Acyl and Benzyl-C-β-D-Glucosides: Synthesis and Biostudies for Glucose-Uptake-Promoting Activity in C2C12 Mytotubes

A Journal of

Accepted Article

Title: Acyl and Benzyl-C-β-D-Glucosides: Synthesis and Biostudies for

Glucose-Uptake Promoting Activity in C2C12 Mytotubes.

Authors: Mannem Rajeswara Reddy, Shanmugam Hemaiswarya,

Harikrishna Kommidi, Indrapal Singh Aidhen, and Mukesh

Doble

This manuscript has been accepted after peer review and appears as an

Accepted Article online prior to editing, proofing, and formal publication

of the final Version of Record (VoR). This work is currently citable by

using the Digital Object Identifier (DOI) given below. The VoR will be

published online in Early View as soon as possible and may be different

to this Accepted Article as a result of editing. Readers should obtain

the VoR from the journal website shown below when it is published

to ensure accuracy of information. The authors are responsible for the

content of this Accepted Article.

To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901037

Link to VoR: http://dx.doi.org/10.1002/ejoc.201901037

Supported by

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

Acyl and Benzyl-C--D-Glucosides: Synthesis and Biostudies for

Glucose-Uptake Promoting Activity in C2C12 Mytotubes

Mannem Rajeswara Reddy,^aShanmugam Hemaiswarya,^bHarikrishna Kommidi,^aIndrapal Singh

Aidhen,^a* Mukesh Doble^b*

Dedication ((optional))

Abstract: A convenient and scalable synthetic approach has been

developed for the synthesis of acyl-C--D-glucosides and benzyl-C-

-D-glucosides. The use of Weinreb-amide (WA) functionality was

crucial for this accomplishment as the other apparently capable

alternatives, had severe limitations for the access to acyl-C-

glucosides. The synthesized compounds, acyl and benzyl-C-

glucosides promote glucose-uptake activity in the C2C12 (mouse

skeletal muscle) cell lines through PPAR-γ mediated GLUT4

expression. The developed synthetic scheme for acyl-and benzyl-C-

-D-glucosides and biostudies evaluating their activity as glucose-

uptake promoters are disclosed herein.

1).⁵Further structural variations in 2014, by Mukherjee and co-

workers through the introduction of one carbon spacer between

indole/substituted-indole/aryl/heteroaryl moiety and kojic acid,

represented by structure 3 lead to identification of new molecules

promoting glucose-uptake by cells, not necessarily through

insulin-initiated pathways.⁶Inspired from structural lead 3, we

envisaged exploring compounds 4/5, wherein the kojic acid unit

present in 2 and 3 has been replaced by non-planer glucosyl

residue. Barring the oxidative state of the pyranyl unit, the close

similarity in the oxygenation pattern, prompted us to target the

synthesis and biological evaluation of compounds 4 and 5 as

possible mimics of 2. Moreover, the proposed acyl-C--D-

glucosides 4 and benzyl-C--D-glucoside 5 are new molecules in

the literature not studied for this objective.

Introduction

Glucose uptake is the rate-limiting step in glucose utilization in

diabetic and non-diabetic skeletal muscle.¹Skeletal muscle has

major contribution in postprandial glucose uptake which accounts

for more than 80% of insulin-dependent glucose disposal in

human.²The glucose uptake here is the result of the enhanced

translocation and redistribution of glucose transporter 4 (GLUT4)

from intracellular vesicles to plasma membrane, where it

facilitates the entry of the glucose inside the cells.³The

impairment in the insulin-stimulated translocation of glucose

transporters (GLUT4) to cell surface and there by reduced/poor

uptake of glucose in the peripheral tissues including skeletal

muscle has contributed to the elevated glucose levels. The

discovery of natural product, Demethylasterriquinone 1 in 1999

created a sensation of being an excellent insulin mimic.⁴Although

it mimicked the action of a protein, it was soon realized that the

presence of potentially problematic quinone substructure, therein,

posed severe safety concerns. Extensive structure modification

by Pirrung and co-workers identified indolylkojic acid 2 as a safer

small molecule insulin mimic, in which the quinone in

demethylasterriquinone 1 was replaced with kojic acid unit (Figure

Figure 1. Structure of natural product demethylasterriquinone B1 (1), Indolyl

kojic acid (2), its derivative (3) and our proposed molecules 4 and 5.

Theoretically four disconnections are possible for the synthesis of

acyl-C--D-glucosides (Figure 2). Disconnection

I and II

visualizes the incorporation of acyl unit at the anomeric center,

with D-glucosyl unit appearing either as nucleophile (synthon A)

or as an electrophilic unit (synthon B). The synthetic route based

on disconnection I demands stringent reaction conditions for the

formation of C1-carbanionic organometallic equivalent for the

synthon A. Although successful, formation of C1-carbanion is

accompanied by elimination of the C-2-benzyloxy group, under

basic conditions and poses purification difficulties for the isolation

of acyl-C--D-glucosides.⁷Although there are no reports on direct

addition of nucleophilic acyl-unit onto synthon B, Dondoni’s work

involving addition of benzothiazole as masked formyl anion onto

protected lactone (equivalent of synthon B) and also enabling

synthesis of acyl-C--D-glucosides, merits a special mention.⁸

Elegantly, the C-2 position of benzothiazole plays a dual role, first

[a]

Dr. Mannem Rajeswara Reddy, Dr. Kommidi Harikrishna, Prof.

Indrapal Singh Aidhen, Department of Chemistry, Indian Institute of

Technology Madras, Chennai 600036, India

E-mail:isingh@iitm.ac.in

Homepage:http://chem.iitm.ac.in/faculty/indrapal/

[b]

Dr. Shanmugam Hemaiswarya, Prof. Mukesh Doble,

Department of Biotechnology, Indian Institute of Technology

Madras, Chennai 600036, India

E-mail:mukeshd@iitm.ac.in

Supporting information for this article is given via a link at the end of

the document.((Please delete this text if not appropriate))

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

as nucleophilic center and later as electrophilic center, for

successful synthesis of acyl-C--D-glucosides. Genuine

difficulties and concerns arise from the use of toxic mercury salts

for unmasking of the carbonyl functionality, particularly while

scaling-up of this method has limitation.⁹No synthetic route is

available based on disconnection III, through utilization of synthon

C.

tempted us to use the building block 6a for the synthesis of our

targeted compounds 4 and 5. Multigram quantities of building

block 6a, 1-formyl--C-glucoside were prepared according to the

method described by Frederic Labeguere.¹⁷The addition of

simple alkynylmagnesium bromide and phenylmagnesium

o

bromide at 0 C, led to the formation of corresponding addition

products 7a⁹and 7b¹⁶along with recovery of starting material 6a

(10-15%)(entry 1 and 2 in Table 1). However, in an attempt to

optimize and generalize the addition of few other Grignard

reagents, extensive formation of elimination product 8 was also

observed. Lowering of temperature did prevent formation of the

side product 8, however the yields of the addition products7c and

7d was only moderate (entry 3 and 4, in Table 1). All these

reactions, when attempted on gram scales, had problems of side

product formation and recovery of unreacted started material 6a.

Table 1. Addition of various Grignard reagents on to the aldehyde 6a.

.

Figure2. Theoretical disconnection for acyl-C--D-glucosides.

Disconnection IV envisaging use of synthon D seems to be the

most attractive, as it demands mere addition of ArMgX onto C-1-

functionalized D-glucose building blocks such as 6a or 6b. The

direct addition of the nucleophile on to the 1-formyl-C-glycoside

building block with D-galacto configuration on glycoside residue

at low temperatures (-78 ^oC) followed by oxidation has been used

for access to acyl-C--D-galactosides.¹⁰Similarly, the use of 1-

formyl--C-glucoside has been made in an attempt to access the

corresponding 1-acyl--C-glucosides.¹¹Although use of building

block 6b was explored for the same objective by us,¹²with the

rationale that low electrophilicity of cyano group (vs CHO) may

obviate the elimination side product, successful use of the same

has been reported only recently by Guillarme and coworkers.¹³

Our observation, parallels with those reported by Guillarme, that

the addition of organometallic agents (M= Li or Mg) onto 6b, is

accompanied by formation of the glycal side product. Gong co-

Entry

Ar

t

0 ^◦C-rt

7 (Yield)^a

7a (68%)

7b (53%)

8 (Yield)

6a

1

2

-

10%

trace

3

4

0 ^◦C-rt

-15 ^◦C

7c (10%)

36%

21%

-

0 ^◦C-rt

-50 ^◦C

-

55%

-

7d (50%)

[a] Isolated

With the above-mentioned unsatisfactory use of aldehyde 6a, we

were intrigued to see, if the Weinreb-amide (WA)-based building

block 6c, as an alternative, would have any advantage. This was

with the rationale that its reactivity would be lower compared to

6a and would be better than nitrile-based building block 6b (Figure

3).

workers reported

a novel Ni-catalyzed coupling of two

electrophilic substrates, viz D-glycosyl bromides and acid

derivatives for the synthesis of acyl-C-glycoside synthesis.¹⁴

Walczak and co-worker have synthesized acyl-C--glucosides

using stereoretentive cross coupling reaction of glycosyl

stannanes and thio esters with palladium catalyst.¹⁵Although

cross-coupling reactions, such as these are emerging for the said

objectives, the use of expensive transition metal catalyst and

scaling up of the reactions are the associated limitations.The

synthesis as well as the biological study assessing glucose-

uptake promoting activity of 4 and 5 in C2C12 (mouse skeletal

muscle) cell lines is presented herein.

Results and Discussion

Figure 3. Synthesis of acyl-C--D-glucosides from Weinreb amid 6c.

The succesful addition of ArMgBr on to 1-formyl--C-glucoside,

and isolated report of addition onto 1-formyl--C-glucoside,¹⁶

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

To our delight, the oxidation of aldehyde 6a, under Pinnick

oxidation reaction with NaClO₄,¹⁸using H₂O₂as scavenger,

afforded the carboxylic acid 9 in quantitative yield and same could

be converted to the desired amide 6c in one pot, with an isolated

yield of 93% (Scheme 1). The Weinreb amide-based building 6c

is a light-yellow color gum, bench stable. Multi-grams (10 g) of this

WA-based building block can be prepared and stored. The nitrile

based building block 6b, being more readily made compared to

aldehyde 6a, was also explored as a starting material to arrive at

WA-amide 6c. Base hydrolysis of compound 6b with alcoholic

NaOH, resulted in the inseparable mixture of acids 9 and 10. The

inevitable glycal derivative 10 is presumably formed from -

anomer of starting nitrile (or from the corresponding acid) under

the basic hydrolysis conditions. The inseparable mixture of acids,

9 and 10 were directly converted to the corresponding amides,

with the hope that 6c and 11 will be separable.¹²Unfortunately,

they could be separated only on a small-scale using silica-gel

based chromatography. The scale, purification difficulties and low

yields of 6c through this approach prevented any further

optimization of this reaction sequence for our needs of 6c as a

building block (Scheme 1).

formation of corresponding ketone product 12m, 12n and 12q

respectively in good yields. Even the freshly prepared, 2-lithio

derivative of benzo[b]thiphene reacted with amide 6c, affording

the corresponding ketone 12p in good yields. The building block

was equally useful towards addition of alkynyl Grignard reagents,

such as ((trimethylsilyl)ethynyl)magnesium bromide, to give

expected ketone 12r in good yield (Table 2).

Table 2. Addition of various organometallic reagents on to the amide 6c

Scheme 1. Synthesis of glucosylated Weinreb amide building block 6c.

[a] Isolated yield

During

initial

attempts,

three

equivalents

of

4-

For the targeted acyl-C--D-glucoside 4, removal of the benzyl

ether under hydrogenation condition was explored on 12a as an

illustrative example. This condition resulted in removal of benzyl

ether as well as concomitant reduction of the carbonyl group too.

To circumvent this over reduction, Lewis acid promoted

debenzylation was attempted using 10 equivalents of BBr₃(1 M

solution in heptane) in anhydrous dichloromethane as solvent.

The desired product 4a was formed but it was found to be

contaminated with inseparable borate impurities. With these

difficulties in the background, alternative protocol was explored

for debenzylation. The ketone 12a was treated with TMSOTf (1.5

eq) in presence of acetic anhydride as solvent at 0 ^oC for 3 h. The

reaction afforded the corresponding per-acetyl derivative 13a in

good yield and subsequent deacetylation was easily achieved

methylphenylmagnesium bromide was added onto 6c, at low

temperature (-10 ^oC). It led to the formation of acyl-C--D-

glycoside 12a in 6 h. The same addition reaction when performed

at room temperature, the reaction was completed in 1.5 hours and

resulted in the formation of desired product 12a as a single

product. There was no formation of the glycal as the side product.

Using these optimized conditions, the amide 6c,was now

subjected to various Grignard reagents. It is noteworthy that

Grignard reagents with different substituents on phenyl ring,

including electron donating groups, halogens and alkyl

substituents, afforded the ketones 12a-12l in good yields.

Moreover, the addition of 4-biphenylmagnesium bromide, 2-

naphthylmagnesium bromide and benzothiazol-2-ylmagnesium

bromide (2-BTMgBr) onto the amide 6c also resulted in the

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

using 0.5 equivalents of sodium methoxide in methanol. The two-

step protocol allowed convenient access to acyl-C--D-glucoside

4a in good yield. This two steps protocol enabled convenient

access to several other acyl-C--D-glucosides 4b-p without any

epimerization at the anomeric position.(Table3). The di and tri

methoxy-substituted substrates 12k and 12l, afforded poor yields

Table 3. Acyl-C--D-glucosides 4a-p and corresponding per-acetylated compounds 13a-p from benzyl protected compounds 12a-p.

[a] Isolated yield

of the corresponding per acetylated products 13k (39%) and 13l

(24%) respectively, using this method. (Table3). The substrate

12q also decomposed under these reaction condition of

debenzylation. Since the methoxy-substituents are important in

biological activities, an alternative was necessary for the efficient

access to 4k and 4l and other methoxy substituted compounds.

This was rendered possible by way of changing the benzyl ether

protection in building block 6c to methoxymethyl ether (MOM)

protection, since MOM protections can be removed under acidic

conditions. The MOM ether protected amide 14 underwent clean

addition reaction with methoxy-substituted arylmagnesium

bromides to afford the corresponding MOM protected acyl-C--D-

glucoside 15a-c in good yields. The facile removal of MOM

protection in compound 15a and 15b with aq. HCl (6 N) afforded

the corresponding compounds 4k and 4l respectively. With

ketone 15c, the same acidic conditions also enabled additional

removal of benzyl ether protection of a phenolic hydroxyl on the

aromatic unit, affording 16 as the only isolated product, in.78%

Scheme 2. Synthesis of methoxy substituted acyl-C--D-glucosides 4k, 4l and

16.

yield (Scheme 2).

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

For our targeted benzyl-C--D-glucosides, complete reduction of

carbonyl group along with the benzyl ether deprotection, in one

pot was the most convenient way. The hydrogenation conditions

indeed afforded the benzyl-C--D-glucosides 5a-e from the

corresponding acyl-C--D-glucosides 12i-l and 7d respectively

(Table 4).

ring increases the glucose uptake as evident with compounds 5a-

5d. Glucose uptake was marginal when treated with acyl series of

glucosides at 10 μM. Among the acyl-C--D-glucosides evaluated

at 10 μM, only three compounds 4c, 4h and 4j showed increase

in glucose uptake (1.5-1.87 fold) under insulin stimulated

conditions. In sharp contrast to acyl-C--D-glucosides, 10 μM of

lipophilic benzyl-C--D-glucosides (5a-e) showed negligible

cytotoxicity and exhibited more than 2 fold increase in the glucose

uptake when compared to control (Table 5).

Table 4. Synthesis of benzyl-C--D-glucosides 5a-e using reductive

hydrogenolysis.

The cytotoxicity associated with the drug, pioglitazone, restricts

its use beyond 5 μM concentration and showed 2.6 fold increase

in glucose uptake at this concentration. However the synthesized

benzyl-C--D-glucosides were safe even at 10M. Pioglitazone,

a peroxisome proliferator-activated receptor γ (PPARγ) agonist,

is a strong insulin-sensitizing agent. However, several evidences

have been raised regarding the safety concerns of this agonist in

therapeutics.^23-25Metformin, a drug commonly used in the

management of diabetes, exhibited 1.7 fold NBDG uptake at 600

µM concentration in comparison to untreated control. Studies

have shown that metformin is required at high concentrations for

in vitro responses as compared to that required for therapeutic

doses for type 2 diabetic patients. Higher in vivo blood glucose

lowering effect of metformin could possibly be explained by its

accumulation in the muscular extracellular space, or by an effect

of the drug at a step distal to that of glucose transport.²⁶The effect

of the four promising benzyl-C--D-glucosides, 5a-d, on the

expressions of glucose transporter 4 (GLUT4), peroxisomal

S.No

12/7d (R)

X

5a (R)

Yield^a

80%

93%

68%

87%

1

2

3

4

5

12i; R=4-OMe

C=O

C-OH

5a R = 4-OMe

12j: R =4-OBn

5b: R = 4-OH

12k: R =3,4-(OMe)₂

12l: R=3,4,5-(OMe)₃

5c: R = 3,4-(OMe)₂

5d: R = 3,4,5-(OMe)₃

7d: R=3,5-(OMe)₂-4-

(OBn)

5e: R= 3,5-(OMe)₂-4-

64%

(OH)

[a] isolated yield.

Incidentally, the obtainment of product 5b, and 5e constitutes the

first synthesis of C-analogues of natural products, Arbutin¹⁹and

Koarboside.²⁰Both are O-glucosides, while the former is present

in large abundance and is isolated from various sources,²¹

displays diverse pharmacological properties, the latter has been

recently isolated from the stem bark of I.difengpi, known for use

in Chinese traditional medicine for rheumatic arthritis. The roots

of perennial herb, Averrhoa carambola L. (Oxalidaceae),

commonly prevalent in India, China, Malaysia, etc also contains

the same, along with other O-glycosides.²²

proliferator-activated

receptors-gamma

(PPAR-γ),

and

phosphoinositide-3-kinase (PI3K) were determined by qPCR in

order to elucidate their mechanism of action and compared with

two known drugs, metformin and pioglitazone. GLUT4 is an

insulin regulated glucose transporter present in the cytoplasm

under basal conditions, and on activation by insulin it is

translocated to the plasma membrane (Figure 4).

Biological Studies:

PI3K

Glut4

PPARγ

Insulin stimulated glucose (NBDG:2-(N-{7-Nitrobenz-2-oxa-1,3-

diazol-4-yl]amino}-2-deoxyglucose) uptake was assessed in

differentiated C2C12 myoblasts, after treatment with 5 and 10 M

of acyl and benzyl-C--D-glucosides,4a-p, 16 and 5a-e, after16h

of incubation. The uptake was measured in a fluorescence

spectrophotometer and the results are expressed with respect to

control (without compound treatment). Pioglitazone and

metformin were used as positive control. Few acyl-C--D-

glucosides (4a-b, 4e-g and 4i) showed high toxicity against the

same cell line, as assessed by MTT assay at 10 μM concentration,

so their NBDG uptake was evaluated at a non-cytotoxic

concentration of 5 μM. At 5 μM, only compounds 4i and 5a

showed about 1.5 fold increase in NBDG uptake when compared

to the control, while other compounds showed no significant effect.

Whereas, a significant increase in the NBDG uptake at 10 μM was

observed under insulin stimulated conditions. The results are

presented in Table 4. The compounds, 5a, 5b, 5c and 5d in

particular exhibited 2.69, 2.7, 2.82 and 2.09 fold increase in

glucose uptake, respectively, when compared to the untreated

control. Presence of methoxy and hydroxyl groups in the aromatic

3

2.5

2

***

*

**

1.5

1

0.5

0

5a

5b

5c

5d

Metformin Pioglitazone

(600 μM) (5 μM)

Treatments

Figure 4: Effect of Compounds 5a, 5b, 5c and 5d at 10 μM, Metformin (600

μM) and pioglitazone (5 μM) on the expression of PI3K, GLUT4, PPAR-γ gene

under insulin stimulated condition. The data was normalized against

expression of β-actin transcript. (*p<0.05, **p<0.01, ***p<0.005 when

compared to control).

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

Table 5: Insulin stimulated NBDG uptake and cytotoxycity of acyl-C--D-glucosides 4a-p, 16and benzyl-C--D-glucosides5a-ein C2C12 mytotubes.

