Stereoselective Synthesis of Ribofuranoid exo-Glycals by One-Pot Julia Olefination Using Ribofuranosyl Sulfones

Julia Ole ﬁ nation Using Ribofuranosyl Sulfones

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Stereoselective Synthesis of Ribofuranoid exo-Glycals by One-Pot

Natsuhisa Oka,* Ayumi Mori, Kanna Suzuki, and Kaori Ando*

Cite This: https://dx.doi.org/10.1021/acs.joc.0c02297

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sı Supporting Information

ABSTRACT: One-pot Julia oleﬁnation using ribofuranosyl sulfones is described. The α-anomers of the ribofuranosyl sulfones were

synthesized with complete α-selectivity via the glycosylation of heteroarylthiols using ribofuranosyl iodides as glycosyl donors and

the subsequent oxidation of the resulting heteroaryl 1-thioribofuranosides with magnesium monoperphthalate (MMPP). The Julia

oleﬁnation of the α-ribofuranosyl sulfones with aldehydes proceeded smoothly in one pot to aﬀord the thermodynamically less stable

(E)-exo-glycals with modest-to-excellent stereoselectivity (up to E/Z = 94:6) under the optimized conditions. The E selectivity was

especially high for aromatic aldehydes. In contrast, the (Z)-exo-glycal was obtained as the main product with low stereoselectivity

when the corresponding β-ribofuranosyl sulfone was used (E/Z = 41:59). The remarkable impact of the anomeric conﬁguration of

the ribofuranosyl sulfones on the stereoselectivity of the Julia oleﬁnation has been rationalized using density functional theory

(

DFT) calculations. The protected ribose moiety of the resulting exo-glycals induced completely α-selective cyclopropanation on the

exocyclic carbon−carbon double bond via the Simmons−Smith−Furukawa reaction. The 2-cyanoethyl group was found to be useful

for the protection of the exo-glycals, as it could be removed without aﬀecting the exocyclic CC bond.

INTRODUCTION

S 1′-type substitution of 1-C-vinylglycosides, and base-

■

promoted alkynol cycloisomerization.

Exo-glycals are enol ether derivatives of sugars with an

exocyclic carbon−carbon double bond. These sugar deriva-

tives have long been used as versatile synthons for a variety of

molecules, such as biologically active natural products

C-glycosyl compounds. They have also been studied as

transition-state analogue inhibitors of sugar-processing en-

zymes such as glycosidases and glycosyltransferases.

In the synthesis of exo-glycals with one substituent or two

diﬀerent substituents on the exocyclic CC bond, the E/Z

selectivity of the reaction is one of the most important factors

to be considered. The thermodynamically more stable (Z)-exo-

glycals are available via various methods. For example, the

halogenation of methylene exo-glycals with bromine and

triethylamine or iodonium di-sym-collidine triﬂuoromethane-

sulfonate (IDCT) gives (Z)-halomethylene exo-glycals ex-

clusively, and the subsequent cross-coupling reactions give

various monosubstituted (Z)-exo-glycals. Z-selective triﬂuor-

omethylation reactions of methylene exo-glycals via photo-

redox and copper catalysis have been reported very recently.

Some of the above-mentioned reactions, i.e., the nucleophilic

addition of organometallic compounds and dehydration,

1b,2

and

b,c,4

Furthermore, they have attracted attention as intermediates

in various biosynthetic pathways.

Many reports of the synthesis of exo-glycals can be found in

the literature. Sugar lactones are the most widely used₆

precursors. A variety of reactions, such as the Julia oleﬁnation,

Wittig reaction, methylenation with the Tebbe reagent or

Petasis reagent, dihalomethylenation with tris-

(

dimethylamino)phosphine or triphenylphosphine and carbon

Keck allylation and dehalogenation, [2,3]-Wittig rearrange-

ment, Claisen rearrangement or S

-C-vinylglycosides, and base-promoted alkynol cycloisomeri-

tetrahalide, as well as nucleophilic addition of organometallic

1′-type substitution of

compounds and subsequent dehydration, are used to

synthesize exo-glycals from sugar lactones. Many other

methods have been reported, such as the Ramberg−Bac

klund

Received: September 26, 2020

rearrangement of glycosyl sulfones, Wittig reaction with

glycosyl phosphonium salts, Keck allylation of 1-bromogly-

cosyl chlorides and dehydrochlorination, Bamford−Stevens

reaction, [2,3]-Wittig rearrangement of 1-C-alkenylglyco-

sides, β-elimination reaction, Claisen rearrangement or

XXXX American Chemical Society

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

zation also provide (Z)-exo-glycals exclusively. The Ram-

Scheme 1. Stereoselective Synthesis of α-Ribofuranosyl

Sulfones 4 and Their Application to the Synthesis of exo-

Glycals 5 by Julia Oleﬁnation

berg−Backlund rearrangement of glycosyl sulfones and the

Wittig reaction of sugar lactones also give (Z)-exo-glycals with

high stereoselectivity in many cases.

In sharp contrast, only a few methods have been reported for

the synthesis of the thermodynamically less stable (E)-exo-

glycals with high stereoselectivity. Vincent et al. have reported

a base-promoted Z-to-E isomerization of phosphono-exo-

glycals. However, the isomerization is not complete and

limited to substrates with an electron-withdrawing substituent

on the exo-methylene group. Wyatt et al. have reported that

the Wittig reaction of sugar lactones is E-selective for a

mannose-derived lactone but Z-selective when glucose- and

galactose-derived substrates are used. Currently, the Julia

oleﬁnation of sugar lactones reported by Gueyrard et al. has

the broadest substrate scope for the stereoselective synthesis of

(

E)-exo-glycals. This reaction aﬀords (E)-exo-glycals that carry

an alkyl substituent on the exocyclic CC bond with high

stereoselectivity of up to E/Z > 9:1. However, it has not been

successfully applied to exo-glycals with an aryl or electron-

withdrawing substituent on the CC bond due to the low

reactivity of both the sugar lactones and the α-carbanions

generated from sulfones with an aryl or electron-withdrawing

group. Additionally, the adducts of the sugar lactones and

sulfones do not undergo the subsequent Smiles rearrangement

smoothly unless treated with an additional base after aqueous

workup.

Table 1. Synthesis of Ribofuranosyl sulfone 4a

Under these circumstances, we initiated a study on the

synthesis of exo-glycals via Julia oleﬁnation using glycosyl

sulfones as Julia reagents with the expectation that this

approach might solve the aforementioned issues associated

with the low reactivity of sugar lactones. As the ﬁrst step

toward this goal, an intensive study of the Julia oleﬁnation

using ribofuranosyl sulfones and aldehydes was carried out. We

have recently reported a novel α-selective synthesis of

heteroaryl 1-thioribofuranosides 3 from 1-O-trimethylsilyl-

ribofuranose derivatives 1 via ribofuranosyl iodides 2. In

this study, the heteroaryl 1-thioribofuranosides 3 were used as

the precursors to α-ribofuranosyl sulfones 4, which were

applied to Julia oleﬁnation with aldehydes for the synthesis of

exo-glycals 5 (Scheme 1). In addition, the eﬀect of the

anomeric conﬁguration of the ribofuranosyl sulfones was

examined experimentally by both α-ribofuranosyl sulfones 4

and the corresponding β-ribofuranosyl sulfone, as well as

theoretically by density functional theory (DFT) calculations.

yield of

entry reagents for the oxidation of 3a

solvent

4a (%)

H O (9 equiv), (NH ) Mo O

EtOH−i-PrOH−

(0.2 equiv)

UHP (3 equiv), TFAA

3 equiv), NaHCO (5 equiv)

AcOEt (4:2:1, v/v/v)

MeCN

(

MMPP (2 equiv)

MMPP (1.5 equiv)

MMPP (1 equiv)

MMPP (2 equiv)

CH Cl −MeOH

RESULTS AND DISCUSSION

■

(10:1, v/v)

Initially, 2-benzothiazolyl 2,3,5-tri-O-benzyl-1-thio-α-D-ribofur-

anoside 3a was synthesized from 2,3,5-tri-O-benzyl-1-O-

trimethylsilyl-ribofuranose 1a via ribofuranosyl iodide using

CH Cl −MeOH

(

10:1, v/v)

CH Cl −MeOH

(10:1, v/v)

our previously reported method in 97% yield with complete

CH Cl −DMF (10:3,

α-selectivity. The oxidation of 3a was then studied (Table 1).

v/v)

An attempt to oxidize 3a using H O and cat. (NH ) Mo O ·

4 6

CH Cl −DMSO

H O did not aﬀord the desired sulfone 4a. Instead, a

(10:3, v/v)

mixture of 2,3,5-tri-O-benzyl-ribofuranose and its ethyl and

isopropyl ribofuranosides was obtained, indicating that the

glycosidic bond of the resulting 4a or the intermediate

sulfoxide was cleaved by water or solvent alcohols (entry 1). In

contrast, 4a was obtained in 85% yield when 3a was treated

with urea hydrogen peroxide (UHP) and triﬂuoroacetic

,3,5-Tri-O-benzyl-D-ribofuranose, ethyl 2,3,5-tri-O-benzyl-D-ribofur-

anoside, and isopropyl 2,3,5-tri-O-benzyl-D-ribofuranoside were

generated as byproducts. The reaction mixture was cooled to −40

°C prior to the addition of a mixture of UHP and TFAA in MeCN

and then warmed to rt.

anhydride (TFAA) in the presence of NaHCO (entry 2).

(MMPP) in CH Cl −MeOH (10:1, v/v) (entry 3).

The yield of 4a was further improved to 99% when 3a was

treated with 2 equiv of magnesium monoperphthalate

Cleavage of the glycosidic bond of 4a was not observed

during oxidation. The solid-state structure of 4a was conﬁrmed

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unequivocally by X-ray crystallography. Oxidation did not

reach completion when the amount of MMPP was reduced to

sulfones 4b−d were synthesized in good yield (entries 1−3),

whereas sulfones 4e−j were not obtained. Instead, 2,3,5-tri-O-

benzyl-ribofuranose and methyl 2,3,5-tri-O-benzyl-ribofurano-

side were formed during oxidation, as was observed in the

oxidation of 3a with H O and (NH ) Mo O (Table 1, entry

1). These results suggest that the glycosidic bonds of

heteroaryl ribofuranosyl sulfones (or the intermediate

sulfoxides) are susceptible to nucleophilic attack and that

this susceptibility is aﬀected by the heteroaryl groups.

−1.5 equiv (entries 4 and 5). Almost no 4a was produced

when N,N-dimethylformamide (DMF) or dimethyl sulfoxide

DMSO) was used as the cosolvent instead of MeOH (entries

(

4 6

and 7).

The optimized conditions were applied to the oxidation of

heteroaryl 1-thio-α-ribofuranosides 3b−j, which were also

synthesized by α-selective ribofuranosylation of heteroarylth-

iols using ribofuranosyl iodide as the glycosyl donor (Table

). 2-Pyridyl, 5-nitro-2-pyridyl, and 5-triﬂuoromethyl-2-pyridyl

With α-ribofuranosyl sulfones 4a−d in hand, we studied the

synthesis of exo-glycal 5a by Julia oleﬁnation using

benzaldehyde as a model compound (Table 3). The reactions

were conducted under Barbier conditions in which sulfones 4

were deprotonated by a base in the presence of benzaldehyde.

The bases were added at low temperatures, and the mixtures

were gradually warmed to room temperature (rt) to promote

the reactions. As shown in entries 1−3, the reactions of 4a with

benzaldehyde using LiHMDS, NaHMDS, and KHMDS in

CH Cl preferentially aﬀorded (E)-5a over (Z)-5a. The

Table 2. Oxidation of 3b−j

stereochemistry of (E)-5a and (Z)-5a was established using

NOESY experiments. The assignment was also conﬁrmed by

the H NMR spectra, in which the exo-CCH signal of (E)-

a was shifted downﬁeld relative to that of (Z)-5a due to the

1b,29

eﬀect of endocylic 4-oxygen of the ribose.

The highest E

entry

Het

yield of 4 (%)

selectivity among these three reactions was obtained using

LiHMDS (entry 1), but the yields were much higher with

NaHMDS and KHMDS (entries 2 and 3). The E selectivity

was improved by changing the solvent from CH Cl to toluene

Sulfones 4e−j were not obtained by the oxidation of 3e−j. Instead,

,3,5-tri-O-benzyl-D-ribofuranose and methyl 2,3,5-tri-O-benzyl-D-

ribofuranoside were generated as byproducts.

(entries 4 and 5). Keeping the temperature at −78 °C

throughout the reaction slowed the reaction without improving

the stereoselectivity (entry 6). Increasing the initial temper-

ature from −60 to −40 °C slightly improved the yield of 5a at

Table 3. Optimization of the Reaction Conditions for the Synthesis of exo-Glycal 5a by Julia Oleﬁnation Using Ribofuranosyl

Sulfones 4a−d and PhCHO

entry

sulfone

base

solvent

conditions

yield (%)

E:Z

LiHMDS

NaHMDS

KHMDS

NaHMDS

KHMDS

LiHMDS

NaHMDS

KHMDS

NaHMDS

KHMDS

NaHMDS

KHMDS

CH Cl₂

−60 °C to rt, then 4 h

−60 °C to rt, then 2.5 h

−60 °C to rt, then 4 h

−60 °C to rt, then 3 h

−78 °C, 4 h

−40 °C to rt, then 3 h

−60 °C to rt, then 3 h

−20 °C to rt, then 3.5 h

−60 °C to rt, then 3 h

−60 °C to rt, then 6 h

−60 °C to rt, then 3 h

90:10

83:17

79:21

90:10

88:12

84:16

86:14

94:6

21:79

23:77

39:61

28:72

44:56

26:74

63:37

92:8

CH Cl₂

toluene

THF

DMF

NMP

DMPU

toluene

71:29

Unless otherwise noted, the bath temperature was gradually elevated from the initial value to rt over 1 h. The bath temperature was gradually

elevated over 0.5 h. Determined using H NMR.

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Table 4. Synthesis of exo-Glycals 5b−m Using Ribofuranosyl Sulfone 4a and Various Aldehydes

entry

product

yield (%)

E:Z

entry

product

yield (%)

E:Z

90:10

88:12

93:7

92:8

87:13

89:11

91:9

84:16

75:25

71:29

70:30

68:32

b−j,m were obtained as (E,Z) mixtures. (E) and (Z) isomers of 5k,l were separated by chromatography. Determined by H NMR.

the cost of a small decrease in stereoselectivity (entry 7). Both

the yield and stereoselectivity were improved using a more

polar solvent tetrahydrofuran (THF, entry 8), whereas the use

of even more polar solvents DMF, N-methyl pyrrolidinone

(

NMP), and N,N’-dimethylpropyleneurea (DMPU) led to

modest Z selectivity (entries 9−14). 2-Pyridyl sulfones 4b−d

also gave 5a but in lower yields than that obtained using 4a

(

entries 15−17). Thus, under the optimized conditions shown

in entry 8, the Julia oleﬁnation of the ribofuranosyl sulfone 4a

with benzaldehyde proceeded almost quantitatively in a one-

pot manner to give exo-glycal 5a with high E selectivity.

Subsequently, sulfone 4a was allowed to react with various

aldehydes under the optimized conditions (Table 4). Aromatic

aldehydes b−h gave the corresponding exo-glycals 5b−h with

high E selectivity (E/Z = 93:7−87:13) (entries 1−7).

Aldehydes d and e with an electron-donating methoxy group

at the para- or ortho-position showed stereoselectivity similar

to that of benzaldehyde (entries 3 and 4), while b and c, which

contain an electron-withdrawing ﬂuoro or nitro group at the

para-position, resulted in a slightly lower stereoselectivity

Figure 1. Optimized structures and energies of (E)- and (Z)-A,

calculated at the B3LYP/6−31G* level.

of ribose and the phenyl group. Thus, (E)-5 are considered to

be kinetic products that are thermodynamically less stable than

(Z)-5. This was also conﬁrmed by the iodine-catalyzed

isomerization of alkenes to thermodynamically more stable

(

entries 1 and 2). Aliphatic aldehydes i−m gave lower E

selectivity (E/Z = 84:16−68:32) compared to the aromatic

aldehydes (entries 8−12).

isomers; 5a (E:Z = 94:6) and 5c (E:Z = 88:12) completely

isomerized to (Z)-5a and (Z)-5c upon heating at 50 °C for 1 h

31c

To estimate the energy diﬀerence between (E)-5a and (Z)-

in the presence of 0.3 equiv of iodine (Table 5, entries 1,

and 2). However, isomerization was not successful for alkenyl-

and alkyl-substituted exo-glycals 5i and 5m (complex mixtures

formed; entries 3 and 4). Therefore, this isomerization should

be useful for the synthesis of stereochemically pure aryl-

substituted (Z)-exo-glycals.

a, (E)-A and (Z)-A were chosen as model compounds

(

Figure 1). Both structures were optimized via DFT

calculations at the B3LYP/6−31G* level of theory, and (Z)-

A was found to be 1.9 kcal/mol more stable than (E)-A.

