Site-Selective Acylation of Pyranosides with Oligopeptide Catalysts

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Alexander Seitz, Ra ﬀ ael C. Wende, Emily Roesner, Dominik Niedek, Christopher Topp,

Avene C. Colgan, Eoghan M. McGarrigle, and Peter R. Schreiner *

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ABSTRACT: Herein, we report the oligopeptide-catalyzed site-

selective acylation of partially protected monosaccharides. We

identiﬁed catalysts that invert site-selectivity compared to N-

methylimidazole, which was used to determine the intrinsic

reactivity, for 4,6-O-protected glucopyranosides (trans-diols) as

well as 4,6-O-protected mannopyranosides (cis-diols). The reaction

yields up to 81% of the inherently unfavored 2-O-acetylated

products with selectivities up to 15:1 using mild reaction

conditions. We also determined the inﬂuence of protecting groups

on the reaction and demonstrate that our protocol is suitable for one-pot reactions with multiple consecutive protection steps.

products toward the typically highly unfavored 4-O-acetylation.

The best catalyst “favoring” 4-OH was able to give an almost

1:1 ratio of the monoacetylated products.¹¹Kirsch’s group

screened a library of oligopeptide catalysts bearing a 4-

(dimethylamino)pyridine (DMAP) moiety, achieving site-

selective acylation for diﬀerent methyl 4,6-O-protected

monosaccharides.¹²An excess of triethylamine was employed,

which, however, also leads to site-selective acylation in some

cases.¹³Recently, we reported the application of photo-

isomerizable azobenzene-based oligopeptides that allowed

switching the site selectivity in the acetylation of carbohydrate

diols and the natural product quercetin through irradiation.¹⁴

Here, we report the site-selective acylation of carbohydrates

using oligopeptide catalysts (Figure 1) bearing Pmh as the

catalytically active site and an adamantane moiety in the

backbone to improve solubility in organic solvents¹⁵and to

provide a dynamic binding pocket for the substrates.¹⁶These

INTRODUCTION

■

Carbohydrates are omnipresent as oligosaccharides and

glycoconjugates and are vital to a variety of biological

processes.¹Among other things, nature uses carbohydrates to

encode information.²Synthesizing these complex compounds

is a challenging task as multiple monosaccharides have to be

selectively linked to each other.³Consequently, much eﬀort

has been devoted to the development of selective glycosylation

reactions, for which temporary site-selective functionalization

(e.g., protection) of the monosaccharide building blocks is

often indispensable.⁴The hydroxy groups in monosaccharides

show reactivities that are depending on various inﬂuences,

some important ones being the intramolecular hydrogen

bonding network, steric eﬀects, the protecting groups already

installed, and the reaction conditions.⁵Hence, a lot of diﬀerent

methods were discovered to change the initial reactivity and

selectively to address speciﬁc hydroxy groups.⁶One way to

accomplish these protections is through the use of catalysts

that can site-selectively distinguish between the diﬀerent

hydroxy groups by using metal-based catalysts,⁷organo-

catalysts,^6a,8and enzymes.^4c,9Given the importance of

carbohydrate recognition in biological systems, oligopeptides

are of special interest among the class of organocatalysts.^8g,10

Pioneering studies in the site-selective acylation of carbohy-

drates using oligopeptide catalysts have been performed by the

Miller group in 2003, screening 150 diﬀerent oligopeptide

catalysts bearing a π-methyl histidine (Pmh) moiety for their

ability to site-selectively acetylate an amino sugar derivative,

and compared the results to N-methylimidazole (NMI), the

reference catalyst.¹¹Most catalysts enhanced the selectivity for

the acetylation at the intrinsically favored 3-hydroxy group, and

the best catalyst aﬀorded up to 97% of the corresponding

monoacetylated product. However, some of the catalysts were

able to change the selectivity and shifted the distribution of the

Figure 1. Site-selective acetylation of methyl 4,6-O-benzylidene-α-D-

glucopyranoside using peptide catalysts.

Received: November 19, 2020

Published: February 22, 2021

https://dx.doi.org/10.1021/acs.joc.0c02772

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Table 1. Acetylation of Methyl 4,6-O-Benzylidene-α-D-glucopyranoside 3 with NMI and Oligopeptide Catalysts 1 and 2

a

b

c

10 mol % cat., rt, [3] = 0.01 mol L⁻¹. 5 mol % cat., rt, [3] = 0.01 mol L⁻¹. Conditions obtained by DoE: 5 mol % cat., 0 °C, [3] = 0.005 mol L⁻¹.

d

1

x = 3a/(3a + 3b + 3c) × 100; product ratios and conversion determined via H NMR.

catalysts permit enantioselective acetylations of cyclic diols

with high yield and selectivity.^15,17We now developed this

class of oligopeptides into site-selective catalysts for the

acylation of monosaccharides that are building blocks for

subsequent glycosylation reactions. Furthermore, we inves-

tigated the substrate−catalyst interactions by changing the 4,6-

O-acetal protecting groups and by modifying the anomeric

center.

2-O-acetylated product 3a. Catalyst 1, for example, which has

proven excellent for the acylation of 1,2-alkane diols,^15,17a,b

achieved an overall yield higher than 95% with a selectivity of

55% for 3a (Table 1, entry 3). Of all tested catalysts,

tetrapeptide 2 with a selectivity of 76% performed best (Table

1, entry 4; 66% of 3a were isolated performing the reaction on

a 5.0 mmol scale). To optimize the reaction conditions, a

design of experiments (DoE) study was carried out (see the

Supporting Information for details).¹⁹We used a Custom

Design approach using JMP and chose ﬁve diﬀerent variables

for optimization: Concentration (0.1−0.005 mmol), catalyst

loading (0.1−10%), amount of acetic anhydride (1.0−10

equiv), reaction time (1−18 h) and temperature (−20 to +20

°C). These starting conditions for DoE optimization contained

a total of 27 experiments in random order for optimization of

all variables, which is much less than would be needed in a

typical step-by-step optimization. After performing the

reactions (plus repeating an additional ﬁve reactions for a

higher accuracy) we were able to generate a prediction proﬁler

(Figure S13), which was used to determine the best reaction

conditions. Using these conditions, we could further increase

the selectivity to 82% (Table 1, entry 5). These results are as

good as the best currently available in the literature (see Table

S3 for comparisons) and use mild reactions conditions, making

the reaction interesting for multi-step sequences.

RESULTS AND DISCUSSION

■

We commenced our investigation using methyl 4,6-O-

benzylidene-α-D-glucopyranoside (3), which is commercially

available and has already been investigated as a substrate in

site-selective acylation reactions.^{8f,9,12a,13,18}First, we synthe-

sized the monoacetylated derivatives 3a and 3b as well as the

diacetylated product 3c, using DMAP as the catalyst. We chose

¹H NMR analysis as our analytical method of choice as it

allowed the unambiguous diﬀerentiation between all products

as well as the starting material, and the product ratios and

conversions could be readily determined (see the Supporting

Information for details).

We tested the peptide catalysts using conditions similar to

those of Griswold and Miller¹¹and used NMI as a reference

catalyst to gauge the intrinsic reactivity. Without catalyst, the

substrates showed no reactivity under these conditions. NMI

favors formation of 3b with a ratio of 20:62:5 (3a:b:c, Table 1,

entry 2). Screening of diﬀerent peptide catalysts (see the

Supporting Information for the complete catalyst library)

showed that most of them preferentially led to the formation of

To investigate the inﬂuence of the 4,6-O-protecting group

and the anomeric center on the pyranoside, we performed

experiments with other monosaccharides as well. Using

methylidene instead of benzylidene as the protecting group,

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Table 2. Acetylation of 4,6-O-Protected Glucopyranoside Derivatives 4−7 with NMI and Tetrapeptide Catalyst 2

a

b

c

10 mol % cat., rt, [X] = 0.01 mol L⁻¹. 5 mol % cat., rt, [X] = 0.01 mol L⁻¹. Conditions obtained by DoE: 5 mol % cat., 0 °C, [X] = 0.005 mol

d

L⁻¹. x = Xa/(Xa + Xb + Xc) × 100; product ratios and conversion determined via H NMR.

1

Table 3. Acylation of 4,6-O-Protected Glucopyranoside Derivatives 3 and 4 Using Isobutyric Anhydride

a

b

c

d

10 mol % cat., rt, c = 0.01 mol L⁻¹. 5 mol % cat., rt, c = 0.01 mol L⁻¹. Conditions obtained by DoE: 5 mol % cat., 0 °C, 0.005 mol L⁻¹. x = Xa/

1

(Xa + Xb + Xc) × 100; product ratios and conversion determined via H NMR.

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Table 4. Acetylation of Methyl 4,6-O-Benzylidene-α-D-mannopyranoside 10 with NMI and Tetrapeptide Catalysts 1 and 2

a

b

c

10 mol % cat., 1.3 equiv Ac₂O, 18 h, rt, c = 0.01 mol L⁻¹. 5 mol % cat., 1.3 equiv Ac₂O, 18 h, rt, c = 0.01 mol L⁻¹. Conditions obtained by DoE:

d

10 mol % cat., 1.0 equiv Ac₂O, 2 h, 20 °C, 0.005 mol L⁻¹. x = 10a/(10a + 10b + 10c) × 100; product ratios and conversion determined via ¹H

NMR.

catalyst 2 was still able to overcome the reactivity and

selectivity of NMI (Table 2, entry 1), giving 76% selectivity for

the desired 2-O-acetylated product 4a (Table 2, entry 2).

Applying the reaction conditions given by DoE, the yield

slightly decreased but the selectivity improved up to 82%

(Table 2, entry 3). Even better selectivity of 86% was observed

with cyclohexylidene-protected derivative 5. No diacetylated

product 5c formed, but the overall conversion was signiﬁcantly

lower (64%; Table 2, entry 5). Note that with 5 as starting

material, NMI no longer favored the formation of 3-O-

acetylated product 5b but rather gave both monoacetylated

products in a 1:1 ratio with only 36% yield (Table 2, entry 4).

The outcome of the reaction was just slightly diﬀerent using

DoE conditions (Table 2, entry 6). With β-anomer 6, NMI

showed similar selectivity to the α-anomer, favoring 6b over

6a; however, an appreciable amount of diacetylated product 6c

formed and the overall conversion was low (Table 2, entry 7).

Catalyst 2 was able to raise the overall conversion to 75% but

still a large amount of diacetylated product 6c ensued.

Interestingly, the selectivity collapses (Table 2, entry 8),

indicating that the anomeric conﬁguration is important. This

must be due to changes in the interactions between the

substrate and the catalyst, which might be owing, in part, to

changes in the diol intramolecular hydrogen bonding patterns

(H-bonding from 2-OH to 1-OMe would be expected to be

stronger for the α-anomer). We also tested β-thioglucopyrano-

side derivative 7, which may be an interesting precursor in

glycosidic bond formation.²⁰We again observed a lower

selectivity of 53% compared to the α-derivatives (Table 2,

entry 11). Compared to NMI (Table 2, entry 10), the

selectivity was again inverted, and the overall conversion

increased. Applying the conditions obtained by DoE, we could

slightly increase the selectivity to 58% and decrease the

amount of diacetylated product 7c (Table 2, entry 12).

2-O-acetylated product 8a (Table 3, entry 2). The selectivity

further increased up to 87% using 4 as the starting material

(Table 3, entry 5). For both derivatives, the selectivity

increased compared to acetic anhydride, the intrinsic reactivity

of NMI was inverted and the overall conversion was high,

although less reactive isobutyric anhydride was used.

To explore whether our peptide-based catalyst would invert

NMI selectivity with other sugars, we also employed methyl

4,6-O-benzylidene-α-^D-mannopyranoside (10) as the substrate.

NMI again favored the formation of 3-O-acetylated product

with an even higher selectivity and overall good conversion of

73% but also accompanied by an appreciable amount of

diacetylated product 10c (Table 4, entry 2). Peptide catalyst 2

catalyzed the acetylation of 10 with an overall good conversion

of 83%. The intrinsic reactivity was not inverted but slightly

altered toward the 2-O-acetylated product, yielding a selectivity

of 30% (Table 4, entry 3). With catalyst 1, we observed high

reactivity and good selectivity of 57%, but also a lot of

diacetylated product 10c formed (Table 4, entry 4). To

decrease the amount of diacetylated product as well as to

further increase the selectivity, we employed a DoE strategy.^19c

As a result, the selectivity increased up to 87% (Table 4, entry

5). The dramatic reduction in the diacetylated product was

accompanied by a slight increase in the 10a:b ratio from 11:1

to 13:1. This was the best ratio of mono-acetylated products

we had observed at this stage; and, to the best of our

knowledge, the best results for a nonenzymatic selective

acetylation at the 2-OH-group of methyl 4,6-O-benzylidene-α-

D-mannopyranoside 10 known (see Table S4 for comparison).

One might have expected that 10b would be acetylated more

rapidly than 10a as it bears the same 2-OH as the starting diol;

the large reduction in 10c might have been expected to have

led to an increase in the amount of 10b versus 10a. Even

allowing for the greater concentration of 10a, the improved

selectivity seems to imply that the diacetylation process

exhibits quite a diﬀerent selectivity for 2-OH versus 3-OH

than in the reaction with diol 10. Performing the reaction on a

larger scale (1.0 mmol), we were able to isolate 68% of the

We also investigated the inﬂuence of the acylation reagent

employing isobutyric anhydride²¹[(iPrCO)₂O] and carbohy-

drate derivatives 3 and 4 as starting materials; these starting

materials were investigated by Xiao et al. as well.^8fWhen 3 was

used, we achieved good reactivity and a selectivity of 85% for

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Table 5. Acetylation of 4,6-O-Protected Mannopyranoside Derivatives 11 and 12 with NMI and Tetrapeptide Catalyst 1

a

b

c

10 mol % cat., 1.3 equiv Ac₂O, 18 h, rt, c = 0.01 mol L⁻¹. 5 mol % cat., 1.3 equiv Ac₂O, 18 h, rt, c = 0.01 mol L⁻¹. Conditions obtained by DoE:

d

10 mol % cat., 1.0 equiv Ac₂O, 2 h, 20 °C, 0.005 mol L⁻¹. x = Xa/(Xa + Xb + Xc) × 100; product ratios and conversion determined via ¹H NMR.

Naph = 2-Naphthyl.

Table 6. Acetylation of Methyl 4,6-O-Benzylidene-α-D-galactopyranoside 13 with NMI and Tetrapeptide Catalysts 1 and 2

a

b

c

10 mol % cat., c = 0.01 mol L⁻¹. 5 mol % cat., c = 0.01 mol L⁻¹. x = 13b/(13a + 13b + 13c) × 100; product ratios and conversion determined

1

via H NMR.

desired methyl 2-O-acetyl-4,6-O-benzylidene-α-D-mannopyra-

noside 10a.

to 88% (Table 5, entry 5). The large amount of diacetylated

product 12c decreased employing the DoE conditions, thereby

achieving a high selectivity of 86% (Table 5, entry 6). As found

for 10, the overall conversion dropped to 69%, but the ratio of

mono-acetylated products 12a:b remained at approximately

15:1the highest we observed.

We also investigated the inﬂuence of the 4,6-O-protecting

group, ﬁrst using again methylidene instead of benzylidene.