Fold increase in NBDG

uptake compared to control

Percentage cytotoxicity

Fold increase in NBDG uptake

compared to control

Percentage cytotoxicity

Entry

Compound

5M

10 M

1

2

4a

1.12±0.07

1.06±0.02

0.95±0.14

0.86±0.06

1.00±0.13

0.86±0.08

1.03±0.11

0.99±0.02

1.42±0.11*

0.87±0.13

1.10±0.75

0.99±4.9

11.65±0.55

18.21±11.9

< 1%

NT

16.59±1.67

30.11±4.4

6.3±0.69

9±0.6

4b

3

4c

1.49±0.29*

1.18±0.21

NT

4

4d

< 1%

5

4e

10.91±5.14

10.47±2.48

2.48±1.14

< 1%

6

4f

NT

< 1%

7

4g

NT

10.44±1.31

< 1%

8

4h

1.57±0.67

NT

9

4i

7.28±3.5

< 1%

16.3±2.62

3.77±0.24

< 1%

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

4j

1.87±0.13*

1.28±0.49

1.17±0.68

NT

4k

< 1%

4l

< 1%

4m

1.07±0.12

0.94±0.13

0.87±0.07

0.99±0.099

1.12±3.4

2.48±1.14

16.99±6.42

< 1%

17.55±1.56

12.85±0.95

20.21±2.91

12.45±1.71

< 1%

4n

NT

4o

NT

4p

11.30±1.31

< 1%

NT

16

1.1±0.36

2.69±0.09*

2.70±0.13*

2.82±0.03*

2.09±0.49*

1.86±0.36*

1.7±0.36 (600M)

2.6±0.06** (5M)

5a

1.48±0.3*

1.04±0.09

1.02±0.19

0.89±0.12

1.0±0.08

< 1%

5b

5c

< 1%

6.08±1.33

8.83±2.62

< 1%

5d

< 1%

5e

< 1%

Metformin

Pioglitazone

NT-Not Tested; *P<0.05, **P<0.01

At 10 μM concentration, compound 5a significantly (2 fold)

enhanced the mRNA expression of GLUT4, followed by

compound 5b (1.8 fold). Metformin and pioglitazone caused a

2.11 and 1.71 fold increase in GLUT4 expression when compared

to β-actin expression (house keeping gene). On the other hand,

PI3K is a downsignaling molecule in the insulin cascade which is

known to enhance glucose uptake through GLUT4 mRNA

expression and translocation. None of the compounds caused

significant changes in the PI3K mRNA expression, while the

commercial drugs increased its expression by 1.4 fold.

Compounds 5a, 5b, 5c and 5d enhanced glucose uptake by

increasing PPAR-γ mRNA expression by approximately 1.6 to 1.7

fold in comparison to the insulin treated control. PPARs are known

to interact with the peroxisome proliferator element (PPRE) in the

promoter region of the target genes involved in lipid catabolism,

fatty acid transport, and glucose homeostasis.Here pioglitazone

did not show an effect in the PPAR-γ mRNA expression levels

which has been proved true in previous studies.^27,28Pioglitazone

the known ligand for the protein PPAR-γ, upon binding,

upregulates GLUT4, mediated glucose uptake.²⁹

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

Insulin

GLUT4

IRS

P85

Pi3k

p110

GLUT4

translocation

1/2

GLUT4

5a

5b

5c

Vesicles

PPARγ

5d

AMPK

Pio

RXR

Nucleus

AMP:ATP

Cell

Figure 5. Proposed mechanism of action of compounds 5a, 5b, 5c and 5d based on mRNA expression of PI3K, GLUT4 and PPARγ genes. The compounds

enhance NBDG uptake through PPAR-γ mediated increase in GLUT4 expression. Pioglitazone (Pio) acts through PPAR-γ mediated and metformin (Met) through

AMPK mediated increase in GLUT4 expression. + means increase in expression.

The oven dried two necked round bottom flask was charged with

magnesium turnings (0.26 g, 10.86 mmol) and a catalytic amount of

molecular iodine was added under nitrogen atmosphere. The reaction

flask was pre-heated under vacuum to activate the magnesium.4-

(benzyloxy)phenyl bromide (1.42 g, 5.43 mmol) in anhydrous THF was

added into the activated magnesium under stirring. To that solution, 1,2-

dibromoethane (0.81 mL, 5.43 mmol) was added at 50 °C, and heating

was continued until the complete consumption of magnesium.After

complete consumption of magnesium, the requisite aldehyde 6a(1.0 g,

1.81 mmol) in anhydrous THF was added to the reaction mixture at 0 ^oC.

After 3 h, saturated NH₄Cl solution was added and the aqueous layer was

extracted with EtOAc. The organic layer was dried over Na₂SO₄and

concentrated under reduced pressure. The product obtained was purified

by silica-gel column chromatography to yield the alcohol 7c (0.48 g,

36.0%) as colorless gum. R_f= 0.5 (EtOAc/ hexanes, 1:4); []²⁵_D=38.4 (c

0.5, CHCl₃);¹H NMR: (400 MHz, CDCl₃); δ = 3.38 (d, J = 9.5 Hz,1 H),3.45-

3.47 (m,1 H), 3.61-3.64 (m, 1 H), 3.65 (s, 2 H),3.71-3.75 (m, 1 H), 3.78-

3.83 (m, 1 H), 4.42-4.48 (m, 2 H), 4.57 (d,J = 11.0 Hz,1 H), 4.74-4.77 (m,

1 H), 4.81-4.86 (m, 2 H), 4.91-4.93 (m, 3 H), 4.95 (s, 2 H),6.87-6.90 (m, 2

H), 7.18-7.19 (m, 2 H), 7.26-7.31 (m, 21 H), 7.36-7.37 (m, 2 H), 7.39-7.41

(m, 2 H) ppm. ¹³CNMR (100 MHz, CDCl₃); δ = 69.0 (CH₂), 70.0 (CH-OH),

70.9 (CH₂), 73.4 (CH₂), 75.0 (CH₂), 75.2 (CH₂), 75.6 (CH₂), 78.2 (CH), 78.6

(CH), 78.7 (CH), 81.5 (CH), 87.2 (CH), 114.5 (CH), 127.5 (CH), 127.6 (CH),

127.7 (CH), 127.8 (2xCH), 127.9 (CH), 128.4 (CH), 128.5 (2xCH), 128.5

(CH), 128.6 (CH), 134.6 (C), 137.1 (C), 138.1 (2xC),138.2 (C), 138.6 (C),

153.3 (C) ppm.IR (CHCl₃): 1118, 1421, 1526, 2896, 2957, 3388 cm^-1.

HRMS: Calcd for C₄₈H₄₉O₇[M+H]⁺737.3478, found 737.3363.

Metformin on the other hand is known to enhance glucose uptake

by GLUT4 via the AMPK pathway.³⁰Although, we have observed

an increase in PI3K mRNA expression with metformin and

pioglitazone, as also reported by others,^31,32the same was not

observed with our set of compounds (5a-d). The gene expression

studies are in corroboration with NBDG uptake, where the

compounds 5a, 5b, 5c and 5d seems to act through PPAR-γ

mediated enhancement of GLUT4 expression (Figure 5).

Conclusions

Finally, to conclude, we have developed a convenient synthetic

route for the synthesis of acyl and benzyl-C--D-glucosides on

multi gram scale, using a key building block, carrying Weinreb-

amide functionality at anomeric position of D-Glucose. The initial

biostudies reveal benzyl-C--D-glucosides 5a-e being far superior

in promoting glucose uptake at 10 µM, when compared to the

corresponding acyl-C--D-glucosides. The studies further

indicate that benzyl-C-glucosides 5a-e enhance glucose uptake

through PPAR-γ mediated enhancement of GLUT4 expression.

The efficacy of the compounds 5a-e needs to be further

ascertained using in vivo animal models, for their possible

development as new antidiabetic lead substances.

2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-C-(3,5-(dimethoxy)-4-

(benzyloxy)phenyl)-D-glycero-D-gulo-heptitol 7d:

Experimental Section

The oven dried two necked round bottom flask was charged with

magnesium turnings (0.35 g, 13.5 mmol) and a catalytic amount of

molecular iodine was added under nitrogen atmosphere. The reaction

flask was pre-heated under vacuum to activate the magnesium. 4-

(benzyloxy)-3,5-dimethoxyphenyl bromide (4.38 g, 13.5 mmol.) in

2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-C-(4-(benzyloxy)phenyl)-D-

glycero-D-gulo-heptitol 7c:

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

anhydrous THF was added into the activated magnesium under stirring.

To that solution, catalytic amount of MeI was added at 50 °C, and heating

was continued until the color change of the reaction mixture. After

complete consumption of magnesium, the requisite aldehyde 6a (1.5 g,

2.71 mmol) in anhydrous THF was added to the reaction mixture at -50^oC.

After 3 h, saturated NH₄Cl solution was added and the aqueous layer was

extracted with EtOAc. The organic layer was dried over Na₂SO₄and

concentrated under reduced pressure. The product obtained was purified

by silica-gel column chromatography to yield the corresponding alcohol 7d

(1.09 g, 50.0%) as light yellow color gum. R_f= 0.3 (EtOAc/ hexanes, 3:7);

The oven dried two necked round bottom flask was charged with

magnesium turnings (3 equiv.) and a catalytic amount of molecular iodine

was added under nitrogen atmosphere. The reaction flask was pre-heated

under vacuum to activate the magnesium. Substituted aryl bromide (3

equiev.) in anhydrous THF was added into the activated magnesiumunder

stirring. After complete consumption of magnesium, the requisite amide 6c

(1 equiv.) in anhydrous THF was added to the reaction mixture at 0 ^oC.

After 3 h, saturated NH₄Cl solution was added and the aqueous layer was

extracted with EtOAc. The organic layer was dried over Na₂SO₄and

concentrated under reduced pressure. The product obtained was purified

by silica-gel column chromatography to yield the corresponding ketones.

[]²⁵=82.3 (c 0.5, CHCl₃);¹H NMR: (400 MHz, CDCl₃); δ = 3.41 (d, J =

D

9.6 Hz, 1 H), 3.51 (d, J = 8.8 Hz, 1 H), 3.65-3.68 (m, 3 H), 3.97 (s, 6 H),

3.75-3.82 (m, 3 H), 4.45 (s, 2 H), 4.75 (d, J = 11.2 Hz, 1 H), 4.72 (d, J =

11.2 Hz, 1 H), 4.82-4.89 (m, 2 H), 4.93-4.96 (m, 4 H), 6..64 (s, 2 H), 7.17-

7.19 (m, 3 H), 7.27-7.32 (m, 21 H), 7.46-7.48 (m, 2 H) ppm. ¹³C NMR (100

MHz, CDCl₃); δ = 56.1 (CH₃), 69.0 (CH₂), 71.3 (CH-OH), 73.5 (CH₂), 75.0

(CH₂), 75.1 (CH₂), 75.3 (CH₂), 75.6 (CH₂), 78.2 (CH), 78.6 (CH), 78.7 (CH),

81.5 (CH), 87.2 (CH), 103.6 (CH), 127.7 (CH), 127.8 (CH), 127.8 (CH),

127.9 (CH), 128.0 (CH), 128.1 (CH), 128.4 (CH), 128.5 (2xCH), 128.6 (CH),

136.0 (C), 137.8 (C), 137.9 (C), 138.0 (C), 138.1 (2xC), 138.5 (C), 153.3

(C) ppm.IR (CHCl₃): 1118, 1421, 1526, 2896, 2957, 3388 cm^-1. HRMS:

Calcd for C₅₀H₅₂O₉Na [M+Na]⁺819.3509, found 819.3485.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(4-(methyl)phenyl)-aldehydo-

D-glycero-D-gulo-heptose (12a):

Building block 6c (0.6 g, 0.98 mmol), magnesium turnings (0.08 g, 3.92

mmol) and 4-bromotoluene (0.49 ml, 3.9 mmol) were treated according to

the general procedure A to give the title compound 36a, after column

chromatography on silica gel to provide 12a (0.59 g, 94.9 %), as a

colorless solid. R_f= 0.5 (EtOAc/ hexanes, 1:4); m.p. = 86-88 ^oC; []²⁵

=

D

12.6 (c 0.5, CHCl₃);¹H NMR (400 MHz, CDCl₃): δ = 2.28 (s, 3 H), 3.58-3.65

(m, 3 H), 3.78 (t, J = 8.8 Hz , 1 H,), 3.96 (t, J = 9.2 Hz,1 H), 4.45 (d, J = 8.8

Hz, 2 H), 4.51 (dd, J = 10.8, 8.8 Hz, 2 H), 4.58 (d, J = 9.6 Hz, 1 H), 4.64

(d, J = 10.4 Hz, 1H), 4.78 (d, J = 10.8 Hz, 1 H), 4.85 (bs, 2 H), 6.89-6.94

(m, 2 H), 7.08-7.15 (m, 5H), 7.17-7.30 (m, 13 H), 7.35 (t,J = 8.0 Hz, 2 H),

7.50 (t, J = 7.6 Hz, 1 H), 8.10 (d, J = 8.0 Hz,2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 69.1 (CH₂), 73.5 (CH₂), 75.1 (CH₂), 75.3 (CH₂), 75.8 (CH₂),

78.1 (CH), 79.0 (CH), 79.0 (CH), 79.7 (CH), 80.1 (CH), 87.1 (CH), 127.7

(CH), 127.8 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.4

(CH), 128.6 (CH), 128.7 (CH), 129.4 (CH), 133.6 (CH), 136.0 (C), 137.8

(C), 138.2 (C), 138.5 (C), 195.0 (CO) ppm.IR (CHCl₃):1355, 1421, 1526,

1701, 3018 cm^-1. HRMS:Calcd for C₄₂H₄₃O₆[M+H]⁺643.3060, found

643.3038.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(N-methoxy-N-methyl)-

aldehydo-D-glycero-D-gulo-heptose (6c) from aldehyde 6a:

Step 1: Into a round bottom flask with aldehyde 6a (9.5 g, 17.2 mmol) in

acetonitrile (60 mL) was added NaH₂PO₄(1.8 g) and H₂O₂(0.48 mL, 20.6

mmol) at rt. To the reaction mixture, a solution of sodium chlorite in water

(2.16 g, 24.1 mmol, 24 mL) was added at 0 ^oC for 30 min slowly. The

reaction was allowed to stir at rt for 3 h and then a solution of sodium sulfite

was added. Finally, the reaction was quenched with 10% HCl and then

aqueous layer was extracted with ethyl acetate (3x200 mL), the organic

layer was dried over Na₂SO₄, concentrated under reduced pressure to

yield the acid 9 (9.6 g, 97.8 %). The resultant acid 9 was used for next step

without further purification.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(4-(ethyl)phenyl)-aldehydo-D-

glycero-D-gulo-heptose (12b):

Step 2: An oven dried round bottom flask was charged with acid 9 (9.5 g,

Building block 6c (0.530 g, 0.866 mmol), magnesium turnings (0.104 g,

4.33 mmol), 1-bromo-4-ethylbenzene (0.801 g, 4.33 mmol) were treated

according to the general procedure A to give the title compound 12b (0.4g,

72%), after column chromatography on silica gel as a colorless solid; R_f=

16.7 mmol) in anhydrous CH₂Cl₂followed by pivaloyl chloride (2.6 mL, 21.7

ͦ

mmol) and triethyl amine (3.62 mL, 25.0 mmol)) at 0 C for 10 min. The

reaction mixture was warmed to rt and stirred for 3 h. Then, N, O-

dimethylhydroxlamine hydrochloride (2.44 g, 25.0 mmol) and triethylamine

(1.5 equiv.) were added slowly at 0 ^oC, and the mixture was stirred for 3 h

at rt. The reaction mixture was quenched with water. The organic layer

was extracted with CH₂Cl₂, dried over Na₂SO₄and concentrated under

reduced pressure to give the crude product, which was further purified by

column chromatography on silica, eluting with ethyl acetate:hexanes, to

give the title compound 6c.(9.5 g , 93%) as light yellow viscous gum. R_f=

0.27 (EtOAc/Hexanes, 1:4); []²⁵_D= 86.6 (c 0.5, CHCl₃); ¹H NMR (400 MHz,

CDCl₃); δ = 3.14 (s, 3 H, NCH₃), 3.44-3.55 (m, 2 H), 3.57 (s, 3 H, OCH₃),

3.61-3.72 (m, 2 H), 3.94 (t, J = 9.6 Hz, 1 H), 4.29 (d, J = 9.6 Hz, 1 H), 4.38-

4.51 (m, 3 H), 4.61 (d, J = 10.8 Hz, 1 H), 4.72 (t, J = 8.0 Hz, 2 H,), 4.83 (d,

J = 11.2 Hz, 2 H,), 7.02-7.12 (m, 2 H, ArH), 7.12-7.20 (m, 9 H), 7.20-7.38

(m, 10 H) ppm. ¹³CNMR (100 MHz, CDCl₃); δ = 32.2 (NCH₃), 62.1 (OCH₃),

69.1 (CH₂), 73.4 (CH₂), 74.1 (CH), 75.1 (CH₂), 75.2 (CH₂), 75.6 (CH), 78.0

(CH), 79.5 (CH), 79.7 (CH), 86.7 (CH), 127.7 (CH), 127.9 (CH), 128.0 (CH),

128.3 (CH), 128.4 (CH), 128.48 (CH), 138.0 (C), 138.3 (C), 138.5 (C),

168.7 (-CO-) ppm. IR (CHCl₃): 1216, 1421, 1526, 1656, 2896, 3988 cm^-1.

HRMS: Calcd for C₃₇H₄₂NO₇[M+H]⁺612.2961, found 612.2966.

ͦ

0.7 (EtOAc/hexanes, 1:4); m.p = 77-79 ^oC; []²⁷_D= 1.79 (c 1.0, CHCl₃); ¹H

NMR (400 MHz, CDCl₃); δ = 1.26 (t, 3 H), 2.70 (q, 2 H), 3.67-3.70 (m, 3 H),

3.76 (d, J = 10.0 Hz, 1 H), 3.85 (t, J = 8.8 Hz1 H,), 4.02 (t, J = 9.2 Hz, 1 H),

4.49-4.57 (m, 3 H), 4.60 (d, J = 10.8 Hz, 1 H), 4.69 (d, J = 10.4 Hz, 1 H),

4.85 (d, J = 10.8 Hz, 1 H), 4.89-4.96 (m, 2 H), 6.96-6.98 (d, J = 7.2 Hz, 1

H), 7.15-7.34 (m, 20 H), 8.00 (d, J = 7.6 Hz, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃);δ = 15.2 (CH₃), 29.0 (CH₂), 69.1 (CH₂), 73.4 (CH₂), 75.0 (CH₂),

75.2 (CH₂), 75.8 (CH₂), 78.0 (CH), 78.8 (CH), 79.7 (CH), 79.9 (CH), 87.0

(CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 128.0 (CH), 128.1 (CH), 128.2

(CH), 128.3 (CH), 128.5 (CH), 129.6 (CH), 133.6 (C), 137.7 (C), 137.9 (C),

138.1 (C), 138.5 (C), 150.7 (C), 194.6 (CO) ppm. IR (CHCl₃): 1266, 1421,

1526, 17698, 3018 cm^-1. Elemental analysis:calcd (%) for C₄₃H₄₄O₆

(656.31): C 78.63, H 6.75; found: C 78.42, H 6.27.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(4-(tetr-butyl)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (12c):

Building block 6c (0.6 g, 0.98 mmol), magnesium turnings (0.118 g, 4.9

mmol), 1-bromo-4-tert-butylbenzene (0.98 g, 4.9 mmol) were treated

according to general procedure A to give the title compound 12c (0.49 g,

73%), after column chromatography on silica gel as a colorless solid; R_f=

0.7 (EtOAc/hexanes, 1:4); m.p = 78-80 ^oC; []²⁷_D= -53.4 (c 0.3, CHCl₃); ¹H

General procedure A for the addition of Grignard reagents on to

Amide 6c:

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

NMR (500 MHz, CDCl₃); δ = 1.33 (s, 9 H, C(CH₃)₃), 3.67-3.71 (m, 3 H),

3.77 (d, J = 10.0 Hz, 1 H), 3.85 (t, J = 8.5 Hz, 1 H), 4.0 (t, J = 9.5 Hz, 1 H),

4.50-4.57 (m, 3 H), 4.56 (t, J = 11.0 Hz, 1 H), 4.64 (d, J = 11.0 Hz, 1 H),

4.68 (d, J = 10.5 Hz, 1 H), 4.85 (d, J = 10.5 Hz, 1 H), 4.90-4.95 (m, 2 H),

6.9-6.97 (m, 2 H), 7.14-7.34 (m, 18 H), 7.43 (d, J = 8.5 Hz, 2 H), 8.0 (d, J

= 8.5 Hz, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃);δ = 31.0 (3 x CH₃), 35.1

(CH), 69.0 (CH₂), 73.4 (CH₂), 75.0 (CH₂), 75.2 (CH₂), 75.7 (CH₂), 78.0 (CH),

79.0 (CH), 79.7 (CH), 80.0 (CH), 87.0 (CH), 125.5 (CH), 127.5 (CH), 127.6

(CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 129.3

(CH), 133.3 (C), 137.7 (C), 137.9 (C), 138.2 (C), 138.5 (C), 157.3 (C),

194.5 (CO) ppm. IR (CHCl₃): 1202, 1456, 1562, 1688, 2998 cm^-1.

