sodium bicarbonate solution and then concentrated.

The resulting residue was puriﬁed by silica gel column chromatog-

Xyl

H, H-4 ), 4.86 (d, 1H, J = 12.2 Hz), 4.77 (d, 1H, J = 7.9 Hz, H-

Glc

Xyl

), 4.70 (d, 1H, J = 12.2 Hz), 4.62 (d, 1H, J = 3.2 Hz, H-1 ), 4.33

Xyl

Glc

(

m, 1H, H-3 ), 4.07 (m, 1H, H-5 ), 3.95 (m, 1H, OCHH-

CH ) N ), 3.87 (m,1H, H-6a ), 3.76 (m, 2H, H-5a , H-5b ),

Glc

Xyl

Glc

.62 (dd, 1H, J = 2.1 Hz, J = 11.2 Hz, H-6b ), 3.51 (m, 1H,

Xyl

OCHH(CH ) N ), 3.44 (dd, 1H, J = 3.2 Hz, J = 8.7 Hz, H-2 ), 3.00

(t, 1H, J = 6.9 Hz O(CH ) CH N ), 1.44 (m, 2H), 1.24 (m, 2H),

2 5 2 3

raphy with eluents EtOAc/PE = 1:2 to aﬀord 24 (23 mg) as a foam

.13 (m, 4H), 0.78 (s, 9H), 0.12 (s, 3H), 0.02 (s, 3H). C{ H} NMR

solid in 87% yield. H NMR (600 MHz, CDCl ): δ 7.96 (d, 1H, J =

(150 MHz, CDCl ): δ 165.9, 165.8, 165.3, 165.2, 165.1, 165.0, 164.5,

.9 Hz, aromatic), 7.90 (d, 1H, J = 8.0 Hz, aromatic), 7.81 (d, 1H, J =

.0 Hz, aromatic), 7.56−7.21 (m, 24H, aromatic), 5.78 (t, 1H, J = 9.7

49.9, 136.9, 135.8, 133.6, 133.3, 133.2, 130.0, 129.9, 129.5, 129.0,

28.6, 128.5, 128.4, 128.0, 127.8, 127.1, 127.0, 126.3, 126.1, 125.4,

01.1, 97.6, 80.0, 74.0, 73.6, 73.2, 72.1, 71.1, 70.1, 69.9, 67.1, 59.0,

Glc

4Glc

2Glc

Hz, H ), 5.46 (m, 2H, H ), 5.40 (t, 1H, J = 9.1 Hz, H ), 4.84

(d, 1H, J = 11.5 Hz, CHHPh), 4.79 (s, 1H), 4.75 (d, 1H, J = 12.0 Hz,

1.2, 29.3, 28.7, 26.4, 25.8, 25.5, 18.1, 4.1, 4.7. HRMS (ESI) m/z: [M

CHHPh), 4.68 (s, 2H), 4.62 (d, 1H, J = 12.0 Hz, CHHPh), 4.58 (d,

H] calcd for C H N O Si, 1109.4574; found, 1109.4566.

Glc

H, J = 8.9 Hz, H ), 4.52 (d, 1H, J = 11.5 Hz, CHHPh), 4.05 (dd,

-Azidohexan-1-yl 3-O-tert-butyldimethylsilyl-4-O-picolinyl-α-D-

xylopyranosyl-(1 → 6)-2,3,4-tri-O-benzoyl-β-D-glucopyranoside

21). The Nap-protected disaccharide 20 (62 mg, 0.054 mmol) and

DDQ (18.4 mg, 0.081 mmol) were added to a mixture of water/DCM

1/5, 2.4 mL). The resulting mixture was stirred overnight until TLC

aGlc

3Xyl

2Ara

1H, J = 5.6 Hz, J = 11.1 Hz, H ), 3.97 (m, 2H, H , H ), 3.83

(m, 5H, H , OCHH(CH ) N

Glc

, H , H ), 3.73 (m, 2H, H⁶^b^G^l^c,

5axyl

3Ara

(

2 5 3

Ara

2Xyl

), 3.66 (m, 3H, H ), 3.43 (m, 1H, OCHH(CH ), 3.33 (d,

) N

2 5 3

Xyl

(

1H, J = 2.1 Hz, H ), 3.02 (t, 2H, J = 6.9 Hz), 1.43 (m, 2H), 1.29

indicated the end of the reaction. The aqueous layer was separated

and re-extracted with DCM, and the organic phase was combined and

concentrated. The resulting residue was puriﬁed by TLC with eluents

(m, 2H), 1.14 (m, 4H), 0.88 (s, 9H, TBS), 0.08 (bd, 6H, TBS).

C{ H} NMR (150 MHz, CDCl ): δ 166.0, 165.4, 165.1, 129.9,

129.8, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 127.5,

127.4, 101.3, 99.1, 96.4, 76.4, 76.3, 74.1, 73.5, 73.4, 73.2, 73.1, 72.1,

71.9, 71.8, 70.5, 69.9, 69.7, 68.1, 66.8, 61.0, 51.3, 29.3, 28.7, 26.4₊,

25.9, 25.5, 18.1. 4.7, 4.8. HRMS (MALDI-TOF) m/z: [M + Na]

calcd for C H N NaO Si, 1288.5389; found, 1288.5388.