NMI prefers formation of 3-O-acetylated product 11b with an

overall moderate conversion of 46% (Table 5, entry 1).

Catalyst 1 showed similar reactivity to 10; the formation of

11a was favored with a selectivity of 68% (Table 5, entry 2).

Applying the conditions from the DoE reduced the amount of

diacetylated product 11c, but the overall conversion (55%)

dropped and the selectivity was just slightly increased to 73%

(Table 5, entry 3). Using methyl 4,6-O-(2-naphthylidene)-α-^D-

mannopyranoside (12), which was already studied by us

previously,¹⁴NMI gave only 22% conversion but was still

favoring 12b (Table 5, entry 4). Catalyst 1 provided a high

selectivity of 70% for 12a, and the overall conversion increased

Isobutyric anhydride was also tested as the acylation reagent.

NMI favored the formation of 3-O-acylated product 18b with

diacetylated product, and a moderate conversion of 54% was

achieved (18a:b:c 6:42:6; Table S2, entry 2). Catalyst 1

provided a good selectivity of 75% for the 2-O-acylated

product, but also a notable amount of the diacylated product

formed. The overall conversion increased to 94% (18a:b:c

70:6:17; Table S2, entry 3).

For 4,6-O-benzylidene-α-^D-galactopyranoside (13), NMI

slightly favored 13b with an overall moderate conversion of

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Figure 2. One-pot double protection of methyl α-D-glucopyranoside.

Table 7. Acetylation of Methyl 4,6-O-Benzylidene-α-D-mannopyranoside 10 with Catalysts with Increasing Size

a

1

x = 10a/(10a + 10b + 10c) × 100; product ratios and conversion determined via H NMR.

63% (Table 6, entry 2). Catalyst 2 did not change the

preference for 13b but slightly ampliﬁed the formation of it

and increased the conversion to >95% (Table 6, entry 3).

Catalyst 1 gave the best selectivity of 72% for 13b and an

overall conversion of 90% (Table 6, entry 4). These results

again indicate that the change from an equatorial to an axial

conﬁguration at the C4-position has a signiﬁcant inﬂuence on

the interaction between the substrate and catalyst. Here too,

this may in part be due to changes in the substrate hydrogen

bonding patterns as the 3,4-cis-conﬁguration in 13 would be

expected to be more favorable for a hydrogen bond between

the 3-OH and the 4-O.

Finally, we decided to determine whether it is possible to

combine benzylidene protection followed by selective

acetylation (Figure 2). Therefore, 14 was ﬁrst benzylidene-

protected using camphor sulfonic acid as the catalyst and

toluene as the solvent, as well as 4 Å molecular sieves to

remove the formed methanol. Subsequently, catalyst 2 and

acetic anhydride were added. This procedure gave 22% 2-O-

acetylated product 3a, 5% 3-O-acetylated product 3b, and 4%

diacetylated product 3c. The ratio (3a/3b/3c = ∼4:1:1)

compares well with the results observed for methyl 4,6-O-

benzylidene-α-^D-glucopyranoside (3) (Table 1, entry 4), and

the overall yield is comparable to just the benzylidene

protection of 14 (30% yield) under the given conditions;

that is, the protection step limits the yield. This result indicates

that the reactivity of the peptide is preserved even in a more

complex system; 3 is selectively acetylated and the protection

of all but one hydroxy group is achieved in a one-pot reaction

sequence.

For almost all investigated pyranoside derivatives, the

inherent reactivity, determined using NMI as the catalyst,

was at the 3-OH group. Catalyst 2 and most other tested

catalysts (Table S1) can switch the selectivity and preferably

acylate the tested α-glucopyranosides at the 2-OH group under

mild conditions with high yields. To do so, we expect the

oligopeptides to form a “dynamic binding pocket,” with which

the monosaccharides can interact.^15,16A ﬁrst insight into the

substrate recognition process is given by the fact that the

selectivity essentially vanishes when using methyl 4,6-O-

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0.2 mm silica gel layer with ﬂuorescent indicator). For visualization,

UV light (254 nm) or staining solutions [KMnO₄: 2.5 g KMnO₄, 8.3

g K₂CO₃, 250 mL H₂O; Hanessian’s stain: 12 g (NH₄)₆Mo₇O₂₄·

4H₂O, 0.5 g (NH₄)₄Ce(SO₄)₄·4H₂O, 15 mL concn H₂SO₄, 235 mL

H₂O] were utilized. NMR spectra were recorded on Bruker AV600,

AV400 or AV400HD spectrometers. Chemical shifts (δ) are given in

parts per million (ppm) relative to the respective solvent residual

peaks (CDCl₃: δ 7.26 and 77.16 ppm; DMSO-d₆: δ 2.50 and 39.52

ppm; MeOH-d₄: δ 3.31 and 49.00 ppm; acetone-d₆: δ 2.05 and 29.84

ppm). ¹H NMR data are reported as follows: chemical shift,

multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sept =

septet, m = multiplet, br = broad, app = apparent, or combinations

thereof), coupling constants (Hz), and integration. For ¹³C NMR, the

chemical shifts are given. High-resolution mass spectrometry

(HRMS) was performed with a Bruker MicrOTof (ESI). IR spectra

were measured with a Bruker Alpha spectrometer.

General Procedures. Procedure 1: Synthesis of Standards. The

pyranoside derivative (1.0 equiv) and 4-dimethylaminopyridine

(DMAP) (0.05 equiv) were dissolved in dichloromethane (DCM)

(10 mL/mmol), the carboxylic acid anhydride (1.3 equiv) was added,

and the solution was stirred at rt for 24 h. The reaction was quenched

with MeOH (1 mL/mmol) and stirred for further 30 min. The

solvent was removed under reduced pressure, and the crude products

were puriﬁed via column chromatography to obtain the three desired

products.

Procedure 2: Amide Bond Formation (Peptide Coupling). The

amino acids (1.0 equiv), 1-ethyl-3-(3-dimethylaminopropyl)-

carbodiimide (EDC·HCl; 1.2 equiv), and 1-hydroxybenzotriazole

(HOBt; 1.2 equiv) were suspended in CH₂Cl₂(10 mL/mmol).

Triethylamine (Et₃N; 1.2 equiv) was added, and the mixture was

stirred at rt for 24 h. It was diluted with EtOAc (50 mL/mmol) and

subsequently washed three times (10 mL/mmol) each with 0.5 m

citric acid solution, saturated aqueous NaHCO₃solution, and brine.

The organic layer was dried over Na₂SO₄, ﬁltered, and concentrated

under reduced pressure to aﬀord the crude peptide as a solid (if

necessary, a column chromatography was performed).

Procedure 3: Boc-Deprotection. The Boc-protected peptide (1.0

equiv) was treated with 2 mL/mmol 4 M HCl in 1,4-dioxane, and the

resulting solution was stirred for 60 min. The reaction ﬂask was

ﬂushed with nitrogen to remove residual HCl, and the solvent was

removed under reduced pressure. After drying in vacuo, the resulting

peptide hydrochloride was directly used for the next coupling step.

Procedure 4: Boc-π-methyl Histidine (Boc-Pmh) Coupling. The

amino acids (1.0 equiv), EDC·HCl (2.2 equiv), and HOBt (2.2

equiv) were suspended in 10 mL/mmol CH₂Cl₂. Et₃N (2.2 equiv)

was added, and the mixture was stirred at rt for 24 h. It was diluted

with EtOAc (50 mL/mmol) and subsequently washed three times (10

mL/mmol) each with saturated aqueous NaHCO₃solution and brine.

The organic layer was dried over Na₂SO₄, ﬁltered, and concentrated

under reduced pressure. The product was obtained after column

chromatography as a colorless solid.

benzylidene-β-D-glucopyranoside (6) and methyl 4,6-O-

benzylidene-α-^D-galactopyranoside (13), which, like the

glucopyranoside derivatives, also bears two trans OH-groups.

This indicates that an axial α-position (the vicinal methoxy

group has a cis relationship with the favored OH group) and an

equatorial 4-O-position are necessary for a beneﬁcial

interaction between monosaccharide and oligopeptide 2. The

interaction seems to be diﬀerent but even more important for

methyl 4,6-O-benzylidene-α-^D-mannopyranoside (10), which

bears two cis OH-groups, as only oligopeptide catalyst 1

provides good selectivity. As shown in Table 7, selectivity

increased with the size of the oligopeptide catalyst, which

indicates that more interactions are beneﬁcial for the reaction.

NMI (5% selectivity; Table 7, entry 1) and Boc-^L-Pmh-OMe

15 (13% selectivity; Table 7, entry 2), two catalysts which we

expect to not interact with the substrates so much, favored the

3-O-position. By increasing the peptide chain length by one

amino acid (Boc-^L-Pmh-^AGly-OMe 16), the interaction is

increased as well, evidenced by the increase in the 2-O-

acetylated product formed (36% selectivity; Table 7, entry 3).

Adding another amino acid (Boc-^L-Pmh-^AGly-L-Cha-OMe 17)

enables the formation of a binding pocket and results in

enough interaction to selectively acylate in the 2-O-position

(69% selectivity, Table 7, entry 4). Finally, catalyst 1 improved

the selectivity further up to 79%. At this stage, we can only

speculate about the exact nature of the interactions between

the catalyst and substrate. We expect that hydrogen bonding

interactions will play a key role as both substrates and catalysts

have competent hydrogen-bonding donor and acceptor groups.

To provide deeper insights into those interactions, we plan on

executing detailed NMR studies in due course.¹⁶

CONCLUSIONS

■

We demonstrate that oligopeptides bearing Pmh as the

catalytic moiety enable site-selective acylation reactions of

pyranosides with anhydrides as the acylation reagents. For

mannopyranoside and glucopyranoside derivatives, we show

that tetrapeptides can selectively acylate the OH-group in the

2-position, leaving the monosaccharides with just one free OH

group in the 3-position. The peptide catalyst structure

overrides the intrinsic preference of the “parent” NMI motif

for the 3-OH. A DoE approach was employed to optimize the

reaction conditions for methyl 4,6-O-benzylidene-protected α-

D-pyranosides; the optimal conditions vary for derivatives with

other protecting groups. As our reaction conditions are mild

and as we have demonstrated that it is possible to perform

benzylidene protection followed by site-selective acylation in a

one-pot reaction, our approach may also be amenable to other

one-pot syntheses of orthogonally protected carbohydrate

derivatives.

General Procedure for the Catalyzed Reactions. The

catalyzed reactions were carried out on a 0.1 mmol scale in dry

toluene. The starting material and the catalyst were dissolved, and

after 15 min stirring at the desired temperature, acetic anhydride was

added. The resulting mixture was stirred for the desired time at the

given temperature. Afterward, some drops of methanol were added to

quench the reaction. All volatiles were removed under reduced

pressure, and the residue was dissolved in a deuterated solvent and

directly transferred to an NMR tube. The choice of the solvent was

based on solubility and stability of all starting materials and the

desired products. Selectivity and yields were determined by

EXPERIMENTAL SECTION

■

General Information. All chemicals were purchased from

commercial suppliers and used without further puriﬁcation. Boc-4-

aminoadamantanecarboxylic acid (Boc-^AGly-OH),²²Boc-Pmh-OH,²³

and H-Pmh-OMe·2HCl²⁴were prepared according to literature

procedures. Solvents for column chromatography, extractions, and

ﬁltrations were distilled prior to use. Dry solvents were purchased

from Acros Organics (AcroSeal) and stored under a N₂atmosphere

and over activated molecular sieves (3 or 4 Å). Acetic anhydride was

distilled and stored under N₂. Column chromatography was carried

out using silica gel 60 M (Macherey-Nagel; 0.040−0.063 mm, 230−

400 mesh ASTM). Thin-layer chromatography was performed using

precoated plastic sheets Polygram SIL G/UV 254 (Macherey-Nagel;

1

integration of signals in the H NMR spectra, as shown in Figures

S1 −S12.

Procedure for Preparative Scale Reactions. The starting

material and the catalyst were dissolved in dry toluene, and after 15

min stirring at the desired temperature, acetic anhydride was added.

The resulting mixture was stirred for the desired time at the given

temperature. Afterward, some drops of methanol were added to

quench the reaction. All volatiles were removed under reduced

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pressure, and the crude product was puriﬁed via column

chromatography to give the desired products.

(4-Methylphenyl)-1-thio-β,D-glucopyranoside (7f).²⁹0.124 g (5.4

mmol, 1.2 equiv) of sodium was dissolved in 20 mL of dry methanol,

and 2.05 g (4.5 mmol, 1 equiv) of 7e were added. After stirring for 18

h, the solution was neutralized with Amberlyst 15(H), ﬁltered oﬀ, and

all volatiles were removed under reduced pressure to give 1.30 g of the

desired product 7f as a colorless solid, which was used in the next step

without any further puriﬁcation.

(4-Methylphenyl)-4,6-O-benzylidene-1-thio-β,^D-glucopyranoside

(7). 1.30 g (4.5 mmol, 1.0 equiv) of 7g, 0.90 g (0.89 mL, 5.9 mmol,

1.3 equiv) of benzaldehyde dimethyl acetal, and 2 mg (0.01 mmol,

0.0025 equiv) of camphor sulfonic acid were suspended in 20 mL of

chloroform. The suspension was placed into a preheated oil bath (90

°C), and chloroform was continuously distilled oﬀ. After distilling oﬀ,

another 15 mL of chloroform were added. This procedure was

repeated ﬁve times, and the mixture was then ﬁltered while hot. After

cooling to rt, all volatiles were removed under reduced pressure, and

the residue was puriﬁed by column chromatography (n-hexane/

EtOAc 1:1) to obtain 7 in 1.18 g (3.2 mmol, 70%) yield as a colorless

solid. R_f= 0.37 (n-hexane/EtOAc 1:1). ¹H NMR (400 MHz, CDCl₃):

δ 7.51−7.40 (m, 4H), 7.44−7.31 (m, 3H), 7.18−7.12 (m, 2H), 5.52

(s, 1H), 4.55 (d, J = 9.7 Hz, 1H), 4.41−4.33 (m, 1H), 3.88−3.69 (m,

2H), 3.54−3.43 (m, 2H), 3.42 (dd, J = 9.7, 8.5 Hz, 1H), 2.88 (s, 1H),

2.72 (s, 1H), 2.36 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

139.0, 137.0, 133.8, 130.0, 129.5, 128.5, 127.4, 126.4, 102.1, 88.8,

80.4, 74.7, 72.6, 70.7, 68.7, 21.3 ppm.³²

Starting Materials. Methyl 4,6-O-Methylidene-α-^D-glucopyra-

noside (4). The title compound was synthesized according to a

literature procedure.²⁵The crude product was puriﬁed via column

chromatography (acetone/Et₂O 1:1), and it was obtained in 2.24 g

yield (10.9 mmol, 22%) as a colorless solid. R_f= 0.23 (acetone/Et₂O

1:1). ¹H NMR (400 MHz, CDCl₃): δ 5.06 (d, J = 6.3 Hz, 1H), 4.74

(d, J = 3.9 Hz, 1H), 4.61 (d, J = 6.3 Hz, 1H), 4.14 (dd, J = 10.3, 4.9

Hz, 1H), 3.86 (td, J = 9.2, 2.1 Hz, 1H), 3.67 (ddd, J = 10.6, 9.5, 4.9

Hz, 1H), 3.57 (td, J = 9.3, 3.9 Hz, 1H), 3.43 (m, 4H), 3.28 (d, J = 2.4

Hz, 1H), 3.21 (t, J = 9.4 Hz, 1H), 2.69 (d, J = 9.4 Hz, 1H) ppm.