Elemental analysis: calcd (%) for C₄₅H₄₈O₆(684.8): C 78.92, H 7.06; found:

C 79.23, H 7.20.

according to the general procedure A to give the title compound 12g, after

column chromatography on silica gel (0.41g, 72%) as a colorless solid. R_f

o

= 0.7 (EtOAc/hexanes, 1:4); m.p = 77-79 C; []²⁷_D= 4.13 (c 1.0, CHCl₃);

¹H NMR (400 MHz, CDCl₃); δ = 3.63-3.71 (m, 3 H), 3.74 (d, J = 9.2 Hz, 1

H), 3.84 (t, J = 8.4 Hz, 1 H), 3.95 (t, J = 9.2 Hz, 1 H), 4.48-4.53 (m, 3 H),

4.56 (d, J = 10.8 Hz, 1 H), 4.60 (d, J = 10.8 Hz, 1 H), 4.74 (d, J = 10.4 Hz,

1 H), 4.85 (d, J = 10.8 Hz, 1 H), 4.93 (s, 2 H), 7.0-7.02 (m, 2 H), 7.18-7.34

(m, 18 H), 7.4 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 8.10 (d, J =

1.6 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃);δ = 68.8 (CH₂), 73.4 (CH₂),

75.0 (CH₂), 75.2 (CH₂), 75.8 (CH₂), 77.8 (CH), 79.2 (CH), 79.5 (CH), 79.8

(CH), 86.9 (CH), 127.7 (CH), 127.8 (CH), 127.8 (CH), 127.9 (CH), 128.0

(CH), 128.1 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 128.7

(CH), 130.6 (CH), 131.2 (CH), 133.2 (C), 135.0 (C), 137.4 (C), 137.8 (C),

137.9 (C), 138.1 (C), 138.3 (C), 192.9 (CO) ppm. IR (CHCl₃): 1092, 1422,

1528, 1710, 3021 cm^-1. Elemental analysis:calcd (%) for C₄₁H₃₈Cl₂O₆

(697.6): C 70.59, H 5.49; found: C 70.28, H 5.06.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(3,5-(dimethyl)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (12d):

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(3,4,5-(trichloro)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (12h):

Building block 6c (0.6 g, 0.98 mmol), magnesium turnings (0.164 g, 6.86

mmol), 1-bromo-3,5-dimethylbenzene (0.67 g, 4.9 mmol) were treated

according to the general procedure A to give the title compound 12d (0.38

g, 60%), after column chromatography on silica gel as a colorless solid. R_f

= 0.7 (EtOAc/hexanes 1:4); m.p = 84-86 ^oC; []²⁷_D= 66.2 (c 0.3, CHCl₃); ¹H

NMR (400 MHz, CDCl₃); δ = 2.31 (s, 6 H), 3.67-3.70 (m, 3 H), 3.76 (d, J =

10.0 Hz, 1 H), 3.85 (t, J = 8.8 Hz, 1 H), 4.02 (d, J = 9.2 Hz, 1 H), 4.50-4.57

(m, 3 H), 4.59 (t, J = 10.8 Hz, 1 H), 4.64 (d, J = 9.6 Hz, 1 H), 4.69 (d, J =

10.0 Hz, 1 H), 4.85 (d, J = 10.8 Hz, 1 H), 4.89-4.95 (m, 2 H), 6.98-6.99 (m,

2 H), 7.17-7.20 (m, 6 H), 7.24-7.33 (m, 13 H), 7.6 (s, J = 8.5 Hz, 2 H) ppm.

¹³C NMR (100 MHz, CDCl₃);δ = 21.0 (2xCH₃), 69.0 (CH₂), 73.4 (CH₂), 75.0

(CH₂), 75.2 (CH₂), 75.7 (CH₂), 78.0 (CH), 79.0 (CH), 79.9 (CH), 80.0 (CH),

87.0 (CH), 127.0 (CH), 127.5 (CH), 127.6 (CH), 127.7 (CH), 127.8 (CH),

127.9 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH),

135.3 (CH), 136.1 (CH), 137.7 (C), 137.9 (C), 138.1 (C), 138.2 (2xC),

138.5 (C), 195.6 (CO) ppm. IR (CHCl₃): 1196, 1413, 1523, 1696, 2996 cm^-

¹.Elemental analysis:calcd (%) for C₄₃H₄₄O₆(656.8): C 78.63, H 6.75;

found: C 78.81, H 6.98.

To an oven dried two necked round bottom flask was charged with

magnesium turning (0.14 g, 5.88 mmol), under nitrogen atmosphere. 1-

bromo-3,4,5-trichlorobenzene (1.28 g, 4.9 mmol) in anhydrous THF was

added into the activated magnesium. To that solution 1,2-dibromoethane

(0.09 mL, 098 mmol) was added at 50 ºC, heating was continued until the

complete consumption of magnesium. Building block 6c (0.5 g, 1.13 mmol)

in anhydrous THF was added to reaction mixture. After 3h saturated NH₄Cl

solution was added and the aqueous layer was extracted with EtOAc, the

organic layer was dried over Na₂SO₄and concentrated in vacuum. The

crude residue was purified by column chromotography on silica gel to yield

title compound 12h (0.48g, 67%) as color less solid. R_f

=

0.8

1

o

(EtOAc/hexanes, 1:4); m.p = 101-103 C; []²⁷_D= 98.6 (c 0.3, CHCl₃); H

NMR (400 MHz, CDCl₃); δ = 3.62-3.72 (m, 4 H), 3.83 (t, J = 8.8 Hz, 1 H),

3.92 (t, J = 9.2 Hz, 1 H), 4.43 (d, J = 9.6 Hz, 1 H), 4.58-4.60 (m, 4 H), 4.75

(d, J = 10.8 Hz, 1 H), 4.85 (d, J = 10.8 Hz, 1 H), 4.93 (s, 2 H), 7.04-7.19

(m, 7 H), 7.2-7.32 (m, 13 H), 7.9 (s, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃);

δ = 68.6 (CH₂), 73.4 (CH₂), 75.0 (CH₂), 75.2 (CH₂), 75.8 (CH₂), 77.8 (CH),

79.0 (CH), 79.8 (CH), 80.1 (CH), 86.9 (CH), 127.7 (CH), 127.8 (2xCH),

127.9 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.5 (CH), 128.6 (CH),

129.2 (CH), 134.6 (C), 134.7 (2xC), 136.7 (C), 137.3 (C), 137.8 (C), 138.2

(C), 191.9 (CO) ppm. IR (CHCl₃):1088, 1496, 1566, 1722, 3078 cm^-

¹Elemental analysis:calcd (%) for C₄₁H₃₇Cl₃O₆(730.17): C 67.27, H 5.09;

found: C 67.34, H 4.66.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(4-(fluoro)phenyl)-aldehydo-

D-glycero-D-gulo-heptose (12e):

Building block 6c (0.45 g, 0.74 mmol), magnesium turnings (0.09 g, 3.68

mmol) and 1-bromo-4-fluro benzene (0.40 mL, 3.68 mmol) were treated

according to the general procedure A to give the title compound 12e (0.38

g, 79.8%), after column chromatography as a colorless solid. R_f=0.5

(EtOAc/ hexanes, 1:4); m.p = 77-79 ^oC; []²⁵_D=12.1 (c 0.5, CHCl₃); All

spectroscopic data for our synthetic molecule (¹H, ¹³C, HRMS) were well

in agreement with those reported for the same.¹⁵

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(4-(methoxy)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (12i):

Building block 6c (0.7 g, 1.14 mmol), magnesium turnings (0.14 g, 5.72

mmol) and 1-bromo-4-methoxy benzene (0.72 mL, 5.72 mmol) were

treated according to the general procedure A to give the title compound

12i, after column chromatography on silica gel to provide the title

compound (0.63 g, 84%). as a colorless solid. R_f= 0.3 (EtOAc/ hexanes,

1:4); m.p = 66-68 ^oC; []²⁵_D=17.1 (c 0.5, CHCl₃); All spectroscopic data for

our synthetic molecule (¹H, ¹³C, HRMS) were well in agreement with those

reported for the same.¹⁵

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(4-(chloro)phenyl)-aldehydo-

D-glycero-D-gulo-heptose (12f):

Building block 6c (0.53 g, 0.87 mmol), magnesium turnings (0.103 g, 4.33

mmol) and 1-bromo-4-chloro benzene (0.83 mL, 4.33 mmol) were treated

according to the general procedure A to give the title compound 12f (0.42

g, 73.7%), after column chromatography on silica as a colorless solid. R_f=

o

0.4 (EtOAc/ hexanes, 1:4); m.p = 75-77 C; []²⁵_D=6.1 (c 0.5, CHCl₃);All

spectroscopic data for our synthetic molecule (¹H, ¹³C, HRMS) were well

in agreement with those reported for the same.¹⁵

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(4-(benzyloxy)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (12j):

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(3,4-(dichloro)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (12g):

Building block 6c (0.5 g, 1.17 mmol), magnesium turnings (0.168 g, 7.02

mmol) and 1-bromo-4-benzyloxy benzene (1.23 mL, 7.02 mmol) were

treated according to the general procedureA, to give the title compound

12j, after column chromatography on silica gel to provide the title

Building block 6c (0.50 g, 0.866 mmol), magnesium turnings (0.097 g, 4.05

mmol), 1-bromo-3,4-dichlorobenzene (0.52 g, 4.05 mmol) were treated

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

compound (0.539 g, 90%). as a colorless solid. R_f= 0.3 (EtOAc/ hexanes,

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(4-(phenyl)phenyl)-aldehydo-

D-glycero-D-gulo-heptose (12m):

1:4); m.p = 82-84 ^oC; []²⁵= 37.1 (c 0.3, CHCl₃);¹H NMR (400 MHz,

D

CDCl₃); δ = 3.65-3.77 (m, 2 H), 3.74 (d, J = 10.4 Hz, 1 H), 3.84 (t, J = 8.8

Hz, 1 H), 4.02 (t, J = 9.6 Hz,1 H), 4.49 (d, J = 12.0 Hz, 1 H), 4.54 (d, J =

10.4 Hz, 1 H), 4.56-4.67 (m, 3 H), 4.69 (d, J = 10.8 Hz, 1 H), ), 4.84 (d, J =

10.8 Hz, 1 H), 4.89-4.92 (m, 2 H), 4.99 (d, J = 10.4 Hz, 1 H), 5.10 (s, 2 H),

6.95 (d, J = 9.2 Hz, 2 H), 6.99-7.01 (m, 2 H), 7.15-7.20 (m, 6 H), 7.25-7.28

(m, 8 H), 7.31-7.35 (m, 4 H), 7.36-7,41 (m, 5H), 8.05 (d, J = 8.8 Hz, 2H)

ppm. ¹³C NMR (100 MHz, CDCl₃); δ = 69.2 (CH₂), 70.2 (CH₂), 73.5 (CH₂),

75.7 (CH₂), 78.1 (CH), 79.1 (CH), 79.8 (CH), 80.1 (CH), 87.1 (CH), 114.6

(CH), 127.5 (CH), 127.6 (CH), 127.9 (CH), 128.1 (CH), 128.2 (CH), 128.3

(CH), 128.4 (CH), 128.5 (CH), 128.8 (CH), 131.8 (C), 136.2 (C), 137.9 (C),

138.1 (C), 138.3 (C), 138.6 (C), 163.1 (C), 193.4 (CO) ppm. IR

(CHCl₃):1119, 1460, 1570, 1689, 2934 cm^-1. Elemental analysis:calcd (%)

for C₄₈H₄₆O₇(734.89): C 78.45, H 6.31; found: C 78.93, H 5.90.

Building block 6c (0.52 g, 0.85 mmol), magnesium turnings (0.108 g, 4.25

mmol), 4-bromobiphenyl (0.99 g, 4.25 mmol) were treated according to the

general procedure in A to give the title compound 12m (0.43g, 73%), after

column chromatography on silica gel as a colorless solid; R_f= 0.6

(EtOAc/hexanes, 1:4); m.p = 110-112 C; []²⁷_D= 3.89 (c 1.0, CHCl₃); H

NMR (500 MHz, CDCl₃): δ = 3.69-3.70 (m, 3 H), 3.78 (d, J = 10.5 Hz, 1 H),

3.87 (t, J = 8.5 Hz, 1 H), 4.04 (t, J = 9.5 Hz, 1 H), 4.50-4.62 (m, 4 H), 4.68

(d, J = 9.5 Hz, 1 H), 4.72 (d, J = 10.5 Hz, 1 H), 4.86 (d, J = 10.5 Hz, 1 H),

4.91-4.96 (m, 2 H), 6.9-7.0 (m, 2 H), 7.15-7.16 (m, 3 H), 7.19-7.21 (m, 2

H), 7.25-7.43 (m, 14 H), 7.47-7.49 (m, 2 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.63

(d, J = 8.5 Hz, 2 H), 8.14 (d, J = 8.0 Hz, 2 H) ppm. ¹³C NMR (125 MHz,

CDCl₃);δ = 69.0 (CH₂), 73.4 (CH₂), 75.0 (CH₂), 75.2 (CH₂), 75.8 (CH₂),

78.0 (CH), 79.1 (CH), 79.7 (CH), 80.0 (CH), 87.0 (CH), 127.2 (CH), 127.3

(CH), 127.5 (CH), 127.7 (CH), 127.9 (CH), 128.0 (CH), 128.1 (CH), 128.2

(CH), 128.3 (CH), 128.5 (CH), 128.9 (CH), 129.9 (CH), 134.6 (C), 137.7

(C), 137.9 (C), 138.1 (C), 138.5 (C), 139.8 (C), 146.2 (C), 194.5 (CO) ppm.

IR (CHCl₃):1120, 1480, 1568, 1663, 2936, 3010 cm^-1. Elemental

analysis:calcd (%) for C₄₇H₄₄O₆(704.8): C 80.09, H 6.29; found: C 80.30,

H 5.90.

o

1

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(3,4-(dimethoxy)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (12k):

Building block 6c (0.7 g, 1.64 mmol), magnesium turnings (0.157 g, 6.55

mmol) and 1-bromo-3,4-dimethoxy benzene (0.95 mL, 6.55 mmol) were

treated according to the general procedure A to give the title compound

12k (0.83 g, 71.67%), after column chromatography on silica gel as a light

brown color solid. R_f= 0.3 (EtOAc/ hexanes, 2:3); m.p = 88-90 ^oC; []²⁵

=

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(naphthalen-2-yl)-aldehydo-

D

-48.6 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃); δ = 3.67-3.70 (m, 3 H),

3.77 (d, J = 10.0 Hz, 1 H), 3.86 (s, 3 H), 3.91-3.94 (s, 5 H), 4.03 (t, J = 9.2

Hz, 1 H), 4.52 (d, J = 4.8 Hz, 1 H), 4.56-4.61 (m, 3 H), 4.71 (d, J = 10.4 Hz,

1 H), 4.86 (d, J = 10.4 Hz, 1 H), 4.93-4.94 (m, 2 H), 6.78 (d, J = 8.4 Hz, 1

H), 7.02-7.11 (m, 3 H), 7.12-7.21 (m, 5 H), 7.28-7.34 (m, 12 H), 7.62 (d, J

= 1.2 Hz, 1 H), 7.74 (dd, J = 8.0, 1.6 Hz, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃); δ = 55.9 (OCH₃), 56.1 (CH₃), 69.1 (CH₂), 73.4 (CH₂), 75.0 (CH₂),

75.2 (CH₂), 75.8 (CH₂), 78.0 (CH), 79.1 (CH), 79.8 (CH), 80.0 (CH), 87.0

(CH), 110.0 (CH), 111.1 (CH), 124.5 (CH), 127.6 (CH), 127.7 (CH), 127.7

(CH), 127.9 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 128.3 (2xCH),

128.4 (CH), 128.5 (CH), 129 0 (C), 134.2 (C), 137.8 (C), 137.9 (C), 138.1

(C), 138.5 (C), 148 (C), 153.7 (C), 193.3 (CO) ppm. IR (CHCl₃: 1120, 1460,

1570, 1689, 2934, 3020 cm^-1. Elemental analysis:calcd (%) for C₄₃H₄₄O₈

(688.3): C 74.98, H 6.44; found: C 75.30, H 6.53.

D-glycero-D-gulo-heptose (12n):

Building block 6c (0.58 g, 0.95 mmol), magnesium turnings (0.114 g, 4.73

mmol), 2-bromonapthalane (0.98 g, 4.73 mmol) were treated according to

the general procedure in A to give the title compound 12n (0.45g, 70%),

after column chromatography on silica gel as a colorless solid. R_f= 0.5

(EtOAc/hexanes, 1:4); m.p = 98-100 ^oC; []²⁷_D= -78.6 (c 0.3, CHCl₃); All

spectroscopic data for our synthetic molecule (¹H, ¹³C, HRMS) were well

in agreement with those reported for the same.¹⁵

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(2-thiophenyl)-aldehydo-D-

glycero-D-gulo-heptose (12o):

Building block 6c (0.51 g, 0.83 mmol), magnesium turnings (0.1 g, 4.16

mmol) and 2-bromothiophene (0.40 mL, 4.16 mmol) were treated

according to the general procedure A to give the title compound 12o (0.37

g, 70%), after column chromatography on silica gel as a brown color solid.

R_f= 0.3 (EtOAc/ hexanes, 1:4); m.p = 72-74 ^oC; []²⁵_D= 8.4(c 0.5, CHCl₃);

¹H NMR (400 MHz, CDCl₃); δ = 3.51-3.58 (m, 1 H). 3.61-3.71 (m, 3 H),

3.75 (t, J = 8.8 Hz, 1 H), 3.87 (t, J = 9.6 Hz, 1 H), 4.43 (d, J = 6.8 Hz, 2 H),

4.47 (d, J = 8.8 Hz, 2 H,), 4.50-4.55 (m, 1H), 4.58 (d, J = 10.0 Hz, 1 H),

4.77 (d, J = 10.8 Hz, 1 H), 4.84 (ABq, J =11.2, 6.0 Hz, 2 H), 6.94-7.01 (m,

3 H), 7.09-7.14 (m, 5 H), 7.17-7.28 (m, 13 H), 7.57- 7.61 (m, 1 H,), 7.86 -

7.88 (m, 1 H) ppm. ¹³CNMR (100 MHz, CDCl₃); δ = 68.9 (CH₂), 73.5 (CH₂),

75.2 (CH₂), 75.3 (CH₂), 75.8 (CH₂), 77.8 (CH), 79.7 (CH), 80.1 (CH), 81.1

(CH), 86.7 (CH), 127.7 (CH), 127.8 (CH), 127.8 (CH), 127.8 (CH), 127.9

(CH), 128.1 (CH), 128.3 (CH), 128.37 (CH), 128.4 (CH), 128.5 (CH), 134.5

(CH), 134.9 (CH), 137.5 (C), 138.0 (C), 138.1 (C), 138.5 (C), 142.5 (C),

188.4 (CO) ppm. IR (CHCl₃);1345, 1434, 1524, 1711, 2094 cm^-1. HRMS:

Calcd for C₃₉H₃₉O₆S [M+H]⁺: 635.2467, found 635.2450.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(3,4,5-(trimethoxy)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (12l):

A oven dried two necked round bottom flask was charged with magnesium

turnings (0.078 g, 3.3 mmol) and catalytic amount of molecular iodine

under nitrogen atmosphere. 1-bromo-3, 4, 5-trimethoxybenzene (0.81 g,

3.3 mmol) in anhydrous THF was added into the activated magnesium. To

that solution catalytic amount of MeI was added at 50 ºC, and heating was

continued until the colour change of the reaction mixture. After complete

consumption of magnesium, building block6c (0.5 g, 0.82 mmol) in

anhydrous THF was added to reaction mixture. After 3 h saturated NH₄Cl

solution was added and the aqueous layer was extracted with EtOAc, the

organic layer was dried over Na₂SO₄and concentrated under reduced

pressure. The crude residue was purified by column chromatography on

silica gel to give the title compound 12l (0.38 g, 65.2%) as colorless solid.