Although both structures have two intramolecular hydrogen

bonds, (Z)-A is more stabilized by a stronger hydrogen bond

between the ribose ring oxygen and one of the o-hydrogens of

the phenyl group (O−H distance, 2.29 Å). Additionally, the

phenylethenyl moiety of (Z)-A has a planar structure and is

stabilized by the overlap of the π-system on C1−C6−C7−C8

One of the objectives of this study was to elucidate the eﬀect

of the anomeric conﬁguration of ribofuranosyl sulfones on Julia

oleﬁnation. For this purpose, the corresponding β-sulfone (β-

4a) was prepared according to Scheme 2 via Mitsunobu-type

β-selective ribofuranosylation (6 → 7) developed by Hocek et

(

dihedral angle, 2.0°). In contrast, the corresponding dihedral

al. and subjected to Julia oleﬁnation with benzaldehyde

under the optimized conditions. In fact, the use of β-sulfone

changed the stereochemistry of the reaction; (Z)-5a was

angle in (E)-A is 31.3°. The reduced overlap of the π-system is

attributed to the avoidance of steric repulsion between the 2-H

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Table 5. Iodine-Catalyzed Isomerization of 5

αZ-TS2, respectively. The length of the CN bond in αE-

TS2 (1.32 Å) is only 0.03 Å longer than that in αE-Int1, while

the length of the C−SO bond increased from 1.84 to 1.88 Å.

Similar structural changes were seen in αZ-TS2. Therefore,

nucleophilic addition to the CN bond and elimination of the

sulfonyl group occur simultaneously. Finally, the elimination of

both SO and a 2(3H)-benzothiazolone anion occurs to give

the alkene via the transition structures αE-TS3 and αZ-TS3,

whose relative Gibbs free energies are −30.9 and −17.9 kcal/

mol, respectively. The rate-determining step is TS1, and αE-

TS1 giving the (E)-alkene is more stable than αZ-TS1 giving

the (Z)-alkene by 3.6 kcal/mol. This suggests that the (E)-

alkene should be formed in high selectivity; thus, these

calculations reproduced the experimentally observed product

selectivity. The reaction of β-B with PhCHO was also analyzed

using DFT calculations at the B3LYP/6−31G* level. The

reaction occurs in a similar manner to that of α-B with

PhCHO, and the rate-determining step is TS1. Figure 3 shows

only the SM complex and TS1. The α-carbanion β-B is more

stable than the β-carbanion α-B, and the Gibbs free energies of

the starting complexes βE-SM and βZ-SM relative to αE-SM

are −9.2 and −8.9 kcal/mol, respectively. Transition structure

βZ-TS1 is favored over βE-TS1 by 0.6 kcal/mol. This energy

diﬀerence corresponds to a product ratio of E:Z = 27:73 at 25

yield

(%)

entry

starting material

product

(Z)-5a

(Z)-5c

trans-PhCH=CH complex mixture

5m (E/Z = 68:32) c-Hex complex mixture

5a (E/Z = 94:6)

5c (E/Z = 88:12) p-NO C H

5i (E/Z = 84:16)

preferentially obtained over (E)-5a with low stereoselectivity

(E/Z = 41:59).

We also prepared 2,3,5-tri-O-benzoyl-β-D-ribofuranosyl

sulfone β-4a′, which was prepared readily via neighboring-

group assistance (Scheme 3). However, its application to Julia

oleﬁnation with benzaldehyde resulted in the formation of

endo-glycal 10 due to 1,2-syn-elimination, which tends to occur

1g,33

when glycosyl sulfones are treated with a strong base.

To elucidate the mechanism of the oleﬁnation reactions of

the α- and β-ribofuranosyl sulfones in detail, DFT calculations

were carried out for the reaction of either α-B or β-B with

PhCHO. The transition structures for the C−C bond

formation from the complex (α-B and PhCHO) were

C, which is consistent with the experimental results. The

distances between the C atoms of the forming C−C bond are

.13 and 2.07 Å in βE-TS1 and βZ-TS1, respectively, and their

relative Gibbs free energies are 7.0 and 6.4 kcal/mol,

respectively. A comparison of the transition structures revealed

the presence of favorable hydrogen bonds between the

aldehyde H and both the 2- and 3-methoxy oxygens in βZ-

TS1 with the distances of 2.54 and 2.56 Å, respectively.

Therefore, the Z-alkene should be obtained as the main

product with low selectivity, which is consistent with the

experimental results.

identiﬁed at the B3LYP/6−31G* level (Figure 2). The

transition structure αE-TS1 is favored by 3.6 kcal/mol over

αZ-TS1. The C−C distances of the forming bond are 2.33 and

.22 Å in αE-TS1 and αZ-TS1, respectively, while the

activation free energies are 4.0 and 6.1 (7.6−1.5) kcal/mol,

respectively. A careful comparison of the transition structures

revealed steric repulsion between the 2-H of ribose and the

aldehyde proton. The H−H distance (2.04 Å) is much shorter

than the sum of their van der Waals radii (2.40 Å). An intrinsic

reaction coordinate (IRC) analysis of these transition

structures furnished intermediates αE-Int1 and αZ-Int1,

from which nucleophilic addition to the ipso carbon of

benzothiazole occurred to give αE-Int2 and αZ-Int2 via

transition structures αE-TS2 and αZ-TS2. The relative Gibbs

free energies are −1.2 and 1.3 kcal/mol and the distances of

the forming O−C bonds are 1.86 and 1.78 Å in αE-TS2 and

As described in the Introduction section, exo-glycals have

been used as versatile precursors for the synthesis of various

compounds through modiﬁcations of the exocyclic CC

bonds. To elucidate the eﬀect of the chiral ribose moiety on

the stereochemistry of exo-CC modiﬁcations, (E)-5a and

(Z)-5a were subjected to the Simmons−Smith−Furukawa

reaction. The cyclopropanation occurred exclusively from the

α-face to aﬀord 11 and its epimer (epi-11) from (E)-5a and

Scheme 2. Synthesis of β-4a and Its Application to Julia Oleﬁnation with PhCHO

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Scheme 3. Synthesis of β-4a′ and Its Attempted Julia Oleﬁnation with PhCHO

Figure 2. Reaction mechanism of the one-pot Julia oleﬁnation of α-ribofuranosyl sulfone with PhCHO, calculated at the B3LYP/6−31G* level (all

distances in Å).

34e

(

Z)-5a, respectively (Schemes 4 and 5). The stereochemistry

derivative bearing a 4′-exo-CC bond. Our study indicates

that the benzyl-group-protected ribose moiety also directs the

zinc carbenoid to the α-face with its 2′- and 3′-ether moieties,

of 11 and epi-11 was conﬁrmed using NOESY experiments.

α-Selectivity in the Simmons−Smith−Furukawa reaction has

also been reported for a benzyloxymethyl-protected uridine

The Journal of Organic Chemistry

J. Org. Chem. XXXX, XXX, XXX−XXX

Article

Figure 3. Rate-limiting step of the one-pot Julia oleﬁnation of β-ribofuranosyl sulfone with PhCHO, calculated at the B3LYP/6−31G* level (all

distances in Å). The Gibbs free energies of SM and TS1 are shown relative to that of αE-SM.

Scheme 4. Cyclopropanation of 5a (E:Z = 94:6)

Scheme 5. Cyclopropanation of (Z)-5a

Scheme 6. Attempted Synthesis of 2-Benzothiazolyl 2,3,5-

tri-O-TBS-ribofuranosyl Sulfone 13

as was proposed for the α-selective cyclopropanation of the

34e

BOM-protected uridine derivative.

Benzyl protection is useful for the synthesis of C-glycosyl

compounds without CC bonds, but a diﬀerent protecting

group must be used for the synthesis of compounds in which

an exocyclic CC bond is to be retained. To expand the

scope of this method, we examined the applicability of other

protecting groups that could be removed in the presence of the

exo-CC bond. Initially, the tert-butyldimethylsilyl (TBS)

group was chosen because it can be removed using ﬂuoride

ions without aﬀecting the CC bond. 2-Benzothiazolyl 2,3,5-

tri-O-TBS-1-thioribofuranoside 12 was synthesized via the α-

selective ribofuranosylation of 2-mercaptobenzothiazole using

sulfone 4a, which could be synthesized virtually quantitatively

under the same oxidation conditions.

Therefore, we turned our attention to the 2-cyanoethyl (CE)

group. The CE group has been used for the synthesis of

oligoribonucleotides and can be removed quickly from the 2′-

hydroxy groups of ribonucleosides by treatment with tetra-n-

the corresponding ribofuranosyl iodide and subjected to

oxidation with MMPP under the optimized conditions for the

benzyl-protected sulfones described above (Scheme 6).

However, the desired sulfone 13 was not obtained, but

hemiacetal 14 was formed during the oxidation. Thus, TBS-

protected sulfone 13 was found to be more sensitive to acids

butylammonium ﬂuoride (TBAF). Scheme 7 depicts the

synthesis of a CE-protected ribofuranosyl sulfone and its

application to Julia oleﬁnation. Ribose 15 was converted into

methyl ribofuranoside 16, and the hydroxy groups were

protected with CE groups via treatment with acrylonitrile and

Cs CO in t-BuOH. The β-isomer of 17 was separated using

due to its silyl-protection compared to benzyl-protected

chromatography and hydrolyzed to give hemiacetal 18, which

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Scheme 7. Stereoselective Synthesis of 2-Benzothiazolyl 2,3,5-tri-O-(2-cyanoethyl)-α-D-ribofuranosyl Sulfone 22 and Its

Application to Julia Oleﬁnation

was then silylated at the anomeric position to give 19.

Treatment of 19 with TMSI gave ribofuranosyl iodide 20,

which was then allowed to react in situ with 2-mercaptobenzo-

thiazole to give 1-thioribofuranoside 21 with complete α-

selectivity. Oxidation with MMPP under the aforementioned

conditions aﬀorded the desired sulfone 22 in good yield. As

expected, 22 was less susceptible to hydrolysis than TBS-

protected sulfone 13 on account of its electron-withdrawing

CE groups. A one-pot Julia oleﬁnation with benzaldehyde was

conducted with a reduced amount of KHMDS to prevent the

undesired cleavage of the CE groups. The desired exo-glycal 23

was obtained in 88% yield with E/Z = 93:7.

sulfones were obtained via α-selective glycosylation of

heteroarylthiols and oxidation with MMPP. Among the

heteroaryl sulfones tested, 2-benzothiazolyl sulfone was the

most advantageous in terms of stability and performance as an

oleﬁnation reagent. Its application to the Julia oleﬁnation with

aldehydes aﬀorded the thermodynamically less stable (E)-exo-

glycals eﬃciently in a one-pot manner with modest-to-excellent

stereoselectivity. The E selectivity was especially high when

aromatic aldehydes were used. Such aryl-substituted (E)-exo-

glycals cannot be easily synthesized using the methods

reported to date. The higher E selectivity observed for aryl-

substituted exo-glycals compared to alkyl-substituted ones in

this novel Julia oleﬁnation is complementary to that of the Julia

oleﬁnation of sugar lactones, which gives alkyl-substituted (E)-

exo-glycals eﬃciently but not aryl-substituted ones. The eﬀect

of the anomeric conﬁguration, which is one of the most

important concerns in using glycosyl sulfones, was elucidated

experimentally by carrying out the Julia oleﬁnation using a β-

ribofuranosyl sulfone, which resulted in slight Z selectivity, as

well as theoretically using DFT calculations. The successful

application of 2-cyanoethyl protection to the synthesis of exo-

glycals suggested that it should be useful for the synthesis of

various sugar derivatives having unsaturated carbon−carbon

bonds.

Finally, the deprotection of 23 was examined. It was ﬁrst

attempted by treatment with 1 M TBAF in THF. The

deprotection was complete after 24 h at 60 °C, and the desired

product (24) was generated almost quantitatively. However,

the isolation of 24 from the residual tetrabutylammonium salts

was diﬃcult. Therefore, we used instead the easily removable

Na₂S and found that the deprotection of 23 could be

completed via treatment with 1.5 equiv of Na S in CH Cl −

MeOH at rt for 3 days (Scheme 8). The fully deprotected exo-

glycal 24 was isolated in 88% yield without any side reactions.

CONCLUSIONS

■

In conclusion, a novel one-pot Julia oleﬁnation using α-

ribofuranosyl sulfones has been developed. Ribofuranosyl

EXPERIMENTAL SECTION

■

General Information. Commercially available reagents were used

without puriﬁcation. Dry organic solvents were prepared by

appropriate procedures prior to use. The other organic solvents

were of reagent grade and used as received. All reactions in dry

solvents were carried out under argon. Analytical thin-layer

chromatography (TLC) was performed on Merck TLC plates (No.

Scheme 8. Deprotection of exo-Glycal 23

715) precoated with silica gel 60 F₂₅₄. Column chromatography on

silica gel was carried out using Kanto silica gel 60N (spherical, neutral,

0−50 or 63−210 μm). Preparative TLC (PTLC) was performed on

silica gel 60 F PLC glass plates (20 cm × 20 cm, 1 mm thickness).

Melting points were determined using a Yanaco MP-J3 micro melting

point apparatus and were uncorrected. Optical rotations were

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

measured using a Horiba SEPA-300 high-sensitivity polarimeter. The

H (400 MHz) and C (100 MHz) NMR spectra were recorded on a

JNM-AL-400 or a JNM-ECS-400 spectrometer (JEOL). Tetrame-

4.70 (s, 2H), 4.59 (t, 1H, J = 5.6 Hz), 4.52 (d, 1H, J = 12.0 Hz),

4.51−4.47 (m, 1H), 4.50 (d, 1H, J = 12.0 Hz), 4.42 (d, 1H, J = 12.0

Hz), 4.41 (d, 1H, J = 12.0 Hz), 4.07 (dd, 1H, J = 7.0, 5.6 Hz), 3.71

thylsilane (TMS; 0.0 ppm in CDCl ) and DMSO-d (2.50 ppm in

(dd, 1H, J = 11.2, 1.8 Hz), 3.53 (dd, 1H, J = 11.2, 2.6 Hz). C{ H}

DMSO-d ) were used as the internal standards for H NMR

NMR (CDCl , 100 MHz): δ 162.1, 145.0, 144.8, 137.6, 137.1, 136.8,

measurements. CDCl (77.0 ppm in CDCl ) and DMSO-d (39.5

132.5, 128.4, 128.4, 128.2, 128.1, 127.8, 127.6, 124.0, 94.5, 82.7, 77.3,

ppm in DMSO-d ) were used as the internal standards for C NMR

measurements. H NMR data are reported as follows: chemical shift

74.4, 73.5, 73.1, 68.0. HRMS (ESI-TOF) m/z: [M + Na] calcd for

NaO

S 613.1615; found 613.1625.

(

multiplicity, integration, coupling constants). Multiplicity is indicated

as follows: s (singlet); d (doublet); dd (doublet of doublets); ddd

doublet of doublet of doublets); dt (doublet of triplets); t (triplet);

td (triplet of doublets); q (quartet); quint (quintet); sext (sextet); m

multiplet). Structural assignments were made with additional

5-Triﬂuoromethyl-2-pyridyl 2,3,5-Tri-O-benzyl-α-D-ribofuranosyl

Sulfone (4d). 4d (white crystals, 1.46 g, 2.38 mmol, 90%) was

obtained from 3d (1.54 g, 2.64 mmol) according to the general

procedure described for 4a. Puriﬁcation was carried out by column

(

chromatography on silica gel (hexane/AcOEt = 19:1 → 17:3, v/v).

(

M.p. = 87−88 °C. H NMR (CDCl , 400 MHz): δ 8.86 (d, 1H, J =

information from NOESY experiments. High-resolution mass spectra

were recorded on a Waters Xevo Q-ToF mass spectrometer (ESI-

ToF).

.2 Hz), 8.09 (d, 1H, J = 8.4 Hz), 7.92 (dd, 1H, J = 8.4, 1.2 Hz),

7.35−7.27 (m, 11H), 7.22−7.18 (m, 4H), 5.65 (d, 1H, J = 5.6 Hz),

4.82 (d, 1H, J = 11.0 Hz), 4.71 (d, 1H, J = 11.0 Hz), 4.60 (t, 1H, J =

5.6 Hz), 4.55 (d, 1H, J = 11.8 Hz), 4.50−4.47 (m, 1H), 4.47 (d, 1H, J

= 12.2 Hz), 4.41 (d, 1H, J = 11.8 Hz), 4.38 (d, 1H, J = 12.2 Hz), 4.04

(dd, 1H, J = 8.0, 5.6 Hz), 3.69 (dd, 1H, J = 11.6, 2.4 Hz), 3.50 (dd,

-Benzothiazolyl 2,3,5-Tri-O-benzyl-1-thio-α-D-ribofuranoside

3a). 3a (pale-yellow oil, 5.53 g, 9.71 mmol, 97%) was synthesized

from 2-mercaptobenzothiazole (1.67 g, 10.0 mmol) and 1a (6.40 g,

(

3.0 mmol) according to the procedure that we reported previously.

The NMR spectra were identical to those previously reported.

1H, J = 11.6, 3.2 Hz). C{ H} NMR (CDCl , 100 MHz): δ 160.6,

-Benzothiazolyl 2,3,5-Tri-O-benzyl-α-D-ribofuranosyl sulfone

146.7 (q, J = 3.8 Hz), 137.6, 137.3, 137.1, 135.0 (q, J = 2.8 Hz),

CF CF

129.3 (q, J = 33.4 Hz), 128.4, 128.3, 128.2, 128.2, 127.9, 127.8,

127.8, 127.7, 127.6, 123.4, 122.5 (q, J = 272.7 Hz), 93.1, 82.1, 77.1,

77.0, 74.6, 73.3, 72.9, 67.7. HRMS (ESI-TOF) m/z: [M + Na] calcd

(

4a): General Procedure for the Synthesis of 4a−d. MMPP (1.55

g, 4.00 mmol) was added to a stirred solution of 3a (1.14 g, 2.00

mmol) in CH Cl /MeOH (10:1, v/v; 44.0 mL) at rt. Stirring was

continued for 24 h before a saturated aqueous solution of NaHCO₃

for C H F NNaO S 636.1638; found 636.1638.