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 99.9, 93.9, 80.8, 73.1, 71.7,

68.8, 62.7, 55.7 ppm.

Methyl 4,6-O-Cyclohexlylidene-α-D-glucopyranoside (5). The

title compound was synthesized according to a literature procedure.²⁷

The crude product was puriﬁed via column chromatography

(EtOAc), and it was obtained in 0.33 g (1.2 mmol, 12%) yield as a

1

colorless solid. R_f= 0.28 (EtOAc). H NMR (400 MHz, MeOH-d₄):

δ 4.67 (d, J = 3.8 Hz, 1H), 3.83−3.71 (m, 2H), 3.64 (t, J = 9.0 Hz,

1H), 3.59−3.43 (m, 3H), 3.39 (s, 3H), 2.15−1.84 (m, 2H), 1.71−

1.35 (m, 8H) ppm. ¹³C{¹H} NMR (100 MHz, MeOH-d₄): δ 102.0,

100.9, 74.5, 74.1, 72.4, 64.9, 62.8, 55.7, 39.1, 28.8, 26.8, 23.8, 23.5

ppm.²⁶

Methyl 4,6-O-Benzylidene-β-D-glucopyranoside (6). The title

compound was synthesized according to a literature procedure.²⁷

The crude product was puriﬁed via column chromatography

(EtOAc), and it was obtained in 5.22 g (18.5 mmol, 88%) yield as

Methyl 4,6-O-Benzylidene-α-D-mannopyranoside (10). The title

compound was synthesized according to a literature procedure.³³The

crude product was puriﬁed via column chromatography, and it was

obtained in 0.97 g (3.4 mmol, 17%) yield as a colorless solid. R_f= 0.34

1

a colorless solid. R_f= 0.39 (EtOAc). H NMR (400 MHz, DMSO-

1

(n-hexane/EtOAc 1:2). H NMR (400 MHz, MeOH-d₄): δ 7.55−

d₆): δ 7.49−7.41 (m, 2H), 7.41−7.34 (m, 3H), 5.57 (s, 1H), 5.31 (dd,

J = 16.9, 5.0 Hz, 2H), 4.26 (d, J = 7.8 Hz, 1H), 4.20 (dd, J = 10.3, 4.1

Hz, 1H), 3.70 (td, J = 8.2, 6.9, 3.6 Hz, 1H), 3.50−3.29 (m, 4H), 3.08

(td, J = 8.0, 4.7 Hz, 1H) ppm. ¹³C{¹H} NMR (100 MHz, DMSO-d₆):

δ 137.8, 128.8, 128.0, 126.3, 104.5, 100.6, 80.6, 74.2, 72.8, 67.9, 65.8,

56.3 ppm.²⁸

7.46 (m, 2H), 7.38−7.29 (m, 3H), 5.60 (s, 1H), 4.67 (s, 1H), 4.20

(dd, J = 10.0, 4.7 Hz, 1H), 3.97−3.86 (m, 3H), 3.81 (t, J = 10.2 Hz,

1H), 3.74−3.67 (m, 1H), 3.39 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, MeOH-d₄): δ 139.3, 129.9, 129.0, 127.5, 103.7, 103.4, 80.2,

72.6, 69.9, 69.6, 65.1, 55.3 ppm.

Methyl 4,6-O-Methylidene-α-^D-mannopyranoside (11). The title

compound was synthesized according to a literature procedure.²⁵The

crude product was puriﬁed via column chromatography (acetone/

Et₂O 2:7), and it was obtained in 0.59 g (2.9 mmol, 29%) yield as a

1,2,3,4,6-Pentaacetate-D-glucopyranose (7d).²⁹19.85 g (110

mmol, 1.0 equiv) of ^D-glucose and 10.75 g (131 mmol, 1.2 equiv)

of sodium acetate were dissolved in 100 mL of acetic anhydride. After

stirring for 8 h at 80 °C, the solution was poured onto 300 mL of ice

and extracted with DCM (3 × 200 mL). The combined organic layers

were washed with sat. aq. NaHCO₃(2 × 150 mL), dried over

Na₂SO₄, and concentrated under reduced pressure. Recrystallization

from ethanol gave 35.0 g (89.7 mmol, 82%) of 7d (mixture α/β 1:4)

1

colorless solid. R_f= 0.47 (acetone/Et₂O 2:7). H NMR (400 MHz,

MeOH-d₄): δ 5.00 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 6.2 Hz, 1H), 4.62

(d, J = 1.5 Hz, 1H), 4.05 (dd, J = 9.5, 3.7 Hz, 1H), 3.87−3.76 (m,

2H), 3.67−3.48 (m, 3H), 3.36 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, MeOH-d₄): δ 103.7, 95.1, 80.1, 72.6, 69.6, 69.5, 65.3, 55.3 ppm.

Methyl 4,6-O-(2-Naphthylidene)-α-^D-mannopyranoside (12).

The title compound was synthesized according to a literature

procedure.¹⁴The crude product was puriﬁed via column chromatog-

raphy (n-hexane/EtOAc 1:2), and it was obtained in 0.85 g (2.6

mmol, 12%) yield as a colorless solid. R_f= 0.31 (n-hexane/EtOAc

1

as a colorless solid. H NMR (400 MHz, CDCl₃): δ 6.27 (d, J = 3.7

Hz, 1H α), 5.65 (d, J = 8.3 Hz, 1H β), 5.41 (t, J = 9.9 Hz, 1H α), 5.19

(t, J = 9.4 Hz, 1H β), 5.11−5.01 (m, 2H α, 2H β), 4.27−4.18 (m, 1H

α, 1H β), 4.09−4.00 (m, 2H α, 1H β), 3.77 (ddd, J = 10.0, 4.5, 2.2

Hz, 1H β), 2.14−1.92 (m, 15H α, 15H β) ppm. ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 170.8, 170.7, 170.4, 170.2, 169.8, 169.5, 169.4,

169.1, 168.9, 91.8, 89.2, 72.9, 72.8, 70.3, 70.0, 69.3, 68.0, 67.9, 61.6,

21.0, 21.0, 20.8, 20.8, 20.7, 20.6 ppm.³⁰

1

1:2). H NMR (400 MHz, MeOH-d₄): δ 8.01−7.98 (m, 1H), 7.91−

7.80 (m, 3H), 7.62 (dd, J = 8.6, 1.7 Hz), 7.53−7.45 (m, 2H), 5.77 (s,

1H), 4.69 (d, J = 1.5 Hz, 1H), 4.25 (dd, J = 10.0, 4.8 Hz, 1H), 4.04−

3.82 (m, 4H), 3.76 (ddd, J = 10.3, 8.8, 4.7 Hz, 1H), 3.41 (s, 3H) ppm.

¹³C{¹H} NMR (100 MHz, MeOH-d₄): δ 136.7, 135.1, 134.3, 129.3,

(4-Methylphenyl)-1-thio-2,3,4,6-pentaacetate-β,D-glucopyrano-

side (7e).²⁹31.2 g (80.0 mmol, 1.0 equiv) of 7d and 10.8 g (88 mmol,

1.1 equiv) of p-toluene thiol were dissolved in 200 mL of dry DCM.

The solution was cooled to 0 °C and 48.4 g (36 mL, 340 mmol, 4.25

equiv) of BF₃·Et₂O was slowly added. After stirring for 18 h at rt, the

solution was poured onto 200 mL of ice and extracted with DCM (3

× 100 mL). The combined organic layers were washed with sat. aq.

NaHCO₃(2 × 150 mL), dried over Na₂SO₄, and concentrated under

reduced pressure. Column chromatography (n-hexane/EtOAc 2:1)

gave 7e as a colorless solid (yield not determined as only a part of the

128.7, 128.7, 127.4, 127.2, 126.8, 125.2, 103.8, 103.4, 80.3, 72.6, 70.0,

69.6, 65.1, 55.4 ppm.

Methyl 4,6-O-Benzylidene-α-^D-galactopyranoside (13). The title

compound was synthesized according to a literature procedure.²⁷The

product was obtained in 4.56 g (16.2 mmol, 90%) yield as a colorless

solid. ¹H NMR (400 MHz, CDCl₃): δ 7.52−7.47 (m, 2H), 7.40−7.34

(m, 3H), 5.54 (s, 1H), 4.92 (d, J = 3.1 Hz, 1H), 4.28 (dd, J = 12.5, 1.6

Hz, 1H), 4.25−4.24 (m, 1H), 4.07 (dd, J = 12.6, 1.8 Hz, 1H), 3.96−

3.86 (m, 2H), 3.68 (d, J = 1.6 Hz, 1H), 3.45 (s, 3H), 2.37 (s, 2H)

ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 137.7, 129.3, 1284, 126.4,

101.4, 100.4, 76.0, 70.0, 69.9, 69.5, 62.9, 55.9 ppm.³⁴

Standards. Methyl 2-O-Acetyl-4,6-O-benzylidene-α,D-glucopyr-

anoside (3a). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-glucopyr-

anoside (282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol,

0.1 equiv), Ac₂O (132.7 mg, 122 μL, 1.3 mmol, 1.3 equiv), and 10 mL

of DCM were used to obtain 3a after column chromatography (n-

1

crude product was puriﬁed). R_f= 0.24 (n-hexane/EtOAc 2:1). H

NMR (400 MHz, CDCl₃): δ 7.42−7.35 (m, 2H), 7.16−7.09 (m, 2H),

5.20 (t, J = 9.4 Hz, 1H), 5.02 (t, J = 9.8 Hz, 1H), 4.93 (dd, J = 10.1,

9.2 Hz, 1H), 4.63 (d, J = 10.0 Hz, 1H), 4.26−4.13 (m, 2H), 3.69

(ddd, J = 10.1, 4.8, 2.7 Hz, 1H), 2.35 (s, 3H), 2.09 (s, 3H), 2.08 (s,

3H), 2.01 (s, 3H), 1.98 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 170.7, 170.3, 169.5, 169.4, 138.9, 134.0, 129.8, 127.7,

86.90, 75.9, 74.2, 70.1, 68.4, 62.3, 21.3, 20.9, 20.9, 20.7, 20.7 ppm.³¹

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hexane/EtOAc 1:1) in 62.1 mg (0.19 mmol, 19%) yield as a colorless

solid. R_f= 0.42 (n-hexane/EtOAc 1:1). ¹H NMR (400 MHz, CDCl₃):

δ 7.53−7.48 (m, 2H), 7.43−7.34 (m, 3H), 5.55 (s, 1H), 4.96 (d, J =

3.7 Hz, 1H), 4.81 (dd, J = 9.7, 3.8 Hz, 1H), 4.30 (dd, J = 9.9, 4.5 Hz,

1H), 4.18 (t, J = 9.5 Hz, 1H), 3.85 (td, J = 9.6, 4.5 Hz, 1H), 3.76 (t, J

= 10.2 Hz, 1H), 3.56 (t, J = 9.3 Hz, 1H), 3.41 (s, 3H), 2.46 (bs, 1H),

2.16 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 170.8, 137.1,

129.5, 128.5, 126.4, 102.2, 97.7, 81.5, 73.7, 69.0, 68.8, 62.1, 55.6, 21.1

ppm.³⁵

Methyl 2,3-O-Diacetyl-4,6-O-methylidene-α,^D-glucopyranoside

(4c). Procedure 1. Methyl 4,6-O-methylidene-α,^D-glucopyranoside

(206.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (132.7 mg, 122 μL, 1.3 mmol, 1.3 equiv), and 10 mL of

DCM were used to obtain 4c after column chromatography (CH₂Cl₂/

MeOH 40:1) in 58.5 mg (0.20 mmol, 20%) yield as a colorless solid.

1

R_f= 0.52 (n-hexane/EtOAc 1:1). H NMR (400 MHz, CDCl₃): δ

5.48 (t, J = 9.8 Hz, 1H), 5.04 (d, J = 6.2 Hz, 1H), 4.89 (d, J = 3.8 Hz,

1H), 4.85 (dd, J = 9.9, 3.8 Hz, 1H), 4.57 (d, J = 6.2 Hz, 1H), 3.81 (td,

J = 9.9, 4.9 Hz, 1H), 3.47 (t, J = 10.3 Hz, 1H), 3.39 (s, 3H), 3.36 (t, J

= 9.7 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 170.5, 170.1, 97.7, 93.9, 79.5, 71.6, 69.1, 68.8, 62.6,

55.5, 20.9, 20.9 ppm.³⁸

Methyl 3-O-Acetyl-4,6-O-benzylidene-α,D-glucopyranoside (3b).

Procedure 1. Methyl 4,6-O-benzylidene-α,^D-glucopyranoside (282.0

mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1 equiv),

Ac₂O (132.7 mg, 122 μL, 1.3 mmol, 1.3 equiv), and 10 mL of DCM

were used to obtain 3b after column chromatography (n-hexane/

EtOAc 1:1) in 183.7 mg (0.51 mmol, 51%) yield as a colorless solid.

Methyl 2-O-Acetyl-4,6-O-cyclohexylidene-α,D-glucopyranoside

(5a). Procedure 1. Methyl 4,6-O-cyclohexylidene-α,^D-glucopyrano-

side (274.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (132.7 mg, 122 μL, 1.3 mmol, 1.3 equiv), and 10 mL of

DCM were used to obtain 5a after column chromatography (n-

hexane/EtOAc 1:1) in 64.7 mg (0.20 mmol, 20%) yield as a colorless

solid. R_f= 0.33 (n-hexane/EtOAc 1:1). ¹H NMR (400 MHz, MeOH-

d₄): δ 4.86−4.84 (m, 1H; overlap with OH of MeOH-d₄), 4.66 (dd, J

= 9.7, 3.8 Hz, 1H), 3.87−3.75 (m, 3H), 3.65−3.54 (m, 2H), 3.35 (s,

3H), 2.09 (s, 3H), 2.07−1.97 (m, 1H), 1.97−1.87 (m, 1H), 1.71−

1.36 (m, 8H) ppm. ¹³C{¹H} NMR (100 MHz, MeOH-d₄): δ 172.2,

101.0, 99.0, 75.3, 74.5, 69.8, 64.8, 62.6, 55.6, 39.1, 28.8, 26.8, 23.8,

23.5, 20.7 ppm. HRMS (ESI-TOF) m/z: [M + Na]⁺calcd for

C₁₅H₂₄O₇Na, 339.1414; found, 339.1416. IR (ATR) ν/cm⁻¹: 3446,

2935, 1741, 1446, 1367, 1235, 1194, 1146, 1124, 1097, 1027, 988,

950, 924.

