Synthesis of derivatives of 5-thio-l -idose

Carbohydrute Reseurch ,2 I6 ( I99 I ) 1 I9- I 2X Elsevier

Science

Publishers

Synthesis

of derivatives

Neil A. Hughes:,

Namboole

Department of‘ Chemistry, (Received

November

119

B.V.. Amsterdam

of 5-thio-L-idose*,+

M. Munkombwe,

The Uniwrsity, Newustk

26th,

1990; accepted

and Nigel D. Todhunter

upon Tyne NE1 7RU (Greur Britainj

for publication

I I th. 199 I)

January

ABSTRACT

1,2-a:5.6-S,O-Di-isopropylidene-5-thio-~-L-idofu~nose

(6) was synthesised

lidenc-3,5,6-tri-O-methanesulphonyl-~-~-glucofuranose

(1). Hydrolysis

I .6-anhydro-5-thio-/-L-idopyranose

as the respective

of 6 gave methyl of 6 gave conformation anomer

5-thio-x-

methyl

(13) character&d

(8) and jkidopyranoside

in solution

thio-/i-L-idopyranoside

(16).

Both

and gave the 2,3:4,6-di-O-isopropylidene

19 was less stable towards

acid than the a anomer

(23), characterised

acetates

(7), but methanolysis

3,6-anhydro-5-thio-a-L-talopyranoside

as the respective

1,2-O-isopropy-

5-thio-L-idose

(11) and

12 and 14. Methanolysis

of the 3-methanesulphonate

7 and

acetals

18. Methyl

from

of 6 yielded

8 adopted

(5)

the unusual

19 and 18, respectively.

‘C, The /J’

2.3- (22) and 3,4-O-isopropylidene-5-

diacetates

20 and 21, were also obtained

from 7.

INTRODUCTION

Some aspects

of the chemistry

Owen in one of the first papers features

of idopyranoid

investigation3m5.

The replacement

derivatives

idose, its methyl

(11) were described

on “sulphur-in-the-ring”

derivatives

effects on the conformational pyranoid

of 5-thio-L-idose have

of oxygen

been

sugars’.

the subject

by sulphur

by Adley and

The conformational

of much

in the pyranoid

comment

and

ring has marked

equilibriah,7

and, therefore,

it was of interest

to synthesise

of 11 and to study

these equilibria.

We now report

on Sthio-L-

glycosides,

and the isopropylidene

derivatives

of these compounds.

DISCUSSION

Most present

syntheses

of 5-thiohexoses

have

involved

(11) and its derivatives

route to 5-thio-L-idose

5,6-epithio

derivatives*.

is closely related

The

to that of Adley

of the readily available’ trimesylate 1 and contains of Sthio-D-glucose and Sthio-D-allose. features employed in the syntheses” Selective displacement of the primary sulphonate group in 1 with potassium and Owen’,

but takes advantage

thiobenzoate

(the thioacetate

with sodium

methoxide,

derivative

3. Opening

* Dedicated

to Professor

was less effective) gave the 6-thiobenzoate

2 underwent of the thiirane

Grant

Buchanan

debenzoylation

and cyclisation

ring in 3 with refluxing

on the occasion

’ 5-Thiopyranoses, Part 13. For Part 12, see ref. 1. t To whom correspondence should be addressed.

2. On treatment to give the thiirane

acetic acid-acetic

of his 65th birthday.

anhydride

I

R

:=

9s=

”

AC

11n

=

H

12 R

=

AC

5-THIO-L-IDOSE

DERIVATIVES

stances. However,

121

Auge and David’indicated

preponderant than predicted previously be Sq than ‘C,. For L-ido derivatives, respectively.

Thus, the replacement

with the 4C, conformation In the major/?

of oxygen by sulphur

resulted

7. CH,OH

in a marked

and MeO-1 are syn-diaxial

is less adverse in a 5-thiopyranoside

change,

tion in 7 and 8 would be destabilised of a/3-oxygen

and, as pointed

than in a normal

because of the greater length of the C-S bond. Moreover, interaction

should be more

being favoured.

anomer

earlier’, this situation

that the 4C, conformation

and that the other conformer was more likely to these conformations become ‘C,, ,‘I$, and 4C,,

the alternative

by the “hockey-stick”

out

pyranoside

‘C, conforma-

effect” i.e., the syn-diaxial

with the axial lone pair of the sulphur.