(

30 mL) was added. The resulting mixture was extracted with CH Cl

3 × 30 mL). The organic layers were combined and washed with a

2,5-Anhydro-3,4,6-tri-O-benzyl-1-deoxy-1-phenyl-D-ribo-hex-1-

enitol (5a): General Procedure for the Synthesis of 5a−m. 4a

(0.602 g, 1.00 mmol) and benzaldehyde (0.153 mL, 1.50 mmol) were

dissolved in dry THF (10.0 mL) under argon and cooled to −60 °C.

Under stirring, a 0.5 M KHMDS solution in toluene (2.80 mL, 1.40

mmol) was added dropwise. The mixture was gradually warmed to rt

over 1 h. Stirring was continued for 3 h, before a saturated aqueous

solution of NH Cl (20 mL) and H O (30 mL) were added. The

saturated aqueous solution of NaHCO (30 mL). The aqueous layer

was re-extracted with CH Cl (30 mL). The organic layers were

combined, dried over Na SO , and ﬁltered, and the ﬁltrate was

concentrated under reduced pressure. The residue was washed with

hexane and dried in vacuo to aﬀord 4a (1.20 g, 1.99 mmol, 99%) as

pale-yellow crystals. M.P. = 111−113 °C. [α] = +148.2 (c 1.02,

CHCl ). H NMR (CDCl , 400 MHz): δ 8.18 (d, 1H, J = 7.6 Hz),

resulting mixture was extracted with CH Cl (3 × 30 mL). The

2 2

7.94 (d, 1H, J = 7.6 Hz), 7.56 (m, 2H), 7.40−7.15 (m, 15H), 5.65 (d,

1H, J = 5.6 Hz), 4.96 (d, 1H, J = 11.4 Hz), 4.73 (d, 1H, J = 11.4 Hz),

4.63 (t, 1H, J = 5.6 Hz), 4.59 (m, 1H), 4.55 (d, 1H, J = 12.0 Hz), 4.45

organic layers were combined and washed with H O (30 mL). The

aqueous layer was re-extracted with CH Cl (30 mL). The organic

layers were combined, dried over Na SO , and ﬁltered, and the ﬁltrate

(

d, 1H, J = 12.0 Hz), 4.38 (d, 1H, J = 12.0 Hz), 4.36 (d, 1H, J = 12.0

was concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (hexane/AcOEt = 1:0 → 9:1, v/

v) to aﬀord 5a (0.474 g, 0.963 mmol, 96%, E:Z = 94:6) as a pale-

Hz), 4.03 (dd, 1H, J = 7.8, 5.6 Hz), 3.70 (dd, 1H, J = 11.6, 1.8 Hz),

.50 (dd, 1H, J = 11.6, 3.2 Hz). C{ H} NMR (CDCl , 100 MHz): δ

66.0, 152.4, 137.6, 137.3, 137.2, 137.1, 128.3, 128.2, 128.2, 128.1,

27.8, 127.7, 127.6, 127.5, 127.2, 125.3, 122.0, 94.6, 82.3, 77.2, 76.8,

yellow oil. [α]_D= −26.3 (c 1.66, CHCl ). H NMR (CDCl , 400

MHz): (E)-5a: δ 7.39−7.26 (m, 17H), 7.19−7.16 (m, 3H), 6.23 (s,

1H, exo-CCH), 4.80 (d, 1H, J = 4.8 Hz), 4.72 (d, 1H, J = 11.5 Hz),

4.65−4.49 (m, 6H), 4.10 (dd, 1H, J = 8.8, 4.8 Hz), 3.81 (dd, 1H, J =

11.3, 2.3 Hz), 3.63 (dd, 1H, J = 11.3, 4.6 Hz). (Z)-5a: 5.42 (s, 1H,

4.6, 73.2, 72.8, 67.6. HRMS (ESI-TOF) m/z: [M + Na] calcd for

C H NNaO S 624.1485; found 624.1498.

6 2

-Pyridyl 2,3,5-Tri-O-benzyl-α-D-ribofuranosyl Sulfone (4b). 4b

(

colorless oil, 1.10 g, 2.01 mmol, 86%) was obtained from 3b (1.20 g,

.33 mmol) according to the general procedure described for 4a.

Puriﬁcation was carried out by column chromatography on silica gel

exo-CCH). C{ H} NMR (CDCl , 100 MHz): (E)-5a: δ 155.4,

137.8, 137.3, 136.0, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8,

127.8, 127.6, 127.5, 125.8, 106.2, 80.3, 78.2, 73.3, 72.7, 72.4, 70.4,

68.7. HRMS (ESI-TOF) m/z: [M + Na] calcd for C H NaO

(

hexane/AcOEt = 1:0 → 1:1, v/v). The H and C NMR spectra

33 32 4

were identical to those previously reported. H NMR (CDCl , 400

MHz): δ 8.69−8.67 (m, 1H), 8.06 (d, 1H, J = 7.6 Hz), 7.80 (dt, 1H, J

515.2193; found 515.2208.

2,5-Anhydro-3,4,6-tri-O-benzyl-1-deoxy-1-(4-ﬂuorophenyl)-D-

ribo-hex-1-enitol (5b). 5b (pale-yellow oil, 0.0464 g, 0.0909 mmol,

91%, E/Z = 90:10) was obtained from 4a (0.0602 g, 0.100 mmol) and

7.6, 2.0 Hz), 7.45−7.40 (m, 3H), 7.34−7.25 (m, 9H), 7.23−7.20

(

m, 2H), 7.18−7.15 (m, 2H), 5.68 (d, 1H, J = 5.4 Hz), 4.95 (d, 1H, J

11.2 Hz), 4.73 (d, 1H, J = 11.2 Hz), 4.61 (t, 1H, J = 5.4 Hz), 4.54

4-ﬂuorobenzaldehyde (0.0161 mL, 0.150 mmol) according to the

(d, 1H, J = 11.8 Hz), 4.52 (m, 1H), 4.44 (d, 1H, J = 12.2 Hz), 4.38

d, 1H, J = 11.8 Hz), 4.36 (d, 1H, J = 12.2 Hz), 4.00 (dd, 1H, J = 8.2,

general procedure described for 5a−m. H NMR (CDCl

, 400 MHz):

(

(E)-5b: δ 7.38−7.17 (m, 17H), 6.98−6.92 (m, 2H), 6.17 (s, 1H, exo-

CCH), 4.75−4.72 (m, 2H), 4.66−4.50 (m, 6H), 4.11 (dd, 1H, J =

8.6, 5.0 Hz), 3.80 (dd, 1H, J = 11.2, 2.4 Hz), 3.62 (dd, 1H, J = 11.2,

.4 Hz), 3.68 (dd, 1H, J = 11.4, 2.2 Hz), 3.50 (dd, 1H, J = 11.4, 3.2

Hz). C{ H} NMR (CDCl , 100 MHz): δ 157.3, 149.9, 137.7, 137.6,

37.5, 137.4, 128.3, 128.3, 128.2, 127.8, 127.8, 127.7, 127.6, 127.5,

27.0, 123.8, 91.9, 81.8, 77.1, 77.0, 74.7, 73.2, 72.7, 67.7. HRMS (ESI-

4.5 Hz). (Z)-5b: δ 5.39 (s, 1H, exo-CCH). C{ H} NMR (CDCl ,

100 MHz): (E)-5b: δ 161.2 (d, J = 244.1 Hz), 155.3, 137.9, 137.8,

TOF) m/z: [M + Na] calcd for C H NNaO S 568.1764; found

137.4, 132.1 (d, J_C_F= 3.8 Hz), 129.5 (d, J_C_F= 7.7 Hz), 128.4, 128.4,

128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.7, 115.3 (d, J_C_F= 21.9

Hz), 105.2, 80.6, 78.3, 73.5, 72.9, 72.7, 70.5, 68.8. HRMS (ESI-TOF)

68.1770.

-Nitro-2-pyridyl 2,3,5-Tri-O-benzyl-α-D-ribofuranosyl Sulfone

4c). 4c (white foam, 1.08 g, 1.83 mmol, 98%) was obtained from

c (1.05 g, 1.87 mmol) according to the general procedure described

(

m/z: [M + Na] calcd for C H FNaO 533.2099; found 533.2060.

33 31 4

2,5-Anhydro-3,4,6-tri-O-benzyl-1-deoxy-1-(4-nitrophenyl)-D-

ribo-hex-1-enitol (5c). 5c (pale-yellow oil, 0.0521 g, 0.0970 mmol,

97%, E:Z = 88:12) was obtained from 4a (0.0602 g, 0.100 mmol) and

for 4a. Puriﬁcation was carried out by column chromatography on

silica gel (hexane/AcOEt = 9:1 → 7:3, v/v). H NMR (CDCl , 400

MHz): δ 9.27 (d, 1H, J = 2.0 Hz), 8.26 (dd, 1H, J = 8.4, 2.2 Hz), 8.06

4-nitrobenzaldehyde (0.0227 g, 0.150 mmol) according to the general

(d, 1H, J = 8.4 Hz), 7.34−7.17 (m, 15H), 5.60 (d, 1H, J = 5.6 Hz),

procedure described for 5a−m. H NMR (CDCl , 400 MHz): (E)-

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

c: δ 8.07 (d, 2H, J = 8.8 Hz), 7.38−7.20 (m, 17H), 6.21 (s, 1H, exo-

5h: δ 7.80−7.66 (m, 4H), 7.45−7.12 (m, 18H), 6.37 (s, 1H, exo-C

CH), 4.86 (d, 1H, J = 4.8 Hz), 4.73 (d, 1H, J = 11.6 Hz), 4.69−4.51

(m, 7H), 4.15 (dd, 1H, J = 8.7, 4.8 Hz), 3.84 (dd, 1H, J = 11.3, 2.4

Hz), 3.65 (dd, 1H, J = 11.3, 4.5 Hz). (Z)-5h: δ 5.59 (s, 1H, exo-C

CCH), 4.81 (d, 1H, J = 5.2 Hz), 4.77−4.52 (m, 7H), 4.19 (dd, 1H,

J = 8.1, 5.2 Hz), 3.81 (dd, 1H, J = 11.3, 2.4 Hz), 3.63 (dd, 1H, J =

1.3, 4.2 Hz). (Z)-5c: δ 5.51 (s, 1H, exo-CCH). C{ H} NMR

(CDCl , 100 MHz): (E)-5c: δ 159.1, 145.4, 143.3, 137.7, 137.4,

CH). C{ H} NMR (CDCl , 100 MHz): (E)-5h: δ 155.9, 137.9,

37.2, 128.5, 128.4, 128.2, 128.2, 128.1, 128.1, 127.8, 127.8, 123.8,

137.9, 137.4, 133.6, 131.8, 128.4, 128.4, 128.2, 128.0, 127.9, 127.9,

127.8, 127.7, 127.6, 127.5, 126.8, 126.3, 126.1, 125.4, 106.3, 80.5,

04.6, 81.5, 78.1, 73.7, 73.6, 72.9, 70.9, 68.5. HRMS (ESI-TOF) m/z:

[

M + H] calcd for C H NO 538.2224; found 538.2194.

78.4, 73.5, 73.1, 72.7, 70.6, 68.7. HRMS (ESI-TOF) m/z: [M + H]

,5-Anhydro-3,4,6-tri-O-benzyl-1-deoxy-1-(4-methoxyphenyl)-D-

ribo-hex-1-enitol (5d). 5d (pale-yellow oil, 0.0495 g, 0.0947 mmol,

5%, E:Z = 93:7) was obtained from 4a (0.0603 g, 0.100 mmol) and

calcd for C H O 543.2530; found 543.2542.

(1E,3E)- and (1E,3Z)-4,7-Anhydro-5,6,8-tri-O-benzyl-1,2,3-tri-

deoxy-1-phenyl-D-ribo-1,3-octadienitol (5i). 5i (pale-yellow oil,

0.0366 g, 0.0706 mmol, 71%, E:Z = 84:16) was obtained from 4a

(0.0602 g, 0.100 mmol) and trans-cinnamaldehyde (0.0189 mL, 0.150

p-anisaldehyde (0.0182 mL, 0.150 mmol) according to the general

procedure described for 5a−m. H NMR (CDCl , 400 MHz): (E)-

d: δ 7.36−7.18 (m, 17H), 6.84−6.80 (m, 2H), 6.19 (s, 1H, exo-C

mmol) according to the general procedure described for 5a−m. H

CH), 4.78 (d, 1H, J = 4.9 Hz), 4.73 (d, 1H, J = 11.5 Hz), 4.65−4.49

m, 6H), 4.09 (dd, 1H, J = 8.8, 4.9 Hz), 3.80 (dd, 1H, J = 11.2, 2.4

Hz), 3.80 (s, 3H), 3.62 (dd, 1H, J = 11.2, 4.6 Hz). (Z)-5d: δ 5.37 (s,

NMR (CDCl , 400 MHz): (E)-5i: δ 7.40−7.16 (m, 20H), 6.70 (dd,

(

1H, J = 15.5, 11.4 Hz), 6.38 (d, 1H, J = 15.5 Hz), 5.97 (d, 1H, J =

11.4 Hz, exo-CCH), 4.82−4.73 (m, 3H), 4.64−4.48 (m, 5H), 4.07

(dd, 1H, J = 8.4, 4.6 Hz), 3.78 (dd, 1H, J = 11.4, 2.4 Hz), 3.60 (dd,

1H, J = 11.4, 4.5 Hz). (Z)-5i: δ 5.39 (d, 1H, J = 11.0 Hz, exo-C

H, exo-CCH). C{ H} NMR (CDCl , 100 MHz): (E)-5d: δ

58.0, 154.2, 138.1, 138.0, 137.5, 129.2, 128.6, 128.4, 128.3, 128.2,

28.2, 127.9, 127.8, 127.6, 127.6, 113.9, 105.9, 80.4, 78.4, 73.4, 72.7,

CH). C{ H} NMR (CDCl , 100 MHz): (E)-5i: δ 156.2, 137.9,

2.6, 70.4, 68.9, 55.2. HRMS (ESI-TOF) m/z: [M + Na] calcd for

137.9, 137.7, 137.4, 128.7, 128.5, 128.5, 128.4, 128.3, 128.1, 128.0,

C H NaO 545.2298; found 545.2294.

127.8, 127.8, 127.7, 127.6, 126.8, 125.9, 124.0, 106.8, 81.0, 77.4, 73.4,

,5-Anhydro-3,4,6-tri-O-benzyl-1-deoxy-1-(2-methoxyphenyl)-D-

72.4, 71.5, 70.0, 68.6. HRMS (ESI-TOF) m/z: [M + H] calcd for

ribo-hex-1-enitol (5e). 5e (pale-yellow oil, 0.0412 g, 0.0788 mmol,

C H O 519.2530; found 519.2544.

9%, E:Z = 92:8) was obtained from 4a (0.0602 g, 0.100 mmol) and

(1E,3E)- and (1E,3Z)-4,7-Anhydro-5,6,8-tri-O-benzyl-1,2,3-tri-

o-anisaldehyde (0.0181 mL, 0.150 mmol) according to the general

deoxy-2-methyl-1-phenyl- D-ribo-1,3-octadienitol (5j). 5j (pale-

yellow oil, 0.0344 g, 0.0646 mmol, 65%, E:Z = 75:25) was obtained

from 4a (0.0603 g, 0.100 mmol) and α-methyl-trans-cinnamaldehyde

procedure described for 5a−m. H NMR (CDCl , 400 MHz): (E)-

e: δ 7.34−7.18 (m, 15H), 7.09 (dd, 2H, J = 6.7, 2.9 Hz), 6.89−6.84

(

m, 2H), 6.32 (s, 1H, exo-CCH), 4.68−4.55 (m, 6H), 4.44 (t, 2H, J

11.2 Hz), 4.06 (dd, 1H, J = 8.8, 4.6 Hz), 3.81 (dd, 1H, J = 11.3, 2.4

Hz), 3.79 (s, 3H), 3.64 (dd, 1H, J = 11.3, 4.8 Hz). (Z)-5e: δ 5.87 (s,

(0.0209 mL, 0.150 mmol) according to the general procedure

described for 5a−m. H NMR (CDCl

, 400 MHz): (E)-5j: δ 7.41−

7.18 (m, 20H), 6.47 (s, 1H), 5.86 (s, 1H, exo-CCH), 4.87 (d, 1H, J

= 4.8 Hz), 4.79−4.46 (m, 7H), 4.11 (dd, 1H, J = 8.8, 4.8 Hz), 3.80

(dd, 1H, J = 11.3, 2.3 Hz), 3.61 (dd, 1H, J = 11.3, 4.4 Hz), 2.03 (s,

H, exo-CCH). C{ H} NMR (CDCl , 100 MHz): (E)-5e: δ

56.8, 155.3, 138.1, 138.0, 137.5, 129.5, 128.4, 128.3, 128.1, 127.9,

27.8, 127.6, 127.6, 127.5, 125.2, 120.5, 110.4, 101.3, 80.4, 78.2, 73.4,

3H). (Z)-5j: δ 5.15 (s, 1H, exo-CCH). C{ H} NMR (CDCl

, 100

2.5, 72.4, 70.3, 69.0, 55.3. HRMS (ESI-TOF) m/z: [M + Na] calcd

MHz): (E)-5j: δ 154.4, 138.2, 138.1, 138.0, 137.5, 133.2, 129.1, 128.4,

128.3, 128.3, 128.1, 128.0, 128.0, 128.0, 127.9, 127.8, 127.6, 127.6,

127.5, 126.1, 111.4, 79.9, 78.6, 73.4, 73.4, 72.7, 70.7, 68.7, 18.2.

for C H NaO 545.2298; found 545.2294.