R_f= 0.3 (EtOAc:hexanes, 3:7); m.p = 98-100 ^oC; []²⁶= 97.5(c 1.0,

D

CHCl₃); ¹H NMR: (400 MHz, CDCl₃);δ = 3.74 (m, 3 H), 3.82 (s, 6 H, 2 ×

OCH₃), 3.86-3.95 (m, 2 H), 3.97 (s, 3 H, OCH₃), 4.09 (t, J = 9.6 Hz, 1 H),

4.55-4.70 (m, 5 H), 4.79 (d, J = 10.8 Hz, 1 H), 4.91-5.00(m, 3 H), 7.10-7.16

(m, 2 H), 7.24-7.28 (m, 5 H), 7.30-7.44 (m, 15 H) ppm. ¹³CNMR (100 MHz,

CDCl₃); δ = 56.2, 61.0, 69.1, 73.6, 75.0, 75.2, 75.9, 78.0, 79.7, 80.0, 80.2,

87.0, 106.9, 127.82, 127.86, 127.95, 127.98, 128.0, 128.1, 128.3, 128.5,

128.6, 137.8, 137.9, 138.0, 138.4, 143.0, 153.0, 193.7 ppm. IR (CHCl₃):

1120, 1480, 1568, 1663, 2936, 3010 cm^-1. HRMS: Calcd for C₄₄H₄₇O₉

[M+H]⁺719.3220, found 719.3224.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(2-benzo[b]thiophenyl)-

aldehydo-D-glycero-D-gulo-heptose (12p):

To an oven dried round bottom flask was charged with 2-

benzo[b]thiophene (0.65 g, 4.9 mmol) in anhydrous THF (8 mL) at room

temperature. The flask was allowed to cool at -60 ^oC, n-BuLi (1.96 mL, 2.5

M in hexane) was added to the solution and stirred for 1 h at same

temperature. To the reaction mixture, building block 6c (0.6 g, 0.98 mmol)

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

was added and stirring was continued at 0 ^oC for 3 h. Then, reaction

mixture was diluted with saturated NH₄Cl solution and the aqueous layer

was extracted with EtOAc. The organic layer was dried over Na₂SO₄and

concentrated under reduced pressure. The resultant residue was purified

by column chromatography on silica gel to give the title compound 12p

(0.48 g, 71.7%) as a colorless solid. R_f= 0.8 (EtOAc/hexanes, 1:4);m.p =

104-106 ^oC; []²⁷_D= -93.6 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃); δ =

3.65-3.80 (m, 4 H), 3.85 (t, J = 8.8 Hz, 1 H), 3.99 (t, J = 9.2 Hz, 1 H), 4.51-

4.60 (m, 4 H), 4.62-4.67 (m, 2 H), 4.88 (d, J = 11.2 Hz, 1 H), 4.93-4.97 (m,

2 H), 7.01-7.11 (m, 5 H), 7.21-7.24 (m, 2 H), 7.29-7.37 (m, 14 H), 7.44-

7.48 (m, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 8.2-8.4

(m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃); δ = 68.9 (CH₂), 73.5 (CH₂),

75.1 (CH₂), 75.2 (CH₂), 75.8 (CH₂), 77.8 (CH), 79.6 (CH), 80.1 (CH), 81.3

(CH), 86.7 (CH), 122.8 (CH), 124.9 (CH), 126.4 (CH), 127.6 (CH), 127.7

(CH), 127.9 (CH), 128.0 (CH), 128.2 (CH), 128.4 (CH), 128.5 (CH), 131.9

(CH), 137.3 (C), 137.9 (C), 138.1 (C), 138.4 (C), 139.1 (C), 141.7 (C),

142.7 (C), 189.9 (CO) ppm. IR (CHCl₃); 1421, 1578, 1711, 2094, 3010 cm^-

¹. HRMS:Calcd for C₄₃H₄₀O₆SNa [M+Na]⁺707.2443, found 707.2448.

residue was purified by column chromatography on silica gel

(EtOAc/hexanes, 85:15 then 1:4) affording the title compound 12r (0.298

g, 63.9%) as a colorless solid. R_f= 0.7 (EtOAc/hexanes 1:4); m.p = 98-100

^oC; []²⁷_D=-113.1 (c 0.3, CHCl₃); All spectroscopic data for our synthetic

molecule (¹H, ¹³C, HRMS) were well in agreement with those reported for

the same.⁸

General procedure B for the synthesis of per acetylated compounds

13a-p:

An oven dried round bottom flask was charged with compound 12a-p (1

equiv.) in acetic anhydried (8 mL, for 1 mmol) at room temperature. To that

solution, trimethylsilyl trifluoromethanesulfonate (1.5 equiv.) was added at

0

^oC, slowly. Then the reaction mixture was allowed to stir at room

temperature for 5 h. The reaction mixture was diluted with H₂O, dropwise,

and extracted with EtOAc. The combined organic layer was washed with

sat. NaHCO₃solution, dried over Na₂SO₄and concentrated under reduced

pressure. The resultant crude product was purified by column

chromatography on silica gel (EtOAc/hexanes) to afford the peracetylated

compound 13a-p.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(2-benzo[d]thiozole)-

aldehydo-D-glycero-D-gulo-heptose (12q):

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(4-(methyl)phenyl)-aldehydo-

D-glycero-D-gulo-heptose (13a):

A dried two necked round bottom flask was charged with magnesium

turnings (0.085 g, 3.464 mmol) and a catalytic amount of I₂was added.

The flask was pre-heated under vacuum to activate the magnesium and

anhydrous THF (25 mL) was added. At stirring isopropylbromide (0.325

mL, 3.46 mmol) was added slowly, after 5 min the mixture was strongly

self-heated As the magnesium turnings were finished, benzo[d]thiazole

(0.285 mL, 2.6 mmol) was added to the reaction mixture at 0 ^oC slowly and

stirring was continued for 30-45 min at the same temperature. To the

resulting yellow color precipitation was added amide 6c (0.53 g, 0.866

mmol) in anhydrous THF for 15 min at 0 ^oC, and the solution was warmed

to rt, allowed to stir 6 h at same temperature. The solution was diluted with

cold aq. NH₄Cl solution, aqueous phase was extracted with EtOAc (3 x

100 mL) and the combined organic layer was washed with brine solution,

dried over Na₂SO₄, and concentrated under reduced pressure. The crude

product was purified by column chromatography on silica gel

(EtOAc/hexanes, 1:3) affording the ketone 12q (0.246 g, 73.2%) as the

light-yellow color gum. R_f= 0.5 (EtOAc/hexanes, 1:4); []²⁷_D=-39.7 (c 0.3,

CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 3.74-3.75 (m, 4 H), 3.92-3.95 (m,

1 H), 4.08 (t, J = 9.5 Hz, 1 H), 4.47-4.51 (m, 2 H), 4.57-4.62 (m, 2 H), 4.75

(d, J = 11.0 Hz, 1 H), 4.85 (d, J = 10.5 Hz, 1 H), 4.92 (s, 2 H), 5.32 (d, J =

10.0 Hz, 1 H), 6.87-6.89 (m, 2 H), 6.99-7.02 (m, 2 H), 7.18-7.19 (m, 2 H),

7.23-7.32 (m, 15 H), 7.56-7.57 (m, 1 H), 7.96-7.97 (m, 1 H), 8.20-8.21 (m,

1 H) ppm. ¹³C NMR (125 MHz, CDCl₃); δ = 68.8 (CH₂), 73.5 (CH₂), 74.9

(CH₂), 75.1 (CH₂), 75.6 (CH₂), 77.5 (CH), 78.0 (CH), 80.0 (CH), 80.1 (CH),

86.7 (CH), 122.3 (CH), 126.0 (CH), 127.1 (CH), 127.5 (CH), 127.6 (CH),

127.8 (CH), 128.0 (CH), 128.1 (CH), 128.1 (CH), 128.3 (CH), 128.5 (CH),

137.5 (C), 138.0 (C), 138.1 (C), 138.4 (C), 153.5 (C), 165.0 (C), 190.0 (CO)

ppm. IR (CHCl₃); 1421, 1578,1614, 1702, 2112, 2968, 3010 cm^-1. HRMS:

Calcd for C₄₂H₄₀O₆NS [M+H]⁺686.2576, found 686.2595.

Compound

12a

(0.44

g,

0.68

mmol),

trimethylsilyl

trifluoromethanesulfonate (0.187 mL, 1.03 mmol), acetic anhydried (7 mL)

were treated according to the general procedure in B to give the title

compound 13a (0.26 g, 84.6%), after column chromatography on silica gel

as a colorless solid. R_f= 0.3 (EtOAc/hexanes, 3:7); m.p = 110-112C; []²⁷

D

= -98.3 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 1.84 (s, 3 H), 2.02

(s, 3 H), 2.06 (s, 3 H), 2.07 (s, 3 H), 2.42 (3 H), 3.89-3.92 (m, 1 H), 4.17

(dd, J = 12.0, 2.0 Hz, 1 H), 4.23 (dd, J = 12.5, 5.5 Hz, 1 H), 4.72 (d, J =

10.0 Hz, 1 H, anomeric proton), 5.16 (t, J = 10.0 Hz, 1 H), 5.35 (t, J = 9.5

Hz, 1 H), 5.49 (t, J = 9.5 Hz, 1 H), 7.27 (d, J = 8.5 Hz, 2 H), 7.89 (d, J = 8.5

Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃); δ = 20.5 (CH₃), 20.6 (CH₃), 20.7

(CH₃), 20.8 (CH₃), 21.8 (CH₃), 62.2 (CH₂), 68.2 (CH), 69.0 (CH), 74.3 (CH),

76.7 (CH), 77.8 (CH), 129.3 (CH), 129.5 (CH), 132.5 (C), 145.1 (C), 169.0

(C), 169.4 (C), 170.5 (C), 170.6 (C), 190.5 (C). IR (CHCl₃): 1284, 1568,

1662, 1668, 2956, 2996 cm^-1; HRMS:Calcd for C₂₂H₂₆O₁₀Na [M+Na]⁺

473.1423, found 473.1419.

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(4-(ethyl)phenyl)-aldehydo-D-

glycero-D-gulo-heptose (13b):

Compound

12b

(0.35

g,

0.532

mmol),

trimethylsilyl

trifluoromethanesulfonate (0.144 mL, 0.79 mmol), acetic anhydried (6 mL)

were treated according to the general procedure in B to give the title

compound 13b (0.24 g, 97.2%), after column chromatography on silica gel

as a colorless solid. R_f= 0.3 (EtOAc/hexanes, 3:7); m.p = 135-137 C;

[]²⁷_D= -103.9 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃); δ = 1.26 (t, J =

8.0 Hz, 3 H), 1.84 (s, 3 H), 2.03 (s, 3 H), 2.06 (s, 3 H), 2.07 (s, 3 H), 2.72

(q, J = 8.0 Hz, 2 H), 3.89-3.93 (m, 1 H), 4.15 (dd, J = 12.4, 2.0 Hz, 1 H),

4.24 (dd, J = 12.4, 5.6 Hz, 1 H), 4.74 (d, J = 10.0 Hz, 1 H, anomeric proton),

5.16 (t, J = 10.0 Hz, 1 H), 5.36 (t, J = 9.2 Hz, 1 H), 5.50 (t, J = 9.6 Hz, 1

H), 7.30 (d, J= 8.0 Hz, 2 H), 7.91 (d, J = 8.4 Hz, 2H). ¹³C NMR (100 MHz,

CDCl₃); δ = 15.2 (CH₃), 20.4 (CH₃), 20.6 (CH₃), 20.7 (CH₃), 20.8 (CH₃),

29.0 (CH₂) ppm. 62.2 (CH₂), 68.2 (CH), 68.9 (CH), 74.2 (CH), 76.6 (CH),

77.6 (CH), 128.1 (CH), 129.5 (CH), 132.6 (C), 151.2 (C), 168.9 (C=O),

169.4 (C=O), 170.5 (C+O), 170.6 (C=O), 191.4 (C=O) ppm. IR (CHCl₃):

1479, 1589, 1662, 1663, 2889, 2996 cm^-1. Elemental analysis:calcd (%)

for C₂₃H₂₈O₁₀(464.47): C 59.48, H 6.08; found: C 60.01, H 5.87.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-trimethylsilylethynyl-

aldehydo-D-glycero-D-gulo-heptose (12r):

(Trimethylsilyl)ethynyl]magnesiumbromide was prepared from magnesium

turnings (0.069 g, 2.88 mmol),ethylbromide (0.219 mL, 2.88 mmol) and

trimethylsilyl acetylene (0.282 mL, 2.88 mmol according to the reported

procedure. To this solution,the building block 6c (0.430 g, 0.72 mmol) in

anhydrous THF (4 mL) was added for 15 min at 0 ^oC, and the solution was

o

allowed to stir 3 h at 0 C. The solution was diluted with cold aq. NH₄Cl

solution, aqueous phase was extracted with EtOAc (3 x 100 mL) and the

combined organic layer was washed with brine solution, dried over Na₂SO₄,

and concentrated under reduced pressure. The resulting yellow color

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(4-(tetr-butyl)phenyl)-

Compound

12f

(0.37

g,

0.558

mmol),

trimethylsilyl

aldehydo-D-glycero-D-gulo-heptose (13c):

trifluoromethanesulfonate (0.152 mL, 0.347 mmol), acetic anhydried (6

mL) were treated according to the general procedure B to give the title

compound 13f (0.21 g, 80.16%), after column chromatography on silica

gel as a colorless solid. R_f= 0.2 (EtOAc/hexanes, 3:7); m.p = 131-133 C;

[]²⁷_D= -26.3 (c 0.5, CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 1.89 (s, 3 H),

2.02 (s, 3 H), 2.06 (s, 3 H), 2.08 (s, 3 H), 3.89-3.92 (m, 1 H), 4.16 (dd, J =

12.5, 2.5 Hz, 1 H), 4.23 (dd, J = 12.5, 5.5 Hz, 1 H), 4.66 (d, J = 9.5 Hz, 1

H, anomeric proton), 5.16 (t, J = 10.0 Hz, 1 H), 5.35 (t, J = 9.5 Hz, 1 H),

5.47 (t, J = 9.5 Hz, 1 H), 7.45 (d, J = 8.5 Hz, 2 H), 7.94 (d, J = 8.5 Hz, 2 H)

ppm. ¹³C NMR (125 MHz, CDCl₃); δ = 20.4 (CH₃), 20.5 (CH₃), 20.6 (CH₃),

20.7 (CH₃), 62.2 (CH₂), 68.1 (CH), 68.8 (CH), 74.0 (CH), 76.7 (CH), 78.2

(CH), 128.9 (CH), 130.7 (CH), 133.1 (C), 140.5 (C), 168.9 (C), 169.3 (C),

170.4 (C), 170.5 (C), 190.9 (CO) ppm. IR (CHCl₃):1186, 1526, 1645, 1692,

2878, 2983 cm^-1. Elemental analysis:calcd (%) for C₂₁H₂₃ClO₁₀(470.86):

C 53.57, H 4.92; found: C 53.96, H 4.60.

Compound

12c

(0.45

g,

0.657

mmol),

trimethylsilyl

trifluoromethanesulfonate (0.18 mL, 0.985 mmol), acetic anhydried (8 mL)

were treated according to the general procedure B to give the title

compound 13c (0.27 g, 83.6%), after column chromatography on silica gel

as a colorless solid. R_f= 0.3 (EtOAc/hexanes, 3:7); m.p = 150-152C;

[]²⁷_D= -129.0 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃); δ = 1.34 (s, 9 H),

1.84 (s, 3 H), 2.03 (s, 3 H), 2.06 (s, 3 H), 2.07 (s, 3 H), 3.89-3.93 (m, 1 H),

4.15 (dd, J = 12.4, 2.0 Hz, 1 H), 4.25 (dd, J = 12.4, 5.6 Hz, 1 H), 4.74 (d, J

= 9.6 Hz, 1 H, anomeric proton), 5.16 (t, J = 10.0 Hz, 1 H), 5.36 (t, J = 9.2

Hz, 1 H), 5.50 (t, J = 9.6 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 2 H), 7.92 (d, J = 8.4

Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃); δ = 20.4 (CH₃), 20.6 (CH₃),

20.7 (CH₃), 20.8 (CH₃), 31.0 (3xCH₃), 35.2 (C), 62.2 (CH₂), 68.1 (CH), 68.9

(CH), 74.2 (CH), 76.6 (CH), 77.6 (CH), 125.6 (CH), 129.3 (CH), 132.2 (C),

157.9 (C), 169.0 (C), 169.4 (C), 170.5 (C), 170.6 (C), 191.4 (CO) ppm. IR

(CHCl₃):1248, 1556, 1648, 1689, 2876, 2986 cm^-1; Elemental

analysis:calcd (%) for C₂₅H₃₂O₁₀(492.52): C 60.97, H 6.55; found: C 61.32,

H 6.05.

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(3,4-(dichloro)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (13g):

Compound

12g

(0.36

g,

0.517

mmol),

trimethylsilyl

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(3,5-(dimethyl)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (13d):

trifluoromethanesulfonate (0.140 mL, 0.820 mmol), acetic anhydried (6

mL) were treated according to the general procedure B to give the title

compound 13g (0.21 g, 80.45%), after column chromatography on silica

gel as a colorless solid. R_f= 0.2 (EtOAc/hexanes, 3:7); m.p = 136-138 C;

[]²⁷_D= 93.2 (c 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃); δ = 1.93 (s, 3 H),

2.03 (s, 3 H), 2.07 (s, 3 H), 2.11 (s, 3 H), 3.90-3.93 (m, 1 H), 4.19-4.20 (m,

2 H), 4.60 (d, J = 10.0 Hz, 1 H, anomeric proton), 5.15 (t, J = 9.6 Hz, 1 H),

5.35 (t, J = 9.6 Hz, 1 H), 5.46 (t, J = 9.2 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H),

7.84 (d, J = 8.4 Hz, 1 H), 8.10 (s, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃);

δ = 20.5 (CH₃), 20.6 (CH₃), 20.7 (CH₃), 20.8 (CH₃), 62.1 (CH₂), 67.9 (CH),

68.7 (CH), 73.8 (CH), 76.7 (CH), 78.7 (CH), 128.9 (CH), 130.7 (CH), 131.4

(CH), 133.2 (C), 134.1 (C), 138.7 (C), 169.0 (C), 169.4 (C), 170.4 (C),

170.5 (C), 190.1 (CO) ppm. IR (CHCl₃): 996, 1552, 1664, 1702, 2896, 3016

cm^-1. Elemental analysis:calcd (%) for C₂₁H₂₂Cl₂O₁₀(505.30): C 49.92, H

4.39; found: C 49.50, H 3.96.

Compound

12d

(0.34

g,

0.51

mmol),

trimethylsilyl

trifluoromethanesulfonate (0.141 mL, 0.77 mmol), acetic anhydried (6 mL)

were treated according to the general procedure B to give the title

compound 13d (0.19 g, 79.2%), after column chromatography on silica gel

as a colorless solid. R_f= 0.3 (EtOAc/hexanes, 3:7); m.p = 160-162C;

[]²⁷_D= -69.0 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃); δ = 1.82 (s, 3 H),

2.03 (s, 3 H), 2.06 (s, 3 H), 2.07 (s, 3 H), 2.38 (6 H), 3.89-3.94 (m, 1 H),

4.16 (dd, J = 12.4, 2.0 Hz, 1 H), 4.23 (dd, J = 12.4, 1.6 Hz, 1 H), 4.76 (d, J

= 10.0 Hz, 1 H, anomeric proton), 5.16 (t, J = 9.6 Hz, 1 H), 5.36 (t, J = 9.2

Hz, 1 H), 5.47 (t, J = 9.6 Hz, 1 H), 7.24 (s, 1 H), 7.58 (s, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃); δ = 20.4 (CH₃), 20.6 (CH₃), 20.7 (CH₃), 20.8 (CH₃),

21.3 (2xCH₃), 62.3 (CH₂), 68.1 (CH), 69.0 (CH), 74.2 (CH), 76.6 (CH), 77.5

(CH), 127.0 (CH), 135.0 (C), 135.7 (CH), 138.3 (2xC), 168.9 (C), 169.4 (C),

170.5 (C), 170.6 (C), 192.2 (CO) ppm. IR (CHCl₃): 1368, 1569, 1652, 1692,

2898, 3012 cm^-1; Elemental analysis:calcd (%) for C₂₃H₂₈O₁₀(464.47): C

59.48, H 6.08; found: C 59.74, H 5.84.