A similar situation

was

reported for a “nitrogen-in-the-ring” sugar, 5-benzyloxycarbonylamino-5,6-dideoxy3-O-methanesulphonyl+L-idopyranose, which also exists in the ‘C, form in solution. The anomers 7 and 8 gave the tetra-acetates 9 and 10, respectively, but only the former was crystalline. Hydrolysis 5-thio-L-idose

of 6 with hot aqueous

(11) appeared

acetic acid gave a syrupy

to be the major

component

mixture

(six major

in which

13C signals

with

chemical shifts typical of a 5-thiohexose; Table 11). Comparison of the chemical shift data with those of 7 and 8 suggested that the major product was the /I anomer II/?. The syrup

was acetylated

to yield, after chromatography,

though the major product indicated raphy

a 3:l mixture

appeared

of two penta-acetates.

failed to separate

two crystalline

to be homogeneous

the isomers,

Repeated

but the major

products.

in t.l.c., its ‘H-n.m.r. crystallisation

component

Al-

spectrum

or chromatog-

appeared

to be (‘H-

n.m.r. data) 1,2,3,4,6-penta-Gacetyl-5-thio-/J-L-idopyranose (12@), which also adopted the 4C, conformation (J,,z 3.2, Jz.? 9.8, Ji,J 9.8, J,,, 1.O Hz). The minor component was identified tentatively as the 3 anomer 12cr on the basis of the J,., value of 7.3 Hz and consideration

of the n.m.r. spectra

of 9 and 10. Adley and Owen’ also found

5-thio+-

idose (II) to be a syrup, acetylation of which gave two crystalline penta-acetates in the ratio 12: 1. However, no ‘H-n.m.r. data were given and, as the nature of the product now reported possible

became

clear only with the availability

that the products

proportions

crystalline

on hydrolysis

product

of high-field

‘H-n.m.r.

by Adley and Owen were mixtures

of 12~ and 12p (see Experimental

The minor ucts obtained

described

isolated

for a comparison after acetylation

it is

of the properties). of the mixture

of 6 with acid was shown by its ‘H-n.m.r.

2,3,4-tri-0-acetyl-1,6-anhydro-5-thio-13-1.-idopyranose

spectra,

with different of prod-

spectrum

(14). The spectrum

to be

contained

only three signals for OAc and H-2,3,4 were axial (& 8.1 and J3,4 8.5 Hz). The J,,, value of 1.5 Hz indicated a planar W arrangement for H-l ,5 in equatorial positions of a 4C, conformation. The isolation of 14 indicated that the anhydrothio sugar 13 was present in the original

hydrolysate.

L-Idose is exceptional

among

the hexoses in that it readily

undergoes conversion into 1,6-anhydro-/&Id-idopyranose’4. but the formation of 13 was unexpected in view of the increased separation of C-l and C-5 in the necessary 4C, conformation. The corresponding 1,6-epithio compound 15 has been reported15, C-l and C-6 are more easily linked because of the larger sulphur atom. The acid-catalysed

methanolysis

of the diacetal

mesylate

but

5 gave a complex

4.80

21

” 1,3-Dioxolane.

” IJDioxane.

4.59

4.34

4.06

49.1 46.6 48.5 37.6 38.3 42.4 41.9

C-5 63.1 62.2 63.7 60.0 60.7 63.0 64.9

C-6

” In D,O.

3.42

3.36

3.36

region.

4.11

5.09

4.33

’ In D,O.