,5-Anhydro-3,4,6-tri-O-benzyl-1-deoxy-1-(2-furanyl)-D-ribo-

hex-1-enitol (5f). 5f (pale-yellow oil, 0.0381 g, 0.0790 mmol, 79%,

E:Z = 87:13) was obtained from 4a (0.0602 g, 0.100 mmol) and

furfural (0.0124 mL, 0.150 mmol) according to the general procedure

HRMS (ESI-TOF) m/z: [M + Na] calcd for C H NaO

36 36 4

555.2506; found 555.2485.

(2R,3R,4R)-3,4-Bis(benzyloxy)-2-benzyloxymethyl-5-octylidene-

tetrahydrofuran (5k). (E)-5k (pale-yellow oil, 0.0229 g, 0.0445

mmol, 45%) and (Z)-5k (pale-yellow oil, 0.0093 g, 0.018 mmol, 18%)

were obtained from 4a (0.0602 g, 0.100 mmol) and octanal (0.0234

mL, 0.150 mmol) according to the general procedure described for

5a−m. Puriﬁcation was carried out by column chromatography on

described for 5a−m. H NMR (CDCl , 400 MHz): (E)-5f: δ 7.34−

7.24 (m, 16H), 6.36 (dd, 1H, J = 3.2, 1.9 Hz), 6.10 (dt, 1H, J = 3.2,

0.7 Hz), 5.98 (s, 1H, exo-CCH), 5.12 (d, 1H, J = 4.6 Hz), 4.75−

4.50 (m, 7H), 4.09 (dd, 1H, J = 8.9, 4.6 Hz), 3.80 (dd, 1H, J = 11.4,

2.3 Hz), 3.61 (dd, 1H, J = 11.4, 4.7 Hz). (Z)-5f: δ 5.54 (s, 1H, exo-

CCH). C{ H} NMR (CDCl , 100 MHz): (E)-5f: δ 154.8, 150.6,

silica gel (hexane/AcOEt = 1:0 → 97:3, v/v) and PTLC (hexane/

40.7, 138.6, 138.0, 137.5, 128.4, 128.3, 128.1, 127.9, 127.9, 127.7,

27.7, 127.6, 127.4, 111.3, 107.0, 95.7, 80.4, 78.0, 73.5, 73.4, 72.4,

0.6, 68.6. HRMS (ESI-TOF) m/z: [M + H] calcd for C H O

AcOEt = 3:1, v/v). (E)-5k: H NMR (CDCl

, 400 MHz): δ 7.38−

7.27 (m, 15H), 5.03 (t, 1H, J = 7.8 Hz, exo-CCH), 4.72 (d, 1H, J =

11.6 Hz), 4.70 (d, 1H, J = 11.4 Hz), 4.60 (d, 1H, J = 12.0 Hz), 4.57

(d, 1H, J = 11.6 Hz), 4.54−4.48 (m, 3H), 4.44 (ddd, 1H, J = 8.8, 4.6,

2.4 Hz), 3.98 (dd, 1H, J = 8.8, 4.8 Hz), 3.75 (dd, 1H, J = 11.4, 2.4

Hz), 3.58 (dd, 1H, J = 11.4, 4.6 Hz), 2.08−1.92 (m, 2H), 1.41−1.19

83.2166; found 483.2186.

,5-Anhydro-3,4,6-tri-O-benzyl-1-deoxy-1-(1-naphthyl)-D-ribo-

hex-1-enitol (5g). 5g (pale-yellow oil, 0.0350 g, 0.0645 mmol, 64%,

E:Z = 89:11) was obtained from 4a (0.0602 g, 0.100 mmol) and 1-

(m, 10H), 0.88 (t, 3H, J = 7.0 Hz). C{ H} NMR (CDCl , 100

naphthaldehyde (0.0204 mL, 0.150 mmol) according to the general

MHz): δ 152.3, 138.4, 138.1, 137.6, 128.4, 128.3, 127.9, 127.9, 127.7,

procedure described for 5a−m. H NMR (CDCl , 400 MHz): (E)-

127.6, 104.5, 79.9, 77.9, 73.4, 72.3, 71.8, 70.2, 69.0, 31.8, 30.6, 29.2,

g: δ 8.09−8.05 (m, 1H), 7.89−7.85 (m, 1H), 7.77 (dd, 1H, J = 7.2,

29.2, 27.3, 22.6, 14.1. HRMS (ESI-TOF) m/z: [M + Na] calcd for

.3 Hz), 7.52−7.11 (m, 17H), 6.77 (d, 2H, J = 7.2 Hz), 6.65 (s, 1H,

C H NaO 537.2975; found 537.2952. (Z)-5k: H NMR (CDCl ,

exo-CCH), 4.69−4.54 (m, 5H), 4.40 (d, 2H, J = 11.7 Hz), 4.14−

400 MHz) δ 7.39−7.27 (m, 15H), 4.74 (d, 1H, J = 12.2 Hz), 4.62 (d,

1H, J = 11.8 Hz), 4.60 (d, 1H, J = 12.2 Hz), 4.55−4.44 (m, 5H,

PhCH × 3, C4-H, exo-CCH), 4.09 (d, 1H, J = 4.4 Hz), 3.95 (dd,

1H, J = 7.8, 4.4 Hz), 3.74 (dd, 1H, J = 11.4, 2.6 Hz), 3.59 (dd, 1H, J =

11.4, 4.6 Hz), 2.17−2.07 (m, 2H), 1.43−1.25 (m, 10H), 0.87 (t, 3H, J

.08 (m, 2H), 3.87 (dd, 1H, J = 11.3, 2.2 Hz), 3.69 (dd, 1H, J = 11.3,

.6 Hz). (Z)-5g: δ 6.10 (s, 1H, exo-CCH). C{ H} NMR (CDCl ,

00 MHz): (E)-5g: δ 156.7, 138.0, 137.6, 137.3, 133.6, 133.3, 132.5,

28.4, 128.0, 127.9, 127.9, 127.7, 127.6, 127.5, 127.1, 126.7, 126.1,

25.9, 125.5, 125.0, 103.0, 80.6, 77.9, 73.5, 72.3, 72.0, 70.3, 68.8.

= 7.0 Hz). C{ H} NMR (CDCl , 100 MHz): δ 151.3, 138.3, 138.1,

HRMS (ESI-TOF) m/z: [M + Na] calcd for C H NaO

137.6, 128.4, 128.3, 128.0, 128.0, 127.8, 127.6, 127.6, 127.5, 104.0,

81.1, 74.8, 73.3, 71.9, 69.3, 69.1, 31.9, 29.8, 29.3, 29.2, 24.7, 22.7,

14.1. HRMS (ESI-TOF) m/z: [M + Na] calcd for C H NaO

34 42 4

hex-1-enitol (5h). 5h (pale-yellow oil, 0.0495 g, 0.0912 mmol, 91%,

E:Z = 91:9) was obtained from 4a (0.0602 g, 0.100 mmol) and 2-

537.2975; found 537.2969.

4,7-Anhydro-5,6,8-tri-O-benzyl-1,3-dideoxy-1-phenyl-D-ribo-oct-

3-en-1-ynitol (5l). (E)-5l (pale-yellow oil, 0.0296 g, 0.0573 mmol,

57%) and (Z)-5l (pale-yellow oil, 0.0131 g, 0.0254 mmol, 25%) were

naphthaldehyde (0.0234 g, 0.150 mmol) according to the general

procedure described for 5a−m. H NMR (CDCl , 400 MHz): (E)-

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

obtained from 4a (0.0602 g, 0.100 mmol) and 3-phenyl-2-propinal

described for (Z)-5a. H NMR (CDCl , 400 MHz): δ 8.15−8.11 (m,

(

0.0195 g, 0.150 mmol) according to the general procedure described

2H), 7.70−7.67 (m, 2H), 7.38−7.22 (m, 15H), 5.51 (s, 1H, exo-C

for 5a−m. Separation of (E)-5l and (Z)-5l was carried out by column

CH), 4.75−4.47 (m, 8H), 4.09 (t, 1H, J = 4.9 Hz), 3.75 (dd, 1H, J =

11.2, 3.1 Hz), 3.63 (dd, 1H, J = 11.2, 3.8 Hz). ¹C{ H} NMR

chromatography on silica gel (hexane/AcOEt = 1:0 → 9:1, v/v). The

H and C NMR spectra of (Z)-5l were identical to those reported in

(CDCl , 100 MHz): δ 158.3, 144.8, 142.8, 137.6, 137.3, 137.2, 128.5,

128.5, 128.4, 128.2, 128.1, 128.1, 128.0, 127.8, 127.5, 123.6, 99.7,

84.5, 77.3, 75.7, 73.4, 72.0, 71.3, 68.8. HRMS (ESI-TOF) m/z: [M +

Na] calcd for C33H31NNaO 560.2044; found 560.2066.

2-Benzothiazolyl 3,5-Di-O-benzyl-1-thio-β-D-ribofuranoside (7).

7 was synthesized according to the β-selective ribofuranosylation

reported by Hocek et al.

mercaptobenzothiazole (0.502 g, 3.00 mmol) were dried by repeated

coevaporation with dry MeCN (5 × 5 mL) and dissolved in dry

MeCN (2.00 mL). The solution was cooled to 0 °C, before dry i-

Pr NEt (0.523 mL, 3.00 mmol), diisopropyl azodicarboxylate (DIAD,

0.827 mL, 4.20 mmol), and Bu

under stirring, and stirring was continued overnight at rt.

Subsequently, the mixture was concentrated under reduced pressure

and the residue was puriﬁed by column chromatography on silica gel

(hexane/AcOEt = 1:0 → 4:1, v/v) to aﬀord 7 (0.479 g, 0.999 mmol,

50%) as a colorless oil. H NMR (CDCl

the literature. (E)-5l: H NMR (CDCl , 400 MHz): δ 7.42−7.26

(

m, 20H), 5.39 (s, 1H, exo-CCH), 4.94 (d, 1H, J = 12.0 Hz), 4.76

d, 1H, J = 12.0 Hz), 4.74 (d, 1H, J = 4.5 Hz), 4.66−4.63 (m, 1H),

.64 (d, 1H, J = 11.7 Hz), 4.58 (d, 1H, J = 12.1 Hz), 4.52 (d, 1H, J =

2.1 Hz), 4.45 (d, 1H, J = 11.7 Hz), 4.05 (dd, 1H, J = 8.8, 4.5 Hz),

.79 (dd, 1H, J = 11.5, 2.2 Hz), 3.60 (dd, 1H, J = 11.5, 4.6 Hz).

(0.661 g, 2.00 mmol) and 2-

C{ H} NMR (CDCl , 100 MHz): δ 165.6, 138.2, 137.8, 137.3,

31.0, 128.4, 128.4, 128.3, 128.3, 128.0, 127.9, 127.7, 127.7, 127.6,

23.8, 91.1, 86.3, 85.1, 82.3, 76.8, 73.4, 73.4, 72.3, 71.4, 68.3. HRMS

(

ESI-TOF) m/z: [M + H] calcd for C H O 517.2373; found

17.2388. (Z)-5l: H NMR (CDCl , 400 MHz): δ 7.45−7.43 (m,

P (0.989 mL, 4.00 mmol) were added

H), 7.37−7.26 (m, 18H), 4.90 (s, 1H, exo-CCH), 4.72 (d, 1H, J =

2.0 Hz), 4.69−4.65 (m, 1H), 4.63−4.51 (m, 5H), 4.32 (d, 1H, J =

.8 Hz), 4.07 (dd, 1H, J = 6.0, 4.8 Hz), 3.77 (dd, 1H, J = 11.5, 3.0

Hz), 3.63 (dd, 1H, J = 11.5, 3.8 Hz). C{ H} NMR (CDCl , 100

MHz): δ 163.1, 137.9, 137.4, 137.3, 131.4, 128.5, 128.4, 128.4, 128.1,

, 400 MHz): δ 7.93 (d, 1H, J

28.1, 128.0, 127.9, 127.7, 127.6, 124.0, 93.0, 84.2, 83.8, 81.8, 76.3,

= 8.4 Hz), 7.77 (d, 1H, J = 8.8 Hz), 7.43 (t, 1H, J = 8.4 Hz), 7.38−

7.28 (m, 11H), 6.00 (d, 1H, J = 4.4 Hz), 4.65 (s, 2H), 4.58 (d, 1H, J =

12.2 Hz), 4.53 (d, 1H, J = 12.2 Hz), 4.45 (q, 1H, J = 4.4 Hz), 4.34 (q,

1H, J = 4.4 Hz), 4.24 (t, 1H, J = 4.4 Hz), 3.62 (dd, 1H, J = 10.8, 4.4

Hz), 3.57 (dd, 1H, J = 10.8, 4.4 Hz), 3.25 (d, 1H, J = 4.4 Hz).

5.5, 73.4, 72.0, 70.6, 68.4. HRMS (ESI-TOF) m/z: [M + H] calcd

for C H O 517.2373; found 517.2380.

,5-Anhydro-3,4,6-tri-O-benzyl-1-cyclohexyl-1-deoxy-D-ribo-hex-

-enitol (5m). 5m (pale-yellow oil, 0.0391 g, 0.0784 mmol, 78%, E:Z

68:32) was obtained from 4a (0.0602 g, 0.100 mmol) and

C{ H} NMR (CDCl , 100 MHz): δ 164.0, 152.9, 137.7, 136.8,

cyclohexanecarboxaldehyde (0.0181 mL, 0.150 mmol) according to

135.4, 128.5, 128.3, 128.2, 128.0, 127.6, 127.6, 126.0, 124.5, 122.0,

the general procedure described for 5a−m. H NMR (CDCl , 400

120.8, 90.3, 82.5, 78.5, 75.2, 73.4, 72.6, 69.7. HRMS (ESI-TOF) m/z:

MHz): δ 7.38−7.27 (m, 15H, (E, Z)-Ar-H), 4.92 (d, 1H, J = 10.5 Hz,

[M + Na] calcd for C H NNaO S 502.1117; found 502.1103.

26 25 4 2

(

E)-exo-CCH), 4.75−4.45 (m, 7H, (E, Z)-PhCH , (E)-C2-H, (Z)-

2-Benzothiazolyl 2,3,5-Tri-O-benzyl-1-thio-β-D-ribofuranoside

(β-3a). 7 (0.250 g, 0.520 mmol) was dried by repeated coevaporation

with dry pyridine (3 × 3 mL) and dry toluene (3 × 3 mL) and

dissolved in dry DMF (0.50 mL) under argon. Cs CO (0.254 g,

C4-H), 4.43 (ddd, 1H, J = 8.8, 4.8, 2.4 Hz, (E)-C4-H), 4.33 (d, 1H, J

9.0 Hz, (Z)-exo-CCH), 4.06 (d, 1H, J = 4.6 Hz, (Z)-C2-H), 3.98

(dd, 1H, J = 8.8, 4.8 Hz, (E)-C3-H), 3.94 (dd, 1H, J = 8.0, 4.6 Hz,

Z)-C3-H), 3.75 (dd, 1H, J = 11.3, 2.4 Hz, (E)-C5-H), 3.74 (dd, 1H,

(

0.780 mmol) was added under stirring at 0 °C and stirring was

continued for 30 min. Subsequently, BnBr (0.0928 mL, 0.780 mmol)

was added dropwise and stirring was continued for 10 min and for 1 d

J = 11.3, 2.5 Hz, (Z)-C5-H), 3.59 (dd, 1H, J = 11.3, 4.8 Hz, (Z)-C5-

H), 3.59 (dd, 1H, J = 11.3, 4.8 Hz, (E)-C5-H), 2.50−2.40 (m, 1H,

(

Z)-CH(CH ) ), 2.05−1.95 (m, 1H, (E)-CH(CH ) ), 1.79−1.62 (m,

at rt, before H O (30 mL) was added. The resulting mixture was

H, (E, Z)-c-Hex), 1.38−1.01 (m, 6H, (E, Z)-c-Hex). C{ H} NMR

extracted with AcOEt (30 mL). The organic layer was washed with

H O (30 mL), and the aqueous layer was re-extracted with AcOEt

CDCl , 100 MHz): δ 151.1, 149.9, 147.4, 142.7, 140.9, 138.3, 138.3,

38.1, 138.1, 137.9, 137.4, 128.5, 128.4, 128.3, 128.3, 128.0, 128.0,

27.9, 127.9, 127.8, 127.7, 127.6, 127.6, 127.6, 127.5, 127.5, 126.9,

10.6, 110.1, 103.9, 81.2, 79.8, 78.2, 74.9, 74.2, 73.4, 73.2, 72.3, 71.8,

1.6, 70.1, 69.1, 69.1, 69.0, 65.3, 64.4, 36.4, 34.5, 34.3, 34.1, 33.6,

3.3, 33.0, 32.7, 26.4, 26.1, 25.9, 25.8. HRMS (ESI-TOF) m/z: [M +

(30 mL). The organic layers were combined, dried over Na SO ,

ﬁltered, and concentrated under reduced pressure. The residue was

puriﬁed by column chromatography on silica gel (hexane/AcOEt =

1:0 → 17:3, v/v) to aﬀord β-3a (0.0571 g, 0.100 mmol, 19%) as a

pale-yellow oil. H NMR spectrum was identical to that we reported

Na] calcd for C H NaO 521.2662; found 521.2654.

previously.