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(3,4,5-(trichloro)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (13h):

Compound

12h

(0.43

g,

0.587

mmol),

trimethylsilyl

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(4-(fluoro)phenyl)-aldehydo-

D-glycero-D-gulo-heptose (13e):

trifluoromethanesulfonate (0.196 mL, 0.88 mmol), acetic anhydried (6 mL)

were treated according to the general procedure B to give the title

compound 13h, after column chromatography on silica gel (0.27 g,

85.17%) as a colorless solid. R_f= 0.3 (EtOAc/hexanes, 3:7); m.p = 146-

148 C; []²⁷_D= -123.5 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃); δ = 1.95

(s, 3 H), 2.03 (s, 3 H), 2.07 (s, 3 H), 2.13 (s, 3 H), 3.90-3.93 (m, 1 H), 4.18-

4.19 (m, 2 H), 4.54 (d, J = 9.6 Hz, 1 H, anomeric proton), 5.15 (t, J = 10.0

Hz, 1 H), 5.34 (t, J = 9.2 Hz, 1 H), 5.43 (t, J = 9.6 Hz, 1 H), 8.02 (s, 2 H)

ppm. ¹³C NMR (100 MHz, CDCl₃); δ = 20.5 (CH₃), 20.6 (CH₃), 20.7 (CH₃),

20.8 (CH₃), 62.1 (CH₂), 67.9 (CH), 68.7 (CH), 73.8 (CH), 76.9 (CH), 79.2

(CH), 129.3 (CH), 133.7 (C), 134.9 (2xC), 137.4 (C), 169.1 (C), 169.4 (C),

170.4 (C), 170.6 (C), 189.4 (CO) ppm. IR (CHCl₃):1022, 123, 1668, 1692,

3016 cm^-1. HRMS:Calcd for C₂₁H₂₁Cl₃O₁₀Na [M+Na]⁺561.0098, found

561.0098.

Compound

12e

(0.15

g,

0.23

mmol),

Trimethylsilyl

trifluoromethanesulfonate (0.06 mL, 0.347 mmol), aceticanhydried (3 mL)

were treated according to the general procedure B to give the title

compound 13e (0.079 g, 75%), after column chromatography on silica gel

as a colorless solid. R_f= 0.2 (EtOAc/hexanes, 3:7); m.p = 129-131 C;

1

[]²⁷_D=78.6 (c 0.3, CHCl₃); H NMR (500 MHz, CDCl₃); δ = 1.88 (s, 3 H),

2.03 (s, 3 H), 2.06 (s, 3 H), 2.07 (s, 3 H), 3.89-3.92 (m, 1 H), 4.16 (dd, J =

12.0, 2.0 Hz, 1 H), 4.23 (dd, J = 12.5, 5.5 Hz, 1 H), 4.83 (d, J = 9.5 Hz, 1

H, anomeric proton), 5.16 (t, J = 10.0 Hz, 1 H), 5.35 (t, J = 9.5 Hz, 1 H),

5.48 (t, J = 9.5 Hz, 1 H), 7.15 (t, J = 8.5 Hz, 2 H), 8.04 (dd, J = 8.5, 5.0 Hz,

2 H) ppm. ¹³C NMR (125 MHz, CDCl₃); δ = 20.4 (CH₃), 20.5 (CH₃), 20.6

(CH₃), 20.7 (CH₃), 62.2 (CH₂), 68.1 (CH), 68.8 (CH), 74.0 (CH), 76.7 (CH),

78.1 (CH), 115.8 (d, J= 21.8 Hz, CH), 131.2 (C), 132.1 (d, J = 9.5 Hz, CH),

166.2 (d, J = 252.8 Hz, C), 168.9 (C), 169.3 (C), 170.4 (C), 170.5 (C), 190.4

(CO) ppm. Elemental analysis:calcd (%) for C₂₁H₂₃FO₁₀(454.4): C 55.51,

H 5.10; found: C 55.96, H 4.69.

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(4-(methoxy)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (13i):

Compound

12i

(0.720

g,

1.09

mmol),

trimethylsilyl

trifluoromethanesulfonate (0.296 mL, 1.638 mmol), acetic anhydried (10

mL) were treated according to the general procedure B to give the title

compound 13i (0.25 g, 49.1%), after column chromatography on silica gel

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(4-(chloro)phenyl)-aldehydo-

D-glycero-D-gulo-heptose (13f):

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

as a colorless solid. R_f= 0.4 (EtOAc/hexanes, 2:3); m.p = 107-109 C;

[]²⁷_D= 46.7 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 1.78 (s, 3 H),

1.94 (s, 3 H), 1.98 (s, 3 H), 1.99 (s, 3 H), 3.80 (s, 3 H, OMe), 3.82-3.85 (m,

1 H), 4.08 (dd, J = 12.5, 2.0 Hz, 1 H), 4.17 (dd, J = 12.5, 5.5 Hz, 1 H), 4.65

(d, J = 9.5 Hz, 1 H, anomeric proton), 5.08 (t, J = 10.0 Hz, 1 H), 5.28 (t, J

= 9.5 Hz, 1 H), 5.41 (t, J = 9.5 Hz, 1 H), 6.87 (d, J = 9.0 Hz, 2 H), 7.95 (d,

J = 9.0 Hz, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃); δ = 20.4 (CH₃), 20.5

(CH₃), 20.6 (CH₃), 20.7 (CH₃), 55.5 (CH3, OMe), 62.2 (CH₂), 68.2 (CH),

69.0 (CH), 74.2 (CH), 76.5 (CH), 77.6 (CH), 113.8 (CH), 127.9 (C), 131.7

(CH), 164.2 (C), 168.9 (C), 169.4 (C), 170.4 (C), 170.5 (C), 190.2 (CO)

ppm. IR (CHCl₃):1186, 1526, 1648, 1690, 2878, 3012 cm^-1. Elemental

analysis:calcd (%) for C₂₂H₂₆O₁₁(466.44): C 56.65, H 5.62; found: C 57.09,

H 5.38.

= 183.7 (c 0.5, CHCl₃). ¹H NMR (400 MHz,CDCl₃); δ = 1.88 (s, 3 H), 2.02

(s, 3 H), 2.04 (s, 3 H), 2.05 (s, 3 H), 3.91 (s, 7 H, 2xOMe), 3.92 (s, 3 H,

OMe), 4.13 (dd, J = 12.4, 2.0 Hz, 1 H), 4.27 (dd, J = 12.4, 5.6 Hz Hz, 1

H),4.71 (d, J = 10.0 Hz, 1 H, anomeric proton), 5.15 (t, J = 10.0 Hz, 1 H),

5.36 (t, J = 9.2 Hz, 1 H), 5.49 (t, J = 9.6 Hz, 1 H), 7.27 (s, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃); δ = 20.5 (CH₃), 20.6 (CH₃), 20.7 (2xCH₃), 56.5

(2xOMe), 61.07 (OMe), 62.1 (CH₂), 68.3 (CH), 69.1 (CH), 74.2 (CH), 76.7

(CH), 77.9 (CH), 107.2 (CH), 129.9 (C), 153.1 (C), 169.0 (C), 169.4 (C),

170.5 (2xC), 190.6 (CO) ppm. IR (CHCl₃): 1142, 1526, 1656, 1698, 2889,

2996 cm^-1. HRMS:Calcd for C₂₄H₃₀O₁₃Na [M+Na]⁺549.1584, found

549.1578.

2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(4-(phenyl)phenyl)-aldehydo-

D-glycero-D-gulo-heptose (13m):

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(4-(acetoxy)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (13j):

Compound

12m

(0.35

g,

0.496

mmol),

trimethylsilyl

trifluoromethanesulfonate (0.165 mL, 0.744 mmol), acetic anhydried (5

mL) were treated according to the general procedure B to give the title

compound 13m 0.235 g, 92.5%), after column chromatography on silica

gel as a colorless solid. R_f= 0.2 (EtOAc/hexanes, 3:7); m.p = 163-165 C;

Compound 12j (0.5 g, 0.68 mmol), trimethylsilyl trifluoromethanesulfonate

(0.25 mL, 1.36 mmol), acetic anhydried (8 mL) were treated according to

the general procedure B to give the title compound 13j (0.23 g, 68.45%),

after column chromatography on silica gel as a colorless solid. R_f= 0.3

(EtOAc/hexanes, 2:3); m.p = 129-131C; []²⁷_D= 56.8(c 0.3, CHCl₃); ¹H

NMR (400 MHz, CDCl₃); δ = 1.86 (s, 3 H), 2.02 (s, 3 H), 2.06 (s, 3 H), 2.07

(s, 3 H), 2.33 (3 H), 3.89-3.93 (m, 1 H), 4.15 (dd, J = 12.4, 2.4 Hz, 1 H),

4.23 (dd, J = 12.4, 7.6, Hz 1 H), 4.71 (d, J = 10.0 Hz, 1 H, anomeric proton),

5.15 (t, J = 10.0 Hz, 1 H), 5.35 (t, J = 9.2 Hz, 1 H), 5.48 (t, J = 9.6 Hz, 1

H), 7.21 (d, J = 8.8 Hz, 2 H), 8.03 (d, J = 8.5 Hz, 2 H) ppm. ¹³C NMR (100

MHz, CDCl₃); δ = 20.5 (CH₃), 20.6 (CH₃), 20.7 (CH₃), 20.7 (CH₃), 21.2

(CH₃), 62.3 (CH₂), 68.2 (CH), 68.9 (CH), 74.2 (CH), 76.7 (CH), 77.9 (CH),

121.9 (CH), 131.0 (CH), 132.5 (C), 155.0 (C), 168.7 (C), 169.0 (C), 169.4

(C), 170.5 (C), 170.6 (C), 190.7 (CO) ppm. IR (CHCl₃): 1216, 1568, 1668,

1716, 2996, 3018 cm^-1. HRMS:Calcd for C₂₃H₂₆O₁₂Na [M+Na]⁺517.1322,

found 517.1318.

1

]²⁷_D= -183.7 (c 0.3, CHCl₃); H NMR (400 MHz, CDCl₃); δ = 1.87 (s, 3

H), 2.04 (s, 3 H), 2.07 (s, 3 H), 2.08 (s, 3 H), 3.92-3.96 (m, 1 H), 4.18 (dd,

J = 12.4, 2.4 Hz, 1 H), 4.26 (dd, J = 12.4, 5.6 Hz, 1 H), 4.78 (d, J = 10.0

Hz, 1 H, anomeric proton), 5.18 (t, J = 9.6 Hz, 1 H), 5.38 (t, J = 9.2 Hz, 1

H), 5.53 (t, J = 9.6 Hz, 1 H), 7.41-7.44 (m, 1 H), 7.47-7.50 (m, 2 H), 7.26

(d, J = 8.0 Hz, 2 H), 7.70 (d, J = 8.8 Hz, 2 H), 8.14 (d, J = 8.4 Hz, 2 H) ppm.

¹³C NMR (100 MHz, CDCl₃); δ = 20.5 (CH₃), 20.6 (CH₃), 20.7 (CH₃), 20.8

(CH₃), 62.2 (CH₂), 68.1 (CH), 68.9 (CH), 74.1 (CH), 76.7 (CH), 77.8 (CH),

127.2 (CH), 127.3 (CH), 128.5 (CH), 129.0 (CH), 129.9 (CH), 133.5 (C),

139.6 (C), 146.7 (C), 169.0 (C), 169.4 (C), 170.5 (C), 170.6 (C), 191.4 (CO)

ppm. IR (CHCl₃):1526, 1664, 1698, 2869, 2998 cm^-1. Elemental

analysis:calcd (%) for C₂₇H₂₈O₁₀(512.51): C 63.28, H 5.51; found: C 63.13,

H 5.06.

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(3,4-(dimethoxy)phenyl)-

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(naphthalen-2-yl)-aldehydo-D-

aldehydo-D-glycero-D-gulo-heptose (13k):

glycero-D-gulo-heptose (13n):

Compound

12k

(0.25

g,

0.363

mmol),

trimethylsilyl

Compound

12n

(0.57

g,

0.84

mmol),

trimethylsilyl

trifluoromethanesulfonate (0.1 mL, 0.544 mmol), acetic anhydried (4 mL)

were treated according to the general procedure B to give the title

compound 13k (0.07 g, 39.0%), after column chromatography on silica gel

as a colorless solid. R_f= 0.3 (EtOAc/hexanes, 1:1): m.p = 150-152 C;

[]²⁷_D= -86.2 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 1.87 (s, 3 H),

2.03 (s, 3 H), 2.06 (s, 3 H), 2.07 (s, 3 H), 3.89-3.91 (m, 1 H), 3.93 (s, 3 H,

OMe), 3.96 (s, 3 H, OMe), 4.15 (dd, J = 12.5, 2.0 Hz, 1 H), 4.26 (dd, J =

12.0, 5.0, Hz 1 H), 4.73 (d, J = 9.5 Hz, 1 H, anomeric proton), 5.17 (t, J =

9.5 Hz, 1 H), 5.36 (t, J = 9.5 Hz, 1 H), 5.51 (t, J = 9.5 Hz, 1 H), 6.90 (d, J =

8.5 Hz, 1 H), 7.55 (d, J = 1.5 Hz, 1 H), 7.65 (dd, J = 8.0, 2.0 Hz, 1 H) ppm.

¹³C NMR (125 MHz, CDCl₃); δ = 20.5 (CH₃), 20.6 (CH₃), 20.7 (CH₃), 20.8

(CH₃), 56.1 (CH₃, OMe), 56.2 (CH₃, OMe) 62.3 (CH₂), 68.3 (CH), 69.1 (CH),

74.3 (CH), 76.7 (CH), 77.7 (CH), 109.9 (CH), 111.3 (CH), 124.3 (CH),

128.1 (C), 149.3 (C), 154.2 (C), 169.0 (C), 169.4 (C), 170.5 (C), 170.6 (C),

190.3 (CO) ppm. IR (CHCl₃): 1126, 1568, 1656, 1692, 2896, 3018 cm^-1.

HRMS:Calcd for C₂₃H₂₈O₁₂Na [M+Na]⁺519.1478, found 519.1466.

trifluoromethanesulfonate (0.23 mL, 1.26 mmol), acetic anhydried (8 mL)

were treated according to the general procedure B to give the title

compound 13n (0.27 g, 66.3%), after column chromatography on silica gel

as a colorless solid. R_f= 0.3 (EtOAc/hexanes, 3:7); m.p = 138-140 C;

]²⁷_D= -64.4 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 1.81 (s, 3 H),

2.03 (s, 3 H), 2.05 (s, 3 H), 2.07 (s, 3 H), 3.97-4.01 (m, 1 H), 4.18 (dd, J =

12.5, 2.5 Hz, 1 H), 4.26 (dd, J = 12.0, 5.5 Hz, 1 H), 4.90 (d, J = 9.5 Hz, 1

H, anomeric proton), 5.19 (t, J = 9.5 Hz, 1 H), 5.41 (t, J = 9.5 Hz, 1 H), 5.55

(t, J = 10.0 Hz, 1 H), 7.56-7.59 (m, 1 H), 7.62-7.65 (m, 1 H), 7.88-7.91 (m,

2 H), 7.97 (d, J = 8.0 Hz, 1 H), 8.01 (dd,J = 8.5, 2.0 Hz, 1 H), 7.91 (s, 1 H)

ppm. ¹³C NMR (125 MHz, CDCl₃); δ = 20.4 (CH₃), 20.6 (CH₃), 20.7 (CH₃),

20.7 (CH₃), 62.3 (CH₂), 68.3 (CH), 69.1 (CH), 74.2 (CH), 76.7 (CH), 77.8

(CH), 124.4 (CH), 127.0 (CH), 127.8 (CH), 128.5 (CH), 129.0 (CH), 129.7

(CH), 131.5 (CH), 132.2 (C), 132.3 (C), 135.9 (C), 168.9 (C), 169.3 (C),

170.5 (C), 170.6 (C), 191.8 (CO) ppm. IR (CHCl₃): 1511, 1663, 1692, 2869,

2998 cm^-1. HRMS:Calcd for C₂₅H₂₆O₁₀Na [M+Na]⁺509.1423, found

509.1416.

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(3,4,5-(trimethoxy)phenyl)-

aldehydo-D-glycero-D-gulo-heptose (13l):

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(2-thiophenyl)-aldehydo-D-

glycero-D-gulo-heptose (13o):

Compound

12l

(0.12

g,

0.167

mmol),

trimethylsilyl

trifluoromethanesulfonate (0.043 mL, 0.25 mmol), acetic anhydried (3 mL)

were treated according to the general procedure B to give the title

compound 13l (0.021 g, 24.2%), after column chromatography on silica gel

Compound

12o

(0.32

g,

0.504

mmol),

trimethylsilyl

trifluoromethanesulfonate (0.138 mL, 0.756 mmol), acetic anhydried (6

mL) were treated according to the general procedure B to give the title

compound 13o (0.180 g, 69.2%), after column chromatography on silica

as a colorless solid. R_f= 0.3 (EtOAc/hexanes, 3:7); m.p = 157-159C; []²⁷

D

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

gel as a colorless solid. R_f= 0.3 (EtOAc/hexanes, 3:7); m.p = 75-77 C;

[]²⁷_D= 36.2 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 1.93 (s, 3 H),

2.02 (s, 3 H), 2.06 (s, 3 H), 2.10 (s, 3 H), 3.87-3.89 (m, 1 H), 4.20 (dd, J =

12.5, 2.5 Hz, 1 H), 4.29 (dd, J = 12.5, 5.0 Hz, 1 H), 4.48 (d, J = 9.5 Hz, 1

H, anomeric proton), 5.18 (t, J = 9.5 Hz, 1 H), 5.34 (t, J = 9.5 Hz, 1 H), 5.41

(t, J = 9.5 Hz, 1 H), 7.16 (dd, J = 5.0, 4.0 Hz, 1 H), 7.29 (dd, J = 5.0, 1.0

Hz, 1 H), 7.96 (dd, J = 4.0, 1.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃);

δ = 20.5 (CH₃), 20.6 (CH₃), 20.7 (CH₃), 20.8 (CH₃), 62.3 (CH₂), 68.1 (CH),

69.2 (CH), 73.9 (CH), 76.5 (CH), 80.1 (CH), 128.1 (CH), 134.4 (CH), 135.4

(CH), 140.8 (C), 169.1 (C), 169.4 (C), 170.4 (C), 170.6 (C), 185.6 (CO)

ppm. IR (CHCl₃):1556, 1648, 1688, 2872, 2982 cm^-1; HRMS:Calcd for

C₁₉H₂₂SO₁₀Na [M+Na]⁺465.0831, found 465.0826.

Compound 13b (0.20 g, 0.43 mmol), sodium methoxide (0.012 g, 0.233

mmol), methanol (5 mL) were treated according to the general procedure

C to give the title compound 4b, after column chromatography on silica gel

(0.102 g,80.3%) as a colorless solid (hygroscopic). R_f= 0.4 (MeOH/CH₂Cl₂

1:9); ²⁷_D= 118.6 (c 0.2, MeOH); ¹H NMR (400 MHz, CD₃OD); δ = 1.27

(t, J = 8.8 Hz, 3 H), 2.73 (q, J = 7.6 Hz, 2 H), 3.46 (d, J = 8.8 Hz, 1 H), 3.4-

3.52 (m, 1 H), 3.57 (t, J = 8.8 Hz, 1 H), 3.68-3.73 (m, 2 H), 3.89 (dd, J =

12.0, 2.0 Hz, 1 H), 4.72 (d, J = 9.6 Hz, 1 H, anomeric proton), 7.36 (d, J =

8.0 Hz, 2 H), 8.03 (d, J = 8.4 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CD₃OD);

δ = 14.3 (CH₃), 28.5 (CH₂), 61.2 (CH₂), 69.8 (CH), 71.6 (CH), 78.0 (CH),

78.8 (CH), 81.0 (CH), 127.7 (CH), 129.3 (CH), 133.8 (C), 150.8 (C), 196.5

(CO) ppm. IR (KBr): 1146, 1586, 1706, 2882, 2926, 3310 cm^-1.

HRMS:Calcd for C₁₅H₂₀O₆Na [M+Na]⁺319.1157, found 319.1146.