EtOAc/PE/DCM = 1:2:1.5 and aﬀorded 21 (51 mg, 0.052 mmol) as

a syrup, yield in 95.9%. H NMR (600 MHz, CDCl ): δ 8.75 (d, 1H, J

4.6 Hz, aromatic), 8.15 (d, 1H, J = 7.9 Hz, aromatic), 8.00−7.78

(

m, 8H, aromatic), 7.58−7.23 (m, 9H, aromatic), 5.87 (t, 1H, J = 9.7

3Glc

4Glc

Hz, H ), 5.66 (t, 1H, J = 9.7 Hz, H ), 5.49 (dd, 1H, J = 8.0 Hz, J

2,3-di-O-Benzoyl-4,6-O-benzylidene-β-D-galactopyranosyl-(1 →

6)-2,3-di-O-benzoyl-4-O-benzyl-β-D-galactopyranosyl trichloroace-

timidate (25). The known p-tolyl 4,6-O-benzylidene-2,3-di-O-

Glc

2Glc

1Xyl

9.7 Hz, H ), 5.08 (m, 2H, H

and H ), 4.77 (d, 1H, J = 7.9

1Glc

3Xyl

5Glc

Hz, H ), 4.07 (t, 1H, J = 8.2 Hz, H ), 4.03−3.86 (m, 4H, H

6aGlc

5aXyl

5bXyl

benzoyl-1-thio-α/β-D-galactopyranosyl (582 mg, 1 mmol) was

dissolved in solution of boron triﬂuoride tetrahydrofuran complex 1

M in THF (5 mL) to which copper(II) triﬂuoromethanesulfonate (18

mg, 0.05 mmol) was added. The resulting mixture was stirred until

TLC indicated the end of the reaction. The reaction was quenched

with triethylamine and methanol carefully and concentrated. The

residue was further co-distilled with methanol twice and puriﬁed by

silica gel column chromatography with gradient eluents EtOAc/PE/

DCM = 1:6:3.5 to 1:4:2.5 and aﬀorded p-tolyl 4-O-benzyl-2,3-di-O-

and OCH (CH )N ), 3.84−3.66 (m, 2H, H

and H

Xyl

6bGlc

.54 (m, 2H, H

and H

), 3.06 (t, 2H, J = 6.9 Hz,

N CH (CH )O), 1.48 (m, 2H), 1.30 (m, 2H), 1.19 (m, 4H), 0.78

(

s, 9H, TBS), 0.18 (s, 3H, TBS), 0.02 (s, 3H, TBS). C{ H} NMR

150 MHz, CDCl ): δ 166.0, 165.5, 165.1, 164.2, 149.8, 147.6, 137.3,

33.3, 130.0, 129.9, 129.5, 129.0, 128.6, 128.5, 128.4, 127.2, 125.6,

01.6, 98.7, 73.9, 73.1, 73.0, 72.9, 72.7, 72.1, 70.0, 69.5, 65.6, 59.8,

1.3, 29.4, 28.7, 26.4, 25.8, 25.5, 18.2, 4.2, 4.7. HRMS (MALDI-TOF)

m/z: [M + Na] calcd for C H N NaO Si, 991.3773; found,

benzoyl-1-thio-β-D-galactopyranoside (314 mg) as a white solid in

91.3434.