Methyl 3-O-Acetyl-4,6-O-cyclohexylidene-α,^D-glucopyranoside

(5b). Procedure 1. Methyl 4,6-O-cyclohexylidene-α,^D-glucopyrano-

side (274.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (132.7 mg, 122 μL, 1.3 mmol, 1.3 equiv), and 10 mL of

DCM were used to obtain 5b after column chromatography (n-

hexane/EtOAc 1:1) in 40.4 mg (0.13 mmol, 13%) yield as a colorless

solid. R_f= 0.39 (n-hexane/EtOAc 1:1). ¹H NMR (400 MHz, MeOH-

d₄): δ 5.13 (t, J = 9.5 Hz, 0H), 4.73 (d, J = 3.8 Hz, 1H), 3.86−3.75

(m, 2H), 3.70−3.60 (m, 3H), 3.43 (s, 3H), 2.09 (d, J = 12.2 Hz, 2H),

2.07 (s, 3H), 1.79−1.67 (m, 1H), 1.63−1.28 (m, 8H) ppm. ¹³C{¹H}

NMR (100 MHz, MeOH-d₄): δ 172.3, 102.0, 100.8, 73.8, 72.6, 72.1,

64.9, 62.8, 55.8, 39.0, 28.7, 26.7, 23.9, 23.7, 21.0 ppm. HRMS (ESI-

TOF) m/z: [M + Na]⁺calcd for C₁₅H₂₄O₇Na, 339.1414; found,

339.1415. IR (ATR) ν/cm⁻¹: 3469, 2936, 1741, 1446, 1366, 1229,

1175, 1144, 1120, 1099, 1082, 1032, 990, 950, 925.

1

R_f= 0.26 (n-hexane/EtOAc 1:1). H NMR (400 MHz, CDCl₃): δ

7.48−7.42 (m, 2H), 7.39−7.33 (m, 3H), 5.49 (s, 1H), 5.32 (t, J = 9.7

Hz, 1H), 4.81 (d, J = 3.8 Hz, 1H), 4.30 (dd, J = 10.2, 4.7 Hz, 1H),

3.87 (td, J = 9.8, 4.7 Hz, 1H), 3.75 (t, J = 10.3 Hz, 1H), 3.66 (dd, J =

9.5, 3.8 Hz, 1H), 3.58 (t, J = 9.6 Hz, 1H), 3.47 (s, 3H), 2.12 (s, 3H)

ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 171.2, 137.1, 129.2,

128.4, 126.3, 101.7, 100.2, 78.8, 72.4, 72.0, 69.0, 62.9, 55.7, 21.2

ppm.³⁶

Methyl 2,3-O-Diacetyl-4,6-O-benzylidene-α,D-glucopyranoside

(3c). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-glucopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (132.7 mg, 122 μL, 1.3 mmol, 1.3 equiv), and 10 mL of

DCM were used to obtain 3b after column chromatography (n-

hexane/EtOAc 1:1) in 43.9 mg (0.12 mmol, 12%) yield as a colorless

solid. R_f= 0.63 (n-hexane/EtOAc 1:1). ¹H NMR (400 MHz, CDCl₃):

δ 7.49−7.41 (m, 2H), 7.40−7.31 (m, 3H), 5.58 (t, J = 9.7 Hz, 1H),

5.51 (s, 1H), 4.96−4.88 (m, 2H), 4.30 (dd, J = 10.3, 4.8 Hz, 1H),

3.93 (td, J = 9.9, 4.8 Hz, 1H), 3.77 (t, J = 10.3 Hz, 1H), 3.65 (t, J =

9.6 Hz, 1H), 3.41 (s, 3H), 2.09 (s, 3H), 2.05 (s, 3H) ppm. ¹³C{¹H}

NMR (100 MHz, CDCl₃): δ 170.6, 169.9, 137.1, 129.2, 128.4, 126.3,

101.7, 97.8, 79.4, 71.7, 69.1, 69.0, 62.5, 55.5, 21.0, 20.9 ppm.³⁷

Methyl 2-O-Acetyl-4,6-O-methylidene-α,D-glucopyranoside (4a).

Procedure 1. Methyl 4,6-O-methylidene-α,^D-glucopyranoside (206.0

mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1 equiv),

Ac₂O (132.7 mg, 122 μL, 1.3 mmol, 1.3 equiv), and 10 mL of DCM

were used to obtain 3a after column chromatography (CH₂Cl₂/

MeOH 40:1) in 46.9 mg (0.19 mmol, 19%) yield as a colorless solid.

1

R_f= 0.17 (CH₂Cl₂/MeOH 40:1). H NMR (600 MHz, CDCl₃): δ

5.02 (d, J = 6.3 Hz, 1H), 4.85 (d, J = 3.8 Hz, 1H), 4.67 (dd, J = 9.7,

3.8 Hz, 1H), 4.58 (d, J = 6.3 Hz, 1H), 4.09 (dd, J = 10.3, 4.9 Hz, 1H),

4.05 (t, J = 9.5 Hz, 1H), 3.66 (td, J = 10.0, 4.9 Hz, 1H), 3.42 (t, J =

10.4 Hz, 1H), 3.32 (s, 3H), 3.23 (t, J = 9.4 Hz, 1H), 2.09 (s, 3H)

ppm. ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 170.9, 97.6, 94.0, 81.2,

77.4, 77.2, 77.0, 73.9, 68.8, 68.8, 62.3, 55.5, 21.1 ppm. HRMS (ESI-

TOF) m/z: [M + Na]⁺calcd for C₁₀H₁₆O₇Na, 271.0788; found,

271.0788. IR (ATR) ν/cm⁻¹: 3542, 3432, 2944, 2852, 1717, 1471,

1374, 1341, 1243, 1226, 1199, 1168, 1142, 1114, 1095, 1042, 1023,

987, 969, 921.

Methyl 2,3-O-Diacetyl-4,6-O-cyclohexylidene-α,^D-glucopyrano-

side (5c). Procedure 1. Methyl 4,6-O-cyclohexylidene-α,^D-glucopyr-

anoside (274.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol,

0.1 equiv), Ac₂O (132.7 mg, 122 μL, 1.3 mmol, 1.3 equiv), and 10 mL

of DCM were used to obtain 5c after column chromatography (n-

hexane/EtOAc 1:1) in 58.5 mg (0.16 mmol, 16%) yield as a colorless

solid. R_f= 0.66 (n-hexane/EtOAc 1:1). ¹H NMR (400 MHz, MeOH-

d₄): δ 5.30 (t, J = 9.6 Hz, 1H), 4.91 (d, J = 3.8 Hz, 1H), 4.88−4.84

(m, 2H), 3.86−3.81 (m, 2H), 3.78 (t, J = 9.6 Hz, 1H), 3.71−3.64 (m,

1H), 3.39 (s, 3H), 2.10 (d, J = 8.9 Hz, 1H), 2.03 (s, 3H), 2.03 (s,

3H), 1.84−1.72 (m, 1H), 1.65−1.28 (m, 7H) ppm. ¹³C{¹H} NMR

(100 MHz, MeOH-d₄): δ 171.7, 171.7, 101.1, 99.0, 72.8, 72.5, 71.0,

64.8, 62.6, 55.7, 38.9, 28.7, 26.6, 23.9, 23.7, 20.7, 20.5 ppm.³⁹

Methyl 2-O-Acetyl-4,6-O-benzylidene-β,D-glucopyranoside (6a).

Procedure 1. Methyl 4,6-O-benzylidene-β,^D-glucopyranoside (282.0

mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1 equiv),

Ac₂O (112.6 mg, 105 μL, 1.1 mmol, 1.1 equiv), and 10 mL of DCM

were used to obtain 6a after column chromatography (n-hexane/

EtOAc 1:1) in 89.0 mg (0.27 mmol, 27%) yield as a colorless solid. R_f

Methyl 3-O-Acetyl-4,6-O-methylidene-α,^D-glucopyranoside (4b).

Procedure 1. Methyl 4,6-O-methylidene-α,^D-glucopyranoside (206.0

mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1 equiv),

Ac₂O (132.7 mg, 122 μL, 1.3 mmol, 1.3 equiv), and 10 mL of DCM

were used to obtain 4b after column chromatography (CH₂Cl₂/

MeOH 40:1) in 40.4 mg (0.16 mmol, 16%) yield as a colorless solid.

1

R_f= 0.26 (CH₂Cl₂/MeOH 40:1). H NMR (600 MHz, CDCl₃): δ

5.23 (t, J = 9.7 Hz, 1H), 5.03 (d, J = 6.3 Hz, 1H), 4.76 (d, J = 3.8 Hz,

1H), 4.56 (d, J = 6.3 Hz, 1H), 4.16 (dd, J = 10.4, 4.9 Hz, 1H), 3.74

(td, J = 9.9, 4.9 Hz, 1H), 3.61 (dd, J = 9.6, 3.9 Hz, 1H), 3.48−3.42

(m, 4H), 3.29 (t, J = 9.6 Hz, 1H), 2.13 (s, 3H) ppm. ¹³C{¹H} NMR

(150 MHz, CDCl₃): δ 171.3, 100.1, 93.8, 78.8, 72.4, 71.8, 68.8, 63.0,

55.7, 21.2. HRMS (ESI-TOF) m/z: [M + Na]⁺calcd for

C₁₀H₁₆O₇Na, 271.0788; found, 271.0789. IR (ATR) ν/cm⁻¹: 3541,

3432, 2943, 2873, 1736, 1431, 1364, 1240, 1225, 1167, 1135, 1094,

1073, 1044, 1023, 985, 971, 920, 892.

1

= 0.42 (n-hexane/EtOAc 1:1). H NMR (400 MHz, DMSO-d₆): δ

7.49−7.34 (m, 5H), 5.61 (s, 1H), 5.54 (d, J = 5.5 Hz, 1H), 4.64 (dd, J

= 9.2, 8.1 Hz, 1H), 4.52 (d, J = 8.1 Hz, 1H), 4.23 (dd, J = 10.2, 4.2

Hz, 1H), 3.80−3.63 (m, 2H), 3.56−3.45 (m, 2H), 3.37 (s, 3H), 2.04

(s, 3H) ppm. ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 169.1, 137.6,

128.9, 128.0, 126.3, 101.4, 100.7, 80.4, 74.1, 70.5, 67.7, 65.8, 56.2,

20.8 ppm.³⁵

3915

https://dx.doi.org/10.1021/acs.joc.0c02772

J. Org. Chem. 2021, 86, 3907−3922

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Methyl 3-O-Acetyl-4,6-O-benzylidene-β,D-glucopyranoside (6b).

Procedure 1. Methyl 4,6-O-benzylidene-β,^D-glucopyranoside (282.0

mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1 equiv),

Ac₂O (112.6 mg, 105 μL, 1.1 mmol, 1.1 equiv), and 10 mL of DCM

were used to obtain 6b after column chromatography (n-hexane/

EtOAc 1:1) in 121.0 mg (0.37 mmol, 37%) yield as a colorless solid.

R_f= 0.29 (n-hexane/EtOAc 1:1). ¹H NMR (400 MHz, DMSO-d₆): δ

7.37 (s, 5H), 5.62 (d, J = 5.5 Hz, 1H), 5.59 (s, 1H), 5.05 (t, J = 9.4

Hz, 1H), 4.42 (d, J = 7.6 Hz, 1H), 4.24 (dd, J = 10.1, 4.9 Hz, 1H),

3.74 (t, J = 10.1 Hz, 1H), 3.64 (t, J = 9.5 Hz, 1H), 3.54 (td, J = 9.7,

4.9 Hz, 1H), 3.43 (s, 3H), 3.33−3.26 (m, 2H), 2.03 (s, 3H) ppm.

¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 169.6, 137.4, 128.8, 128.1,

(0.34 mmol, 26%) yield as a colorless solid. R_f= 0.56 (n-hexane/

EtOAc 2:1). H NMR (400 MHz, CDCl₃): δ 7.47−7.32 (m, 7H),

1

7.15 (d, J = 7.9 Hz, 2H), 5.49 (s, 1H), 5.33 (t, J = 9.3 Hz, 1H), 4.97

(dd, J = 10.0, 8.9 Hz, 1H), 4.74 (d, J = 10.0 Hz, 1H), 4.38 (dd, J =

10.5, 4.9 Hz, 1H), 3.78 (t, J = 10.2 Hz, 1H), 3.64 (t, J = 9.5 Hz, 1H),

3.55 (td, J = 9.6, 4.9 Hz, 1H), 2.36 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H)

ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 170.1, 169.5, 138.8,

136.8, 133.7, 129.8, 129.2, 128.3, 127.7, 126.2, 101.5, 86.8, 78.1, 73.0,

70.8, 70.7, 68.5, 21.2, 20.9, 20.8 ppm.⁴¹

Methyl 4,6-O-Benzylidene-2-O-isobutyryl-α,D-glucopyranoside

(8a). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-glucopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), isobutyric anhydride (205.6 mg, 215 μL, 1.3 mmol, 1.3 equiv),

and 10 mL of DCM were used to obtain 8a after column

chromatography (n-hexane/EtOAc 3:1) in 101.4 mg (0.29 mmol,

126.0, 104.2, 100.2, 77.9, 73.6, 71.8, 67.8, 65.5, 56.5, 20.8 ppm.³⁶

Methyl 2,3-O-Diacetyl-4,6-O-benzylidene-β,D-glucopyranoside

(6c). Procedure 1. Methyl 4,6-O-benzylidene-β,^D-glucopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (112.6 mg, 105 μL, 1.1 mmol, 1.1 equiv), and 10 mL of

DCM were used to obtain 6c after column chromatography (n-

hexane/EtOAc 1:1) in 66.1 mg (0.18 mmol, 18%) yield as a colorless

solid. R_f= 0.62 (n-hexane/EtOAc 1:1). ¹H NMR (400 MHz, DMSO-

d₆): δ 7.37 (s, 5H), 5.63 (s, 1H), 5.29 (t, J = 9.4 Hz, 1H), 4.81 (dd, J

= 9.2, 7.9 Hz, 1H), 4.74 (d, J = 7.9 Hz, 1H), 4.27 (dd, J = 9.9, 4.7 Hz,

1H), 3.82 (t, J = 9.6 Hz, 1H), 3.79 (t, J = 9.6 Hz, 1H), 3.70 (td, J =

9.7, 4.7 Hz, 1H), 3.39 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H) ppm.

¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 169.5, 169.1, 137.2, 128.9,

1

29%) yield as a colorless solid. R_f= 0.14 (n-hexane/EtOAc 3:1). H

NMR (400 MHz, acetone-d₆): δ 7.53−7.46 (m, 2H), 7.37 (m, 3H),

5.63 (s, 1H), 4.88 (d, J = 3.8 Hz, 1H), 4.70 (dd, J = 9.6, 3.8 Hz, 1H),

4.27−4.19 (m, 1H), 4.09−4.01 (m, 1H), 3.83−3.72 (m, 2H), 3.65−

3.54 (m, 1H), 3.39 (s, 3H), 2.59 (sept, J = 7.0 Hz, 1H), 1.15 (dd, J =

7.0, 3.8 Hz, 6H) ppm. ¹³C{¹H} NMR (100 MHz, acetone-d₆): δ

176.9, 139.1, 129.6, 128.8, 127.3, 102.4, 98.7, 82.6, 74.6, 69.4, 69.1,

69.0, 63.4, 55.6, 34.5, 29.8, 19.3, 19.1 ppm.^8f

Methyl 4,6-O-Benzylidene-3-O-isobutyryl-α,D-glucopyranoside

(8b). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-glucopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), isobutyric anhydride (205.6 mg, 215 μL, 1.3 mmol, 1.3 equiv),

and 10 mL of DCM were used to obtain 8b after column

chromatography (n-hexane/EtOAc 3:1) in 100.4 mg (0.28 mmol,

128.1, 126.1, 101.0, 100.3, 77.5, 71.7, 71.4, 67.5, 65.4, 56.5, 20.4, 20.4

ppm.³⁷

4-Methylphenyl 2-O-Acetyl-4,6-O-benzylidene-1-thio-β,D-gluco-

pyranoside (7a). Procedure 1. 4-Methylphenyl 4,6-O-benzylidene-1-

thio-β,^D-glucopyranoside (480.0 mg, 1.3 mmol, 1.0 equiv), DMAP

(15.7 mg, 0.13 mmol, 0.1 equiv), Ac₂O (169.9 mg, 170 μL, 1.7 mmol,

1.3 equiv), and 10 mL of DCM were used to obtain a mixture of 7a

and 7b after column chromatography (n-hexane/EtOAc 2:1) as a

colorless solid. Analytical amounts of the mixture were subsequently

separated by HPLC. R_f= 0.36 (n-hexane/EtOAc 2:1). Retention time

= 9.25 min (Eurospher II CN column, eluent: 15% EtOAc/n-hexane,

0.477 CV/min, UV-detector λ = 254 nm). ¹H NMR (400 MHz,

CDCl₃): δ 7.51−7.43 (m, 2H), 7.42−7.33 (m, 5H), 7.14 (d, J = 7.8

Hz, 2H), 5.53 (s, 1H), 4.91 (dd, J = 10.0, 8.8 Hz, 1H), 4.68 (d, J =

10.0 Hz, 1H), 4.38 (dd, J = 10.5, 4.7 Hz, 1H), 3.91 (td, J = 8.8, 2.3

Hz, 1H), 3.78 (dd, J = 10.5, 9.5 Hz, 1H), 3.58−3.45 (m, 2H), 2.50 (d,

J = 3.2 Hz, 1H), 2.35 (s, 3H), 2.19 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 170.2, 138.8, 137.0, 133.7, 129.5, 128.5, 128.2,

126.4, 102.1, 86.9, 80.8, 73.8, 72.6, 70.4, 68.7, 21.3, 21.2 ppm.⁴⁰

4-Methylphenyl 3-O-Acetyl-4,6-O-benzylidene-1-thio-β,D-gluco-

pyranoside (7b). Procedure 1. 4-Methylphenyl 4,6-O-benzylidene-1-

thio-β,^D-glucopyranoside (480.0 mg, 1.3 mmol, 1.0 equiv), DMAP

(15.7 mg, 0.13 mmol, 0.1 equiv), Ac₂O (169.9 mg, 170 μL, 1.7 mmol,

1.3 equiv), and 10 mL of DCM were used to obtain a mixture of 7a

and 7b after column chromatography (n-hexane/EtOAc 2:1) as a

colorless solid. Analytical amounts of the mixture were subsequently

separated by HPLC. R_f= 0.37 (n-hexane/EtOAc 2:1). Retention time

= 8.14 min (Eurospher II CN column, eluent: 15% EtOAc/n-hexane,

0.477 CV/min, UV-detector λ = 254 nm). ¹H NMR (400 MHz,

CDCl₃): δ 7.49−7.39 (m, 4H), 7.39−7.31 (m, 3H), 7.16 (d, J = 7.6

Hz, 2H), 5.48 (s, 1H), 5.23 (t, J = 9.0 Hz, 1H), 4.62 (d, J = 9.6 Hz,

1H), 4.38 (dd, J = 10.5, 4.5 Hz, 1H), 3.77 (dd, J = 10.6, 9.4 Hz, 1H),

3.62−3.46 (m, 3H), 2.73 (s, 1H), 2.37 (s, 3H), 2.11 (s, 3H) ppm.

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 171.1, 139.1, 137.0, 134.0,

1

28%) yield as a colorless solid. R_f= 0.19 (n-hexane/EtOAc 3:1). H

NMR (400 MHz, acetone-d₆): δ 7.46−7.40 (m, 2H), 7.38−7.31 (m,

3H), 5.60 (s, 1H), 5.30 (t, J = 9.6 Hz, 1H), 4.80 (d, J = 3.7 Hz, 1H),

4.31−4.21 (m, 1H), 3.89−3.75 (m, 2H), 3.73−3.62 (m, 2H), 3.45 (s,

3H), 2.82 (bs, 1H), 2.56 (sept, J = 7.0 Hz, 1H), 1.12 (dd, J = 7.0, 2.6

Hz, 6H) ppm. ¹³C{¹H} NMR (100 MHz, acetone-d₆): δ 176.7, 138.9,

129.5, 128.8, 127.0, 101.9, 101.7, 80.2, 72.7, 72.1, 69.5, 63.7, 55.8,

34.7, 19.5, 19.2 ppm.^8f

Methyl 4,6-O-Benzylidene-2,3-O-diisobutyryl-α,D-glucopyrano-

side (8c). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-glucopyrano-

side (282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), isobutyric anhydride (205.6 mg, 215 μL, 1.3 mmol, 1.3 equiv),

and 10 mL of DCM were used to obtain 8c after column

chromatography (n-hexane/EtOAc 3:1) in 98.1 mg (0.23 mmol,

1

23%) yield as a colorless solid. R_f= 0.50 (n-hexane/EtOAc 3:1). H

NMR (400 MHz, acetone-d₆): δ 7.47−7.41 (m, 2H), 7.39−7.30 (m,

3H), 5.66 (s, 1H), 5.57−5.50 (m, 1H), 4.96 (d, J = 3.7 Hz, 1H), 4.90

(dd, J = 9.9, 3.7 Hz, 1H), 4.34−4.23 (m, 1H), 3.91−3.80 (m, 3H),

3.44 (s, 3H), 2.54 (sept, J = 7.0 Hz, 1H), 2.53 (sept, J = 7.0 Hz, 1H),

1.13−1.08 (m, 12H) ppm. ¹³C{¹H} NMR (100 MHz, acetone-d₆): δ

176.4, 176.2, 138.7, 129.6, 128.8, 127.0, 102.0, 98.7, 80.0, 72.04, 69.5,

69.3, 63.6, 55.8, 34.6, 34.5, 19.4, 19.2, 19.2, 19.1 ppm. HRMS (ESI-

TOF) m/z: [M + Na]⁺calcd for C₂₂H₃₀O₈Na, 455.1835; found,

455.1833. IR (ATR) ν/cm⁻¹: 2973, 2931, 1745, 1738, 1454, 1370,

1342, 1257, 1184, 1147, 1121, 1093, 1049, 1026, 1004, 989, 923, 750,

699.

Methyl 4,6-O-Methylidene-2-O-isobutyryl-α,^D-glucopyranoside

(9a). Procedure 1. Methyl 4,6-O-methylidene-α,^D-glucopyranoside

(206.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), isobutyric anhydride (205.6 mg, 215 μL, 1.3 mmol, 1.3 equiv),

and 10 mL of DCM were used to obtain 9a after column

chromatography (n-hexane/EtOAc 2:1) in 65.4 mg (0.24 mmol,

130.1, 129.3, 128.4, 127.2, 126.3, 101.6, 89.5, 78.4, 74.9, 74.9, 71.6,

71.0, 68.7, 21.3, 21.1. HRMS (ESI-TOF) m/z: [M + Na]⁺calcd for

C₂₂H₂₄O₆SNa, 439.1186; found, 439.1188. IR (ATR) ν/cm⁻¹: 3387,

2866, 1743, 1716, 1494, 1453, 1366, 1311, 1237, 1076, 1028, 964,

808, 741, 695.

4-Methylphenyl 2,3-O-Diacetyl-4,6-O-benzylidene-1-thio-β,^D-

glucopyranoside (7c). Procedure 1. 4-Methylphenyl 4,6-O-benzyli-

dene-1-thio-β,^D-glucopyranoside (480.0 mg, 1.3 mmol, 1.0 equiv),

DMAP (15.7 mg, 0.13 mmol, 0.1 equiv), Ac₂O (169.9 mg, 170 μL,

1.7 mmol, 1.3 equiv), and 10 mL of DCM were used to obtain 7c

after column chromatography (n-hexane/EtOAc 2:1) in 154.0 mg

1

24%) yield as a colorless solid. R_f= 0.22 (n-hexane/EtOAc 2:1). H

NMR (400 MHz, CDCl₃): δ δ 5.22 (t, J = 9.7 Hz, 1H), 5.03 (d, J =

6.2 Hz, 1H), 4.75 (d, J = 3.8 Hz, 1H), 4.56 (d, J = 6.3 Hz, 1H), 4.16

(dd, J = 10.1, 5.0 Hz, 1H), 3.74 (td, J = 10.0, 4.9 Hz, 1H), 3.61 (dd, J

= 9.6, 3.9 Hz, 1H), 3.45 (t, J = 10.3 Hz, 1H), 3.45 (s, 3H), 3.30 (t, J =

9.6 Hz, 1H), 2.62 (sept, J = 7.0 Hz, 1H), 2.09 (s, 1H), 1.19 (dd, J =

7.0, 5.0 Hz, 6H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 177.4,

100.2, 100.1, 93.8, 79.0, 72.1, 71.9, 68.8, 63.0, 55.7, 34.2, 19.1, 19.1

ppm.^8f

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J. Org. Chem. 2021, 86, 3907−3922

The Journal of Organic Chemistry

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Article

Methyl 4,6-O-Methylidene-3-O-isobutyryl-α,D-glucopyranoside

(9b). Procedure 1. Methyl 4,6-O-methylidene-α,^D-glucopyranoside

(206.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), isobutyric anhydride (205.6 mg, 215 μL, 1.3 mmol, 1.3 equiv),

and 10 mL of DCM were used to obtain 9b after column

chromatography (n-hexane/EtOAc 2:1) in 69.2 mg (0.25 mmol,

3H) ppm. ¹³C{¹H} NMR (100 MHz, MeOH-d₄): δ 171.8, 171.6,

138.9, 130.1, 129.1, 127.5, 103.3, 101.0, 77.3, 71.1, 70.0, 69.7, 65.2,

55.6, 20.9, 20.6, 20.6 ppm.⁴⁴

Methyl 2-O-Acetyl-4,6-O-methylidene-α,D-mannopyranoside

(11a). Procedure 1. Methyl 4,6-O-methylidene-α,^D-mannopyranoside

(128.0 mg, 0.62 mmol, 1.0 equiv), DMAP (8.0 mg, 0.06 mmol, 0.1

equiv), Ac₂O (82.0 mg, 76 μL, 0.81 mmol, 1.3 equiv), and 10 mL of

DCM were used to obtain 11a after column chromatography (n-

hexane/EtOAc 1:1) in 30.0 mg (0.12 mmol, 12%) yield as a colorless

solid. R_f= 0.24 (n-hexane/EtOAc 1:1). ¹H NMR (400 MHz, MeOH-

d₄): δ 5.07−5.03 (m, 1H), 4.97 (d, J = 6.3 Hz, 1H), 4.65 (d, J = 6.3

Hz, 1H), 4.63 (dd, J = 5.8, 1.6 Hz, 1H), 4.09−4.06 (m, 1H), 4.01 (dd,

J = 3.4, 1.7 Hz, 1H), 3.87−3.81 (m, 1H), 3.74−3.67 (m, 1H), 3.60−

3.52 (m, 2H), 3.39 (s, 3H), 2.08 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, MeOH-d₄): δ 172.2, 103.5, 95.0, 77.3, 72.3, 70.2, 69.5, 65.4,

55.4, 20.9 ppm.¹⁴

1

25%) yield as a colorless solid. R_f= 0.23 (n-hexane/EtOAc 2:1). H

NMR (400 MHz, CDCl₃): δ δ 5.22 (t, J = 9.7 Hz, 1H), 5.03 (d, J =

6.2 Hz, 1H), 4.75 (d, J = 3.8 Hz, 1H), 4.56 (d, J = 6.3 Hz, 1H), 4.16

(dd, J = 10.1, 5.0 Hz, 1H), 3.74 (td, J = 10.0, 4.9 Hz, 1H), 3.61 (dd, J

= 9.6, 3.9 Hz, 1H), 3.45 (t, J = 10.3 Hz, 1H), 3.45 (s, 3H), 3.30 (t, J =

9.6 Hz, 1H), 2.62 (sept, J = 7.0 Hz, 1H), 2.09 (s, 1H), 1.19 (dd, J =

7.0, 5.0 Hz, 6H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 177.4,

100.2, 100.1, 93.8, 79.0, 72.1, 71.9, 68.8, 63.0, 55.7, 34.2, 19.1, 19.1

ppm.^8f

Methyl 4,6-O-Methylidene-2,3-O-diisobutyryl-α,D-glucopyrano-

side (9c). Procedure 1. Methyl 4,6-O-methylidene-α,^D-glucopyrano-

side (206.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), isobutyric anhydride (205.6 mg, 215 μL, 1.3 mmol, 1.3 equiv),

and 10 mL of DCM were used to obtain 9c after column

chromatography (n-hexane/EtOAc 2:1) in 89.1 mg (0.26 mmol,

Methyl 3-O-Acetyl-4,6-O-methylidene-α,D-mannopyranoside

(11b). Procedure 1. Methyl 4,6-O-methylidene-α,^D-mannopyranoside

(128.0 mg, 0.62 mmol, 1.0 equiv), DMAP (8.0 mg, 0.06 mmol, 0.1

equiv), Ac₂O (82.0 mg, 76 μL, 0.81 mmol, 1.3 equiv), and 10 mL of

DCM were used to obtain 11b after column chromatography (n-

hexane/EtOAc 1:1) in 3.1 mg (0.01 mmol, 2%) yield as a colorless

solid. R_f= 0.08 (n-hexane/EtOAc 1:1). ¹H NMR (400 MHz, MeOH-

d₄): δ 5.13 (d, J = 0.8 Hz, 1H), 4.97−4.95 (m, 1H), 4.93−4.92 (m,

1H), 4.39 (dd, J = 11.9, 2.3 Hz, 1H), 4.17 (dd, J = 11.8, 6.4 Hz, 1H),

4.11−4.07 (m, 1H), 3.86 (dd, J = 5.6, 0.8 Hz, 1H), 3.70 (dddd, J =

10.4, 6.4, 2.3, 0.6 Hz, 1H), 3.44 (dd, J = 10.4, 7.4 Hz, 1H), 3.39 (s,

3H), 2.06 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz, MeOH-d₄): δ

172.7, 99.4, 95.6, 79.3, 77.6, 69.1, 67.9, 64.8, 55.2, 20.7 ppm.¹⁴

Methyl 2,3-O-Diacetyl-4,6-O-methtylidene-α,D-mannopyrano-

side (11c). Procedure 1. Methyl 4,6-O-methylidene-α,^D-mannopyr-

anoside (128.0 mg, 0.62 mmol, 1.0 equiv), DMAP (8.0 mg, 0.06

mmol, 0.1 equiv), Ac₂O (82.0 mg, 76 μL, 0.81 mmol, 1.3 equiv), and

10 mL of DCM were used to obtain 11c after column

chromatography (n-hexane/EtOAc 1:1) in 82.0 mg (0.10 mmol,

1

26%) yield as a colorless solid. R_f= 0.57 (n-hexane/EtOAc 2:1). H

NMR (400 MHz, CDCl₃): δ 5.52 (t, J = 9.7 Hz, 1H), 5.04 (d, J = 6.2

Hz, 1H), 4.89 (d, J = 3.8 Hz, 1H), 4.85 (dd, J = 9.7, 3.8 Hz, 1H), 4.57

(d, J = 6.2 Hz, 1H), 4.17 (dd, J = 10.3, 4.9 Hz, 1H), 3.82 (td, J = 9.9,

4.9 Hz, 1H), 3.48 (t, J = 10.3 Hz, 1H), 3.38 (s, 3H), 3.36 (t, J = 9.7

Hz, 1H), 2.54 (dp, J = 8.1, 7.0 Hz, 2H), 1.13 (t, J = 6.9 Hz, 12H)

ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 176.6, 176.1, 97.7, 93.9,

79.6, 71.3, 68.8, 68.7, 62.6, 55.6, 34.1, 33.9, 19.1, 19.0, 18.9 ppm.