2,6-Anhydro-3,4,5,7-tetra-O-acetyl-1-C-(2-benzo[b]thiophenyl)-

aldehydo-D-glycero-D-gulo-heptose (13p):

2,6-Anhydro-1-C-(4-(tert-butyl)phenyl)-aldehydo-D-glycero-D-gulo-

heptose (4c):

Compound

12p

(0.43

g,

0.62

mmol),

trimethylsilyl

trifluoromethanesulfonate (0.209 mL, 0.942 mmol), acetic anhydried (8

mL) were treated according to the general procedure B to give the title

compound 13p (0.140 g, 46.35%), after column chromatography on silica

gel as a colorless solid. R_f= 0.3 (EtOAc/hexanes, 3:7); m.p = 122-124 C;

[]²⁷_D= 96.5 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 1.93 (s, 3 H),

2.02 (s, 3 H), 2.07 (s, 3 H), 2.13 (s, 3 H), 3.90-3.94 (m, 1 H), 4.23-4.25 (m,

1 H), 4.31 (dd, J = 12.5, 5.5, Hz 1 H), 4.58 (d, J = 10.0 Hz, 1 H, anomeric

proton), 5.22 (t, J = 9.5 Hz, 1 H), 5.38 (t, J = 9.5 Hz, 1 H), 5.46 (t, J = 9.5

Hz, 1 H), 7.41-7.43 (m, 1 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.87 (d, J = 8.0 Hz,

1 H), 7.90 (d, J = 8.0 Hz, 1 H), 8.23 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃);

δ = 20.5 (CH₃), 20.6 (CH₃), 20.7 (CH₃), 20.8 (CH₃), 62.1 (CH₂), 68.1 (CH),

69.3 (CH), 73.8 (CH), 76.5 (CH), 80.2 (CH), 122.9 (CH), 125.2 (CH), 126.3

(CH), 128.1 (CH), 131.8 (CH), 138.9 (C), 140.8 (C), 142.9 (C), 169.1 (C),

169.4 (C), 170.3 (C), 170.5 (C), 187.2 (CO). IR (CHCl₃):1512, 1642, 1683,

2882, 2996 cm^-1; Elemental analysis:calcd (%) for C₂₃H₂₄O₁₀S (492.50): C

56.09, H 4.91; found: C 56.37, H 4.81.

Compound 13c (0.213 g, 0.43 mmol), sodium methoxide (0.015 g, 0.216

mmol), methanol (4 mL) were treated according to the general procedure

C to give the title compound 4c, after column chromatography on silica gel

(0.108 g, 77.14%) as a colorless solid. R_f= 0.4 (MeOH/CH₂Cl₂1:9); m.p =

o

1

80-82 C; []²⁷=98.4 (c 0.6, MeOH) ; H NMR (400 MHz, CD₃OD); δ =

D

1.37 (s, 9 H), 3.43 (d, J = 9.0 Hz, 1 H), 3.48-3.51 (m, 1 H), 3.55 (t, J = 9.0

Hz, 1 H), 3.69-3.71 (m, 1 H), 3.71-3.73 (m, 1 H), 3.88 (dd, J = 12.0, 2.0 Hz,

1 H), 4.70 (d, J = 9.5 Hz, 1 H, anomeric proton), 7.57 (d, J = 8.5 Hz, 2 H),

8.04 (d, J = 8.5 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CD₃OD); δ = 30.0 (CH₃),

34.6 (C), 61.3 (CH₂), 69.8 (CH), 71.5 (CH), 78.1 (CH), 78.9 (CH), 81.1 (CH),

125.1 (CH), 129.0 (CH), 133.5 (C), 157.3 (C), 196.4 (CO) ppm. IR

(KBr):1216, 1552, 1689, 2926, 3280 cm^-1; HRMS: Calcd for C₁₇H₂₅O₆

[M+H]⁺: 325.1651, found 325.1652.

2,6-Anhydro-1-C-(3,5-(dimethyl)phenyl)-aldehydo-D-glycero-D-gulo-

heptose (4d):

General procedure C for the synthesis of acyl-C--D-glucosides 4a-

p:

Compound 13d (0.18 g, 0.387 mmol), sodium methoxide (0.01 g, 0.193

mmol), methanol (3 mL) were treated according to the general procedure

C to give the title compound 4d, after column chromatography on silica gel

(0.095 g, 82.6%) as a colorless solid (hygroscopic). R_f= 0.3 (MeOH/CH₂Cl_2,

1:9); []²⁷_D= -68.3 (c 0.3, MeOH);¹H NMR (500 MHz, CD₃OD); δ = 2.25 (s,

6 H), 3.31 (d, J = 9.0 Hz, 1 H), 3.50-3.52 (m, 1 H), 3.44 (t, J = 9.0 Hz, 1 H),

3.56-3.60 (m, 2 H), 3.76 (d, J = 12.0, 2.0 Hz 1 H), 4.58 (d, J = 9.0 Hz, 1 H,

anomeric proton), 7.17 (s, 1 H), 7.58 (s, 2 H) ppm. ¹³C NMR (125 MHz,

CD₃OD ₃); δ = 19.8 (2×CH₃), 61.3 (CH₂), 69.9 (CH), 71.6 (CH), 78.0 (CH),

78.8 (CH), 81.1 (CH), 126.7 (CH), 134.9 (CH), 136.2 (C), 138.0 (C), 194.6

(CO) ppm. IR (KBr):1196, 1556, 1701, 2926, 3296 cm^-1. HRMS: Calcd for

C₁₅H₂₁O₆[M+H]⁺: 297.1338, found 297.1337.

A round bottom flask was charged with compound 13a-p (1 equiv.) in

MeOH (10 mL, for 1 mmol) at room temperature. To that solution, NaOMe

(0.5 equiv.) was added and stirred the reaction mixture for 2 h at rt. Then

the reaction mixture was neutralized with 10% HCl (1 mL) and

concentrated under reduced pressure. The resultant crude product was

purified by column chromatography on silica gel (MeOH/CH₂Cl₂, 1:9) to

afford the title compound 4a-p.

2,6-Anhydro-1-C-(4-(methyl)phenyl)-aldehydo-D-glycero-D-gulo-

heptose (4a):

2,6-Anhydro-1-C-(4-(fluoro)phenyl)-aldehydo-D-glycero-D-gulo-

heptose (4e):

Compound 13a (0.21 g, 0.466 mmol), sodium methoxide (0.01 g, 0.233

mmol), methanol (5 mL) were treated according to the general procedure

C to give the title compound 4a, after column chromatography on silica gel

(0.103 g, 78.6%) as a colorless solid (hygroscopic). R_f= 0.4 (MeOH/CH₂Cl_2,

1:9); []²⁷_D= -36.4 (c 0.3, MeOH); ¹H NMR (400 MHz, CD₃OD); δ = 2.3 (s,

3 H), 3.32 (d, J = 8.8 Hz, 1 H), 3.4-3.52 (m, 1 H), 3.55 (t, J = 8.8 Hz, 1 H),

3.68-3.73 (m, 2 H), 3.89 (dd, J = 12.0, 2.0 Hz, 1 H), 4.59 (d, J = 9.2 Hz, 1

H, anomeric proton), 7.21 (d, J = 8.0 Hz, 2 H), 7.88 (d, J = 8.4 Hz, 2 H)

ppm. ¹³C NMR (100 MHz, CD₃OD); δ = 20.3 (CH₃), 61.2 (CH₂), 69.8 (CH),

71.6 (CH), 78.0 (CH), 78.8 (CH), 81.0 (CH), 128.8 (CH), 129.2 (CH), 133.6

(C), 144.7 (C), 196.5 (CO) ppm. IR (KBr):1498, 1711, 2882, 2996, 3297

cm^-1.HRMS: Calcd for C₁₄H₁₉O₆[M+H]⁺: 283.1181, found 283.1169.

Compound 13e (0.07 g, 0.128 mmol), sodium methoxide (0.04 mL, 0.064

mmol), methanol (3 mL) were treated according to the general procedure

C to give the title compound 4e, after column chromatography on silica gel

(0.035 g, 79.5%) as a colorless solid (hygroscopic). R_f= 0.3 (MeOH/CH₂Cl_2,

1:9); []²⁷_D= -109.3 (c 0.4, MeOH); ¹H NMR (500 MHz, CD₃OD); δ = 3.44

(d, J = 9.5 Hz, 1 H), 3.50-3.52 (m, 1 H), 3.56 (t, J = 11.5 Hz, 1 H), 3.69-

3.74 (m, 2 H), 3.89 (d, J = 13.5 Hz, 1 H), 4.70 (t, J = 12.0 Hz, 1 H, anomeric

proton), 7.26 (t, J = 11.0 Hz, 2 H), 8.20 (dd, J = 11.0, 7.0 Hz, 2 H) ppm.

¹³C NMR (125 MHz, CD₃OD); δ = 61.2 (CH₂), 69.8 (CH), 71.5 (CH), 78.0

(CH), 79.1 (CH), 81.1 (CH), 115.1 (d, J = 22.0 Hz, CH), 132.1 (d, J = 9.5

Hz, CH), 132.6 (C), 166.0 (d, J = 252.5 Hz, C), 190.4 (CO) ppm. IR

(KBr):918, 1216, 1556, 1721, 2991, 3233 cm^-1. HRMS: Calcd for

C₁₃H₁₆FO₆[M+H]⁺: 287.0930, found 287.0922.

2,6-Anhydro-1-C-(4-(ethyl)phenyl)-aldehydo-D-glycero-D-gulo-

heptose (4b):

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

2,6-Anhydro-1-C-(4-(chloro)phenyl)-aldehydo-D-glycero-D-gulo-

heptose (4f):

3281 cm^-1. HRMS: Calcd for C₁₄H₁₈O₇Na [M+Na]⁺321.095, found

321.0943.

Compound 13f (0.16 g, 0.33 mmol), sodium methoxide (0.01 g, 0.17 mmol),

methanol (5 mL) were treated according to the general procedure C to give

the title compound 4f, after column chromatography on silica gel (0.07 g,

68.6%) as a colorless solid (hygroscopic). R_f= 0.3 (MeOH/CH₂Cl_2,1:9);

[]²⁷_D=52.1 (c 0.3, MeOH); ¹H NMR (400 MHz, CD₃OD); δ = 3.43 (d, J =

9.2 Hz, 1 H), 3.49-3.52 (m, 1 H), 3.55 (t, J = 8.8 Hz, 1 H), 3.68-3.73 (m, 2

H), 3.89 (dd, J = 12.0, 2.0 Hz, 1 H), 4.68 (d, J = 12.0 Hz, 1 H, anomeric

proton), 7.53 (d, J = 8.4 Hz, 2 H), 8.10 (d, J = 8.4 Hz, 2 H) ppm. ¹³C NMR

(125 MHz, CD₃OD); δ = 61.2 (CH₂), 69.8 (CH), 71.5 (CH), 78.0 (CH), 79.1

(CH), 81.1 (CH), 128.4 (CH), 130.7 (CH), 134.5 (C), 139.6 (C), 195.5 (CO)

ppm. IR (KBr): 972, 1218, 1556, 1713, 2992, 3301 cm^-1. HRMS: Calcd for

C₁₃H₁₅ClO₆K [M+K]⁺341.0194, found 341.0203.

2,6-Anhydro-1-C-(4-(hydroxy)phenyl)-aldehydo-D-glycero-D-gulo-

heptose (4j):

Compound 13j (0.18 g, 0.36 mmol), sodium methoxide (0.01 g, 0.18 mmol),

methanol (4 mL) were treated according to the general procedure C to give

the title compound 4j, after column chromatography on silica gel (0.108 g,

85.98%) as a colorless solid. R_f= 0.2 (MeOH/CH₂Cl₂1:9);m.p = 158-160

C); []²⁷_D= 13.4 (c 1.0, MeOH); ¹H NMR (500 MHz, CD₃OD); δ = 3.32 (d,

J = 9.0 Hz, 1 H), 3.34-3.38 (m, 1 H), 3.43 (t, J = 9.0 Hz, 1 H), 3.54-3.57 (m,

1 H), 3.58-3.61 (m, 1 H), 3.75 (dd, J = 12.5, 2.0 Hz, 1 H), 4.56 (d, J = 9.5

Hz, 1 H, anomeric proton), 6.75 (d, J = 8.5 Hz, 2 H), 7.89 (d, J = 9.0 Hz, 2

H) ppm. ¹³C NMR (125 MHz, CD₃OD); δ = 62.7 (CH₂), 71.3 (CH), 73.2

(CH), 79.6 (CH), 80.2 (CH), 82.4 (CH), 116.3 (CH), 129.4 (C), 133.3 (CH),

164.5 (C), 196.9 (CO) ppm. IR (KBr): 1218, 1576, 1706, 2992, 3281, 3456

cm^-1. HRMS: Calcd for C₁₃H₁₇O₇[M+H]⁺285.0974, found 285.0973.

2,6-Anhydro-1-C-(3,4-(dichloro)phenyl)-aldehydo-D-glycero-D-gulo-

heptose (4g):

Compound 13g (0.18 g, 0.356 mmol), sodium methoxide (0.01 g, 0.18

mmol), methanol (5 mL) were treated according to the general procedure

C to give the title compound 4g, after column chromatography on silica gel

(0.09 g, 75.0%) as a colorless solid (hygroscopic). R_f= 0.2 (MeOH/CH₂Cl_2,

1:9); []²⁷_D= 19.5 (c 0.3, MeOH);¹H NMR (400 MHz, CD₃OD); δ = 3.42 (d,

J = 9.2 Hz, 1 H), 3.50-3.52 (m, 1 H), 3.55 (t, J = 9.2 Hz, 1 H), 3.66-3.72 (m,

2 H), 3.89 (d, J = 10.0 Hz, 1 H), 4.67 (d, J = 9.6 Hz, 1 H, anomeric proton),

2,6-Anhydro-1-C-(3,4-(dimethoxy)phenyl)-aldehydo-D-glycero-D-

gulo-heptose (4k):

Compound 13k (0.3 g, 0.594 mmol), sodium methoxide (0.02 g, 0.29

mmol), methanol (3 mL) were treated according to the general procedure

C to give the title compound 4k, after column chromatography on silica gel

(0.09 g, 75.0%).as a colorless solid; R_f= 0.3 (MeOH/CH₂Cl_2,1:9);.m.p =

7.69 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 8.22 (s, 1 H) ppm. ¹³

C

1

132-134 C; []²⁷_D=84.3 (c 0.3, MeOH); H NMR (400 MHz,CD₃OD); δ =

NMR (100 MHz, CD₃OD); δ = 61.2 (CH₂), 69.7 (CH), 71.4 (CH), 77.9 (CH),

79.2 (CH), 81.1 (CH), 128.6 (CH), 130.5 (CH), 130.8 (CH), 132.5 (C),

135.8 (C), 137.4 (C), 194.6 (CO) ppm. IR (KBr):988, 1118, 1526, 1688,

2992, 3281 cm^-1. HRMS: Calcd for C₁₃H₁₄Cl₂O₆Na [M+Na]⁺359.0065,

found 359.0057.

3.45 (d, J = 9.2 Hz, 1 H), 3.51-3.59 (m, 2 H), 3.70-3.73 (m, 2 H), 3.91 (s, 4

H), 3.94 (s, 3 H), 4.69 (d, J = 9.6 Hz, 1 H, anomeric proton), 7.07 (d, J =

8.4 Hz, 1 H), 7.66 (s, 1 H). 7.82 (d, J = 8.0 Hz, 1 H) ppm. ¹³C NMR (100

MHz, CD₃OD); δ = 56.5 (CH₃), 56.6 (CH₃), 62.8 (CH₂), 71.4 (CH), 73.2

(CH), 79.6 (CH), 80.4 (CH), 82.6 (CH), 111.7 (CH), 112.8 (CH), 126.1 (CH),

130.6 (C), 150.4 (C), 155.7 (C), 196.8 (CO) ppm. IR (KBr):1242, 1548,

1686 2982, 3296 cm^-1. HRMS: Calcd for C₁₅H₂₁O₈[M+H]⁺: 329.1236,

found 329.1236.

2,6-Anhydro-1-C-(3,4,5-(trichloro)phenyl)-aldehydo-D-glycero-D-

gulo-heptose (4h):

Compound 13h (0.234 g, 0.43 mmol), sodium methoxide (0.012 g, 0.217

mmol), methanol (5 mL) were treated according to the general procedure

C to give the title compound 4h, after column chromatography on silica gel

(0.099 g, 63.97%) as a colorless solid. R_f= 0.3 (MeOH/CH₂Cl_2,1:9); m.p =

2,6-Anhydro-1-C-(3,4,5-(trimethoxy)phenyl)-aldehydo-D-glycero-D-

gulo-heptose (4l):

Compound 13l (0.230 g, 0.430 mmol), sodium methoxide (0.02 g, 0.22

mmol), methanol (3 mL) were treated according to the general procedure

C to give the title compound 4l, after column chromatography on silica gel

(0.11 g, 71.4%) as a colorless solid. R_f= 0.3 (MeOH/CH₂Cl_2,1:9);m.p =

152-154 C; []²⁷_D= 98.2 (c 0.2, MeOH); ¹H NMR (500 MHz, CD₃OD); δ =

3.41 (d, J = 9.5 Hz, 1 H), 3.51-3.53 (m, 1 H), 3.55 (t, J = 9.0 Hz, 1 H), 3.68

(dd, J = 12.5, 5.5 Hz 1 H), 3.73 (t, J = 9.0 Hz, 1 H), 3.86 (s, 3 H), 3.89-

3.92 (m, 7 H), 4.63 (d, J = 9.6 Hz, 1 H, anomeric proton), 7.45 (s, 2 H)

ppm.¹³C NMR (125 MHz, CD₃OD); δ = 55.3 (2xCH₃), 59.7 (CH₃), 61.3

(CH₂), 69.9 (CH), 71.5 (CH), 78.0 (CH), 79.5 (CH), 81.3 (CH), 106.8 (CH),

131.2 (C), 142.8 (C), 152.9 (C), 195.2 (CO) ppm.IR (KBr): 1218, 1568,

1697 2948, 3256 cm^-1; HRMS: Calcd for C₁₆H₂₂O₉K [M+K]⁺397.0900,

found 397.0902.

1

66-68 C); []²⁷_D= 33.2 (c 0.3, MeOH); H NMR (500 MHz, CD₃OD); δ =

3.40 (d, J = 9.0 Hz, 1 H), 3.51-3.56 (m, 2 H), 3.66 (t, J = 9.0 Hz, 1 H), 3.68

(dd, J = 12.5, 5.5 Hz, 1 H), 3.90 (dd, J = 12.5, 2.0 Hz, 1 H), 4.64 (d, J = 9.5

Hz, 1 H, anomeric proton), 8.1 (s, 2 H) ppm. ¹³C NMR (125 MHz, CD₃OD);

δ = 62.8 (CH₂), 71.4 (CH), 73.0 (CH), 79.4 (CH), 80.9 (CH), 82.7 (CH),

130.6 (CH), 135.7 (C), 137.1 (C), 137.3 (C), 195.2 (CO) ppm. IR (KBr):

988, 1118, 1526, 1688, 2992, 3281 cm^-1. Elemental analysis:calcd (%) for

C₁₃H₁₃Cl₃O₆(369.98): C 42.02, H 3.53; found: C 42.54, H 3.55.

2,6-Anhydro-1-C-(4-(methoxy)phenyl)-aldehydo-D-glycero-D-gulo-

heptose (4i):

Compound 13i (0.22 g, 0.47 mmol), sodium methoxide (0.012 g, 0.236

mmol), methanol (5 mL) were treated according to the general procedure

C to give the title compound 4i, after column chromatography on silica gel

2,6-Anhydro-1-C-(4-(phenyl)phenyl)-aldehydo-D-glycero-D-gulo-

heptose (4m):

(0.102 g, 72.85%) as a colorless solid. R_f=0.4 (MeOH/CH₂Cl_2,1:9); []²⁷

D

1

= -56.0 (c 0.3, MeOH); H NMR (500 MHz, CD₃OD); δ = 3.43 (d, J = 8.5

Compound 13m (0.21 g, 0.409 mmol), sodium methoxide (0.012 g, 0.217

mmol), methanol (5 mL) were treated according to the procedure C to give

the title compound 4m, after column chromatography on silica gel (0.12 g,

85.1%) as a colorless solid. R_f= 0.4 (MeOH/CH₂Cl₂1:9); m.p = 176-178

C); []²⁷_D= -118.1 (c 0.3, MeOH); ¹H NMR (500 MHz, CD₃OD); δ = 3.23

(d, J = 9.5 Hz, 1 H), 3.39-3.42 (m, 1 H), 3.44 (t, J = 9.0 Hz, 1 H), 3.59-3.61

(m, 1 H), 3.62-3.64 (m, 1 H), 3.79 (dd, J = 12.5, 2.5 Hz, 1 H), 4.63 (d, J =

Hz, 1 H), 3.47-3.50 (m, 1 H), 3.55 (t, J = 8.5 Hz, 1 H), 3.68-3.73 (m, 1 H),

3.70-3.72 (m, 1 H), 3.87 (d, J = 12.0 Hz, 1 H), 3.90 (s, 3 H), 4.68 (d, J =

9.0 Hz, 1 H, anomeric proton), 7.03 (d, J = 8.0 Hz, 2 H), 8.1 (d, J = 9.0 Hz,

2 H) ppm. ¹³C NMR (125 MHz, CD₃OD); δ = 56.2 (OMe), 62.8 (CH₂), 71.4

(CH), 73.2 (CH), 79.6 (CH), 80.3 (CH), 82.6 (CH), 114.9 (CH), 130.5 (C),

133.0 (CH), 165.9 (C), 196.9 (CO) ppm. IR (KBr): 1222, 1576, 1691, 2916,

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

9.5 Hz, 1 H, anomeric proton), 7.28-7.31 (m, 1 H), 7.36-7.39 (m, 2 H), 7.59

(dd, J = 8.0, 1.0 Hz, 2 H) ), 7.67 (d, J = 8.5 Hz,2 H), 8.07 (d, J = 8.5 Hz, 2

H) ppm. ¹³C NMR (125 MHz, CD₃OD); δ = 62.8 (CH₂), 71.4 (CH), 73.1

(CH), 79.6 (CH), 80.6 (CH), 82.7 (CH), 128.2 (CH), 128.3 (CH), 129.5 (CH),

130.2 (CH), 131.2 (CH), 136.3 (C), 141.1 (C), 147.7 (C), 195.2 (CO) ppm.