Synthesis of (Z)-5a by Iodine-Catalyzed Isomerization. A

2-Benzothiazolyl 2,3,5-Tri-O-benzyl-β-D-ribofuranosyl Sulfone

(β-4a). β-4a (pale-yellow oil, 0.0495 g, 0.0823 mmol, 82%) was

obtained from β-3a (0.0571 g, 0.100 mmol) according to the general

procedure described for 4a. Puriﬁcation was carried out by column

solution of 5a (E:Z = 94:6, 0.0493 g, 0.100 mmol) and I (0.0076

g, 0.030 mmol) in dry 1,2-dichloroethane (1.00 mL) was stirred for 1

h at 50 °C in an oil bath under argon. Subsequently, the mixture was

cooled to rt, before a saturated aqueous solution of Na S O (2 mL)

chromatography on silica gel (hexane/AcOEt = 1:0 → 4:1, v/v). H

and a saturated aqueous solution of NaHCO (2 mL) were added.

NMR (CDCl , 400 MHz): δ 8.24 (dd, 1H, J = 7.4, 1.0 Hz), 7.98 (dd,

The resulting mixture was extracted with CH Cl (3 × 10 mL). The

1H, J = 7.2, 1.6 Hz), 7.66−7.57 (m, 2H), 7.41−7.21 (m, 15H), 5.51

(d, 1H, J = 1.6 Hz), 4.80 (d, 1H, J = 12.0 Hz), 4.70 (dd, 1H, J = 5.2,

1.6 Hz), 4.61 (d, 1H, J = 12.0 Hz), 4.51 (d, 1H, J = 11.4 Hz), 4.42 (d,

1H, J = 12.0 Hz), 4.45 (d, 1H, J = 12.0 Hz), 4.45−4.41 (m, 1H), 4.40

(d, 1H, J = 11.4 Hz), 4.08 (dd, 1H, J = 8.2, 5.2 Hz), 3.65 (dd, 1H, J =

organic layers were combined, dried over Na SO , and ﬁltered, and

the ﬁltrate was concentrated under reduced pressure. The residue was

puriﬁed by column chromatography on silica gel (hexane/AcOEt =

9:1 → 9:1, v/v) to aﬀord (Z)-5a (yellow solid, 0.0408 g, 0.0828

mmol, 83%). [α] = +83.5 (c 1.06, CHCl ). H NMR (CDCl , 400

11.2, 3.4 Hz), 3.60 (dd, 1H, J = 11.2, 6.0 Hz). C{ H} NMR

MHz): δ 7.61 (d, 2H, J = 7.2 Hz), 7.41−7.26 (m, 17H), 7.17−7.13

(CDCl , 100 MHz): δ 163.2, 152.8, 137.9, 137.5, 137.0, 136.3, 128.5,

(

m, 1H), 5.42 (s, 1H, exo-CCH), 4.78 (d, 1H, J = 12.1 Hz), 4.72

128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.6, 127.5, 125.6, 122.1,

(

ddd, 1H, J = 7.0, 4.4, 2.8 Hz), 4.67−4.51 (m, 5H), 4.33 (d, 1H, J =

96.7, 83.1, 78.2, 75.5, 73.2, 72.5, 72.3, 70.0. HRMS (ESI-TOF) m/z:

.7 Hz), 4.06 (dd, 1H, J = 7.0, 4.7 Hz), 3.81 (dd, 1H, J = 11.3, 2.8

[M + Na] calcd for C H NNaO S 624.1485; found 624.1495.

33 31 6 2

Hz), 3.66 (dd, 1H, J = 11.3, 4.4 Hz). C{ H} NMR (CDCl , 100

2-Benzothiazolyl 2,3,5-Tri-O-benzoyl-1-thio-β-D-ribofuranoside

(β-3a′). 1-O-Acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (8) (0.328

g, 0.650 mmol) was dried by repeated coevaporation with dry toluene

(3 × 5 mL) and dissolved in dry CH Cl (6.00 mL) under argon.

MHz): δ 153.4, 138.0, 137.8, 137.5, 135.5, 128.4, 128.4, 128.4, 128.2,

28.1, 128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 125.8, 102.8, 83.0,

6.7, 76.3, 73.3, 72.0, 70.0, 69.0. HRMS (ESI-TOF) m/z: [M + Na]

calcd for C H NaO 515.2193; found 515.2181.

Subsequently, MS4A (1.0 g) were added, and the mixture was cooled

to −20 °C. Under stirring, TMSI (0.0891 mL, 0.650 mmol) was

added dropwise, and stirring was continued for 1 h. 2-

Mercaptobeozothiazole (0.0836 g, 0.500 mmol) and a solution of

Synthesis of (Z)-5c by Iodine-Catalyzed Isomerization. (Z)-5c

pale-yellow solid, 0.0448 g, 0.0833 mmol, 83%) was obtained from

(

5c (E:Z = 88:12, 0.0537 g, 0.100 mmol) according to the procedure

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

dry N,N-diethylaniline (0.0800 mL, 0.500 mmol) in dry CH Cl (0.50

mL) were added successively, and stirring was continued for 4 h,

saturated aqueous solution of NaCl (20 mL). The aqueous layer was

re-extracted with CH Cl (20 mL). The organic layers were

before a saturated aqueous solution of NaHCO (20 mL) was added.

combined, dried over Na SO , and ﬁltered, and the ﬁltrate was

2 4

The mixture was extracted with CH Cl (3 × 30 mL). The organic

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (hexane/AcOEt = 1:0 → 17:3,

v/v) to aﬀord 11 (0.412 g, 0.814 mmol, 90%, pale-yellow oil) and epi-

layers were combined, dried over Na SO , ﬁltered, and concentrated

under reduced pressure. The residue was puriﬁed by column

chromatography on silica gel (hexane/AcOEt = 1:0 → 177:23, v/v)

11 (0.0029 g, 0.0057 mmol, 6%, pale-yellow oil). 11: H NMR

to aﬀord β-3a′ (0.172 g, 0.280 mmol, 56%) as a white foam. H NMR

(CDCl , 400 MHz): δ 7.38−7.21 (m, 13H), 7.16−7.12 (m, 5H),

(

CDCl , 400 MHz): δ 8.09 (d, 2H, J = 8.0 Hz), 8.01 (d, 2H, J = 8.0

6.78−6.74 (m, 2H), 4.59 (d, 2H, J = 11.8 Hz), 4.50 (d, 1H, J = 11.8

Hz), 4.48 (d, 1H, J = 12.1 Hz), 4.38 (d, 1H, J = 11.8 Hz), 4.32 (d,

1H, J = 12.1 Hz), 4.32−4.28 (m, 1H), 3.97 (dd, 1H, J = 7.4, 4.7 Hz),

3.67 (dd, 1H, J = 10.6, 3.1 Hz), 3.55 (dd, 1H, J = 10.6, 4.3 Hz), 3.33

(d, 1H, J = 4.7 Hz), 2.22 (dd, 1H, J = 9.8, 8.0 Hz), 1.47−1.40 (m,

Hz), 7.94−7.91 (m, 3H), 7.75 (d, 1H, J = 8.4 Hz), 7.56 (quint, 3H, J

8.0 Hz), 7.44−7.30 (m, 8H), 6.46 (d, 1H, J = 3.6 Hz), 6.07 (dd,

H, J = 5.6, 3.6 Hz), 6.00 (t, 1H, J = 5.6 Hz), 4.83 (dt, 1H, J = 5.6, 4.0

Hz), 4.76 (dd, 1H, J = 12.0, 4.0 Hz), 4.60 (dd, 1H, J = 12.0, 4.0 Hz).

C{ H} NMR (CDCl , 100 MHz): δ 166.0, 165.2, 164.8, 161.9,

2H). C{ H} NMR (CDCl , 100 MHz): δ 138.3, 138.1, 137.5, 137.4,

52.9, 135.6, 133.5, 133.5, 133.1, 129.8, 129.7, 129.7, 129.3, 128.7,

28.6, 128.4, 128.3, 126.1, 124.8, 122.2, 120.9, 87.4, 80.7, 75.4, 71.9,

128.3, 128.2, 128.2, 128.2, 128.1, 128.0, 127.8, 127.7, 127.5, 127.2,

125.7, 79.5, 78.6, 75.4, 73.3, 72.4, 71.6, 70.5, 69.8, 27.8, 12.1. HRMS

3.6. HRMS (ESI-TOF) m/z: [M + Na] calcd for C H NNaO S

(ESI-TOF) m/z: [M + Na] calcd for C34

529.2350. The H NMR spectrum of epi-11 was identical to that of

the product obtained from (Z)-5a shown below.

34NaO

529.2349; found

7 2

34.0965; found 634.0966.

-Benzothiazolyl 2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl Sulfone

(

β-4a′). β-4a′ (white foam, 0.257 g, 0.399 mmol, 68%) was obtained

(1R,3R,5R,6R,7R)-6,7-Bis(benzyloxy)-5-benzyloxymethyl-1-phe-

nyl-4-oxaspiro[2.4]heptane (epi-11). epi-11 (pale-yellow oil, 0.0990

g, 0.195 mmol, 98%) was obtained from (Z)-5a (0.0988 g, 0.201

mmol) according to the procedure described for 11. Puriﬁcation was

from β-3a′ (0.361 g, 0.591 mmol) according to the general procedure

described for 4a. Puriﬁcation was carried out by column

chromatography on silica gel (hexane/AcOEt = 1:0 → 1:1, v/v).

H NMR (CDCl , 400 MHz): δ 8.22 (dd, 1H, J = 7.4, 1.2 Hz), 8.06

carried out by column chromatography on silica gel (hexane/AcOEt =

:0 → 37:3, v/v). H NMR (CDCl , 400 MHz): δ 7.39−7.21 (m,

(

dd, 2H, J = 8.0, 1.2 Hz), 7.97−7.94 (m, 3H), 7.87 (dd, 2H, J = 8.0,

5H), 7.18−7.09 (m, 5H), 4.82 (d, 1H, J = 11.9 Hz), 4.71 (d, 1H, J =

1.9 Hz), 4.66 (d, 1H, J = 11.8 Hz), 4.57 (d, 1H, J = 11.8 Hz), 4.34

.2 Hz), 7.64−7.50 (m, 5H), 7.40 (dt, 4H, J = 8.0, 3.2 Hz), 7.32 (t,

H, J = 8.0 Hz), 6.52 (dd, 1H, J = 5.4, 2.8 Hz), 6.03 (dd, 1H, J = 6.2,

.4 Hz), 5.81 (d, 1H, J = 2.8 Hz), 4.82 (m, 1H), 4.69 (dd, 1H, J =

(

td, 1H, J = 6.2, 3.8 Hz), 4.22 (d, 1H, J = 12.1 Hz), 4.06 (d, 1H, J =

2.1 Hz), 4.00 (dd, 1H, J = 6.2, 4.8 Hz), 3.88 (d, 1H, J = 4.8 Hz),

.27 (dd, 1H, J = 10.6, 3.8 Hz), 2.98 (dd, 1H, J = 10.6, 6.2 Hz), 1.86

2.4, 4.0 Hz), 4.59 (dd, 1H, J = 12.4, 5.4 Hz). C{ H} NMR

CDCl , 100 MHz): δ 166.0, 164.8, 164.4, 162.7, 152.7, 137.4, 133.8,

(

dd, 1H, J = 10.2, 7.2 Hz), 1.55 (dd, 1H, J = 10.2, 7.2 Hz), 1.36 (t,

33.6, 133.2, 129.8, 129.8, 129.7, 129.2, 128.5, 128.4, 128.3, 128.3,

28.2, 127.7, 125.6, 122.2, 95.3, 81.8, 72.1, 71.2, 63.3. HRMS (ESI-

H, J = 7.2 Hz). C{ H} NMR (CDCl , 100 MHz): δ 138.4, 138.3,

9 2

37.8, 137.7, 128.3, 128.1, 127.9, 127.8, 127.7, 127.7, 127.6, 127.4,

27.3, 125.6, 80.8, 80.1, 79.8, 73.0, 72.2, 71.7, 70.8, 69.8, 26.5, 13.9.

TOF) m/z: [M + Na] calcd for C H NNaO S 666.0863; found

666.0881.

HRMS (ESI-TOF) m/z: [M + Na] calcd for C H NaO

(

4S,5R)-2-Benzothiazolylsulfonyl-4-benzoyloxy-5-benzoyloxy-

34 34

methyl-4,5-dihydrofuran (10). β-4a′ (0.0644 g, 0.100 mmol) and

529.2349; found 529.2359.

benzaldehyde (0.0153 mL, 0.150 mmol) were dissolved in dry THF

Methyl 2,3,5-Tri-O-(2-cyanoethyl)-β-D-ribofuranoside (β-17).

AcCl (0.725 mL, 10.0 mmol) was mixed with dry MeOH (30.0

mL) under argon and added to a stirred mixture of ribose (7.51 g,

50.0 mmol) in dry MeOH (100.0 mL) at rt. The stirring was

(

1.00 mL) under argon, and the solution was cooled to −60 °C.

Under stirring, a 0.5 M KHMDS solution in toluene (0.28 mL, 0.140

mmol) was added dropwise. The temperature was gradually increased

to rt over 1 h. Stirring was continued for 3 h, before a saturated

aqueous solution of NH Cl (2 mL) and H O (3 mL) were added.

continued for 6 h, before NaHCO (5.05 g, 60.0 mmol) was added.

After the insoluble materials were removed by suction ﬁltration, the

ﬁltrate was concentrated under reduced pressure. The residue was

then dried by repeated coevaporation with dry pyridine (3 × 10 mL)

and dry toluene (3 × 10 mL) and dissolved in dry t-BuOH (250 mL).

The resulting mixture was then extracted with CH Cl (3 × 10 mL).

The organic layers were combined and washed with H O (10 mL).

The aqueous layer was re-extracted with CH Cl (15 mL). The

organic layers were combined, dried over Na SO , and ﬁltered, and

Acrylonitrile (197 mL, 3.00 mol) and Cs CO (48.9 g, 150 mmol)

2 3

the ﬁltrate was concentrated under reduced pressure. The residue was

puriﬁed by column chromatography on silica gel (hexane/AcOEt =

were added to the solution under stirring at rt under argon. The

stirring was continued for 1 h, before insoluble materials were

removed by suction ﬁltration through a pad of celite. The ﬁltrate was

concentrated under reduced pressure to give a crude mixture

containing α-17 and β-17 (ca. 2:8). Puriﬁcation by column

:0 → 7:3, v/v) to aﬀord 10 (0.0484 g, 0.0928 mmol, 93%) as a pale-

yellow oil. H NMR (CDCl , 400 MHz): δ 8.07−8.03 (m, 3H),

.90−7.86 (m, 1H), 7.72 (d, 2H, J = 7.8 Hz), 7.61 (t, 1H, J = 7.6 Hz),

.57−7.44 (m, 5H), 7.30 (t, 2H, J = 7.8 Hz), 6.50 (d, 1H, J = 3.2 Hz),

.17 (t, 1H, J = 3.2 Hz), 5.19−5.17 (m, 1H), 4.66 (dd, 1H, J = 12.0,

chromatography on silica gel (CH

Cl /AcOEt = 1:0 → 7:3 then

AcOEt/MeOH = 4:1, v/v) aﬀorded β-17 (12.3 g, 37.9 mmol, 76%

.4 Hz), 4.57 (dd, 1H, J = 12.0, 4.0 Hz). C{ H} NMR (CDCl , 100

from ribose) as a pale-yellow oil. H NMR (CDCl , 400 MHz): δ 4.90

MHz): δ 165.9, 165.6, 162.8, 157.8, 152.5, 137.4, 133.8, 133.2, 129.8,

(d, 1H, J = 1.4 Hz), 4.19 (dt, 1H, J = 6.5, 4.7 Hz), 4.09 (dd, 1H, J =

6.5, 4.7 Hz), 3.90−3.74 (m, 7H), 3.69−3.62 (m, 2H), 3.38 (s, 3H),

29.5, 128.7, 128.5, 128.3, 128.3, 127.7, 125.8, 122.1, 109.2, 87.8,

7.5, 63.5. HRMS (ESI-TOF) m/z: [M + Na] calcd for

2.69−2.62 (m, 6H). C{ H} NMR (CDCl , 100 MHz): δ 118.0,

C H NNaO S 544.0495; found 544.0485.

117.9, 117.9, 106.1, 81.5, 79.9, 79.7, 71.8, 66.0, 65.5, 65.4, 55.3, 19.2,

7 2

(

1S,3R,5R,6R,7R)-6,7-Bis(benzyloxy)-5-benzyloxymethyl-1-phe-

19.1, 18.9. HRMS (ESI-TOF) m/z: [M + Na] calcd for

nyl-4-oxaspiro[2.4]heptane (11). 5a (E/Z = 94:6, 0.443 g, 0.900

C H N NaO 346.1373; found 346.1382.

2,3,5-Tri-O-(2-cyanoethyl)-D-ribofuranose (18). A mixture of β-17

2 2

(12.3 g, 37.9 mmol) with AcOH (190.0 mL) and 1 M HCl aq. (95.0

mL) was stirred for 4 h at 80 °C in an oil bath. The mixture was then

cooled to rt and concentrated under reduced pressure. The residue

was dissolved in AcOEt (150 mL) and washed successively with

saturated aqueous solutions of NaHCO (150 mL) and NaCl (100

mL). The aqueous layers were combined and extracted with AcOEt

(10 × 100 mL). The organic layers were combined, dried over

Na SO , and ﬁltered, and the ﬁltrate was concentrated under reduced

pressure. The residue was puriﬁed by column chromatography on

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.0c02297.