HRMS (ESI-TOF) m/z: [M + Na]⁺calcd for C₁₆H₂₆O₈Na, 369.1520;

found, 369.1523 IR (ATR) ν/cm⁻¹: 2976, 2878, 1735, 1471, 1389,

1352, 1232, 1191, 1149, 1122, 1107, 1073, 1047, 1021, 991, 971, 921,

849.

Methyl 2-O-Acetyl-4,6-O-benzylidene-α,^D-mannopyranoside

(10a). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-mannopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (113.4 mg, 105 μL, 1.1 mmol, 1.1 equiv), and 10 mL of

DCM were used to obtain 10a after column chromatography (n-

hexane/EtOAc 2:1) in 48.0 mg (0.15 mmol, 15%) yield as a colorless

solid. R_f= 0.45 (n-hexane/EtOAc 2:1). ¹H NMR (400 MHz, MeOH-

d₄): δ 7.53−7.46 (m, 2H), 7.38−7.31 (m, 3H), 5.64 (s, 1H), 5.10 (dd,

J = 3.7, 1.5 Hz, 1H), 4.67 (d, J = 1.6 Hz, 1H), 4.22 (dd, J = 9.7, 4.4

Hz, 1H), 4.12−4.06 (m, 1H), 3.91 (dd, J = 10.0, 9.0 Hz, 1H), 3.86−

3.80 (m, 1H), 3.79−3.72 (m, 1H), 3.40 (s, 3H), 2.13 (s, 3H) ppm.

¹³C{¹H} NMR (100 MHz, MeOH-d₄): δ 172.0, 139.2, 129.9, 129.3,

1

17%) yield as a colorless solid. R_f= 0.51 (n-hexane/EtOAc 1:1). H

NMR (400 MHz, MeOH-d₄): δ 5.24 (dd, J = 3.6, 1.6 Hz, 1H), 5.22−

5.17 (m, 1H), 5.00−4.95 (m, 1H), 4.69 (d, J = 6.3 Hz, 1H), 4.67 (d, J

= 1.6 Hz, 1H), 4.14−4.07 (m, 1H), 3.84−3.74 (m, 2H), 3.57 (t, J =

10.1 Hz, 1H), 3.41 (s, 3H), 2.12 (s, 3H), 1.98 (s, 3H) ppm. ¹³C{¹H}

NMR (100 MHz, MeOH-d₄): δ 171.7, 171.5, 100.9, 95.0, 77.3, 71.1,

69.9, 69.3, 65.3, 55.6, 20.6, 20.6 ppm.¹⁴

Methyl 2-O-Acetyl-4,6-O-(2-naphthylidene)-α,D-mannopyrano-

side (12a). Procedure 1. Methyl 4,6-O-naphthylidene-α,^D-mannopyr-

anoside (169.0 mg, 0.51 mmol, 1.0 equiv), DMAP (6.1 mg, 0.05

mmol, 0.1 equiv), Ac₂O (66.4 mg, 61 μL, 0.66 mmol, 1.3 equiv), and

5 mL of DCM were used to obtain 12a after column chromatography

(n-hexane/EtOAc 1:2) in 110.0 mg (0.29 mmol, 58%) yield as a

colorless solid. R_f= 0.50 (n-hexane/EtOAc 1:2). ¹H NMR (400 MHz,

MeOH-d₄): δ 7.99 (s, 1H), 7.89−7.82 (m, 3H), 7.62 (dd, J = 8.5, 1.7

Hz, 1H), 7.52−7.46 (m, 2H), 5.80 (s, 1H), 5.13 (dd, J = 3.7, 1.6 Hz,

1H), 4.69 (d, J = 1.5 Hz, 1H), 4.28 (dd, J = 9.8, 4.5 Hz, 1H), 4.13

(dd, J = 10.0, 3.7 Hz, 1H), 3.98 (dd, J = 10.1, 9.0 Hz, 1H), 3.92−3.85

(m, 1H), 3.84−3.77 (m, 1H), 3.41 (s, 3H), 2.15 (s, 3H) ppm.

¹³C{¹H} NMR (100 MHz, MeOH-d₄): δ 172.0, 136.5, 135.1, 134.3,

129.0, 127.8, 127.5, 103.3, 100.9, 80.2, 74.0, 69.7, 67.9, 65.0, 55.5,

20.8 ppm.⁴²

Methyl 3-O-Acetyl-4,6-O-benzylidene-α,D-mannopyranoside

(10b). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-mannopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (113.4 mg, 105 μL, 1.1 mmol, 1.1 equiv), and 10 mL of

DCM were used to obtain 10b after column chromatography (n-

hexane/EtOAc 2:1) in 224.5 mg (0.69 mmol, 69%) yield as a

colorless solid. R_f= 0.29 (n-hexane/EtOAc 2:1). ¹H NMR (400 MHz,

MeOH-d₄): δ 7.47−7.39 (m, 2H), 7.39−7.30 (m, 3H), 5.59 (s, 1H),

5.13 (dd, J = 10.3, 3.4 Hz, 1H), 4.69 (d, J = 1.6 Hz, 1H), 4.28−4.17

(m, 1H), 4.17−4.08 (m, 1H), 4.06 (dd, J = 3.7, 1.9 Hz, 1H), 3.90−

3.77 (m, 2H), 3.41 (s, 3H), 2.07 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, MeOH-d₄): δ 172.3, 139.0, 130.0, 129.1, 127.5, 103.6, 103.3,

77.3, 72.4, 70.1, 69.8, 65.3, 55.4, 20.9, 20.9 ppm.⁴³

Methyl 2,3-O-Diacetyl-4,6-O-benzylidene-α,D-mannopyranoside

(10c). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-mannopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (113.4 mg, 105 μL, 1.1 mmol, 1.1 equiv), and 10 mL of

DCM were used to obtain 10c after column chromatography (n-

hexane/EtOAc 2:1) in 43.9 mg (0.12 mmol, 12%) yield as a colorless

solid. R_f= 0.59 (n-hexane/EtOAc 2:1). ¹H NMR (400 MHz, MeOH-

d₄): δ 7.48−7.40 (m, 2H), 7.37−7.30 (m, 3H), 5.63 (s, 1H), 5.31−

5.25 (m, 2H), 4.72 (d, J = 1.3 Hz, 1H), 4.31−4.20 (m, 1H), 4.15−

4.08 (m, 1H), 3.94−3.82 (m, 2H), 3.43 (s, 3H), 2.14 (s, 3H), 1.97 (s,

129.3, 128.8, 128.7, 127.5, 127.2, 126.8, 125.2, 103.4, 100.9, 80.3,

74.0, 69.8, 68.0, 65.1, 55.5, 20.8 ppm.¹⁴

Methyl 3-O-Acetyl-4,6-O-(2-naphthylidene)-α,D-mannopyrano-

side (12b). Procedure 1. Methyl 4,6-O-naphthylidene-α,^D-mannopyr-

anoside (169.0 mg, 0.51 mmol, 1.0 equiv), DMAP (6.1 mg, 0.05

mmol, 0.1 equiv), Ac₂O (66.4 mg, 61 μL, 0.66 mmol, 1.3 equiv), and

5 mL of DCM were used to obtain 12b after column chromatography

(n-hexane/EtOAc 1:2) in 33.1 mg (0.09 mmol, 17%) yield as a

colorless solid. R_f= 0.69 (n-hexane/EtOAc 1:2). ¹H NMR (400 MHz,

MeOH-d₄): δ 7.92−7.88 (m, 1H), 7.86−7.79 (m, 3H), 7.54 (dd, J =

8.5, 1.7 Hz, 1H), 7.48−7.43 (m, 2H), 5.72 (s, 1H), 5.19 (dd, J = 10.3,

3.3 Hz, 1H), 4.71 (d, J = 1.7 Hz, 1H), 4.33−4.18 (m, 2H), 4.10 (dd, J

= 3.4, 1.6 Hz, 1H), 3.95−3.85 (m, 2H), 3.39 (s, 3H), 2.06 (s, 3H)

ppm. ¹³C{¹H} NMR (100 MHz, MeOH-d₄): δ 172.2, 136.3, 135.0,

3917

https://dx.doi.org/10.1021/acs.joc.0c02772

J. Org. Chem. 2021, 86, 3907−3922

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

134.2, 129.3, 128.9, 128.7, 127.5, 127.2, 126.8, 125.0, 103.5, 103.4,

77.4, 72.4, 70.1, 69.8, 65.3, 55.4, 20.9 ppm.¹⁴

TOF) m/z: [M + Na]⁺calcd for C₁₈H₂₄O₇Na, 375.1414; found,

375.1415 IR (ATR) ν/cm⁻¹: 3468, 2974, 2935, 1736, 1456, 1386,

1316, 1255, 1199, 1158, 1130, 1097, 1069, 1026, 969, 924, 883, 795,

751, 699.

Methyl 2,3-O-Diacetyl-4,6-O-(2-naphthylidene)-α,D-mannopyra-

noside (12c). Procedure 1. Methyl 4,6-O-naphthylidene-α,^D-

mannopyranoside (169.0 mg, 0.51 mmol, 1.0 equiv), DMAP (6.1

mg, 0.05 mmol, 0.1 equiv), Ac₂O (66.4 mg, 61 μL, 0.66 mmol, 1.3

equiv), and 5 mL of DCM were used to obtain 12c after column

chromatography (n-hexane/EtOAc 1:2) in 44.0 mg (0.11 mmol,

Methyl 3-O-Isobutyryl-4,6-O-benzylidene-α,^D-mannopyranoside

(18b). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-mannopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), isobutyric anhydride (206 mg, 217 μL, 1.3 mmol, 1.3 equiv),

and 10 mL of DCM were used to obtain 18b after column

chromatography (n-hexane/EtOAc 3:1) in 207.0 mg (0.59 mmol,

1

21%) yield as a colorless solid. R_f= 0.79 (n-hexane/EtOAc 1:2). H

NMR (400 MHz, MeOH-d₄): δ 7.92 (s, 1H), 7.89−7.82 (m, 3H),

7.56 (dd, J = 8.5, 1.7 Hz, 1H), 7.51−7.46 (m, 2H), 5.80 (s, 1H),

5.34−5.28 (m, 2H), 4.74 (d, J = 1.3 Hz, 1H), 4.34−4.27 (m, 1H),

4.20−4.13 (m, 1H), 3.98−3.90 (m, 2H), 3.45 (s, 3H), 2.15 (s, 3H),

1.97 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz, MeOH-d₄): δ 171.9,

171.6, 136.2, 135.2, 134.3, 129.3, 128.9, 128.7, 127.5, 127.3, 126.9,

125.0, 103.4, 101.0, 77.4, 71.1, 70.1, 69.7, 65.2, 55.6, 20.7, 20.6 ppm.¹⁴

Methyl 2-O-Acetyl-4,6-O-benzylidene-α,D-galactopyranoside

(13a). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-mannopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (113.4 mg, 105 μL, 1.1 mmol, 1.1 equiv), and 10 mL of

DCM were used to obtain 13a after column chromatography (n-

hexane/EtOAc 1:2) in 115.3 mg (0.36 mmol, 36%) yield as a

colorless solid. R_f= 0.29 (n-hexane/EtOAc 1:2). ¹H NMR (400 MHz,

CDCl₃): δ 7.56−7.46 (m, 2H), 7.43−7.32 (m, 3H), 5.56 (s, 1H), 5.15

(dd, J = 10.3, 3.5 Hz, 1H), 4.98 (d, J = 3.5 Hz, 1H), 4.30 (dd, J = 4.9,

1.4 Hz, 1H), 4.28 (dd, J = 3.8, 1.4 Hz, 1H), 4.14−4.04 (m, 2H), 3.73

(q, J = 1.6 Hz, 1H), 3.42 (s, 3H), 2.14 (s, 3H) ppm. ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 171.2, 137.5, 129.4, 128.4, 126.5, 101.5, 98.3,

76.2, 71.4, 69.3, 67.4, 62.5, 55.7, 21.2 ppm.^18e

Methyl 3-O-Acetyl-4,6-O-benzylidene-α,D-galactopyranoside

(13b). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-mannopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (113.4 mg, 105 μL, 1.1 mmol, 1.1 equiv), and 10 mL of

DCM were used to obtain 13b after column chromatography (n-

hexane/EtOAc 1:2) in 151.7 mg (0.48 mmol, 48%) yield as a

colorless solid. R_f= 0.38 (n-hexane/EtOAc 1:2). ¹H NMR (400 MHz,

CDCl₃): δ 7.55−7.45 (m, 2H), 7.41−7.30 (m, 3H), 5.51 (s, 1H), 5.12

(dd, J = 10.4, 3.4 Hz, 1H), 4.95 (d, J = 3.7 Hz, 1H), 4.37 (dd, J = 3.6,

1.2 Hz, 1H), 4.27 (dd, J = 12.5, 1.6 Hz, 1H), 4.17 (dd, J = 10.4, 3.8

Hz, 1H), 4.06 (dd, J = 12.5, 1.8 Hz, 1H), 3.72 (q, J = 1.7 Hz, 1H),

3.47 (s, 3H), 2.14 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

171.5, 137.8, 129.1, 128.3, 126.3, 100.9, 100.4, 77.5, 77.2, 76.8, 74.4,

71.8, 69.3, 66.9, 62.7, 55.8, 21.2 ppm.^18e

1

59%) yield as a colorless solid. R_f= 0.12 (n-hexane/EtOAc 3:1). H

NMR (400 MHz, MeOH-d₄): δ 7.46−7.39 (m, 2H), 7.37−7.28 (m,

3H), 5.60 (s, 1H), 5.16 (dd, J = 10.4, 3.4 Hz, 1H), 4.68 (d, J = 1.7 Hz,

1H), 4.26−4.20 (m, 1H), 4.18−4.10 (m, 1H), 4.03 (dd, J = 3.5, 1.7

Hz, 1H), 3.90−3.78 (m, 2H), 3.42 (s, 3H), 2.62 (hept, J = 7.0 Hz,

1H), 1.15 (dd, J = 7.0, 4.6 Hz, 6H) ppm. ¹³C{¹H} NMR (100 MHz,

MeOH-d₄): δ 178.3, 139.1, 129.9, 129.0, 127.3, 103.8, 103.1, 77.5,

72.0, 70.3, 69.8, 65.3, 55.4, 35.2, 19.5, 19.1 ppm. HRMS (ESI-TOF)

m/z: [M + Na]⁺calcd for C₁₈H₂₄O₇Na, 375.1414; found, 375.1416

IR (ATR) ν/cm⁻¹: 3521, 2968, 2932, 1721, 1469, 1451, 1369, 1317,

1205, 1161, 1119, 1097, 1060, 1024, 970, 911, 800, 747, 697.