-Azidohexan-1-yl 2,3,4-tri-O-benzyl-α-L-arabinosyl-(1 → 2)-3-

O-tert-butyldimethylsilyl-4-O-picolinyl-α-D-xylopyranosyl-(1 → 6)-

,3,4-tri-O-benzoyl-β-D-glucopyranoside (23). The known tribenzyl-

4% yield. H NMR (600 MHz, CDCl ): δ 7.98 (m, 4H, aromatic),

7.51 (m, 2H, aromatic), 7.38 (m, 7H, aromatic), 7.25 (m, 4H,

aromatic), 7.06 (m, 2H, aromatic), 5.87 (t, 1H, J = 10 Hz, H-2), 5.37

(dd, 1H, J = 2.9 Hz, J = 10 Hz, H-3), 4.89 (d, 1H, J = 9.9 Hz, H-1),

4.75 (d, 1H, J = 11.6 Hz), 4.50 (d, 1H, J = 11.6 Hz), 4.17 (d, 1H, J =

2.8 Hz, H-4), 3.99 (dd, 1H, J = 7.0 Hz, J = 11.3 Hz), 3.77 (t, 1H, J =

protected arabinoside donor 22 (55 mg, 0.13 mmol) and

disaccharide acceptor 21 (51 mg, 0.052 mmol) were dissolved in

DCM (2 mL) in the presence of molecular sieves. The mixture was

stirred for another 15 min. NIS (29 mg, 0.13 mmol) was added to the

mixture which was cooled in ice bath. TfOH (2.3 μL, 26 μmol) was

injected into the mixture dropwise, and the reaction mixture was

stirred for another 2.5 h. The resulting mixture was neutralized by

triethylamine, ﬁltered, and concentrated. The residue was puriﬁed by

silica gel column chromatography with eluents EtOAc/PE = 1:1 and

aﬀorded 23 (30 mg) as a syrup yield in 45% with a little impurity

5.6 Hz), 3.61 (dd, 1H, J = 5.0 Hz, J = 11.4 Hz), 2.33 (s, 3H). C{ H}

NMR (150 MHz, CDCl ): δ 166.1, 165.4, 138.3, 137.5, 133.6, 133.3,

133.2, 130.0, 129.9, 129.8, 129.7, 129.1, 128.9, 128.7, 128.6, 128.5,

128.3, 128.1, 87.0, 79.1, 76.2, 74.8, 73.9, 68.7, 62.1. 21.3. The

galactosyl donor 4,6-O-benzylidene-2,3-di-O-benzoyl-1-thio-α/β-D-

galactopyranosyl trichloroacetimidate (100 mg, 0.16 mmol) and the

galactosyl acceptor p-tolyl 4-O-benzyl-2,3-di-O-benzoyl-1-thio-β-D-

galactopyranoside (86 mg, 0.15 mmol) were dissolved in DCM (3

mL), and the mixture was continue stirred for another 15 min in the

presence of molecular sieves under nitrogen. The reaction was then

cooled in ice bath to which triﬂuoromethanesulfonic acid (2.6 μL,

0.030 mmol) was added. The mixture was stirred for another 1.5 h

and was allowed to warm to RT gradually. The resulting mixture was

which was supposed to be β-byproduct. Here, the NMR of α-structure

is shown. H NMR (600 MHz, CDCl ): δ 8.67 (d, 1H, J = 3.9 Hz,

aromatic), 8.15 (d, 1H, J = 7.7 Hz, aromatic), 8.00−7.77 (m, 6H,

aromatic), 7.58−7.21 (m, 26H, aromatic), 5.75 (t, 1H, J = 9.7 Hz,

Glc

4Glc

), 5.41 (t, 1H, J = 9.8 Hz, H ), 5.32 (dd, 1H, J = 8.0 Hz, J =

.8 Hz, H²), 5.26 (d, 1H, J = 3.4 Hz, H ), 5.00 (m, 2H, H and

Glc

1Xyl

1Ara

957

J. Org. Chem. 2021, 86, 9945−9960

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.1c00187.

Article

quenched with triethylamine, ﬁltered, and concentrated. The residue

was puriﬁed by silica gel column chromatography with eluents

EtOAc/PE/DCM = 1:4:2.5 and then puriﬁed with eluents EtOAc/PE

(m, 1H, OCHH(CH ) N ), 3.00 (t, 2H, J = 6.3 Hz, O-

2 5 3

(CH ) CH N ), 1.67 (m, 2H), 1.29 (m, 2H), 1.10 (m, 4H), 0.79

(s, 9H, TBS), 0.13 (s, 3H, TBS), −0.02 (s, 3H, TBS). C{ H} NMR

(150 MHz, CDCl ): δ 207.4, 166.2, 165.9, 165.8, 165.5, 165.3, 165.2,

1:3 to aﬀord p-tolyl 2,3-di-O-benzoyl-4,6-O-benzylidene-β-D-

galactopyranosyl-(1 → 6)-2,3-di-O-benzoyl-4-O-benzyl-β-D-galacto-

165.0, 139.4, 139.1, 138.6, 138.5, 137.7, 133.5, 133.3, 130.1, 130.0,

129.9, 129.8, 129.7, 129.6, 129.1, 128.7, 128.6, 128.5, 128.4, 128.3,

128.2, 127.9, 127.7, 127.6, 127.4, 127.2, 126.4, 101.0, 100.7, 100.5,

99.4, 95.5, 93.6, 76.5, 76.2, 75.9, 74.8, 74.4, 74.1, 73.7, 73.6, 73.2,

73.0, 72.8, 72.7, 72.0, 71.1, 70.3, 69.4, 69.2, 68.9, 66.9, 66.7, 66.0,

60.8, 59.6, 51.3, 32.1, 31.6, 30.8, 30.6, 30.4, 30.3, 30.1, 30.0, 29.8,

pyranoside (90 mg) in 59% yield. H NMR (600 MHz, CDCl ): δ

.04−7.83 (m, 8H, aromatic), 7.56−7.43 (m, 6H, aromatic), 7.41−

.28 (m, 13H, aromatic), 7.28−7.17 (m, 5H, aromatic), 7.06 (m, 2H,

aromatic), 5.86 (dd, 1H, J = 8.0 Hz, J = 10.4 Hz, H-2′), 5.78 (t, 1H, J

10 Hz, H-2), 5.56 (s, 1H, PhCH), 5.35 (dd, 1H, J = 3.6 Hz, J = 10.4

Hz, H-3′), 5.30 (dd, 1H, J = 2.9 Hz, J = 10.4 Hz, H-3), 4.88 (d, 1H, J

8.0 Hz, H-1′), 4.74 (d, 1H, J = 9.9 Hz, H-1), 4.68 (d, 1H, J = 11.5

Hz), 4.61 (m, 2H, H-4′ and PhCHH), 4.35 (d, 1H, J = 11.6 Hz, H-

a′), 4.12 (m, 2H, H-6b′ and H-4), 4.05 (dd, 1H, J = 6.4 Hz, J = 10.8

Hz, H6a), 3.99 (dd, 1H, J = 5.9 Hz, J = 10.8 Hz, H6b), 3.86 (t, 1H, J

29.5, 29.0, 28.7, 26.4, 26.2, 25.5, 22.8, 18.2, 14.2, −3.5, −3.9. HRMS

(MALDI-TOF) m/z: [M + Na] calcd for C124

129

NaO31Si,

2206.8277; found, 2206.7831.

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

■

6.1 Hz, H-5), 3.65 (s, 1H, H-5′), 2.30 (s, 3H). C{ H} NMR (150

MHz, CDCl ): δ 166.3, 165.8, 165.4, 165.3, 138.3, 138.0, 137.6,

33.5, 133.4, 133.2, 130.1, 130.0, 129.9, 129.8, 129.7, 129.3, 129.2,

29.0, 128.8, 128.5, 128.4, 128.3, 128.2, 128.0, 127.6, 126.4, 101.0,

00.8, 86.9, 77.9, 75.6, 74.9, 74.3, 73.7, 72.9, 69.3, 69.0, 68.7, 67.0,

Analytic graph of ¹H NMR of xylosyl donor 11a,

6.7, 21.3. HRMS (ESI) m/z: [M + Na] calcd for C H NaO S,

reaction condition screening of conversion from

065.3132; found, 1065.3127. The disaccharide building block p-tolyl

,3-di-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranosyl-(1 → 6)-

,3-di-O-benzoyl-4-O-benzyl-β-D-galactopyranoside (56 mg, 0.054

compound 6−9, and H, C, and 2D NMR spectra

(PDF )