Article

silica gel (CH Cl /AcOEt = 6:4 → 0:1 then AcOEt/MeOH = 4:1, v/

v) to aﬀord 18 (10.5 g, 33.8 mmol, 89%) as a pale-yellow oil. H

under argon and cooled to −60 °C. Under stirring, a 0.5 M KHMDS

solution in toluene (0.210 mL, 0.105 mmol) was added dropwise.

The mixture was gradually warmed to rt over 1 h and stirring was

NMR (CDCl , 400 MHz): δ 5.37−5.33 (m, 1H), 4.31−3.56 (m,

1H), 2.80−2.61 (m, 6H). C{ H} NMR (CDCl , 100 MHz): δ

18.2, 118.0, 117.8, 99.9, 95.7, 82.3, 80.8, 79.9, 79.2, 78.8, 78.8, 71.1,

0.6, 66.2, 66.0, 65.8, 65.3, 65.3, 65.0, 19.2, 19.1, 19.1, 18.9, 18.8.

continued for 3 h, before a saturated aqueous solution of NH Cl (2

mL) and H

with CH Cl

washed with H

O (3 mL) were added. The mixture was then extracted

(3 × 10 mL). The organic layers were combined and

O (10 mL). The aqueous layer was re-extracted with

HRMS (ESI-TOF) m/z: [M + Na] calcd for C H N NaO

32.1217; found 332.1205.

-O-Trimethylsilyl-2,3,5-tri-O-(2-cyanoethyl)-D-ribofuranose

19). 18 (10.5 g, 33.8 mmol) was dried by repeated coevaporation

(15 mL). The organic layers were combined, dried over

, and ﬁltered, and concentrated under reduced pressure. The

(

residue was puriﬁed by column chromatography on silica gel (hexane/

AcOEt = 1:0 → 17:3, v/v) to aﬀord 23 (0.0336 g, 0.0881 mmol, 88%,

with dry toluene (3 × 10 mL) and dissolved in dry MeCN (169.0

mL) under argon. N,O-Bis(trimethylsilyl)acetamide (16.5 mL, 67.6

mmol) was added to the solution at rt under stirring. After 2 h of

E:Z = 93:7) as a pale-yellow oil. [α] = −52.6 (c 1.29, CHCl ). H

NMR (CDCl , 400 MHz): (E)-23: δ 7.35−7.20 (m, 5H), 6.24 (s, 1H,

stirring, H O (100 mL) was added, and the mixture was extracted

exo-CCH), 4.84 (d, 1H, J = 5.0 Hz), 4.38 (ddd, 1H, J = 8.6, 3.7, 2.4

Hz), 4.18 (dd, 1H, J = 8.6, 5.0 Hz), 3.97 (dt, 1H, J = 9.5, 5.8 Hz),

3.90−3.67 (m, 7H), 2.71 (t, 2H, J = 6.0 Hz), 2.65 (t, 2H, J = 6.0 Hz),

with AcOEt (3 × 100 mL). The organic layers were combined and

washed with H O (100 mL). The aqueous layer was extracted with

AcOEt (100 mL). The organic layers were combined, dried over

2.60−2.47 (m, 2H). (Z)-23: δ 5.48 (s, 1H, exo-CCH). C{ H}

NMR (CDCl , 100 MHz): (E)-23: δ 153.7, 135.1, 128.5, 127.7,

Na SO , and ﬁltered, and the ﬁltrate was concentrated under reduced

pressure. The residue was puriﬁed by column chromatography on

126.3, 117.9, 117.8, 117.8, 107.0, 79.8, 78.6, 73.3, 69.2, 66.0, 65.2,

silica gel (CH Cl /AcOEt = 1:0 → 2:1, v/v) to aﬀord 19 (10.7 g, 28.1

63.1, 18.9, 18.9, 18.7. HRMS (ESI-TOF) m/z: [M + Na] calcd for

mmol, 83%, α:β = 7:93) as a pale-yellow oil. H NMR (CDCl , 400

NaO

404.1581; found 404.1573.

MHz): δ 5.46 (d, 1H, J = 3.8 Hz, α), 5.28 (d, 1H, J = 1.5 Hz, β),

2,5-Anhydro-1-deoxy-1-phenyl-D-ribo-hex-1-enitol (24). A solu-

tion of 23 (0.0382 g, 0.100 mmol) and Na S (0.0117 g, 0.150 mmol)

in CH Cl /MeOH (2:1, v/v; 0.30 mL) was stirred for 3 days at rt,

before being concentrated under reduced pressure. The residue was

then puriﬁed by column chromatography on silica gel (CH Cl

MeOH = 1:0 → 94:6, v/v) to aﬀord 24 (0.0195 g, 0.0877 mmol, 88%,

E:Z = 93:7) as a pale-yellow solid. [α] = −293.8 (c 2.19, MeOH).

, 400 MHz): (E)-24: δ 7.40 (d, 2H, J = 7.4 Hz),

.25−4.04 (m, 2H, α, β), 4.00−3.64 (m, 9H, α, β), 2.73−2.60 (m,

H, α, β), 0.19 (s, 9H, α), 0.16 (s, 9H, β). C{ H} NMR (CDCl ,

00 MHz): α-19: δ 118.2, 117.9, 96.4, 80.1, 79.6, 70.3, 66.1, 65.5,

5.5, 19.2, 18.9, 0.2. β-19: 117.9, 117.9, 117.8, 99.9, 83.3, 79.6, 79.5,

2.0, 65.8, 65.4, 19.2, 19.1, 18.9, 0.0. HRMS (ESI-TOF) m/z: [M +

Na] calcd for C H N NaO Si 404.1612; found 404.1626.

-Benzothiazolyl 2,3,5-Tri-O-(2-cyanoethyl)-α-D-ribofuranoside

21). 19 (2.48 g, 6.50 mmol) was dried by repeated coevaporation

with dry toluene (3 × 10 mL) and dissolved in dry CH Cl (60.0 mL)

H NMR (DMSO-d

(

7.26 (t, 2H, J = 7.4 Hz), 7.11 (t, 1H, J = 7.4 Hz), 5.82 (s, 1H), 5.32

(d, 1H, J = 5.0 Hz), 5.23 (d, 1H, J = 6.8 Hz), 4.85 (t, 1H, J = 5.6 Hz),

4.37 (t, 1H, J = 5.0 Hz), 4.03 (ddd, 1H, J = 8.8, 5.0, 2.2 Hz), 3.85

(ddd, 1H, J = 8.8, 6.8, 5.6 Hz), 3.72 (ddd, 1H, J = 12.4, 5.6, 2.2 Hz),

3.45 (dt, 1H, J = 12.4, 5.6 Hz). (Z)-24: δ 5.30 (s, 1H, exo-CCH).

under argon. Subsequently, MS4A (10.0 g) were added, and the

mixture was cooled to −20 °C. Under stirring, TMSI (0.891 mL, 6.50

mmol) was added dropwise to the mixture, and stirring was continued

for 1 h at the same temperature. 2-Mercaptobenzothiazole (0.836 g,

C{ H} NMR (DMSO-d , 100 MHz): (E)-24: δ 159.2, 136.5, 128.3,

.00 mmol) and a solution of dry N,N-diethylaniline (0.799 mL, 5.00

127.1, 125.1, 102.9, 82.5, 70.4, 68.7, 60.4. HRMS (ESI-TOF) m/z:

mmol) in dry CH Cl (5.00 mL) were added dropwise, and stirring

was continued for 4 h before a saturated aqueous solution of

[M + Na] calcd for C H NaO 245.0784; found 245.0767.

12 14

NaHCO (50 mL) was added. The mixture was warmed to rt and

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

■

extracted with CH Cl (3 × 50 mL). The organic layers were

combined, dried over Na SO , and ﬁltered, and the ﬁltrate was

concentrated under reduced pressure. The residue was then puriﬁed

by column chromatography on silica gel (CH Cl /AcOEt = 1:0 →

:1, v/v) to aﬀord 21 (2.09 g, 4.57 mmol, 91%, α:β > 99:1) as a pale-

FAIR data includes the primary NMR FID ﬁles for

compounds 4a−d, 5a−m, (Z)-5a,c, 7, β-4a, β -3a′, β-4a′,

10, 11, epi-11, β-17, 18, 19, and 21−24 (ZIP)

yellow oil. H NMR (CDCl , 400 MHz): δ 7.91 (d, 1H, J = 8.0 Hz),

.77 (d, 1H, J = 8.0 Hz), 7.42 (t, 1H, J = 8.0 Hz), 7.32 (t, 1H, J = 8.0

Hz), 6.80 (d, 1H, J = 5.6 Hz), 4.45 (t, 1H, J = 5.6 Hz), 4.35 (q, 1H, J

3.0 Hz), 4.19 (dd, 1H, J = 5.6, 3.8 Hz), 4.11 (dt, 1H, J = 9.7, 5.6

Hz), 3.97 (dt, 1H, J = 9.1, 5.6 Hz), 3.89−3.69 (m, 6H), 2.79−2.63

X-ray crystal data for 4a; X-ray structure analysis, crystal

data, structure reﬁnement results, bond lengths, and

bond angles of 4a; computational details; NMR spectra

(PDF)

_m_,₆_H₎_.1 C{ H} NMR (CDCl , 100 MHz): δ 165.4, 152.9, 135.5,

(

26.0, 124.5, 121.9, 120.9, 118.0, 117.5, 88.8, 82.0, 79.9, 78.5, 69.7,

6.2, 66.1, 65.8, 19.3, 19.0, 18.9. HRMS (ESI-TOF) m/z: [M + Na]

calcd for C H N NaO S 481.0975; found 481.0974.

4 2

Accession Codes

-Benzothiazolyl 2,3,5-Tri-O-(2-cyanoethyl)-α-D-ribofuranosyl

Sulfone (22). 22 (white foam, 1.83 g, 3.73 mmol, 82%) was obtained

from 21 (2.09 g, 4.57 mmol) according to the general procedure

described for 4a. Puriﬁcation was carried out by column

CCDC 2009571 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif , or by emailing

data_request@ccdc.cam.ac.uk , or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

chromatography on silica gel (hexane/AcOEt = 1:0 → 0:1, v/v).

[

α]_D= +154.4 (c 1.05, CHCl ). H NMR (CDCl , 400 MHz): δ

.25−8.23 (m, 1H), 8.04−8.01 (m, 1H), 7.67−7.58 (m, 2H), 5.69 (d,

1H, J = 5.8 Hz), 4.72 (t, 1H, J = 5.8 Hz), 4.56 (dt, 1H, J = 6.8, 2.3

Hz), 4.26−4.19 (m, 2H), 4.02−3.92 (m, 2H), 3.80−3.76 (m, 1H),

.75−3.74 (m, 2H), 3.68 (t, 2H, J = 6.0 Hz), 2.87−2.48 (m, 6H).

AUTHOR INFORMATION

■

C{ H} NMR (CDCl , 100 MHz): δ 165.1, 152.3, 137.2, 127.9,

Corresponding Authors

27.4, 125.3, 122.2, 118.0, 117.9, 117.8, 94.1, 82.3, 79.1, 77.9, 68.4,

Natsuhisa Oka − Department of Chemistry and Biomolecular

Science, Faculty of Engineering, Center for Highly Advanced

Integration of Nano and Life Sciences, and Institute for

Glyco-core Research (iGCORE), Tokai National Higher

Education and Research System Furo-cho, Gifu University,

7.7, 66.2, 65.8, 18.8, 18.7. HRMS (ESI-TOF) m/z: [M + Na] calcd

6 2

for C H N NaO S 513.0873; found 513.0883.

,5-Anhydro-3,4,6-tri-O-(2-cyanoethyl)-1-deoxy-1-phenyl-D-ribo-

hex-1-enitol (23). 22 (0.0491 g, 0.100 mmol) and benzaldehyde

0.0112 mL, 0.110 mmol) were dissolved in dry THF (1.00 mL)

(

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Unprecedented Sulfonylated Phosphono-exo -Glycals Designed as

Article

Gifu 501-1193, Japan; orcid.org/0000-0002-3114-9233 ;

Email: oka@gifu-u.ac.jp

Kaori Ando − Department of Chemistry and Biomolecular

Science, Faculty of Engineering, Gifu University, Gifu 501-

Inhibitors of the Three Mycobacterial Galactofuranose Processing

Enzymes. Chem. − Eur. J. 2016, 22, 15913−15920.

5) (a) Bender, S. L.; Widlanski, T.; Knowles, J. R. Dehydroquinate

Synthase: The Use of Substrate Analogs to Probe the Early Steps of

193, Japan; orcid.org/0000-0001-5345-2754;

the Catalyzed Reaction. Biochemistry 1989, 28 , 7560 −7572.

Email: ando@gifu-u.ac.jp

(b) Widlanski, T.; Bender, S. L.; Knowles, J. R. Dehydroquinate

Synthase: The use of Substrate Analogs to Probe the Late Steps of the

Catalyzed Reaction. Biochemistry 1989 , 28 , 7572 −7582. (c) Yamauchi,

N.; Kakinuma, K. Enzymic Carbocycle Formation in Microbial

Secondary Metabolism. The Mechanism of the 2-Deoxy-scyllo -Inosose

Synthase Reaction as a Crucial Step in the 2-Deoxystreptamine

Biosynthesis in Streptomyces fradiae . J. Org. Chem. 1995, 60, 5614−

5619. (d) Yang, X.; Hu, Y.; Yin, D. H.; Turner, M. A.; Wang, M.;

Borchardt, R. T.; Howell, P. L.; Kuczera, K.; Schowen, R. L. Catalytic

Strategy of S -Adenosyl-L-Homocysteine Hydrolase: Transition-State

Stabilization and the Avoidance of Abortive Reactions. Biochemistry

Authors

Ayumi Mori − Department of Chemistry and Biomolecular

Science, Faculty of Engineering, Gifu University, Gifu 501-

193, Japan

Kanna Suzuki − Department of Chemistry and Biomolecular

Science, Faculty of Engineering, Gifu University, Gifu 501-

193, Japan

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02297

2003, 42, 1900−1909. (e) Wyszynski, F. J.; Lee, S. S.; Yabe, T.; Wang,

H.; Gomez-Escribano, J. P.; Bibb, M. J.; Lee, S. J.; Davies, G. J.; Davis,

B. G. Biosynthesis of the Tunicamycin Antibiotics Proceeds via

Unique exo-Glycal Intermediates. Nat. Chem. 2012, 4, 539−546.

Notes

The authors declare no competing ﬁnancial interest.

(f) Kean, K. M.; Codding, S. J.; Asamizu, S.; Mahmud, T.; Karplus, P.

ACKNOWLEDGMENTS

A. Structure of a Sedoheptulose 7-Phosphate Cyclase: ValA from

■

Streptomyces hygroscopicus . Biochemistry 2014, 53, 4250−4260.

We thank Toshifumi Maruyama (Gifu University) for his

skilled assistance in X-ray crystallographic analysis. This work

was partially supported by JST CREST Grant Number

JPMJCR18S1, Japan, and the Koshiyama Research Grant.

(6) Julia oleﬁnation: (a) Gueyrard, D.; Haddoub, R.; Salem, A.;

Bacar, N. S.; Goekjian, P. G. Synthesis of Methylene Exoglycals Using

a Modified Julia Olefination. Synlett 2005, 520−522. (b) Bourdon, B.;

Corbet, M.; Fontaine, P.; Goekjian, P. G.; Gueyrard, D. Synthesis of

Enol Ethers from Lactones Using Modified Julia Olefination

Reagents: Application to the Preparation of Tri- and Tetrasubstituted

Exoglycals. Tetrahedron Lett. 2008, 49, 747−749. (c) Tomas, L.; Boije

REFERENCES

■

Glycals. Chem. Rev. 2004 , 104 , 263 −292. (b) Lin, C.-H.; Lin, H.-C.;

1) (a) Taillefumier, C.; Chapleur, Y. Synthesis and Uses of exo -

Af Gennas, G.; Hiebel, M. A.; Hampson, P.; Gueyrard, D.; Pelotier,

Yang, W.-B. exo -Glycal Chemistry: General Aspects and Synthetic

Applications for Biochemical Use. Curr. Top. Med. Chem. 2005 , 5 ,

B.; Yli-Kauhaluoma, J.; Piva, O.; Lord, J. M.; Goekjian, P. G. Total

Synthesis of Bistramide A and Its 36(Z ) Isomers: Differential Effect

on Cell Division, Differentiation, and Apoptosis. Chem. − Eur. J.

431 −1457. (c) Fred

Glycals and Their Biochemical Applications. Tetrahedron 2018, 74,

512−6519.

2) (a) Kobayashi, Y.; Fujimoto, T.; Fukuyama, T. Stereocontrolled

Total Synthesis of (+)-K252a. J. Am. Chem. Soc. 1999 , 121 , 6501 −

502. (b) Ueda, A.; Yamamoto, A.; Kato, D.; Kishi, Y. Total Synthesis

eric, C. J.-M.; Vincent, S. P. Synthesis of exo -

T.; Fenet, B.; Goekjian, P. G.; Gueyrard, D. Synthesis of Fluorinated

012, 18, 7452−7466. (d) Habib, S.; Larnaud, F.; Pfund, E.; Lequeux,

Gueyrard, D. Synthesis of Substituted exo -Glucals via a Modified

exo -Glycals through Modified Julia Olefination. Eur. J. Org. Chem.