Methyl 2,3-O-Isobutyryl-4,6-O-benzylidene-α,^D-mannopyrano-

side (18c). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-mannopyr-

anoside (282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol,

0.1 equiv), isobutyric anhydride (206 mg, 217 μL, 1.3 mmol, 1.3

equiv), and 10 mL of DCM were used to obtain 18c after column

chromatography (n-hexane/EtOAc 3:1) in 125.0 mg (0.29 mmol,

1

29%) yield as a colorless solid. R_f= 0.45 (n-hexane/EtOAc 3:1). H

NMR (400 MHz, MeOH-d₄): δ 7.49−7.40 (m, 2H), 7.40−7.32 (m,

3H), 5.67 (s, 1H), 5.36−5.29 (m, 2H), 4.71 (s, 1H), 4.33−4.24 (m,

1H), 4.16−4.07 (m, 1H), 3.95−3.85 (m, 2H), 3.46 (s, 3H), 2.69

(hept, J = 6.9 Hz, 1H), 2.50 (hept, J = 7.0 Hz, 1H), 1.24 (dd, J = 14.2,

7.0 Hz, 6H), 1.11 (dd, J = 7.0, 1.5 Hz, 6H) ppm. ¹³C{¹H} NMR (100

MHz, MeOH-d₄): δ 177.6, 177.3, 138.9, 130.0, 129.1, 127.3, 103.1,

101.1, 77.7, 70.9, 70.0, 69.7, 65.2, 55.6, 35.2, 19.5, 19.2, 19.2, 19.1

ppm. HRMS (ESI-TOF) m/z: [M + Na]⁺calcd for C₂₂H₃₀O₈Na,

445.1833; found, 445.1834 IR (ATR) ν/cm⁻¹: 2975, 2936, 1741,

1469, 1387, 1283, 1251, 1195, 1128, 1073, 1012, 967, 914, 892, 750,

698.

Catalysts. Boc-^L-Pmh-^AGly-L-Cha-L-Phe-OMe (1). The synthesis

and characterization data for 1 can be found in the literature.¹⁶

Boc-D-Pmh-^AGly-L-Val-L-Phe-OMe (2). Procedure 2. The coupling

of H-^L-Phe-OMe·HCl and Boc-L-Val-OH was performed on a 5.0

mmol scale to obtain 1.90 g (5.0 mmol, quant.) of Boc-^L-Val-L-Phe-

OMe as a colorless solid. Procedure 3: 5.0 mmol of Boc-^L-Val-L-Phe-

OMe was deprotected and directly used for the next coupling.

Procedure 2: The coupling of H-^L-Val-L-Phe-OMe·HCl and

Boc-^AGly-OH was performed on a 5.0 mmol scale to obtain 2.83 g

(5.0 mmol, quant.) of Boc-^AGly-L-Val-L-Phe-OMe as a colorless solid.

Procedure 3: 2.1 mmol Boc-^AGly-L-Val-L-Phe-OMe was deprotected

and directly used for the next coupling. Procedure 4: The coupling of

H-^AGly-L-Val-L-Phe-OMe·HCl and Boc-D-Pmh-OH was performed

on a 2.1 mmol scale to obtain 0.82 g (1.16 mmol, 55%) of 2 after

column chromatography (CH₂Cl₂/MeOH 10:1) as a colorless solid.

Methyl 2,3-O-Diacetyl-4,6-O-benzylidene-α,D-galactopyranoside

(13c). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-mannopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), Ac₂O (113.4 mg, 105 μL, 1.1 mmol, 1.1 equiv), and 10 mL of

DCM were used to obtain 13c after column chromatography (n-

hexane/EtOAc 1:2) in 50.4 mg (0.15 mmol, 15%) yield as a colorless

solid. R_f= 0.65 (n-hexane/EtOAc 1:2). ¹H NMR (400 MHz, CDCl₃):

δ 7.54−7.47 (m, 2H), 7.41−7.32 (m, 3H), 5.51 (s, 1H), 5.39−5.29

(m, 2H), 5.08 (d, J = 3.0 Hz, 1H), 4.46 (dd, J = 3.2, 1.2 Hz, 1H), 4.28

(dd, J = 12.5, 1.6 Hz, 1H), 4.06 (dd, J = 12.6, 1.8 Hz, 1H), 3.75 (q, J

= 1.6 Hz, 1H), 3.42 (s, 3H), 2.08 (s, 3H), 2.08 (s, 3H) ppm. ¹³C{¹H}

NMR (100 MHz, CDCl₃): δ 170.8, 170.4, 137.7, 129.2, 128.3, 126.4,

101.0, 97.9, 74.1, 69.2, 68.7, 68.3, 62.2, 55.7, 21.1, 21.0 ppm.⁴⁵

Methyl 2-O-Isobutyryl-4,6-O-benzylidene-α,D-mannopyranoside

(18a). Procedure 1. Methyl 4,6-O-benzylidene-α,^D-mannopyranoside

(282.0 mg, 1.0 mmol, 1.0 equiv), DMAP (12.2 mg, 0.1 mmol, 0.1

equiv), isobutyric anhydride (206 mg, 217 μL, 1.3 mmol, 1.3 equiv),

and 10 mL of DCM were used to obtain 18a after column

chromatography (n-hexane/EtOAc 3:1) in 43.7 mg (0.12 mmol,

1

R_f= 0.38. (CH₂Cl₂/MeOH 10:1). H NMR (400 MHz, CDCl₃): δ

7.30 (s, 1H), 7.23−7.12 (m, 3H), 7.09−7.04 (m, 2H), 6.90 (d, J = 7.9

Hz, 1H), 6.76 (s, 1H), 6.39 (s, 1H), 6.23 (d, J = 8.5 Hz, 1H), 5.29 (d,

J = 8.5 Hz, 1H), 4.76 (td, J = 7.5, 5.8 Hz, 1H), 4.23 (dd, J = 8.5, 6.4

Hz, 2H), 3.62 (s, 3H), 3.44 (s, 3H), 3.09 (dd, J = 14.0, 5.9 Hz, 1H),

2.98 (dd, J = 14.0, 7.4 Hz, 1H), 2.90 (d, J = 6.8 Hz, 2H), 2.21−2.04

(m, 4H), 2.01−1.80 (m, 2H), 1.77−1.49 (m, 9H), 1.35 (s, 9H), 0.80

(t, J = 7.1 Hz, 6H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 176.4,

171.8, 171.2, 169.8, 155.5, 138.2, 136.1, 129.2, 128.8, 128.8, 128.5,

127.2, 80.4, 57.7, 54.2, 53.6, 53.4, 52.4, 52.4, 42.8, 40.1, 38.7, 38.2,

37.8, 35.2, 31.8, 31.5, 29.3, 29.2, 28.4, 27.5, 19.2, 18.2 ppm.^17d

Boc-L-Pmh-OMe (15). The synthesis and characterization data for

15 can be found in the literature.^17d

1

12%) yield as a colorless solid. R_f= 0.29 (n-hexane/EtOAc 3:1). H

NMR (400 MHz, MeOH-d₄): δ 7.56−7.47 (m, 2H), 7.39−7.29 (m,

3H), 5.64 (s, 1H), 5.09 (dd, J = 3.7, 1.6 Hz, 1H), 4.63 (d, J = 1.6 Hz,

1H), 4.23 (dd, J = 9.5, 4.1 Hz, 1H), 4.11 (dd, J = 10.0, 3.7 Hz, 1H),

3.91 (t, J = 9.4 Hz, 1H), 3.87−3.72 (m, 2H), 3.41 (s, 3H), 2.67 (hept,

J = 6.9 Hz, 1H), 1.21 (d, J = 7.0 Hz, 7H) ppm. ¹³C{¹H} NMR (100

MHz, MeOH-d₄): δ 178.0, 139.2, 129.9, 129.0, 127.5, 103.4, 101.0,

80.3, 73.8, 69.8, 68.0, 65.0, 55.6, 35.2, 19.4, 19.2 ppm. HRMS (ESI-

H-^AGly-OMe·HCl (19). 6 mL of dry methanol was cooled to 0 °C,

and thionyl chloride (0.83 g, 0.50 mL, 7.0 mmol, 3.5 equiv) was

added. The solution was stirred at 0 °C for 30 min, then Boc-^AGly-

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OH (0.59 g, 2.0 mmol, 1.0 equiv) was added. The solution was stirred

at rt for 20 h. The solvent was removed under reduced pressure to

aﬀord 19 in 0.49 g (2.0 mmol, quant.) yield as a colorless solid. H

NMR (400 MHz, CDCl₃): δ 8.46 (s, 3H), 3.63 (s, 3H), 2.31−2.23

(m, 2H), 2.18 (s, 2H), 2.08−1.96 (m, 4H), 1.92−1.77 (m, 4H),

1.73−1.60 (m, 2H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

175.9, 53.2, 52.0, 42.6, 41.5, 39.7, 37.3, 34.4, 28.8 ppm.⁴⁶

Boc-L-Trp-^AGly-L-Pmh-OMe (25). The synthesis and character-

ization data for 25 can be found in the literature.²⁴

Boc-L-Phe-^AGly-L-Pmh-OMe (26). The synthesis and character-

ization data for 26 can be found in the literature.²⁴

1

Boc-D-Pmh-^AGly-OMe (27). Procedure 4. The coupling of H-^AGly-

OMe·HCl and Boc-^D-Pmh-OH was performed on a 0.20 mmol scale

to obtain 0.056 g (0.12 mmol, 61%) of 27 after column

chromatography (CH₂Cl₂/MeOH 10:1) as a colorless solid. R_f=

0.33 (CH₂Cl₂/MeOH 10:1). ¹H NMR (400 MHz, CDCl₃): δ 7.35 (s,

1H), 6.78 (s, 1H), 5.78 (s, 1H), 5.18 (d, J = 8.3 Hz, 1H), 4.15−4.02

(m, 1H), 3.58 (s, 3H), 3.54 (s, 3H), 2.98−2.86 (m, 2H), 2.08−2.13

(m, 2H), 2.07−1.95 (m, 2H), 1.90−1.66 (m, 8H), 1.53−1.57 (m,

2H), 1.37 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 176.9,

169.8, 155.5, 138.4, 128.3, 127.4, 80.5, 54.6, 52.3, 51.9, 42.6, 42.2,

40.6, 40.5, 37.9, 35.3, 31.7, 29.1, 28.4, 26.9 ppm. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₂₄H₃₆N₄O₅H, 461.2758; found, 461.2761,

[M + Na]⁺calcd for C₂₄H₃₆N₄O₅Na, 483.2578; found, 483.2575. IR

(ATR) ν/cm⁻¹: 3305, 2912, 2858, 1711, 1661, 1505, 1454, 1435,

1391, 1365, 1342, 1320, 1239, 1164, 1124, 1105, 1053, 929, 873, 816,

778, 757, 661.

Boc-L-Pmh-^AGly-OMe (16). Procedure 4. The coupling of H-^AGly-

OMe·HCl and Boc-^L-Pmh-OH was performed on a 0.20 mmol scale

to obtain 0.049 g (0.11 mmol, 53%) of 16 after column

chromatography (CH₂Cl₂/MeOH 10:1) as a colorless solid. R_f=

0.31 (CH₂Cl₂/MeOH 10:1). ¹H NMR (400 MHz, CDCl₃): δ 7.46 (s,

1H), 6.80 (2, 1H), 5.90 (s, 1H), 5.20 (d, J = 8.2 Hz, 1H), 4.16−4.05

(m, 1H), 3.58 (s, 3H), 3.56 (s, 3H), 2.93 (d, J = 6.8 Hz, 2H), 2.14−

2.08 (m, 2H), 2.06−1.96 (m, 2H), 1.91−1.69 (m, 8H), 1.61−1.52

(m, 2H), 1.37 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

176.9, 169.7, 155.5, 138.1, 127.8, 127.4, 80.6, 52.4, 51.9, 42.7, 42.2,

40.6, 40.5, 37.9, 35.3, 31.9, 29.1, 28.4, 27.0 ppm. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₂₄H₃₆N₄O₅H, 461.2758; found, 461.2762,

[M + Na]⁺calcd for C₂₄H₃₆N₄O₅Na, 483.2578; found, 483.2580. IR

(ATR) ν/cm⁻¹: 3308, 2911, 2857, 1796, 1712, 1661, 1506, 1454,

1391, 1365, 1343, 1241, 1164, 1125, 1106, 1050, 977, 928, 856, 833,

771, 662.

Boc-^L-Pmh-^AGly-L-Val-OMe (28). Procedure 2. The coupling of H-

L-Val-OMe·HCl and Boc-^AGly-OH was performed on a 0.30 mmol

scale to obtain 0.13 g (0.30 mmol, quant.) of Boc-^AGly-L-Val-OMe as

a colorless solid. Procedure 3: 0.30 mmol Boc-^AGly-L-Val-OMe was

deprotected and directly used for the next coupling. Procedure 4: The

coupling of H-^AGly-L-Val-OMe·HCl and Boc-L-Pmh-OH was

performed on a 0.30 mmol scale to obtain 0.064 g (0.12 mmol,

40%) of 28 after column chromatography (CH₂Cl₂/MeOH 10:1) as a

colorless solid. R_f= 0.25 (CH₂Cl₂/MeOH 10:1). ¹H NMR (400

MHz, CDCl₃): δ 7.56 (s, 1H), 6.87 (s, 1H), 6.07 (d, J = 8.5 Hz, 1H),

6.01 (s, 1H), 5.27 (d, J = 8.2 Hz, 1H), 4.53 (dd, J = 8.6, 5.0 Hz, 1H),

4.25−4.14 (m, 1H), 3.73 (s, 3H), 3.63 (s, 3H), 3.05−2.94 (m, 2H),

2.25−2.18 (m, 2H), 2.18−2.09 (m, 1H), 2.03 (s, 2H), 1.99−1.74 (m,

8H), 1.71−1.56 (m, 2H), 1.43 (s, 9H), 0.90 (t, J = 6.9 Hz, 6H) ppm.

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 176.4, 172.9, 169.7, 155.0,

138.1, 127.8, 127.3, 80.6, 56.8, 52.5, 52.3, 42.9, 42.5, 40.5, 40.4, 38.4,

38.3, 35.3, 31.9, 31.5, 29.3, 28.4, 27.0, 19.1, 18.1 ppm. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₂₉H₄₅N₅O₆H, 560.3443; found,

560.3443, [M + Na]⁺calcd for C₂₉H₄₅N₅O₆Na, 582.3262; found,

582.3261. IR (ATR) ν/cm⁻¹: 3308, 2910, 2855, 1795, 1699, 1652,

1506, 1453, 1390, 1365, 1286, 1248, 1230, 1165, 1110, 1082, 976,

928, 855, 833, 768, 664.