mmol) was added to DCM (1 mL) together with NIS (18 mg,

0.080 mmol) and TFA (4 μL, 0.054 mmol). The resulting mixture

AUTHOR INFORMATION

Corresponding Author

■

was stirred until TLC indicated the end of the reaction and then

diluted with DCM (2 mL) and treated with sodium bicarbonate and

sodium thiosulfate aqueous solution. The organic layer was

concentrated and co-distilled with toluene twice. The resulting

residue was taken up with DCM (1 mL) to which trichloroacetonitrile

Kan Ding − University of Chinese Academy of Sciences, Beijing

00049, China; Glycochemistry and Glycobiology Lab,

Shanghai Institute of Materia Medica, Chinese Academy of

Sciences, Shanghai 201203, China; orcid.org/0000-0002-

(21 μL, 0.215 mmol) and DBU (6.5 μL, 0.043 mmol) were added.

8140-9259; Email: dingkan@simm.ac.cn

The mixture was continued stirred until TLC indicated the end of the

reaction and then puriﬁed by silica gel column chromatography with

Authors

eluents EtOAc/PE = 1:2 with 0.5% triethylamine to aﬀord 25 (43

Deqin Cai − University of Chinese Academy of Sciences,

mg) in 74% yield. H NMR (600 MHz, CDCl ): α structure: δ 8.30

Beijing 100049, China; Glycochemistry and Glycobiology

Lab, Shanghai Institute of Materia Medica, Chinese Academy

of Sciences, Shanghai 201203, China

(

s, 1H), 8.01−7.88 (m, 8H, aromatic), 7.53−7.42 (m, 6H, aromatic),

.39−7.28 (m, 14H, aromatic), 7.25−7.19 (m, 2H, aromatic), 6.63 (d,

H, J = 3.5 Hz, H-1), 5.90 (dd, 1H, J = 3.5 Hz, J = 10.7 Hz), 5.82 (m,

H), 5.55 (s, 1H, PhCH), 5.34 (dd, 1H, J = 3.6 Hz, J = 10.4 Hz), 4.82

Ya Bian − Glycochemistry and Glycobiology Lab, Shanghai

Institute of Materia Medica, Chinese Academy of Sciences,

Shanghai 201203, China; Interdisciplinary Science Research

Institute, Shanghai University of Traditional Chinese

Medicine, Shanghai 201203, China

Shengjie Wu − University of Chinese Academy of Sciences,

Beijing 100049, China; Glycochemistry and Glycobiology

Lab, Shanghai Institute of Materia Medica, Chinese Academy

of Sciences, Shanghai 201203, China

(

d, 1H, J = 8.0 Hz, H-1′), 4.71 (m, 2H), 4.59 (d, 1H, J = 3.7 Hz), 4.35

(m, 2H), 4.24 (d, 1H), 4.13 (m, 2H), 3.84 (dd, 1H, J = 5.9 Hz, J =

0.1 Hz), 3.68 (s, 1H). C{ H} NMR (150 MHz, CDCl ): δ 166.3,

65.8, 165.4, 137.8, 137.6, 133.5, 130.1, 129.9, 129.8, 129.2, 129.0,

28.6, 128.5, 128.3, 128.2, 127.9, 126.4, 101.0, 96.3, 94.2, 75.5, 75.0,

4.0, 73.7, 72.8, 72.7, 72.1, 70.7, 69.3, 69.0, 68.5, 67.0, 66.7, 29.8.

-Azidohexan-1-yl 2,3-di-O-benzoyl-4,6-O-benzylidene-β-D-gal-

actopyranosyl-(1 → 6)-2,3-di-O-benzoyl-4-O-benzyl-β-D-galacto-

pyranosyl-(1 → 4)-2-O-(2,3,4-tri-O-benzyl-α-L-arabinosyl)-3-O-tert-

butyldimethylsilyl-α-D-xylopyranosyl-(1 → 6)-2,3,4-tri-O-benzoyl-

β-D-glucopyranoside (26). The disaccharide donor 25 (23 mg, 0.021

mmol) and the trisaccharide acceptor 24 (21 mg, 0.018 mmol) were

dissolved in DCM (2 mL), and the mixture was stirred for another 15

min in the presence of molecular sieves under nitrogen. The mixture

was then cooled in ice bath to which triﬂuoromethanesulfonic acid

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00187

Author Contributions

∥

Contributed equally to this work

(

1.0 μL, 0.011 mmol) was added. The mixture was further stirred for

Notes

another 1 h, quenched by triethylamine, puriﬁed by TLC (EtOAc/PE

The authors declare no competing ﬁnancial interest.

1:2), and aﬀorded 26 (22 mg) in 58% yield. H NMR (600 MHz,

CDCl ): δ 8.01−7.76 (m, 14H, aromatic), 7.59−7.12 (m, 46H,

ACKNOWLEDGMENTS

aromatic), 5.86 (dd, 1H, J = 8.1 Hz, J = 10.3, H2 ), 5.68 (dd, 1H, J =

■

.9 Hz, J = 10.3, H2 ), 5.57 (t, 1H, J = 7.9 Hz, H3 ), 5.53 (s, 1H,

We appreciate funding supported by the Key New Drug

Creation and Manufacturing Program (2019ZX09735001),

National Key R&D Program of China (2019YFC1711000),

and Ministry of Science and Technology.