013, 2013, 1872−1875. (e) Habib, S.; Larnaud, F.; Pfund, E.; Mena

Barragan, T.; Lequeux, T.; Ortiz Mellet, C.; Goekjian, P. G.;

Julia Olefination and Identification as Selective β -Glucosidase

Inhibitors. Org. Biomol. Chem. 2014 , 12 , 690 −699. (f) Habib, S.;

Gueyrard, D. Modified Julia Olefination on Sugar-Derived Lactones:

Synthesis of Difluoro-exo -Glycals. Eur. J. Org. Chem. 2015, 2015,

of Halichondrin A, the Missing Member in the Halichondrin Class of

Natural Products. J. Am. Chem. Soc. 2014, 136, 5171−5176.

3) Pellegrini-Moïse, N.; Richard, M. Cycloaddition Reactions of

Sugar-Based Oleﬁns, Nitrones and Nitrile Oxides: En Route to

Saccharidic Spiroisoxazoli(di)nes. In Carbohydrate-spiro-heterocycles.

Topics in Heterocyclic Chemistry; Somsak

019; Vol. 57.

4) (a) Lehmann, J.; Schwesinger, B. Attempted Affinity-Labelling of

(

871−875. (g) Liu, X.; Yin, Q.; Yin, J.; Chen, G.; Wang, X.; You, Q.-

, L., Ed.; Springer: Cham,

D.; Chen, Y.-L.; Xiong, B.; Shen, J. Highly Stereoselective

Nucleophilic Addition of Difluoromethyl-2-Pyridyl Sulfone to Sugar

Lactones and Efficient Synthesis of Fluorinated 2-Ketoses. Eur. J. Org.

Chem. 2014, 2014, 6150−6154.

β -D-Galactosidase from Escherichia coli with 2,6:3,4-Dianhydro-1-

Deoxy-D-talo -Hept-1-Enitol. Carbohydr. Res. 1982 , 107 , 43 −53.

b) Muller, B.; Schaub, C.; Schmidt, R. R. Efficient Sialyltransferase

(7) Wittig reaction: (a) Hanessian, S.; Tyler, P. C.; Demailly, G.;

Chapleur, Y. Convergent Stereocontrolled Synthesis of Substituted

exo -Glycals by Stille Cross-Coupling of Halo-exo -Glycals and

Stannanes. J. Am. Chem. Soc. 1981, 103, 6243−6246. (b) Lakhrissi,

Y.; Taillefumier, C.; Lakhrissi, M.; Chapleur, Y. Efficient Conditions

for the Synthesis of C -Glycosylidene Derivatives: A Direct and

Stereoselective Route to C -Glycosyl Compounds. Tetrahedron:

Asymmetry 2000, 11, 417−421. (c) Taillefumier, C.; Lakhrissi, Y.;

Lakhrissi, M.; Chapleur, Y. Facile Synthesis of Fused Furanosyl β -

Amino Acids from Protected Sugar Lactones: Incorporation into a

Peptide Chain. Tetrahedron: Asymmetry 2002, 13, 1707−1711.

Inhibitors Based on Transition-State Analogues of the Sialyl Donor.

Angew. Chem. Int. Ed 1998, 37, 2893−2897. (c) Stolz, F.; Reiner, M.;

Blume, A.; Reutter, W.; Schmidt, R. R. Novel UDP-Glycal Derivatives

as Transition State Analogue Inhibitors of UDP-GlcNAc 2-Epimerase.

J. Org. Chem. 2004 , 69 , 665 −679. (d) Caravano, A.; Vincent, S. P.;

Sinay, P. Efficient Synthesis of a Nucleoside-Diphospho-exo -Glycal

Displaying Time-Dependent Inactivation of UDP-Galactopyranose

Mutase. Chem. Commun. 2004, 183, 1216 −1217. (e) Caravano, A.;

Dohi, H.; Sinay, P.; Vincent, S. P. A New Methodology for the

Synthesis of Fluorinated exo -Glycals and Their Time-Dependent

Inhibition of UDP-Galactopyranose Mutase. Chem. − Eur. J. 2006, 12,

(d) Thien, H.-T. T.; Novoa, A.; Pellegrini-Moïse, N.; Chretien, F.;

114−3123. (f) Dumitrescu, L.; Eppe, G.; Tikad, A.; Pan, W.; El

Didierjean, C.; Chapleur, Y. Tetrasubstituted C -Glycosylidenes and C -

Glycosyl Compounds from Di- and Monobromo-Substituted exo -

Glycals. Eur. J. Org. Chem. 2011, 2011, 6939−6951. (e) Richard, M.;

Chateau, A.; Jelsch, C.; Didierjean, C.; Manival, X.; Charron, C.;

Maigret, B.; Barberi-Heyob, M.; Chapleur, Y.; Boura, C.; Pellegrini-

Moïse, N. Carbohydrate-Based Peptidomimetics Targeting Neuro-

pilin-1: Synthesis, Molecular Docking Study and in Vitro Biological

Bkassiny, S.; Gurcha, S. S.; Arda, A.; Jimenez-Barbero, J.; Besra, G. S.;

Vincent, S. P. Selectfluor and NFSI exo -Glycal Fluorination Strategies

Applied to the Enhancement of the Binding Affinity of Galactofur-

anosyltransferase Gl f T2 Inhibitors. Chem. − Eur. J. 2014, 20, 15208−

5215. (g) Frederic, C. J.-M.; Tikad, A.; Fu, J.; Pan, W.; Zheng, R. B.;

́ ́

Koizumi, A.; Xue, X.; Lowary, T. L.; Vincent, S. P. Synthesis of

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Czernecki, S.; Xie, J. Stereocontrolled Synthesis of β -C -Glycosides

Article

Activities. Bioorg. Med. Chem. 2016 , 24 , 5315 −5325. (f) Molina, A.;

and Amino β -C -Glycosides by Wittig Olefination of Perbenzylated

Glyconolactones Derivatives. Tetrahedron Lett. 1998 , 39 , 7507 −7510.

Spiro Bis-C ,C -α -Arylglycosides by Tandem Heck Type C -Glyco-

sylation and Friedel −Crafts Cyclization. J. Org. Chem. 2016 , 81 ,

3007 −3016. (i) Gueyrard, D.; Fontaine, P.; Goekjian, P. G. Synthesis

of C -Glucoside endo -Glycals from C -Glucosyl Vinyl Sulfones. Synthesis

2006, 2006, 1499 −1503. (j) Thiery, E.; Reniers, J.; Wouters, J.;

Vincent, S. P. Stereoselective Synthesis of Boat-Locked Glycosides

Designed as Glycosyl Hydrolase Conformational Probes. Eur. J. Org.

Chem. 2015, 2015, 1472−1484.

g) Knapp, S.; Amorelli, B.; A. Doss, G. A. Fused GalNAc-Thiazole

from a Singular and Unanticipated Fragmentation. Tetrahedron Lett.

004, 45, 8507−8510. (h) Gascon-Lopez, M.; Motevalli, M.;

Paloumbis, G.; Bladon, P.; Wyatt, P. B. C -Glycosylidene Derivatives

exo -Glycals): Their Synthesis by Reaction of Protected Sugar

Lactones with Tributylphosphonium Ylids, Conformational Analysis

(11) Ramberg−Bac

klund rearrangement: (a) Taylor, R. J. K.;

klund Reaction for

McAllister, G. D.; Franck, R. W. The Ramberg-Bac

and Stereoselective Reduction. Tetrahedron 2003, 59, 9349−9360.

the Synthesis of C -Glycosides, C -Linked-Disaccharides and Related

Compounds. Carbohydr. Res. 2006, 341, 1298−1311. (b) Griffin, F.

K.; Murphy, P. V.; Paterson, D. E.; Taylor, R. J. K. A Ramberg-

(i) Coumbarides, G. S.; Motevalli, M.; Muse, W. A.; Wyatt, P. B.

Stereoselective Synthesis of (E )-Mannosylidene Derivatives Using the

Wittig Reaction. J. Org. Chem. 2006, 71, 7888−7891.

Bac

8182. (c) Griffin, F. K.; Paterson, D. E.; Taylor, R. J. K. Ramberg-

Backlund Approaches to the Synthesis of C -Linked Disaccharides.

Angew. Chem., Int. Ed. 1999, 38, 2939−2942. (d) Paterson, D. E.;

Griffin, F. K.; Alcaraz, M.-L.; Taylor, R. J. K. A Ramberg −Backlund

klund Approach to exo-Glycals. Tetrahedron Lett. 1998, 39 , 8179 −

(8) Tebbe and Petasis reagents: (a) Wilcox, C. S.; Long, G. W.; Suh,

H. A New Approach to C -Glycoside Congeners: Metal Carbene

Mediated Methylenation of Aldonolactones. Tetrahedron Lett. 1984 ,

5 , 395 −398. (b) RajanBabu, T. V.; Reddy, G. S. 1-Methylene Sugars

as C -Glycoside Precursors. J. Org. Chem. 1986 , 51 , 5458 −5461.

c) Csuk, R.; I. Glanzer, B. Methylenation of Aldonolactones.

Tetrahedron 1991 , 47 , 1655 −1664. (d) Haudrechy, A.; Sinay, P.

Cyclization of Hydroxy Enol Ethers: A Stereocontrolled Approach to

-Deoxy-D-Manno-2-Octulosonic Acid Containing Disaccharides. J.

Approach to the Synthesis of C -Glycosides, C -Linked Disaccharides,

and C -Glycosyl Amino Acids. Eur. J. Org. Chem. 2002, 2002, 1323−

1336. (e) Griffin, F. K.; Paterson, D. E.; Murphy, P. V.; Taylor, R. J.

(

K. A New Route to exo -Glycals Using the Ramberg −Backlund

Rearrangement. Eur. J. Org. Chem. 2002, 2002, 1305 −1322.

Org. Chem. 1992 , 57 , 4142 −4151. (e) Li, X.; Ohtake, H.; Takahashi,

H.; Ikegami, S. An Efficient Synthesis of New 1 ′-C -Methyl-α -O -

Disaccharides Using 1-Methylenesugars as the Glycosyl Donors.

Tetrahedron 2001, 57, 4283−4295.

(f) McAllister, G. D.; Paterson, D. E.; Taylor, R. J. K. A Simplified

Ramberg −Backlund Approach to Novel C -Glycosides and C -Linked

Disaccharides. Angew. Chem., Int. Ed. 2003, 42, 1387−1391. (g) Yang,

G.; Franck, R. W.; Byun, H. S.; Bittman, R.; Samadder, P.; Arthur, G.

(9) Dihalomethylenation: (a) Chapleur, Y. A Convenient Synthesis

Convergent C -Glycolipid Synthesis via the Ramberg-Backlund

of Substituted Chiral Tetrahydrofurans from Sugar γ -Lactones. J.

Chem. Soc. Chem. Commun. 1984 , 449 −450. (b) Bandzouzi, A.;

Chapleur, Y. Dichloromethylenation of Sugar γ -Lactones: A Stereo-

specific Synthesis of L-(+)-Muscarine and L-(+)-Epimuscarine

Toluene-p -Sulphonates. J. Chem. Soc. Perkin Trans. 1 1987 , 661 −

Reaction: Active Antiproliferative Glycolipids. Org. Lett. 1999, 1,

2149 −2151. (h) Pasetto, P.; Chen, X.; Drain, C. M.; Franck, R. W.

Synthesis of Hydrolytically Stable Porphyrin C - and S -Glycoconju-

gates in High Yields. Chem. Commun. 2001, 81−82. (i) Yang, G.;

Franck, R. W.; Bittman, R.; Samadder, P.; Arthur, G. Synthesis and

Growth Inhibitory Properties of Glucosamine-Derived Glycerolipids.

Org. Lett. 2001 , 3 , 197 −200. (j) Pasetto, P.; Franck, R. W. Synthesis

of Both Possible Isomers of the Northwest Quadrant of Altromycin B.

J. Org. Chem. 2003 , 68 , 8042 −8060. (k) Yang, G.; Schmieg, J.; Tsuji,

M.; Franck, R. W. The C -Glycoside Analogue of the Immunostimu-

lant α -Galactosylceramide (KRN7000): Synthesis and Striking

Enhancement of Activity. Angew. Chem., Int. Ed. 2004, 43, 3818−

3822.

664. (c) Lakhrissi, M.; Chapleur, Y. Dichloromethylenation of

Lactones. 6. Efficient Synthesis of Dichloroolefins from Lactones

and Acetates Using Triphenylphosphine and Tetrachloromethane. J.

Org. Chem. 1994, 59, 5752−5757. (d) Novoa, A.; Pellegrini-Moïse,

N.; Lamande-Langle, S.; Chapleur, Y. Efficient Access to Disub-

stituted exo -Glycals. Application to the Preparation of C -Glycosyl

Compounds. Tetrahedron Lett. 2009, 50, 6484−6487. (e) Novoa, A.;

Pellegrini-Moïse, N.; Bourg, S.; Thoret, S.; Dubois, J.; Aubert, G.;

Cresteil, T.; Chapleur, Y. Design, Synthesis and Antiproliferative

Activities of Biarylolefins Based on Polyhydroxylated and Carbohy-

drate Scaffolds. Eur. J. Med. Chem. 2011, 46 , 3570 −3580. (f) Mother-

well, W. B.; Tozer, M. J.; Ross, B. C. A Convenient Method for

Replacement of the Anomeric Hydroxy Group in Carbohydrates by

Difluoromethyl Functionality. J. Chem. Soc. Chem. Commun. 1989,

(12) Glycosyl phosphonium salts: (a) Godoy, J.; Ley, S. V.; Lygo, B.

Synthesis of the Spiroacetal Unit Related to the Avermectins and

Milbemycins. J. Chem. Soc. Chem. Commun. 1984, 1381 −1382.

(b) Ousset, J. B.; Mioskowski, C.; Yang, Y.-L.; Falck, J. R. Enol Ethers:

Preparation and Synthetic Applications. Tetrahedron Lett. 1984 , 25 ,

5903 −5906. (c) Jaouen, V.; Jegou, A.; Veyrieres, A. A Novel

́ ̀

(

437−1439.

Approach to Furanoid Sugars via 1,4-Iodocyclization of Pyranoid D-

Galactal. Synlett 1996, 1996, 1218−1220. (d) Lieberknecht, A.;

Griesser, H.; Bravo, R. D.; Colinas, P. A.; Grigera, R. J. Stereoselective

Synthesis of Olefinated Sugars. Tetrahedron 1998, 54, 3159−3168.

10) Nucleophilic addition and dehydration: (a) Bischofberger, K.;

Hall, R. H.; Jordan, A. Synthesis of Glycosyl α -Amino Acids. J. Chem.

Soc. Chem. Commun. 1975, 806 −807. (b) Hall, R. H.; Bischofberger,

K.; Eitelman, S. J.; Jordaan, A. Synthesis of C -Glycosyl Compounds.

Part 1. Reaction of Ethyl Isocyanoacetate with 2,3:5,6-Di-O -

Isopropylidene-D-Mannono-1,4-Lactone. J. Chem. Soc. Perkin Trans.

(e) Lieberknecht, A.; Griesser, H.; Kramer, B.; Bravo, R. D.; Colinas,

P. A.; Grigera, R. J. Diastereoselective Synthesis of β -(3,4,6-Tri-O -

Benzyl-2-Deoxy-β -D-Galactopyranosyl)-N -tert -Butoxycarbonyl-D-Ala-

nine. Tetrahedron 1999, 55, 6475−6482. (f) Colinas, P. A.;

Ponzinibbio, A.; Lieberknecht, A.; Bravo, R. D. Wittig Reaction of

Glycosyl Phosphonium Salts: A stereoselective route to C -

Disaccharides and C ,O -Trisaccharides. Tetrahedron Lett. 2003, 44,

7985−7988.

1977 , 743 −753. (c) Trost, B. M.; Runge, T. A. Palladium-Catalyzed

,3-Oxygen-to-Carbon Alkyl Shifts. A Cyclopentanone Synthesis. J.

Am. Chem. Soc. 1981, 103, 7559 −7572. (d) Lay, L.; Nicotra, F.;

Panza, L.; Russo, G.; Caneva, E. Synthesis of C -Disaccharides through

Dimerization of exo -Glycals. J. Org. Chem. 1992, 57, 1304−1306.

(e) Yang, W.-B.; Chang, C.-F.; Wang, S.-H.; Teo, C.-F.; Lin, C.-H.

(13) Keck allylation: (a) Praly, J.-P.; Chen, G.-R.; Gola, J.; Hetzer,

G.; Raphoz, C. A Stereocontrolled Radical Access to C -Allyl β -D-

Glycopyranosides from Glycopyranosylidene Dihalides Found en

route to C -Glycodienes. Tetrahedron Lett. 1997, 38, 8185 −8188.

(b) Praly, J.-P.; Chen, G.-R.; Gola, J.; Hetzer, G. C-C Bond

Formation with Acetylated 1-Chloroglycopyranos-1-yl Radicals, 2.

Stereocontrolled Access to Higher Sugars (Non-1-en-4-ulopyranosyl

Derivatives) and Glycomimetics [3-(β -D-Glycopyranosyl)-1-Pro-

penes and (3 Z )-4,8-Anhydro-nona-1,3-dienitols]. Eur. J. Org. Chem.

2000, 2831−2838.