Boc-^L-Pmh-^AGly-L-Cha-OMe (17). Procedure 2. The coupling of

H-^L-Cha-OMe·HCl and Boc-^AGly-OH was performed on a 0.50

mmol scale to obtain 0.26 g (0.50 mmol, quant.) of Boc-^L-Cha-^AGly-

OMe as a colorless solid. Procedure 3: 0.50 mmol of Boc-^L-Cha-^AGly-

OMe was deprotected and directly used for the next coupling.

Procedure 4: The coupling of H-^L-Cha-^AGly-OMe·HCl and Boc-L-

Pmh-OH was performed on a 0.50 mmol scale to obtain 0.12 g (0.19

mmol, 38%) of 17 after column chromatography (CH₂Cl₂/MeOH

10:1) as a colorless solid. R_f= 0.35 (CH₂Cl₂/MeOH 10:1). ¹H NMR

(400 MHz, CDCl₃): δ 7.75 (s, 1H), 6.93 (s, 1H), 6.22 (s, 1H), 6.00

(d, J = 8.2 Hz, 1H), 5.34 (d, J = 8.3 Hz, 1H), 4.62 (td, J = 8.7, 5.5 Hz,

1H), 4.31−4.19 (m, 1H), 3.72 (s, 3H), 3.68 (s, 3H), 3.01 (d, J = 6.8

Hz, 2H), 2.26−2.16 (m, 2H), 2.10−2.00 (m, 2H), 2.00−1.86 (m,

4H), 1.86−1.57 (m, 12H), 1.53 (ddd, J = 14.2, 9.0, 5.9 Hz, 1H), 1.43

(s, 9H), 1.29−1.10 (m, 4H), 1.01−0.82 (m, 2H) ppm. ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 176.3, 173.9, 169.6, 137.5, 128.2, 80.4, 52.5,

52.3, 49.9, 42.5, 42.2, 40.4, 40.0, 38.2, 38.1, 35.2, 34.3, 33.4, 32.6,

32.1, 29.1, 29.1, 28.3, 27.1, 26.4, 26.2, 26.0 ppm. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₃₃H₅₁N₅O₆H, 614.3912; found, 614.3904,

[M + Na]⁺calcd for C₃₃H₅₁N₅O₆Na, 636.3732; found, 636.3730. IR

(ATR) ν/cm⁻¹: 3307, 2924, 2851, 1795, 1699, 1507, 1450, 1389,

1377, 1286, 1255, 1229, 1179, 1166, 1146, 1081, 976, 947, 928, 912,

899, 855, 834, 768, 753, 733, 718, 667.

Boc-^D-Pmh-^AGly-L-Val-OMe (29). Procedure 2. The coupling of H-

L-Val-OMe·HCl and Boc-^AGly-OH was performed on a 0.30 mmol

scale to obtain 0.13 g (0.30 mmol, quant.) of Boc-^AGly-L-Val-OMe as

a colorless solid. Procedure 3: 0.30 mmol Boc-^AGly-L-Val-OMe was

deprotected and directly used for the next coupling. Procedure 4: The

coupling of H-^AGly-L-Val-OMe·HCl and Boc-D-Pmh-OH was

performed on a 0.30 mmol scale to obtain 0.059 g (0.11 mmol,

35%) of 29 after column chromatography (CH₂Cl₂/MeOH 10:1) as a

colorless solid. R_f= 0.25 (CH₂Cl₂/MeOH 10:1). ¹H NMR (400

MHz, CDCl₃): δ 7.54 (s, 1H), 6.86 (s, 1H), 6.07 (d, J = 8.6 Hz, 1H),

5.99 (s, 1H), 5.26 (d, J = 8.3 Hz, 1H), 4.53 (dd, J = 8.5, 5.0 Hz, 1H),

4.25−4.14 (m, 1H), 3.73 (s, 3H), 3.62 (s, 3H), 3.05−2.94 (m, 2H),

2.24−2.18 (m, 2H), 2.18−2.09 (m, 1H), 2.06−1.99 (m, 2H), 1.97−

1.75 (m, 8H), 1.69−1.57 (m, 2H), 1.42 (s, 9H), 0.90 (t, J = 6.9 Hz,

6H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 176.4, 172.9, 169.8,

155.5, 138.1, 127.8, 127.4, 80.6, 56.8, 52.5, 52.3, 42.8, 42.5, 40.5, 40.5,

38.4, 38.3, 35.3, 31.9, 31.5, 29.3, 28.4, 27.0, 19.1, 18.1 ppm. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₂₉H₄₅N₅O₆H, 560.3443; found,

560.3445, [M + Na]⁺calcd for C₂₉H₄₅N₅O₆Na, 582.3262; found,

582.3256. IR (ATR) ν/cm⁻¹: 3307, 2911, 2857, 1652, 1506, 1454,

1391, 1365, 1245, 1207, 1162, 1110, 1050, 1020, 929, 815, 661.

Boc-^L-Pmh-^AGly-L-Phe-OMe (30). The synthesis and character-

ization data for S13 can be found in the literature.²²

Boc-^D-Pmh-OMe (20). Procedure 4. The esteriﬁcation of methanol

and Boc-^D-Pmh-OH was performed on a 2.0 mmol scale to obtain

0.42 g (1.5 mmol, 75%) of 20 after column chromatography

(CH₂Cl₂/MeOH 10:1) as a colorless solid. R_f= 0.40 (CH₂Cl₂/

MeOH 10:1). ¹H NMR (400 MHz, CDCl₃): δ 7.43 (s, 1H), 6.78 (s,

1H), 5.20 (d, J = 7.8 Hz, 1H), 4.53 (q, J = 6.4 Hz, 1H), 3.73 (s, 3H),

3.58 (s, 3H), 3.09 (qd, J = 15.4, 5.9 Hz, 2H), 1.41 (s, 9H) ppm.

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 171.8, 154.7, 140.0, 129.6,

126.7, 80.4, 53.1, 52.7, 31.5, 28.9, 27.0 ppm. HRMS (ESI-TOF) m/z:

[M + H]⁺calcd for C₁₃H₂₁N₃O₄H, 284.1605; found, 284.1600, [M +

Na]⁺calcd for C₁₃H₂₁N₃O₄Na, 306.1424; found, 306.1423. IR (ATR)

ν/cm⁻¹: 3155, 2979, 2011, 1733, 1694, 1535, 1509, 1451, 1437, 1420,

1390, 1365, 1322, 1289, 1258, 1243, 1219, 1200, 1163, 1110, 1073,

1053, 1038, 990, 934, 814, 752, 663.

Boc-^AGly-L-Pmh-OMe (21). The synthesis and characterization data

for 21 can be found in the literature.²⁴

3,5-(Bis(triﬂuoromethyl)phenyl)thiourea-^AGly-L-Pmh-OMe (22).

The synthesis and characterization data for 22 can be found in the

literature.²⁴

Boc-D-Pmh-^AGly-L-Cha-L-Phe-OMe (31). Procedure 2. The cou-

pling of H-^L-Phe-OMe·HCl and Boc-L-Cha-OH·DCHA was per-

formed on a 0.82 mmol scale to obtain 0.29 g (0.66 mmol, 80%) of

Boc-^L-Cha-L-Phe-OMe as a colorless solid. Procedure 3: 0.66 mmol of

Boc-^L-Cha-L-Phe-OMe was deprotected and directly used for the next

Boc-D-Val-^AGly-L-Pmh-OMe (23). The synthesis and character-

ization data for 23 can be found in the literature.²⁴

Boc-L-Cha-^AGly-L-Pmh-OMe (24). The synthesis and character-

ization data for 24 can be found in the literature.²⁴

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coupling. Procedure 2: The coupling of H-L-Cha-L-Phe-OMe·HCl

and Boc-^AGly-OH was performed on a 0.66 mmol scale to obtain 0.40

g (0.65 mmol, 99%) of Boc-^AGly-L-Cha-L-Phe-OMe as a colorless

solid. Procedure 3: 0.65 mmol Boc-^AGly-L-Cha-L-Phe-OMe was

deprotected and directly used for the next coupling. Procedure 4: The

coupling of H-^AGly-L-Cha-L-Phe-OMe·HCl and Boc-D-Pmh-OH was

performed on a 0.65 mmol scale to obtain 0.29 g (0.38 mmol, 59%) of

31 after column chromatography (CH₂Cl₂/MeOH 10:1) as a

colorless solid. R_f= 0.42. (CH₂Cl₂/MeOH 10:1). ¹H NMR (400

MHz, CDCl₃): δ 7.38 (s, 1H), 7.30−7.19 (m, 3H), 7.13−7.08 (m,

2H), 6.83 (s, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.13−6.02 (m, 2H), 5.27

(d, J = 8.4 Hz, 1H), 4.83−4.75 (m, 1H), 4.47 (td, J = 8.3, 6.2 Hz,

1H), 4.26−4.14 (m, 1H), 3.69 (s, 3H), 3.54 (s, 3H), 3.13 (dd, J =

14.0, 5.8 Hz, 1H), 3.04 (dd, J = 14.0, 6.9 Hz, 1H), 2.96 (d, J = 6.9 Hz,

2H), 2.22−2.16 (m, 2H), 2.03−1.93 (m, 3H), 1.93−1.80 (m, 3H),

1.77−1.55 (m, 12H), 1.49−1.39 (m, 1H), 1.41 (s, 9H), 1.28−1.06

(m, 4H), 0.96−0.77 (m, 2H) ppm. ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 176.4, 172.1, 171.8, 169.8, 155.5, 138.3, 136.1, 129.3,

128.7, 128.4, 127.3, 127.2, 80.5, 53.4, 52.5, 52.4, 50.8, 42.7, 42.5, 40.4,

40.3, 39.9, 38.4, 38.2, 37.9, 35.3, 34.3, 33.6, 32.9, 31.6, 29.3, 29.2,

28.5, 28.5, 27.2, 26.5, 26.3, 26.2 ppm. HRMS (ESI-TOF) m/z: [M +

H]⁺calcd for C₄₂H₆₀N₆O₇H, 761.4596; found, 761.4594, [M + Na]⁺

calcd for C₄₂H₆₀N₆O₇Na, 783.4416; found, 783.4418. IR (ATR) ν/

cm⁻¹: 3298, 2918, 2852, 1745, 1659, 1505, 1449, 1391, 1365, 1282,

1245, 1215, 1166, 1110, 1050, 1021, 929, 890, 814, 747, 700, 670,

665, 542, 495, 439.

AUTHOR INFORMATION

Corresponding Author

■

Peter R. Schreiner − Institute of Organic Chemistry, Justus

Liebig University, 35392 Giessen, Germany; orcid.org/

0000-0002-3608-5515; Email: prs@uni-giessen.de

Authors

Alexander Seitz − Institute of Organic Chemistry, Justus Liebig

University, 35392 Giessen, Germany

Raﬀael C. Wende − Institute of Organic Chemistry, Justus

Liebig University, 35392 Giessen, Germany; orcid.org/

0000-0002-2242-4723

Emily Roesner − Institute of Organic Chemistry, Justus Liebig

University, 35392 Giessen, Germany

Dominik Niedek − Institute of Organic Chemistry, Justus

Liebig University, 35392 Giessen, Germany

Christopher Topp − Institute of Organic Chemistry, Justus

Liebig University, 35392 Giessen, Germany

Avene C. Colgan − Centre for Synthesis & Chemical Biology,

UCD School of Chemistry, University College Dublin, Dublin

4, Ireland; orcid.org/0000-0003-3842-6077

Eoghan M. McGarrigle − Centre for Synthesis & Chemical

Biology, UCD School of Chemistry, University College

Dublin, Dublin 4, Ireland; orcid.org/0000-0001-8160-

6431

Boc-^L-Pmh-^AGly-L-Val-L-Phe-OMe (32). The synthesis and charac-

terization data for 32 can be found in the literature.¹⁵

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02772

Boc-D-Pmh-^AGly-D-Val-L-Phe-OMe (33). The synthesis and char-

acterization data for 33 can be found in the literature.^17d

Notes

Boc-L-Pmh-^AGly-^AGly-L-Phe-OMe (34). The synthesis and charac-

The authors declare no competing ﬁnancial interest.

terization data for 34 can be found in the literature.¹⁵

Methyl 4,6-O-Benzylidene-α-D-glucopyranoside (3). 194.2 mg

(1.00 mmol, 1.00 equiv) of methyl α-^D-glucopyranoside, 152.2 mg

(150.7 μL, 1.00 mmol, 1.00 equiv) of benzaldehyde dimethyl acetal,

0.3 mg (0.001 mmol, 0.001 equiv) of camphor sulfonic acid, and 5000

mg 4 Å were suspended in 100 mL of dry toluene and reﬂuxed for 3 h.

It was then ﬁltered and concentrated under reduced pressure. The

crude product was puriﬁed via column chromatography (EtOAc) to

obtain 68.2 mg (0.24 mmol, 24%) of product as a colorless solid. R_f=

0.30 (EtOAc).

Procedure for the One-Pot Protection and Acetylation. 194.2 mg

(1.00 mmol, 1.00 equiv) of methyl α-^D-glucopyranoside, 152.2 mg

(150.7 μL, 1.00 mmol, 1.00 equiv) of benzaldehyde dimethyl acetal,

0.3 mg (0.001 mmol, 0.001 equiv) of camphor sulfonic acid, and 5000

mg 4 Å were suspended in 100 mL of dry toluene and reﬂuxed for 3 h.

After cooling to rt, 35.5 mg (0.05 mmol, 0.05 equiv) of peptide

catalyst 2 and 132.7 mg (122.9 μL, 1.30 mmol, 1.3 equiv) of acetic

anhydride were added and stirred for 18 h. It was then ﬁltered,

quenched with 1 mL methanol, and concentrated under reduced

pressure. The crude product was puriﬁed via column chromatography

(n-hexane/EtOAc 4:1 → 1:1) to obtain 15.3 mg (0.04 mmol, 4%) of

3c, 70.0 mg (0.22 mmol, 22%) of 3a, and 16.8 mg (0.05 mmol, 5%) of

3b.

ACKNOWLEDGMENTS

■

We gratefully acknowledge ﬁnancial support by the Deutsche

Forschungsgemeinschaft (SPP1807 Dispersion, Schr 597/27-

1). R.C.W. thanks the EU COST action CM0905 (organo-

catalysis) for a Short-Term Scientiﬁc Mission grant, and E.R.

acknowledges support through the Liebig-College. A.C.C.

thanks the Irish Research Council for funding (GOIPG/2013/

301) and E.M.M. thanks Science Foundation Ireland & the

Marie-Curie Action COFUND (11/SIRG/B2154). We thank

Gary Bradshaw for the synthesis of protected glucose 5.

REFERENCES

■

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ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02772.

Additional results, superimposed ¹H NMR spectra,

catalyst screening and DoE, and NMR spectra of all

compounds (PDF)

(5) (a) Taylor, M. S. Catalyst-controlled regioselective reactions of

carbohydrate derivatives. Top. Curr. Chem. 2016, 372, 125. (b) Law-

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andi, J.; Rocheleau, S.; Moitessier, N. Regioselective acylation,

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Site-Selective Acylation of Pyranosides with Oligopeptide Catalysts

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