IR (KBr):1496, 1568, 1721, 2989, 3276 cm^-1. HRMS: Calcd for C₁₉H₂₀O₆K

[M+K]⁺383.0896, found 383.0901.

2,6-Anhydro-3,4,5,7-tetra-O-methoxymethyl-1-C-(N-methyl-N-

methoxy)-aldehydo-D-glycero-D-gulo-heptose 14:

Step 1: Toastirred solution ofbuilding block 6c (3.8 g, 6.2 mmol) in THF

(40 mL) was added Pd-C (0.66 g, 10 mol %) at rt. The reaction mixture

was stirred under an atmosphere of H₂with balloon pressure until starting

material was disappeared on TLC. The mixture was filtered through celite

and the solvent was removed in vacuo. The resultant tetrol was used for

the next step without further purification.

2,6-Anhydro-1-C-(naphthalen-2-yl)-aldehydo-D-glycero-D-gulo-

heptose (4n):

Step 2: In a flame dried two necked round bottom flask under nitrogen

atmosphere, tetrol (1.6 g, 6.3 mmol) was combined with anhydrous

dichloromethane (25 mL), upon cooling the suspension on a ice bath (0

^oC) diisopropylethylamine (8.6 mL, 50.4 mmol) was added drop wise. The

suspension was stirred at the same temperature for an additional 10 min

and then chloromethylmethylether (4.0 mL, 50.4 mmol) was added slowly.

After stirring for another 15 min at the same temperature

tetrabutylammoniumiodide (8.3 g, 25.2 mmol) was added and then

solution was allowed to attain rt. The reaction was stirred in darkness for

72 hours, the solution gradually turned red in color and was cooled to 0 ^oC,

saturated NH₄Cl (30 ml) solution was added and the organic layer was

extracted with dichloromethane (3x100 ml), dried over Na₂SO₄, and

concentrated to give the crude product, which was further washed with

Et₂O afforded the title compound 14 (2.1 g , 77.2%) as a yellow color oil.

R_f= 0.3 (EtOAc/hexanes, 1:1); []²⁷_D= -78.2 (c 0.6, CHCl₃); ¹H NMR (400

MHz, CDCl₃); δ = 3.22 (s, 3 H), 3.33 (s, 3 H), 3.34 (s, 3 H), 3.43 (2 x s, 6

H), 3.50 (s, 2 H), 3.67 (m, 2 H), 3.77 (s, 3 H), 3.87-3.96 (m, 2 H), 4.32 (d,

J = 9.6 Hz, 1H), 4.63 (s, 2 H), 4.72-4.74 (m, 3 H), 4.85-4.90 (m, 3 H) ppm.

¹³C NMR (100 MHz, CDCl₃); δ = 32.2 (CH_3,N-Me), 55.2 (CH₃, OMe), 56.4

(CH₃, OMe), 56.5 (CH₃, OMe), 61.9 (CH₃, OMe), 66.9 (CH₂), 74.5 (CH),

76.6 (CH), 77.2 (CH), 79.1 (CH), 83.1 (CH), 96.7 (CH₂), 98.1 (CH₂), 98.5

(CH₂), 98.6 (CH₂), 168.4 (CO) ppm. IR (CHCl₃): 1214,1584, 1718, 2979,

3012 cm^-1. HRMS: Calcd for C₁₇H₃₃NO₁₁Na [M+Na]⁺450.1951, found

450.1949.

Compound 13n (0.23 g, 0.472 mmol), sodium methoxide (0.012 g, 0.217

mmol), methanol (5 mL) were treated according to the general procedure

C to give the title compound 4n, after column chromatography on silica gel

(0.09 g, 60%) as a colorless solid. R_f= 0.3 (MeOH/CH₂Cl₂1:9); m.p = 77-

79 C); []²⁷_D= -96.3 (c 0.3, MeOH) ; ¹H NMR (500 MHz, CD₃OD); δ = 3.49

(d, J = 9.5 Hz, 1 H), 3.58-3.61 (m, 1 H), 3.63 (t, J = 9.0 Hz, 1 H), 3.75 (dd,

J = 12.0, 5.5 Hz, 1 H), 3.79 (d, J = 9.5 Hz, 1 H), 3.92 (dd, J = 12.5, 2.0 Hz,

1 H), 4.90 (d, J = 9.5 Hz, 1 H, anomeric proton), 7.56-7.60 (m, 1 H), 7.62-

7.66 (m, 1 H), 7.93 (t, J = 8.0 Hz, 2 H)), 8.06 (d, J = 8.5 Hz, 1 H), 8.09 (dd,

J = 9.5 Hz, 2.0 Hz, 1 H), 8.73 (s, 1 H) ppm. ¹³C NMR (125 MHz, CD₃OD);

δ = 61.3 (CH₂), 69.9 (CH), 71.7 (CH), 78.1 (CH), 79.0 (CH), 81.2 (CH),

123.9 (CH), 126.5 (CH), 127.3 (CH), 127.9 (CH), 128.5 (CH), 129.5 (CH),

131.6 (CH), 132.5 (C), 133.3 (C), 135.9 (C), 196.7 (CO) ppm. IR(KBr):

1496, 1576, 1706, 2992, 3284 cm^-1. HRMS: Calcd for C₁₇H₁₉O₆[M+H]⁺

319.1181, found 319.1182.

2,6-Anhydro-1-C-(2-thiophenyl)-aldehydo-D-glycero-D-gulo-heptose

(4o):

Compound 13o (0.25 g, 0.56 mmol), sodium methoxide (0.015 g, 0.28

mmol), methanol (5 mL) were treated according to the general procedure

C to give the title compound 4o, after column chromatography on silica gel

(0.13 g, 71.03%) as a colorless solid. R_f=0.3 (MeOH/CH₂Cl₂1:9); []²⁷_D=-

86.4 (c 0.3, MeOH); ¹H NMR (500 MHz, CD₃OD); δ = 3.43-3.49 (m, 2 H),

3.52 (t, J = 9.0 Hz, 1 H), 3.67 (t, J = 9.5 Hz, 1 H), 3.73 (dd, J = 12.5, 5.0

Hz, 1 H), 3.90 (dd, J = 12.5, 2.0 Hz, 1 H), 4.50 (d, J = 9.5 Hz, 1 H, anomeric

proton), 7.23 (dd, J = 5.0 Hz, 4.0 Hz, 1 H), 7.91 (dd, J = 5.0, 1.0 Hz, 1 H),

8.09 (dd, J = 4.0, 1.0 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CD₃OD); δ = 61.3

(CH₂), 69.8 (CH), 71.8 (CH), 78.0 (CH), 81.0 (CH), 81.1 (CH), 128.0 (CH),

134.9 (CH), 135.1 (CH), 142.4 (C), 189.9 (CO) ppm. IR (KBr): 1576, 1720,

2992, 3284 cm^-1. HRMS: Calcd for C₁₁H₁₅O₆S [M+H]⁺275.0586, found

275.0589.

2,6-Anhydro-3,4,5,7-tetra-O-methoxymethyl-1-C-(3,4-

(dimethoxy)phenyl)-aldehydo-D-glycero-D-gulo-heptose 15a:

Building block 14 (0.4 g, 0.936 mmol), magnesium turnings (0.107 g, 4.68

mmol), 1-bromo-3,4-dimethoxybenzene (0.68 g, 4.68 mmol) were treated

according to the procedure used in compound 12l to give the title

compound 15a, after column chromatography on silica gel (0.4 g,

72.3%)as a colorless gum. R_f= 0.3 (EtOAc/hexanes, 2:3); []²⁷_D=-14.2 (c

0.6, CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 3.08 (s, 3 H, OMe), 3.29 (s, 3

H, OMe), 3.44(s, 6 H), 3.45 (s, 2H), 3.59-3.60 (m, 1 H), 3.68-3.70 (m, 1 H),

3.77-3.81 (m, 3 H), 3.93 (s, 3 H), 3.95 (s,1 H), 3.99-4.01 (m, 1 H), 4.11-

4.12, (m, 1 H ), 4.55-4.65 (m, 5 H), 4.75-4.77 (m, 1 H), 4.85-4.91 (m, 3 H),

6.88-6.90 (m, 1 H), 7.61 (s, 1 H), 7.73-7.74 (m, 1 H) ppm.¹³C NMR (125

MHz, CDCl₃); δ = 55.2 (CH₃, OMe), 55.9 (CH₃, OMe), 56.0 (CH₃, OMe),

56.3(CH₃, OMe), 56.4 (CH₃, OMe), 56. 5(CH₃, OMe), 66.7 (CH₂), 76.5

(CH), 77.5(CH), 79.1 (CH), 79.3 (CH), 83.3 (CH), 96.7 (CH₂), 97.9(CH₂),

98.6 (2 x CH₂), 109.9 (CH), 111.1 (CH), 124.2 (CH), 128.9 (C), 149.0(C),

153.7 (C), 192.8 (CO) ppm. IR (CHCl₃):1178, 1584, 1712, 2986, 3113 cm^-

¹. HRMS: Calcd for C₂₃H₃₆O₁₂Na [M+Na]⁺527.2104, found 527.2106.

2,6-Anhydro-1-C-(2-benzo[b]thiophenyl)-aldehydo-D-glycero-D-gulo-

heptose (4p):

Compound 13p (0.1 g, 0. mmol), sodium methoxide (0.009 g, 0.10 mmol),

methanol (3 mL) were treated according to the general procedure C to give

the title compound 4p, after column chromatography on silica gel (0.04 g,

61.5%) as a colorless solid. R_f=0.3 (MeOH/CH₂Cl₂1:9); m.p = 70-72 ^oC;

[]²⁷_D= -98.2 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CD₃OD); δ = 3.36 (d, J =

9.0 Hz, 1 H), 3.43-3.49 (m, 1 H), 3.45 (t, J = 9.0 Hz, 1 H), 3.60 (t, J = 9.5

Hz, 1 H), 3.62-3.65 (m, 1 H), 3.81 (dd, J = 12.5, 2.0 Hz, 1H), 4.54 (d, J =

9.5 Hz, 1 H, anomeric proton), 7.35-7.39 (m, 1 H), 7.39-7.42 (m, 1 H), 7.82

(d, J = 8.0 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 8.29 (s, 1 H) ppm. ¹³C NMR

(125 MHz, CD₃OD); δ = 62.8 (CH₂), 71.3 (CH), 73.4 (CH), 79.6 (CH), 82.2

(CH), 82.7 (CH), 123.9 (CH), 126.3 (CH), 127.8 (CH), 129.2 (CH), 134.1

(CH), 140.8 (CH), 143.4 (C), 144.2 (C), 193.0 (CO) ppm.IR (KBr):1584,

1718, 2979, 3213 cm^-1. HRMS: Calcd for C₁₅H₁₇O₆S [M+H]⁺325.0745,

found 325.0745.

2,6-Anhydro-3,4,5,7-tetra-O-methoxymethyl-1-C-(3,4,5-

(trimethoxy)phenyl)-aldehydo-D-glycero-D-gulo-heptose 15b:

Building block 14 (0.5 g, 1.17 mmol), magnesium turnings (0.107 g, 4.68

mmol), 1-bromo-3,4,5-trimethoxybenzene (1.15 g, 4.68 mmol) were

treated according to the procedure used in compound 12l to give the title

compound 15b, after column chromatography on silica gel (0.29 g, 59.3%)

as a colorless gum. R_f= 0.3 (EtOAc/hexanes, 1:1); []²⁷_D= -68.2 (c 0.6,

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 3.14 (s, 3 H, OMe), 3.28 (s, 3 H,

OMe), 3.43 (s, 3 H, OMe), 3.45 (s, 3 H, OMe), 3.53-3.62 (m, 2 H), 3.64-

3.70 (m, 1 H), 3.77-3.87 (m, 2 H), 3.91 (s, 6 H, 2xOMe), 3.92 (s, 3 H, OMe),

4.01 (t, J = 11.5 Hz, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.61 (s, 2 H), 4.63 (d,

J = 7.5 Hz, 1 H), 4.68 (d, J = 7.5 Hz, 1 H), 4.75 (d, J = 8.5 Hz, 1 H), 4.85-

4.91 (m, 3 H),7.37 (s, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃); δ = 55.2 (CH₃,

OMe), 56.2 (CH₃, OMe), 56.3(2 x CH₃, OMe), 56.5 (2 x CH₃, OMe), 60.9

(CH₃, OMe), 66.6 (CH₂), 76.5 (CH), 77.3 (CH), 79.3 (CH), 79.8 (CH), 83.2

(CH), 96.6 (CH₂), 97.9 (CH₂), 98.5 (CH₂), 106.7 (CH), 130.7 (C), 142.9 (C),

152.9 (2 x C), 192.8 (CO) ppm. IR (CHCl₃):1112, 1556, 1701, 2987, 3110

cm^-1. HRMS: Calcd for C₂₄H₃₉O₁₃[M+H]⁺535.2390, found 535.2390.

Compound 15c (0.66 g, 1.08 mmol), 6 N HCl (50 mL), methanol (6 mL)

were treated according to the general procedure D, to give the title

compound 16, after column chromatography on silica gel (0.29 g, 78.4%)

as a colorless solid. R_f= 0.4 (MeOH/CH₂Cl_2,1:4); m.p = 178-180 C; []²⁷

D

= -168.2 (c 0.3, MeOH); ¹H NMR (500 MHz, CD₃OD); δ = 3.42 (d, J = 9.5

Hz, 1 H), 3.50-3.53 (m, 1 H), 3.56 (t, J = 9.0 Hz, 1 H), 3.68-3.70 (m, 1 H),

3.71-3.74 (m, 1 H), 3.88-3.89 (m, 1 H), 3.92 (s, 6 H), 4.65 (d, J = 9.5 Hz, 1

H, anomeric proton), 7.46 (s, 2 H) ppm. ¹³C NMR (125 MHz, CD₃OD); δ =

56.9 (2xCH₃), 62.8 (CH₂), 71.4 (CH), 73.2 (CH), 79.6 (CH), 80.7 (CH), 82.7

(CH), 108.6 (CH), 128.2 (C), 143.1 (C), 149.0 (C), 196.6 (CO) ppm. IR

(KBr): 1568, 1682, 2896, 3264, 3420 cm^-1. Elemental analysis:calcd (%)

for C₁₅H₂₀O₉(344.32): C 52.33, H 5.86; found: C 51.98, H 5.54.

2,6-Anhydro-3,4,5,7-tetra-O-methoxymethyl-1-C-(3,5-(dimethoxy)-4-

benzyloxy)phenyl)-aldehydo-D-glycero-D-gulo-heptose15c:

General procedure E for the synthesis of benzyl-C--glucosides:

Building block 14 (0.6 g, 1.40 mmol), magnesium turnings (0.112 g, 4.68

mmol), 1-bromo-3,5-dimethoxy-4-benzyloxybenzene (1.51 g, 4.68 mmol)

were treated according to the procedure used in compound 12l to give the

title compound 15c, after column chromatography on silica gel (0.66 g,

77.3%) as a colorless gum. R_f= 0.3 (EtOAc/hexanes, 2:3); []²⁷_D=-136.2

(c 0.6, CHCl₃); ¹H NMR (400 MHz,CDCl₃); δ = 3.09 (s, 3 H, OMe), 3.28 (s,

3 H, OMe), 3.37-3.39 (m, 1 H), 3.43 (s, 3 H, OMe), 3.45 (s, 3 H, OMe),

3.53-3.62 (m, 2 H), 3.65-3.69 (m, 1 H), 3.79 (t, J = 8.8 Hz, 1 H), 3.87 (s, 6

H), 3.89-3.92 (m, 1 H), 4.00 (t, J = 9.2 Hz, 1 H), 4.52 (d, J = 9.2 Hz, 1 H),

4.60-4.62 (m, 2 H), 4.65 (d, J = 6.0 Hz, 1 H), 4.75 (d, J = 6.8 Hz, 1 H),

4.85-4.91 (m, 3 H), 5.11 (s, 2 H), 7.26-7.28 (m, 1 H), 7.30-733 (m, 2 H),

7.34 (s, 2H), 7.45 (d, J = 8.4 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃); δ

= 55.2 (CH₃, OMe), 56.2 (CH₃, OMe), 56.3 (2 x CH₃, OMe), 56.5 (CH₃,

OMe), 66.6 (CH₂), 74.9 (CH), 76.6 (CH), 79.3 (CH), 79.6 (CH), 83.2 (CH),

96.6 (CH₂), 98.0 (CH₂), 98.6 (2 x CH₂), 106.7 (CH), 128.0 (CH), 128.1 (CH),

130.9(C), 137.2 (C), 141.7 (C), 153.2 (2 x C), 192.9 (CO) ppm. IR

(CHCl₃):1216, 1557, 1698, 2987, 3017 cm^-1. HRMS: Calcd for C₃₀H₄₃O₁₃

[M+H]⁺611.2703, found 611.2698.

To obtained benzyl ether protected compound (1 eq.) in MeOH (5 mL) was

added Pd/C (0.1 eq., 10 mol%) followed by catalytic amount of con.c HCl

at rt. The reaction mixture was stirred under H₂atmosphere (balloon

pressure) for 24-36 h. The solution was filtered through a pad of celite, and

the filtrate was concentrated under reduced pressure. The residue was

purified by column chromatography on silica gel (MeOH/CH₂Cl₂, 1:9) to

give the title compound 5a-e as a colorless solids.

2,6-anhydro-1-deoxy-1-C-(4-(methoxy)phenyl)-D-glycero-D-gulo-

heptitol (5a):

Compound 12i (0.16 g, 0.536 mmol), Pd-C (0.058 g, 0.0536) and MeOH

(3 mL) were treated according to the general procedure E, to give the title

compound 5a (0.05 g, 79.7%) as a colorless solid. R_f= 0.4 (MeOH/CH₂Cl_2,

1:9); m.p = 94-96 C; []²⁷_D=-98.2 (c 0.7, MeOH);¹H NMR (400 MHz,

CD₃OD); δ = 2.66 (dd, J = 14.4, 8.4 Hz, 1 H), 3.09-3.10 (m, 1 H), 3.13-3.17

(m, 1 H), 3.27-3.29 (m, 1 H), 3.32-3.37 (m, 3 H), 3.64 (dd, J = 12.0, 5.6 Hz,

1 H), 3.75-3.81 (m, 4 H), 6.81 (d, J = 7.2 Hz, 2 H), 7.23 (s, J = 8.4 Hz, 2

H). ¹³C NMR (100 MHz, CD₃OD); δ = 36.3 (CH₂), 54.2 (CH₃, OMe), 61.6

(CH2), 70.5 (CH), 73.4 (CH), 78.5 (CH), 79.9 (CH), 80.4 (CH), 113.0 (CH),

130.2 (CH), 130.9 (C), 158.1 (C). IR (KBr):1213, 1571, 1696, 2896, 3264

cm^-1. Elemental analysis:calcd (%) forC₁₄H₂₀O₆(284.13): C 59.15, H 7.09;

found: C 59.55, H 7.39.

General procedure D for the MOM deprotection:

The methoxy methyl ether protected compound 15a-c was dissolved in

methanol (2 mL) in a round bottom flask with magnetic stir bar and kept

the stirring at room temperature. To the reaction mixture, 6N HCl was

added and stirring was continued until the starting material was disappear

on TLC. The wine-red colored solution was concentrated in vacuum. The

black colored residual material was purified by column chromatography on

silica gel to give the title compounds 4k,4l and16.