Expeditious Synthesis of C -Glycosyl Conjugated Dienes and

Aldehydes from Sugar Lactones. Tetrahedron Lett. 2001, 42, 4657−

4660. (f) Yang, W.-B.; Wu, C.-Y.; Chang, C.-C.; Wang, S.-H.; Teo, C.-

F.; Lin, C.-H. Facile Synthesis of Conjugated exo -Glycals. Tetrahedron

Lett. 2001, 42, 6907−6910. (g) Yang, W.-B.; Yang, Y.-Y.; Gu, Y.-F.;

Wang, S.-H.; Chang, C.-C.; Lin, C.-H. Stereochemistry in the

Synthesis and Reaction of exo -Glycals. J. Org. Chem. 2002, 67, 3773−

3782. (h) Chen, Y.-B.; Liu, S.-H.; Hsieh, M.-T.; Chang, C.-S.; Lin, C.-

H.; Chen, C.-Y.; Chen, P.-Y.; Lin, H.-C. Stereoselective Synthesis of

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

14) Bamford −Stevens reaction: (a) Tot

h, M.; Somsak

, L. exo -

Practical Way to Achieve C -Glycosidic Disaccharides. Tetrahedron

Lett. 2013, 54, 6101−6104.

Glycals from Glycosyl Cyanides. First Generation of C -Glycosyl-

methylene Carbenes from 2,5- and 2,6-Anhydroaldose Tosylhydra-

zones. J. Chem. Soc., Perkin Trans. 1 2001 , 942 −943. (b) Tot

Kover, K. E.; Benyei, A.; Somsak, L. C -Glycosylmethylene Carbenes:

Synthesis of Anhydro-Aldose Tosylhydrazones as Precursors;

Generation and a New Synthetic Route to exo -Glycals. Org. Biomol.

(21) Frederic, C. J.-M.; Cornil, J.; Vandamme, M.; Dumitrescu, L.;

́ ́

h, M.;

Tikad, A.; Robiette, R.; Vincent, S. P. Highly (Z )-Diastereoselective

Synthesis of Trifluoromethylated exo -Glycals via Photoredox and

Copper Catalysis. Org. Lett. 2018, 20, 6769−6773.

(22) Eppe, G.; Dumitrescu, L.; Pierrot, O.; Li, T.; Pan, W.; Vincent,

S. P. A Novel Base-Induced Isomerization Gives Access to

Unprecedented (E )-exo -Glycals. Chem. − Eur. J. 2013, 19, 11547−

11552.

(23) Oka, N.; Mori, A.; Ando, K. Stereoselective Synthesis of 1-

Thio-α -D-Ribofuranosides Using Ribofuranosyl Iodides as Glycosyl

Donors. Eur. J. Org. Chem. 2018, 2018, 6355−6362.

(24) (a) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. New Catalysts

for the Oxidation of Sulfides to Sulfones with Hydrogen Peroxide. J.

Org. Chem. 1963 , 28 , 1140 −1142. (b) Baudin, J. B.; Hareau, G.; Julia,

S. A.; Ruel, O. A Direct Synthesis of Olefins by Reaction of Carbonyl

Compounds with Lithio Derivatives of 2-[Alkyl- or (2 ′-Alkenyl)- or

Benzyl-Sulfonyl]-Benzothiazoles. Tetrahedron Lett. 1991, 32, 1175−

1178.

Chem. 2003, 1, 4039−4046. (c) Kaszas

Ehlers, P.; Langer, P.; Somsak, L. Pd-Catalyzed Coupling Reactions of

Anhydro-Aldose Tosylhydrazones with Aryl Bromides to Produce

Substituted exo -Glycals. Carbohydr. Res. 2018 , 466 , 30 −38. (d) Jozsef,

J.; Juhasz, L.; Somsak, L. Thio-click Reaction of 2-Deoxy-exo -Glycals

, T.; Ivanov, A.; Toth, M.;

Towards New Glycomimetics: Stereoselective Synthesis of C -2-

Deoxy-D-glycopyranosyl Compounds. New J. Chem. 2019, 43, 5670−

5686. (e) Joz

sef, J.; Debreczeni, N.; Eszenyi, D.; Borbas, A.; Juhasz,

́ ́ ́

L.; Somsak

, L. Synthesis and Photoinitiated Thiol −Ene Reactions of

exo -Mannals − a New Route to C -β -D-Mannosyl Derivatives. RSC

Adv. 2020, 10, 34825−34836.

(

15) [2,3]-Wittig rearrangement: (a) Tomooka, K.; Nakamura, Y.;

Nakai, T. [2,3]-Wittig Rearrangement Using Glucose as a Chiral

Auxiliary: Asymmetric Transmission from the Anomeric Center.

Synlett 1995, 1995, 321 −322. (b) Lay, L.; Meldal, M.; Nicotra, F.;

Panza, L.; Russo, G. Stereoselective Synthesis of the C -Analogue of β -

D-Glucopyranosyl Serine. Chem. Commun. 1997 , 1469 −1470.

(25) Oh, S.; Jeong, I. H.; Ahn, C. M.; Shin, W.-S.; Lee, S. Synthesis

and Antiangiogenic Activity of Thioacetal Artemisinin Derivatives.

Bioorg. Med. Chem. 2004, 12, 3783 −3790.

(26) Crich, D.; Ritchie, T. J. Preparation of 2-Deoxy-β -D-lyxo -

Hexosides (2-Deoxy-β -D-Galactosides). Carbohydr. Res. 1989, 190,

C3−C6.

c) Sugimura, H.; Hasegawa, Y.; Osumi, K. Studies Relating to the

Synthesis of Laurenenynes: Construction of the Alkylidene Side

Chain via [2,3]-Wittig-Still Rearrangement at the Anomeric Center of

a Ruranoside Derivative. Heterocycles 2000, 52, 99−102.

(27) See the Supporting Information.

(28) These heteroaryl groups except for 5-nitro-2-pyridyl and 5-

triﬂuoromethyl-2-pyridyl groups were selected from other types of

Julia sulfones reported in the literature. To the best of our knowledge,

5-nitro-2-pyridyl and 5-triﬂuoromethyl-2-pyridyl sulfones have not

been used for Julia-type oleﬁnation. (a) Baudin, J. B.; Hareau, G.;

L. Formation and Hydroboration of an Olefinic Sugar. J. Am. Chem.

16) β -Elimination: (a) Arzoumanian, H.; Acton, E. M.; Goodman,

Soc. 1964 , 86 , 74 −77. (b) Lerner, L. M. Interconversion of

Hexofuranosyl Nucleosides. III. Synthesis of a 4 ′,5 ′-Unsaturated

Hexofuranosyl Nucleoside. J. Org. Chem. 1972 , 37 , 477 −481.

c) Aebischer, B.; Meuwly, R.; Vasella, A. Deoxy-Nitrosugars. 9th

Communication. Chain Elongation of 1-C -Nitroglycosyl Halides by

Substitution with Some Weakly Basic Carbanions. Helv. Chim. Acta

Julia, S. A.; Ruel, O. Ster

Partir de β-Hydroxy-Sulfones Het

Chim. Fr. 1993, 130 , 336 −357. (b) Fabris, J.; Casar, Z.; Smilovic, I.

chimie de la Formation des Olef

ines a

́ ̀

G.; Crnugelj, M. Highly Stereoselective Formal Synthesis of

erocycliques Anti et Syn. Bull. Soc.

Rosuvastatin and Pitavastatin Through Julia-Kocienski Olefination

Using the Lactonized Statin Side-Chain. Synthesis 2014, 46 , 2333 −

2346. (c) Ando, K.; Kobayashi, T.; Uchida, N. Practical

Methylenation Reaction for Aldehydes and Ketones Using New

Julia-Type Reagents. Org. Lett. 2015, 17, 2554−2557. (d) Ando, K.;

Oguchi, M.; Kobayashi, T.; Asano, H.; Uchida, N. Methylenation for

Aldehydes and Ketones Using 1-Methylbenzimidazol-2-yl Methyl

Sulfone. J. Org. Chem. 2020 , 85 , 9936 −9943. (e) Ando, K.; Kawano,

D.; Takama, D.; Semii, Y. 1-Methyl-1 H -tetrazol-5-yl (MT) Sulfones

in the Julia-Kocienski Olefination: Comparison With the PT and the

TBT Sulfones. Tetrahedron Lett. 2019 , 60 , 1566 −1569. (f) Ando, K.;

Takama, D. Stereoselective Synthesis of Trisubstituted (Z )-Alkenes

from Ketones via the Julia −Kocienski Olefination Using 1-Methyl-

and 1-tert -Butyl-1 H -Tetrazol-5-yl Alkyl Sulfones. Org. Lett. 2020, 22,

984 , 67 , 2236 −2241. (d) Molas, P.; Matheu, M. I.; Castillon, S.

Stereoselective Iodine-Induced Cyclisation of Alkene Acetals.

Application to the Synthesis of 3-Deoxy-exo -Glycals and Substituted

Tetrahydrofurans. Tetrahedron Lett. 2004, 45, 3721−3724.

(

17) Claisen rearrangement: Van Hooft, P. A. V.; Van Swieten, P. F.;

Van der Marel, G. A.; Van Boeckel, C. A. A.; Van Boom, J. H.

Montmorillonite K-10 Cay Assisted Transformation of Vinylketoses

into Spirochromans and Arylketoses. Synlett 2001, 2001, 0269−0271.

(

18) S 1′-type substitution: (a) Yamanoi, T.; Nara, Y.; Matsuda, S.;

Oda, Y.; Yoshida, A.; Katsuraya, K.; Watanabe, M. Synthetic

Approach to exo -Glycals from 1-C -Vinyl-D-Glycopyranose Derivatives

via an S 1 ′-Substitution Mechanism. Synlett 2007, 2007, 0785−0789.

b) Yamanoi, T.; Matsuda, S.; Nakgawa, J.; Watanabe, M.; Oda, Y.;

(

Yoshida, A. A Synthetic Approach to Derive exo -Glucal Derivatives

through the Reaction of a 1-C -Vinylated Glucopyranose Derivative

with Phenols. Heterocycles 2018, 97, 170−177.

6907−6910. (g) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.;

Morley, A. A Stereoselective Synthesis of trans -1,2-Disubstituted

Alkenes Based on the Condensation of Aldehydes with Metallated 1-

Phenyl-1 H -tetrazol-5-yl Sulfones. Synlett 1998, 1998 , 26 −28.

(h) Kocienski, P. J.; Bell, A.; Blakemore, P. R. 1-tert -Butyl-1 H -

tetrazol-5-yl Sulfones in the Modified Julia Olefination. Synlett 2000,

2000, 365−366. (i) Pandya, V. P.; Richhariya, S.; Divya, P.; Meeran,

H. N. P. N.; Tewari, N. Novel Intermediates for the Preparation of

HMG-CoA Reductase Inhibitors. WO2011/132172 A1, Oct 27,

2011, CAN: 155:589162.

(

19) Alkynol cycloisomerization: Xu, M.; Miao, Z.; Bernet, B.;

Vasella, A. Functionalised Monocyclic Five- to Seven-Membered exo -

Glycals by Alkynol Cycloisomerisation of Hydroxy Buta-1,3-diynes

and 1-Haloalkynols. Helv. Chim. Acta 2005, 88, 2918−2937.

(

20) (a) Gom

ez, A. M.; Danelon, G. O.; Pedregosa, A.; Valverde, S.;

Lopez, J. C. A General Method for Convergent Synthesis of

Functionalized exo -Glycals Based on Halogenation and Suzuki

Cross-Coupling of 1-exo -Methylene Sugars. Chem. Commun. 2002,

5, 2024−2025. (b) Gom

S.; Jarosz, S.; Lopez, J. C. Convergent Stereocontrolled Synthesis of

Substituted exo -Glycals by Stille Cross-Coupling of Halo-exo -Glycals

and Stannanes. Tetrahedron Lett. 2006, 47, 6243−6246. (c) Gomez,

A. M.; Barrio, A.; Pedregosa, A.; Uriel, C.; Valverde, S.; Lopez, J. C.

ez, A. M.; Barrio, A.; Amurrio, I.; Valverde,

(29) Lerner, L. M. Preparation of the E and Z Isomers of 9-(5,6-

Dideoxy-β -D-erythro -Hex-4-enofuranosyl)adenine. J. Org. Chem.

1979, 44, 4359−4364.

(30) (a) Charette, A. B.; Lebel, H. Enantioselective Total Synthesis

of (+)-U-106305. J. Am. Chem. Soc. 1996 , 118 , 10327 −10328.

(b) Liu, P.; Jacobsen, E. N. Total Synthesis of (+)-Ambruticin. J. Am.

Chem. Soc. 2001, 123, 10772−10773.

Sonogashira Couplings of Halo- and Epoxy-Halo-exo -Glycals: Concise

Entry to Carbohydrate-Derived Enynes. Eur. J. Org. Chem. 2010 ,

010 , 2910 −2920. (d) Tao, Y.; Ding, N.; Ren, S.; Li, Y. Heck-Type

Cross-Coupling Between Halo-exo -Glycals and endo -Glycals: A

(31) (a) Benson, S. W.; Bose, A. N. The Iodine-Catalyzed, Positional

Isomerization of Olefins. A New Tool for the Precise Measurement of

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Thermodynamic Data. J. Am. Chem. Soc. 1963 , 85 , 1385 −1387.

b) Back, M. H.; Cvetanovic, R. J. Reactions of Iodine Atoms with n -

Butenes: I. Cis-Trans Isomerization of Butene-2. Can. J. Chem 1963,

1, 1396−1405. (c) Li, Z.-J.; Cai, L.; Mei, R.-F.; Dong, J.-W.; Li, S.-

Q.; Yang, X.-Q.; Zhou, H.; Yin, T.-P.; Ding, Z.-T. A Highly Efficient

Transformation of cis - to trans -Cinnamic Acid Derivatives by Iodine.

Tetrahedron Lett. 2015, 56, 7197−7200.

32) Downey, A. M.; Pohl, R.; Roithova, J.; Hocek, M. Synthesis of

Nucleosides through Direct Glycosylation of Nucleobases with 5-O -

Monoprotected or 5-Modified Ribose: Improved Protocol, Scope, and

Mechanism. Chem. − Eur. J. 2017 , 23 , 3910 −3917.

(33) (a) Qiu, D.; Schmidt, R. R. A Convenient Synthesis of Pyranoid

Ene Lactones from Phenyl Glycosyl Sulfones. Synthesis 1990 , 1990 ,

75 −877. (b) Zhang, H.-C.; Brakta, M.; Daves, G. D., Jr Preparation

of 1-(Tri-n-butylstannyl) Furanoid Glycals and Their Use in

Palladium-Mediated Coupling Reactions. Tetrahedron Lett. 1993, 34,

c) Furukawa, J.; Kawabata, N.; Nishimura, J. Synthesis of

571−1574.

34) (a) Simmons, H. E.; Smith, R. D. A New Synthesis of

Cyclopropanes From Olefins. J. Am. Chem. Soc. 1958 , 80 , 5323 −5324.

b) Furukawa, J.; Kawabata, N.; Nishimura, J. A Novel Route to

Cyclopropanes from Olefins. Tetrahedron Lett. 1966, 7 , 3353 −3354.

Cyclopropanes by the Reaction of Olefins with Dialkylzinc and

Methylene Iodide. Tetrahedron 1968 , 24 , 53 −58. (d) Brand, C.;

Granitzka, M.; Stalke, D.; Werz, D. B. Reducing the Conformational

Flexibility of Carbohydrates: Locking the 6-Hydroxyl Group by

Cyclopropanes. Chem. Commun. 2011, 47, 10782−10784. (e) Koll-

mann, C.; Wiechert, S. M.; Jones, P. G.; Pietschmann, T.; Werz, D. B.

Synthesis of 4 ′/5 ′-Spirocyclopropanated Uridine and D-Xylouridine

Derivatives and Their Activity against the Human Respiratory

Syncytial Virus. Org. Lett. 2019, 21 , 6966 −6971.

35) Bols, M.; Pedersen, C. M. Silyl-Protective Groups Influencing

the Reactivity and Selectivity in Glycosylations. Beilstein J. Org. Chem.

017, 13, 93−105.

36) (a) Saneyoshi, H.; Ando, K.; Seio, K.; Sekine, M. Chemical

Sekine, M. A Theoretical Study on the Elimination Reaction of

Synthesis of RNA via 2 ′-O -Cyanoethylated Intermediates. Tetrahe-

dron 2007, 63 , 11195 −11203. (b) Ando, K.; Saneyoshi, H.; Seio, K.;

Acrylonitrile from 2 ′-O -Cyanoethylated Nucleosides by Bu NF.

Tetrahedron 2019, 75, 1−9.

(37) Saneyoshi, H.; Seio, K.; Sekine, M. A General Method for the

Synthesis of 2 ′-O -Cyanoethylated Oligoribonucleotides Having

Promising Hybridization Affinity for DNA and RNA and Enhanced

Nuclease Resistance. J. Org. Chem. 2005, 70, 10453−10460.

(38) Ogawa, T.; Hatayama, K.; Maeda, H.; Kita, Y. Mild and Facile

Cleavage of 2-Cyanoethyl Ester Using Sodium Sulfide or

Tetrabutylammonium Fluoride. Synthesis of 1,4-Dihydropyridine

Monocarboxylic Acids and Unsymmetrical 1,4-Dihydropyridine

Dicarboxylates. Chem. Pharm. Bull. 1994 , 42 , 1579 −1589.

(39) Wang, J.; Gasc, F.; Prandi, J. Samarium Diiodide Mediated

Coupling of 2-Pyridylsulfonyl Furanosides with Aldehydes and

Ketones: A General Synthesis of C -Furanosides. Eur. J. Org. Chem.

(

015, 2015, 2691−2697.

40) Jiangseubchatveera, N.; Bouillon, M. E.; Liawruangrath, B.;

Liawruangrath, S.; Nash, R. J.; Pyne, S. G. Concise Synthesis of

−)-Steviamine and Analogues and Their Glycosidase Inhibitory

Activities. Org. Biomol. Chem. 2013, 11, 3826−3833.