PhCH), 5.35 (dd, 1H, J = 3.5 Hz, J = 10.4, H3 ), 5.21 (m, 2H, H2 ,

H3 ), 5.08 (m, 2H, H4 , H1 ), 4.93 (d, 1H, J = 2.6 Hz, H1 ), 4.89

d, 1H, J = 2.6 Hz, H1 ), 4.78 (d, 1H, J = 2.6 Hz, H1B), 4.75−4.62

m, 6H), 4.59 (d, 1H, J = 11.5 Hz, PhCHH), 4.56 (d, 1H, J = 3.5 Hz,

(

H4 ), 4.50 (d, 1H, J = 7.8 Hz, H1 ), 4.30 (d, 1H, J = 12.2 Hz), 4.09−

REFERENCES

.96 (m, 6H, H1 , H2 ), 3.90 (dd, 1H, J = 5.3 Hz, J = 10.7), 3.83 (t,

■

H, J = 8.8 Hz, H3 ), 3.76 (m, 3H, H3 ), 3.67−3.57 (m, 5H, H6a ,

(1) Takeuchi, H.; Kantharia, J.; Sethi, M. K.; Bakker, H.;

Haltiwanger, R. S. Site-specific o-glucosylation of the epidermal

growth factor-like (EGF) repeats of notch: efficiency of glycosylation

H4 , OCHH(CH ) N ), 3.49 (m, 2H, H2 ), 3.41 (t, 1H, J = 8.7 Hz,

H5 ), 3.30 (d, 1H, J = 10.2 Hz, H6b ), 3.24 (d, 1H, J = 10.9 Hz), 3.17

958

J. Org. Chem. 2021, 86, 9945−9960

The Journal of Organic Chemistry

is affected by proper folding and amino acid sequence of individual

Article

Potent macrophages activators. Chem.-Biol. Interact. 2011, 189, 127−

133.

EGF repeats. J. Biol. Chem. 2012, 287, 33934−33944.

(

2) Thorsheim, K.; Siegbahn, A.; Johnsson, R. E.; Stal

brand, H.;

(20) Yamatoya, K.; Shirakawa, M.; Baba, O. Eﬀects of xyloglucan on

lipid metabolism; Hydrocolloids, Nishinari, K., Eds.; Elsevier Science:

Amsterdam, 2000; pp 405−410.

(21) Yamatoya, K.; Shirakawa, M.; Kuwano, K.; Suzuki, J.; Baba, O.

Hypolipidemic effects of hydrolyzed xyloglucan. Macromol. Symp.

1997, 120, 231−236.

Manner, S.; Widmalm, G.; Ellervik, U. Chemistry of xylopyranosides.

Carbohydr. Res. 2015, 418, 65−88.

(3) Hase, S.; Kawabata, S.-i.; Nishimura, H.; Takeya, H.; Sueyoshi,

T.; Miyata, T.; Iwanaga, S.; Takao, T.; Shimonishi, H.; Ikenaka, I. A

New Trisaccharide Sugar Chain Linked to a Serine Residue in Bovine

Blood Coagulation Factors VII and IX1. J. Biochem. 1988, 104, 867−

(22) Kulkarni, A. D.; Joshi, A. A.; Patil, C. L.; Amale, P. D.; Patel, H.

M.; Surana, S. J.; Belgamwar, V. S.; Chaudhari, K. S.; Pardeshi, C. V.

Xyloglucan: A functional biomacromolecule for drug delivery

applications. Int. J. Biol. Macromol. 2017, 104, 799−812.

4) Whitworth, G. E.; Zandberg, W. F.; Clark, T.; Vocadlo, D. J.

68.

Mammalian Notch is modified by D-Xyl-α 1-3-D-Xyl-α 1-3-D-Glc-β 1-

O-Ser: implementation of a method to study O-glucosylation.

Glycobiology 2010, 20, 287−299.

(

23) Miyazaki, S.; Suisha, F.; Kawasaki, N.; Shirakawa, M.;

Yamatoya, K.; Attwood, D. Thermally reversible xyloglucan gels as

vehicles for rectal drug delivery. J. Controlled Release 1998, 56, 75−83.

(5) Fukase, K.; Hase, S.; Ikenaka, T.; Kusumoto, S. Synthesis of New

(24) Itoh, K.; Yahaba, M.; Takahashi, A.; Tsuruya, R.; Miyazaki, S.;

Serine-Linked Oligosaccharides in Blood-Clotting Factors VII and IX

and Protein Z. The Syntheses of O-α -D- Xylopyranosyl-(1 →3)-D-

glucopyranose, O-α -D-Xylopyranosyl-(1 →3)-O-α -D-xylopyranosyl-

Dairaku, M.; Togashi, M.; Mikami, R.; Attwood, D. In situ gelling

xyloglucan/pectin formulations for oral sustained drug delivery. Int. J.

Pharm. 2008, 356, 95−101.

(25) McDougall, G. J.; Fry, S. C. Xyloglucan oligosaccharides

1 →3)-D-glucopyranose, and Their Conjugates with Serine. Bull.

Chem. Soc. Jpn. 1992, 65, 436−445.

6) Saliba, M.; Ramalanjaona, N.; Gulberti, S.; Bertin-Jung, I.;

promote growth and activate cellulase: evidence for a role of cellulase

(

in cell expansion. Plant Physiol. 1990, 93, 1042−1048.

Thomas, A.; Dahbi, S.; Lopin-Bon, C.; Jacquinet, J. C.; Breton, C.;

Ouzzine, M.; Fournel-Gigleux, S. Probing the acceptor active site

organization of the human recombinant β 1,4-galactosyltransferase 7

and design of xyloside-based inhibitors. J. Biol. Chem. 2015, 290,

(26) York, W. S.; Darvill, A. G.; Albersheim, P. Inhibition of 2,4-

Dichlorophenoxyacetic Acid-Stimulated Elongation of Pea Stem

Segments by a Xyloglucan Oligosaccharide. Plant Physiol. 1984, 75,

27) Pauly, M.; Keegstra, K. Biosynthesis of the plant cell wall matrix

95.

polysaccharide xyloglucan. Annu. Rev. Plant Biol. 2016, 67, 235−259.