2,6-anhydro-1-deoxy-1-C-(4-(hydroxy)phenyl)-D-glycero-D-gulo-

heptitol (5b):

Compound 12j (0.22 g, 0.298 mmol), Pd-C (0.03 g, 0.0298) and MeOH (4

mL) were treated according to the general procedure E, to give the title

compound 5b (0.08 g, 93%) as a colorless solid. R_f= 0.4 (MeOH/CH₂Cl_2,

1:4); []²⁷_D= 95.2 (c 0.3, MeOH); ¹H NMR (500 MHz, CD₃OD); δ = 2.62-

2.67 (m, 1 H), 3.09-3.17 (m, 1 H), 3.29-3.38 (m, 5 H), 3.64-3.66 (m, 1 H),

3.67-3.80 (m, 1 H), 6.01 (d, J = 7.5 Hz, 2 H), 7.16 (d, J = 7.5 Hz, 2 H) ppm.

¹³C NMR (125 MHz, CD₃OD); δ = 36.4 (CH₂), 61.6 (CH₂), 70.5 (CH), 73.4

(CH), 78.5 (CH), 79.9 (CH), 80.5 (CH), 114.3 (CH), 129.7 (C), 130.2 (CH),

155.2 (C) ppm. IR (KBr): 1568, 1682, 2896, 3264, 3420 cm^-1. HRMS: Calcd

for C₁₃H₁₈O₆Na [M+Na]⁺293.1001, found 293.1001.

2,6-Anhydro-1-C-(3,4-(dimethoxy)phenyl)-aldehydo-D-glycero-D-

gulo-heptose (4k):

Compound 15b (0.3 g, 0.544 mmol), 6 N HCl (30 mL), methanol (3 mL)

were treated according to the general procedure D, to give the title

compound 4k, after column chromatography on silica gel as a colorless

solid (0.11 g, 67%).

2,6-Anhydro-1-C-(3,4,5-(trimethoxy)phenyl)-aldehydo-D-glycero-D-

gulo-heptose (4l):

2,6-anhydro-1-deoxy-1-C-(3,4-(dimethoxy)phenyl)-D-glycero-D-gulo-

heptitol (5c):

Compound 15b (0.23 g, 0.544 mmol), 6 N HCl (20 mL), methanol (3 mL)

were treated according to the general procedure D, to give the title

compound 4l, after column chromatography on silica gel as a colorless

solid (0.11 g, 71.4%).

Compound 12k (0.22 g, 0.298 mmol), Pd-C (0.03 g, 0.0298) and MeOH (4

mL) were treated according to the general procedure E, to give the title

compound 5c (0.055 g, 68%) as a light brown color solid. R_f=0.4

(MeOH/CH₂Cl_2,1:4); []²⁷_D= 95.2 (c 0.3, MeOH); ¹H NMR (500 MHz,

CD₃OD); δ = 2.56 (dd, J = 15.5,8.0 Hz, 1 H), 2.97-2.99 (m, 1 H), 3.04-3.07

(m, 1 H), 3.13-3.17 (m, 1 H), 3.22-3.23 (s, 1 H), 3.53 (dd, J = 12.0, 6.0 Hz,

1H), 3.69 (s, 3 H), 3.71(s, 3 H), 3.73 (m, 1 H), 4.47 (s, 2 H), 6.73 (s, 2 H),

2,6-Anhydro-1-C-(3,5-(dimethoxy)-4-hydroxy)phenyl)-aldehydo-D-

glycero-D-gulo-heptose(16):

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

6.89 (s, 1 H) ppm.¹³C NMR (125 MHz, CD₃OD); δ = 36.7 (CH₂), 55.0 (CH₃,

OMe), 55.1 (CH₃, OMe), 61.7 (CH₂), 70.5 (CH), 73.4 (CH), 78.5 (CH), 80.0

(CH), 80.4 (CH), 111.3 (CH), 113.4 (CH), 121.6 (CH), 132.0 (C), 147.4 (C),

148.5 (C) ppm. IR (KBr):1568, 1682, 2896, 3264, 3420 cm^-1. HRMS: Calcd

for C₁₅H₂₂O₇K [M+K]⁺353.1002, found 353.1007.

C- β -D-glucosides (5 and 10 µM) for 16 hrs followed by addition of insulin

(100nM) and incubated for 30 minutes. After insulin stimulation the

mytotubes were washed once with PBS. 2-NBDG, a fluorescent glucose

analogue (50μM) in no glucose medium was added to each well and the

plates were further incubated for 1 hour. The cells were thoroughly washed

thrice with ice cold 1X PBS and 200 μl lysis buffer was added to each well

and incubated for 10 mins.³³The lysate was added to 96 black well

microtitre plate and fluorescence (λex = 467 nm, λem = 542 nm) was

measured for NBDG uptake using Perkin Elmer multimode plate reader.

Results were expressed as mean±SD. Data was analysed using one way

ANOVA (GraphPad Prism 6 software).

2,6-anhydro-1-deoxy-1-C-(3,4,5-(trimethoxy)phenyl)-D-glycero-D-

gulo-heptitol (5d):

Compound 12l (0.23 g, 0.326 mmol), Pd-C (0.035 g, 0.032) and MeOH (5

mL) were treated according to the general procedure E, to give the title

compound 5d (0.097 g, 86.6%) as

a colorless solid. R_f= 0.4

(MeOH/CH₂Cl_2,1:9); m.p = 128-130 C; []²⁷_D=102.2 (c 0.3, MeOH);¹H

NMR (500 MHz, CD₃OD); δ = 2.57 (dd, J = 16.0, 8.5 Hz, 1 H), 2.98-3.02

(m, 2 H), 3.07-3.10 (m, 1 H), 3.14-3.17 (m, 1 H), 3.21-3.23 (m, 1 H), 3.53

(dd, J = 12.0, 5.5 Hz, 1 H), 3.63 (s, 3 H, OMe), 3.71 (s, 6 H, 2 x OMe ),

4.48 (s, 2H), 6.55 (s, 2 H) ppm. ¹³C NMR (125 MHz, CD₃OD); δ = 37.4

(CH₂), 55.1 (2 x CH₃, OMe), 59.7 (CH₃, OMe), 61.7 (CH2), 70.5 (CH), 73.3

(CH), 78.5 (CH), 80.0 (CH), 80.3 (CH), 106.6 (CH), 135.3 (CH), 135.8 (C),

152.5 (C) ppm. IR (KBr):1566, 1689, 2896, 3214, 3410 cm^-1. HRMS: Calcd

for C₁₆H₂₄O₈K [M+K]⁺383.1108, found 383.1107.

Real time PCR quantification

The differentiated C2C12 cells were serum starved for 16 hrs and treated

with pioglitazone (5 µM), metformin (600 µM) and acyl and benzyl-C- β -

D-glucosides (5 and 10 µM) for 16hrs. This was followed by insulin (100

nM) for 30 min. The cells were harvested and the total RNA was isolated

using RNAiso Plus(Total RNA extraction reagent, Takara Bio Inc., Japan).

RNA (1 µg) was transcribed using cDNA Reverese Transcription

Kit(Applied Biosystems, Thermo Fischer Scientific, USA) with Applied

Biosystems Veriti^TMDx Thermal Cycler (Thermo Fischer Scientific, USA).

The mRNA expressions of PI3K, GLUT4 and PPARγ genes were

quantified using a SYBR^ⓇPremix Ex Taq^TMII kit (Takara Bio, USA) with a

Mastercycler ep realplex PCR system (Eppendorf, Australia). The primer

sequences GLUT4 (Forward: 5ʹ-CCAGCCTACGCCACCATAG-3ʹ,

Reverse: 5ʹ-TTCCAGCAGCAGCAGAGC-3ʹ), PPAR-γ (Forward: 5ʹ-

AGGGCCCTGTCTGCTCTGTG-3ʹ,

TACCAGCTTGAGCAGCACAAGTCG-3ʹ) and PI3K (Forward: 5ʹ-

TGACGCTTTCAAACGCTATC-3ʹ, Reverse: 5ʹ-

CAGAGAGTACTCTTGCATTC-3ʹ). The PCR cycle was set as follows:

95°C for 30s, followed by 40 cycles at 95°C for 5s and at 60°C for 35 s.

The expression levels were normalized to the house keeping β-actin

mRNA and the fold change were determined using ΔΔCt method.

2,6-anhydro-1-deoxy-1-C-(3,5-(dimethoxy)-4-(hydroxy)phenyl)-D-

glycero-D-gulo-heptitol (5e):

Compound 7d (0.47 g, 0.589 mmol), Pd-C (0.05 g, 0.048), aq. HCl (1 mL)

and MeOH (8 mL) were treated according to the general procedure E, to

give the title compound 5e (0.06 g, 64 %) as a colorless solid. R_f= 0.4

Reverse:

5ʹ-

(MeOH/CH₂Cl_2,1:4); []²⁷= 95.2 (c 0.3, MeOH);¹H NMR (500 MHz,

D

CD₃OD); δ = 2.54 (dd, J = 15.5, 8.5 Hz, 1 H), 2.96-2.99 (m, 1 H), 3.00-3.02

(m, 1 H), 3.06-3.09 (m, 1 H), 3.13-3.17 (m, 1 H), 3.24-3.25 (m, 2 H), 3.53

(dd, J = 12.0, 5.5 Hz, 1 H), 3.72 (s, 7H), 6.53 (s, 2 H) ppm. ¹³C NMR (125

MHz, CD₃OD); δ = 37.0 (CH₂), 55.3 (2 x CH₃, OMe), 61.7 (CH2), 70.6 (CH),

73.3 (CH), 78.5 (CH), 80.0 (CH), 80.5 (CH), 106.5 (CH), 129.6 (C), 129.7

(C), 133.2 (C), 147.3 (C) ppm. IR (KBr):1572, 1676, 2886, 3281, 3320 cm^-

¹.HRMS: Calcd for C₁₅H₂₂O₈Na [M+Na]⁺353.1212, found 353.1214.

Acknowledgments

Cell cytotoxicity

We thank Department of Science and Technology (DST) New

Delhi for funding towards the 400 MHz NMR spectrometer to the

Department of Chemistry, IIT-Madras under the IRPHA Scheme

and the ESI-MS facility under the FIST program. The Council of

C2C12 myoblasts were procured from NCCS, Pune and maintained in

Minimum Eagles Medium (MEM) containing essential antibiotics, fetal

bovine serum (10% of FBS) and maintained with 5% CO2 at 37°C. The

compatibility of the compounds and the commercial drugs (Pioglitazone

and Metformin) was tested against C2C12 myoblast by MTT assay. The

cells were seeded at 10⁴cells/well into 96 well plate and cultured overnight.

The cells were treated with pioglitazone (5 µM), metformin (600 µM) and

acyl and benzyl-C-β-D-glucosides (5 and 10 µM) for 24 hrs. MTT (1 mg/ml)

was added to the wells and incubated for 4 hrs. The formazan precipitates

formed were dissolved in DMSO and the absorbance was measured at

570 nm using a microplate reader (EnSpire, Perkin Elmer, Singapore). The

percentage cytotoxic cells were calculated relative to the untreated control

cells.

Scientific

&

Industrial Research (CSIR) New Delhi is

acknowledged for funding of the project in 2015

[02(0228)/15/EMR-II]. M. R. Reddy is thankful to the IIT-Madras

for a Senior Research Fellowship (SRF). Funding from IITM,

through ERP proposal, CHY/17-18/850/RFER/INDR, is also

acknowledged.

Keywords: Weinreb amide•acyl-C-glucosides•benzyl-C-

glucosides•glucose uptake• GLUT4

NBDG uptake

[1]

[2]

F. H. Ziel, N. Venkatesan, M. B. Davidson, Diabetes1988, 37, 885–890.

R. A. Defronzo, E. Jacot, E. Jequier, E. Maeder, J. Wahren, J. P.

FelberDiabetes1981, 30, 1000–1007.

For differentiation of C2C12 myoblast into myotubes, the cells were

cultured in MEM with 2% FBS (differentiation medium) for 6 days. The

C2C12 cells (10⁴to 10⁵cells /ml) were seeded in 24 well plate, after the

cells reached 70% confluency, the differentiation media was added and

maintained in 5% CO2 incubator at 37˚C for 6 days. Once the elongated

myotubes were formed the cells were serum starved in low glucose (1%)

MEM without serum for 16 hrs. The differentiated mytotubes were then

treated with pioglitazone (5 µM), metformin (600 µM) and acyl and benzyl-

[3]

[4]

N. J. Bryant, R. Govers, D. E. James, Nat. Rev. Mol. Cell Biol.2002, 3,

267–277.

D. V. Zhang, B. Gino Salituro, Deborah Szalkowski, Zhihua Li, Yan

Zhang, Inmaculada Royo, P. G. Maria Teresa Diez, Fernando Pelaez,

Caroline Ruby, Richard L. Kendall, Xianzhi Mao, D. E. M. Jimmy

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

Calaycay, Juleen R. Zierath, James V. Heck, Roy G. Smith, Science1999,

284, 974–977.

Geng, A. Kumar, H. M. Faidallah, H. A. Albar, I. A. Mhkalid, R. R. Schmidt,

Bioorg. Med. Chem.2013, 21, 4793–4802. (d) A. Dondoni, P. Formaglio,

A. Marra, A. Massi, Tetrahedron2001, 57, 7719–7727. (e) A. Dondoni, A.

Marra, M. Mizuno, P. P. Giovannini, J. Org. Chem.2002, 67, 4186–4199.

[18] P. S. Eal, W. E. Childers, H. W. Pinnick, Tetrahedron1981, 37, 2091–

2096.

[5]

[6]

[7]

M. C. Pirrung, L. Deng, B. Lin, N. J. G. Webster, ChemBioChem2008, 9,

360–362.

D. K. Sharma, J. Pandey, A. K. Tamrakar, D. Mukherjee, Eur. J. Med.

Chem.2014, 85, 727–736.

(a) P. Lesimple, J. M. Beau, Bioorg. Med. Chem. 1994, 2, 1319–1330.

(b) O. Frey, M. Hoffmann, V. Wittmann, H. Kessler, Helv. Chim.

Acta.1994, 77, 2060–2069. (c) Y. Y. Belosludtsev, R. K. Bhatt, J. R. Falck,

Tetrahedron Letters1995, 36, 5881–5882.

[19] D. Frohne, Planta Med.1970, 18, 1–25.

[20] C. Li, Z. Wu, W. Chen, Nat. Prod. Res.2015, 29, 1793–1797.

[21] P. Migas, M. Krauze-baranowska, Phytochem Lett.2015, 13, 35–40.

[22] Q. Wen, X. Lin, Y. Liu, X. Xu, T. Liang, N. Zheng, K. Kintoko, R. Huang,

Molecules2012, 17, 12330–12340.

[8]

[9]

A. Dondoni, N. Catozzi, A. Marra, J. Org. Chem.2005, 70, 9257–9268.

M. R. Reddy, I. S. Aidhen, Eur. J. Org. Chem.2018, 5744–5753.

[23] S. Horita, M. Nakamura, N. Satoh, M. Suzuki, G. Seki, PPAR

Res.2015,1-6.

[10] M. Kolympadi, M. Fontanella, C. Venturi, S. André, H.-J. Gabius, J.

Jiménez-Barbero, P. Vogel, Chem - A Eur. J.2009, 15, 2861–2873.

[11] Y. Geng, A. Kumar, H. M. Faidallah, H. A. Albar, I. A. Mhkalid, R. R.

Schmidt, Bioorg. Med. Chem.2013, 21, 4793–4802.

[24] M. Komajda, J. J. V. McMurray, H. Beck-Nielsen, R. Gomis, M. Hanefeld,

S. J. Pocock, P. S. Curtis, N. P. Jones, P. D. Home, Eur. Heart J.2010,

31, 824–831.

[12] K. Harikrishna. ,Ph.D. Thesis, IIT Madras, 2014.pp. 171-199.

[13] (a) N. E. S. Guisot, I. Ella Obame, P. Ireddy, A. Nourry, C. Saluzzo, G.

Dujardin, D. Dubreuil, M. Pipelier, S. Guillarme, J. Org. Chem.2016, 81,

2364–2371. (b) I. Ella Obame, P. Ireddy, N. E. S. Guisot, A. Nourry, C.

Saluzzo, G. Dujardin, D. Dubreuil, M. Pipelier, S. Guillarme, Eur. J. Org.

Chem.2018, 2018, 1735–1738.

[25] R. A. Lubet, S. M. Fischer, V. E. Steele, M. M. Juliana, R. Desmond, C.

J. Grubbs, Int. J. Cancer.2008, 123, 2254–2259.

[26] D. Galuska, L. A. Nolte, J. R. Zierath, K. Hospital, Diabetologia1994, 37,

826–832.

[27] R. P. Nankar, M. Doble, J. Funct. Foods.2015, 15, 1–10.

[28] B. I, X. H, B. GA, S. SR, Diabetes care2004, 1660–1667.

[29] S. Yasmin, V. Jayaprakash, Eur. J. Med. Chem. 2017, 126, 879–893

[30] G. Zhou, R. Myers, Y. Li, Y. Chen, X. Shen, J. Fenyk-Melody, M. Wu, J.

Ventre, T. Doebber, N. Fujii, et al., J. Clin. Invest.2001, 108, 1167–1174.

[31] S. Rice, L. J. Pellatt, S. J. Bryan, S. A. Whitehead, H. D. Mason, J. Clin.

Endocrinol. Metab.2011, 427–435

[14] (a) C. Zhao, X. Jia, X. Wang, H. Gong, J. Am. Chem. Soc.2014, 136,

17645–17651. (b) X. Jia, X. Zhang, Q. Qian, H. Gong, Chem.

Commun.2015, 51, 10302–10305.

[15] F. Zhu, J. Rodriguez, S. O’Neill, M. A. Walczak, ACS Cent. Sci.2018, 4,

1652–1662.

[16] M. D. P. Risseeuw, J. Mazurek, A. Van Langenvelde, G. A. Van Der

Marel, H. S. Overkleeft, M. Overhand, Org. Biomol. Chem.2007, 5, 2311–

2314.

[32] N. Yu, X. Fang, D. Zhao, Q. Mu, J. Zuo, Y. Ma, Y. Zhang, F. Mo, D. Zhang,

G. Jiang, et al., PLoS ONE2017, 1–16.

[33] S. Rice, L. J. Pellatt, S. J. Bryan, S. A. Whitehead, H. D. Mason, J. Clin.

Endocrinol. Metab.2011, 427–435

[17] (a) F. Labéguère, J.-P. Lavergne, J. Martinez, Tetrahedron Lett.2002, 43,

7271–7272.Another methods for the synthesis of 1-formyl--C-glucoside:

(b) S. Sipos, I. Jablonkai, Carbohydr. Res.2011, 346, 1503–1510. (c) Y.

10.1002/ejoc.201901037

European Journal of Organic Chemistry

FULL PAPER

Entry for the Table of Contents (Please choose one layout)

Layout 1:

FULL PAPER

Text for Table of Contents (about 350

characters)

Key Topic*

Author(s), Corresponding Author(s)*

Page No. – Page No.

Title

((Insert TOC Graphic here: max.

width: 5.5 cm; max. height: 5.0 cm;

NOTE: the final letter height should

not be less than 2 mm.))

*one or two words that highlight the emphasis of the paper or the field of the study

Layout 2:

FULL PAPER

Acyl and benzyl-C--D-glucosides*

Dr. Mannem Rajeswara Reddy, Dr.

Shanmugam Hemaiswarya, Dr.

Harikrishna Kommidi, Prof. Indrapal

Singh Aidhen*, Prof. Mukesh Doble *

Page No. – Page No.

A convenient and scalable approach was developed for the synthesis of acyl-C--

D-glucosides and benzyl-C--D-glucosides using Weinreb amide (WA) functionality.

Addition of organometallic reagents followed by chemo selective deprotection afford

the acyl-C--D-glucoside and complete reduction of the same could resulted the

benzyl-C--D-glucosides. The synthesis and biostudies of envisaged C-glucosides

are presented in this paper.

Acyl and Benzyl-C--D-Glucosides:

Synthesis and Biostudies for

Glucose-Uptake Promoting Activity in

C2C12 Mytotubes

*one or two words that highlight the emphasis of the paper or the field of the study

Article Doi

Acyl and Benzyl-C-β-D-Glucosides: Synthesis and Biostudies for Glucose-Uptake-Promoting Activity in C2C12 Mytotubes

DOI: 10.1002/ejoc.201901037

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201901037

Full text of DOI:10.1002/ejoc.201901037

Products guided by the article

R&D Labs maybe for 1188523-22-9

Relevant to this article

Hot Product