28) Coleman, C. M.; Auker, K. M.; Killday, K. B.; Azadi, P.; Black,

(

658−7670.

7) Siegbahn, A.; Manner, S.; Persson, A.; Tykesson, E.; Holmqvist,

K.; Ochocinska, A.; Rönnols, J.; Sundin, A.; Mani, K.; Westergren-

Thorsson, G.; Widmalm, G.; Ellervik, U. Rules for priming and

inhibition of glycosaminoglycan biosynthesis; probing the β 4GalT7

active site. Chem. Sci. 2014, 5, 3501−3508.

(

I.; Ferreira, D. Arabinoxyloglucan Oligosaccharides May Contribute

to the Antiadhesive Properties of Porcine Urine after Cranberry

Consumption. Nat. Prod. J. 2019, 82, 589−605.

(8) Tang, Y.; Zhang, S.; Chang, Y.; Fan, D.; Agostini, A.; Zhang, L.;

(29) Cheng, J.; Jiang, X.; Li, J.; Zhou, S.; Bai, T.; Qin, W.; Li, H.;

Jiang, T. Aglycone Ebselen and β -D-xyloside primed glycosaminogly-

cans co-contribute to Ebselen β -D-xyloside-induced cytotoxicity. J.

Med. Chem. 2018, 61, 2937−2948.

Luo, Y.; Huang, Z.; Liu, Y.; Wu, D.; Yu, B.; Chen, D.; Chen, H.

Xyloglucan affects gut-liver circulating bile acid metabolism to

improve liver damage in mice fed with high-fat diet. J. Funct. Foods

(9) Tsuzuki, Y.; Nguyen, T. K.; Garud, D. R.; Kuberan, B.; Koketsu,

(

020, 64, 103651.

30) Dallabernardina, P.; Schuhmacher, F.; Seeberger, P. H.;

M. 4-Deoxy-4-fluoro-xyloside derivatives as inhibitors of glycosami-

noglycan biosynthesis. Bioorg. Med. Chem. Lett 2010, 20, 7269−7263.

Pfrengle, F. Automated glycan assembly of xyloglucan oligosacchar-

(10) Scheller, H. V.; Ulvskov, P. Hemicelluloses. Annu. Rev. Plant

ides. Org. Biomol. Chem. 2016, 14, 309−313.

Biol. 2010, 61, 263−289.

(31) Faure, R.; Saura-Valls, M.; Brumer, H.; Planas, A.; Cottaz, S.;

(11) Chen, Z.; Li, S.; Fu, Y.; Li, C.; Chen, D.; Chen, H.

Driguez, H. Synthesis of a library of xylogluco-oligosaccharides for

active-site mapping of xyloglucan endo-transglycosylase. J. Org. Chem.

Arabinoxylan structural characteristics, interaction with gut micro-

biota and potential health functions. J. Funct. Foods 2019, 54, 536−

006, 71, 5151−5161.

32) Lopez, M.; Fort, S.; Bizot, H.; Buléon, A.; Driguez, H. Chemo-

51.

12) Kinnaert, C.; Daugaard, M.; Nami, F.; Clausen, M. H. Chemical

enzymatic synthesis of xylogluco-oligosaccharides and their inter-

Synthesis of Oligosaccharides Related to the Cell Walls of Plants and

actions with cellulose. Carbohydr. Polym. 2012, 88, 185−193.

Algae. Chem. Rev. 2017, 117, 11337 −11405.

(33) Nawaji, M.; Izawa, H.; Kaneko, Y.; Kadokawa, J.-i. Enzymatic

(13) Hsieh, Y. S.; Harris, P. J. Structures of xyloglucans in primary

synthesis of α -D-xylosylated malto-oligosaccharides by phosphorylase-

catalyzed xylosylation. J. Carbohydr. Chem. 2008 , 27 , 214 −222.

cell walls of gymnosperms, monilophytes (ferns sensu lato) and

lycophytes. Phytochemistry 2012, 79, 87−101.

(34) Sakai, K.; Nakahara, Y.; Ogawa, T. Total synthesis of

(14) Piqué, N.; Gómez-Guillén, M. D. C.; Montero, M. P.

nonasaccharide repeating unit of plant cell wall xyloglucan: An

endogenous hormone which regulates cell growth. Tetrahedron Lett.

Xyloglucan, a Plant Polymer with Barrier Protective Properties over

the Mucous Membranes: An Overview. Int. J. Mol. Sci. 2018 , 19 , 673.

(15) Cao, Y.; Ikeda, I. Antioxidant activity and antitumor activity (in

990, 31, 3035−3038.

35) Hayakawa, S.; Koide, R.; Hinou, H.; Nishimura, S. Synthetic

vitro ) of xyloglucan selenious ester and surfated xyloglucan. Int. J. Biol.

Macromol. 2009, 45, 231−235.

human NOTCH1 EGF modules unraveled molecular mechanisms for

the structural and functional roles of calcium ions and O-glycans in

the ligand-binding region. Biochemistry 2016 , 55 , 776 −787.

(36) Kunz, H.; Sager, W. Stereoselective glycosylation of alcohols

and silyl ethers using glycosyl fluorides and boron trifluoride etherate.

Helv. Chim. Acta 1985, 68, 283−287.

(16) Lim, S. H.; Lee, J. Xyloglucan intake attenuates myocardial

injury by inhibiting apoptosis and improving energy metabolism in a

rat model of myocardial infarction. Nutr. Res. 2017 , 45 , 19 −29.

(17) Naresh, W.; Dilip, D.; Sunil, K. Xyloglucan Based Nasal in situ

Gel Formulation of Mirtazapine for Treatment of Depression. Indian

J. Pharm. Educ. Res. 2020, 54, s210−s219.

(37) Nishizawa, M.; Kan, Y.; Yamada, H. Thermal glycosidation with

benzylated glycosyl chlorides : A very simple procedure for O-

glycosidation. Chem. Pharm. Bull. 1989, 37, 565−567.

(18) do Rosário, M. M. T.; Noleto, G. R.; de Oliveira Petkowicz, C.

L. Degalactosylation of xyloglucans modify their pro-inflammatory

properties on murine peritoneal macrophages. Int. J. Biol. Macromol.

(38) Hu, J. C.; Feng, A. W.; Chang, B. Y.; Lin, C. H.; Mong, K. T. A

flexible 1,2-cis α -glycosylation strategy based on in situ adduct

transformation. Org. Biomol. Chem. 2017, 15 , 5345 −5356.

017, 105, 533−540.

19) do Rosário, M. M. T.; Kangussu-Marcolino, M. M.; do Amaral,

A. E.; Noleto, G. R.; Petkowicz, C. L. d. O. Storage xyloglucans:

(

(39) Luning, B.; Norberg, T.; Tejbrant, J. Synthesis of glycosylated

amino acids for use in solid phase glycopeptide synthesis, part 2: N-

959

J. Org. Chem. 2021, 86, 9945−9960

The Journal of Organic Chemistry

Article

9-fluorenylmethyloxycarbonyl)-3-O-[2,4,6-tri-O -acetyl-3-O -(2,3,4-

(58) Tamura, J.-i.; Nishihara, J. Stereoselective syntheses of

phosphorylated and sulfated glycosyl serines in glycosaminoglycan

for biological probes. Bioorg. Med. Chem. Lett. 1999, 9, 1911−1914.

(59) Oniciu, D. C.; Bell, R. P. L.; McCosar, B. H.; Bisgaier, C. L.;

Dasseux, J. L. H.; Verdijk, D.; Relou, M.; Smith, D.; Regeling, H.;

Leemhuis, F. M. C.; Ebbers, E. J.; Mueller, R.; Zhang, L.; Pop, E.;

Cramer, C. T.; Goetz, B.; McKee, A.; Pape, M. E.; Krause, B. R.

Syntheses of Pantolactone and Pantothenic Acid Derivatives as

Potential Lipid Regulating Agents. Synth. Commun. 2006, 36, 365−

tri-O -acetyl-α -D-xylopyranosyl)-β -D-glucopyranosyl]-L-serine. J. Car-

bohydr. Chem. 1992, 11, 933−943.

(40) Bulman Page, P. C.; Chan, Y.; Liddle, J.; Elsegood, M. R. J.

Carbohydrate-derived iminium salt organocatalysts for the asym-

metric epoxidation of alkenes. Tetrahedron 2014, 70, 7283−7305.

(41) Krylov, V.; Ustyuzhanina, N.; Grachev, A.; Bakker, H.;

Nifantiev, N. Stereoselective synthesis of the 3-aminopropyl glyco-

sides of α -D-Xyl-(1 →3)-β -D-Glc and α -D-Xyl-(1 →3)-α -D-Xyl-(1 →

391.

)-β -D-Glc and of their corresponding N-octanoyl derivatives.

Synthesis 2007, 2007, 3147−3154.

42) Okamoto, N.; Kanie, O.; Huang, Y. Y.; Fujii, R.; Watanabe, H.;

(60) Schmidt, D.; Schuhmacher, F.; Geissner, A.; Seeberger, P. H.;

Pfrengle, F. Automated synthesis of arabinoxylan-oligosaccharides

enables characterization of antibodies that recognize plant cell wall

glycans. Chemistry 2015, 21, 5709−5713.

(

Shimamura, M. Synthetic α -mannosyl ceramide as a potent stimulant

for an NKT cell repertoire bearing the invariant V α 19-J α 26 TCR α

chain. Chem. Biol. 2005, 12, 677−683.

(61) Phanumartwiwath, A.; Hornsby, T. W.; Jamalis, J.; Bailey, C.

D.; Willis, C. L. Silyl migrations in D-xylose derivatives: Total

(43) Nifantiev, N.; Ustyuzhanina, N.; Komarova, B.; Zlotina, N.;

synthesis of a marine quinoline alkaloid. Org. Lett. 2013, 15, 5734−

Krylov, V.; Gerbst, A.; Tsvetkov, Y. Stereoselective α -glycosylation

with 3-O-acetylated D-gluco donors. Synlett 2006 , 2006 , 921 −923.

62) Cai, D.; Guan, D.; Ding, K.; Huang, W. Regioselective

737.

(44) Yasomanee, J. P.; Demchenko, A. V. Effect of Remote Picolinyl

protection of xylose for efficient synthesis of arabino-α -1,3-xylosides.

and Picoloyl Substituents on the Stereoselectivity of Chemical

Glycosylation. J. Am. Chem. Soc. 2012, 134, 20097−20102.

Tetrahedron Lett. 2017, 58, 4293−4295.

(63) Yang, B.; Yoshida, K.; Yin, Z.; Dai, H.; Kavunja, H.; El-

(45) Mannino, M. P.; Yasomanee, J. P.; Demchenko, A. V.

Dakdouki, M. H.; Sungsuwan, S.; Dulaney, S. B.; Huang, X. Chemical

synthesis of a heparan sulfate glycopeptide: syndecan-1. Angew. Chem.,

Int. Ed. 2012, 51, 10185−10189.

Investigation of the H-bond-mediated aglycone delivery reaction in

application to the synthesis of beta-glucosides. Carbohydr. Res. 2018,

70, 1−7.

(64) Yu, Y.; Ko, K.-S.; Zea, C. J.; Pohl, N. L. Discovery of the

(46) Yasomanee, J. P.; Demchenko, A. V. Hydrogen-bond-mediated

Chemical Function of Glycosidases: Design, Synthesis, and

Evaluation of Mass-Differentiated Carbohydrate Libraries. Org. Lett.

aglycone delivery (HAD): a highly stereoselective synthesis of 1,2-cis

α -D-glucosides from common glycosyl donors in the presence of

bromine. Chemistry 2015, 21, 6572−6581.

65) Mizumoto, S.; Ikegawa, S.; Sugahara, K. Human genetic

004, 6, 2031−2033.

(47) Pistorio, S. G.; Yasomanee, J. P.; Demchenko, A. V. Hydrogen-

disorders caused by mutations in genes encoding biosynthetic

enzymes for sulfated glycosaminoglycans. J. Biol. Chem. 2013, 288,

bond-mediated aglycone delivery: focus on β -mannosylation. Org.

Lett. 2014, 16, 716−719.

(48) Yasomanee, J. P.; Demchenko, A. V. Hydrogen bond mediated

0953−10961.

66) Chua, J. S.; Kuberan, B. Synthetic Xylosides: Probing the

aglycone delivery: synthesis of linear and branched α -glucans. Angew.

Chem., Int. Ed. 2014, 53, 10453−10456.

Glycosaminoglycan Biosynthetic Machinery for Biomedical Applica-

tions. Acc. Chem. Res. 2017, 50, 2693 −2705.

(49) Smoot, J. T.; Pornsuriyasak, P.; Demchenko, A. V. Develop-

(67) Esko, J. D.; Montgomery, R. I. Synthetic Glycosides as Primers

ment of an Arming Participating Group for Stereoselective

Glycosylation and Chemoselective Oligosaccharide Synthesis.

Angew. Chem., Int. Ed. 2005, 44, 7123 −7126.

of Oligosaccharide Biosynthesis and Inhibitors of Glycoprotein and

Proteoglycan Assembly. Curr. Protoc. Mol. Biol. 1995, 32, 17.11.1−

17.11.6.

(68) Nilsson, U.; Johnsson, R.; Fransson, L. A.; Ellervik, U.; Mani, K.

Attenuation of tumor growth by formation of antiproliferative

glycosaminoglycans correlates with low acetylation of histone H3.

Cancer Res. 2010, 70, 3771−3779.

50) Smoot, J. T.; Demchenko, A. V. How the Arming Participating

Moieties can Broaden the Scope of Chemoselective Oligosaccharide

Synthesis by Allowing the Inverse Armed −Disarmed Approach. J.

Org. Chem. 2008, 73, 8838−8850.

(51) Zhu, X.; Kawatkar, S.; Rao, Y.; Boons, G.-J. Practical Approach

(69) Mani, K.; Belting, M.; Ellervik, U.; Falk, N.; Svensson, G.;

Sandgren, S.; Cheng, F.; Fransson, L.-Å. Tumor attenuation by 2(6-

hydroxynaphthyl)-β -D-xylopyranoside requires priming of heparan

sulfate and nuclear targeting of the products. Glycobiology 2004, 14,

387−397.

for the Stereoselective Introduction of β -Arabinofuranosides. J. Am.

Chem. Soc. 2006, 128, 11948−11957.

(52) Huang, J. S.; Huang, W.; Meng, X.; Wang, X.; Gao, P. C.; Yang,

J. S. Stereoselective synthesis of α -3-Deoxy-D-manno -oct-2-ulosonic

acid (α -Kdo) glycosides using 5,7-o-Di-tert -butylsilylene-protected

Kdo ethyl thioglycoside donors. Angew. Chem., Int. Ed. 2015, 54,

(70) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.;

Wong, C.-H. Programmable One-Pot Oligosaccharide Synthesis. J.

Am. Chem. Soc. 1999, 121, 734 −753.

(

0894−10898.

71) Peng, P.; Ye, X.-S. O,O-Dimethylthiophosphonosulfenyl

53) Komura, N.; Kato, K.; Udagawa, T.; Asano, S.; Tanaka, H.-N.;

bromide-silver triflate: a new powerful promoter system for the

preactivation of thioglycosides. Org. Biomol. Chem. 2011, 9, 616−622.

Imamura, A.; Ishida, H.; Kiso, M.; Ando, H. Constrained sialic acid

donors enable selective synthesis of α -glycosides. Science 2019, 364,

77.

54) Crich, D. Mechanism of a Chemical Glycosylation Reaction.

Acc. Chem. Res. 2010, 43, 1144−1153.

55) Huang, T.-Y.; Zulueta, M. M. L.; Hung, S.-C. One-Pot

(

Strategies for the Synthesis of the Tetrasaccharide Linkage Region of

Proteoglycans. Org. Lett. 2011, 13, 1506−1509.

(56) Shimawaki, K.; Fujisawa, Y.; Sato, F.; Fujitani, N.; Kurogochi,

M.; Hoshi, H.; Hinou, H.; Nishimura, S. Highly efficient and versatile

synthesis of proteoglycan core structures from 1,6-anhydro-β -lactose

as a key starting material. Angew. Chem., Int. Ed. 2007, 46, 3074−

57) Tamura, J.-i.; Nishihara, J. Synthesis of Phosphorylated and

079.

Sulfated Glycosyl Serines in the Linkage Region of the Glycosami-

noglycans. J. Org. Chem. 2001, 66, 3074−3083.

960