77.6.76.6,72.4 77.5,75.1,75.0 76.3,76.0,72.6 79.9,78.2,70.9 79.3,75.1,72.0 78.5.76.0.70.6 79.9.74.7.70.2

87.1 85.5 78.0 86. I 83.5 84.0 83.9

11

4.19

4.02

4.63

in the aromatic

5.06

3.92

3.85

I’ 8 11’ 18 19 20 21

TABLE

signals

4.69

20

’ Also showed

4.80

19

56.1 57.2 56.5 57.2

58.6 60.3

OMe

4.31

4.21

3.75

100.2 98.4

OKMe,”

111.8 109.6 109.3 109.3

OXMe,”

27.1,22.2 29.8,24.9

O,CMe,

3.3

(C-J 3.40 (OMe); 2.16,2.09 (OAc): 1.45,1.42 (CMeJ

2.4

2.6

(CMe,) 3.48 (OMe); 2. I I ,2.02 (OAc); 1.39,1.38

3.48 (OMe); 1.59,1.48,1.46,1.44

9.4

9.2

9.3

26.9,25.5 27.1,26.3 26.8,26.4 26.9.26.5

O,CMi?,

9.4

10.6

10.4

4.6

5.7

6.0

8.4

7.6

5.4

170.4.170.4 170.5,170.1

OCOMe

5.8

5.6

12.0

2 I .0,20.8 21.0,20.8

OCOMe

11.4

11.4

11.8

E

5-THI0-L-ID~SEDERIVATIVES

The instability diacetal18

125

of the /I-idoside

was reflected

acetals

formation

22 and 23, and a product of the 3,4-acetal23

to 7 was complete reaction stability

and

the a anomer

were detected

to that of the cc-idoside of the j? anomer

during

the glycoside

as the 4,6-acetal had occurred.

18 required

by the 2,3-acetal,

and the CMe2 groups. Both 18 and 19 are unusual

axial.

A similar

situation

in methyl

7, the 24. The

Hydrolysis

The relative

4,6-diacetals

from the 2,3-carbonate

of

in which C-6 is

4,6-O-benzylidene-cc-D-idopyranoside

was obtained

in-

locked in the

that is due to the interaction

in that they are c&fused

exists

but this compound

there is steric strain

19 in

18 h for complete

the hydrolysis.

19 may be due to the fact that, with the molecule

MeO-1

carbonate4,

identified

that acetal migration

in 20 min. In contrast,

of the panomer

“C’, conformation

tentatively

indicated

no monoacetals

compared For a solution

t.1.c. after 1 min revealed

aq. 80% acetic acid at room temperature, monoacetals

I921

in the rates of hydrolysis.

2,3-

which is locked in

the ‘C, conformation. In contrast, the ‘C, conformation in 7 and 8 is favoured. Treatment of either 7 or 8 with acidified acetone gave poor yields of complex mixtures. Under

these conditions,

yield”.

The lack of reactivity

the hydroxymethyl

methyl

of I%20 had chemical

It was not surprising from

the furanoid

5-thio-D-glucose

shifts that were outside

that 5-thio-r_-idose

2,2_dimethoxypropane which

gave the 4,6-acetal

in good

with the axial orientation

of

group, which may also be the reason why some of the ‘jC resonances

for the CMe, groups When

5-thio-a-D-glucopyranoside

of 7 and 8 must be associated

was added, 1,2:5,6_diacetal

gave the pyranoid

the expected

(11) did not react with acidified

11 was converted 6 was isolated.

into

a complex

Under

similar

ranges. acetone. mixture

conditions,

2,3:4.6-diacetal”.

EXPERIMENTAL

General methods. ~ corded

at 90 or 300 MHz

unless

otherwise

stated.

chromatography size of IO&200

Melting

points

are uncorrected.

(‘H) and 22.63 or 75.47 MHz

T.1.c. was performed

on Kieselgel

(Merck,

and a DVB content

N.m.r.

(‘C)

spectra

for solutions

on silica gel SA (Gelman)

7734). The Zerolit-FF

(HO-)

were rein CDCl,

and column

resin had a mesh

of 2-3%.

6-S-Benzo~I-1,2-O-isoprop~lidene-3,5-di-O-merhanesulphon~~-6-thio-~-~-g~uco-

furarzose (2). -

A mixture

of 1,2-O-isopropylidene-3,5,6-tri-O-methanesulphonyl-~-D-

glucofuranose’ (1, 9.0 g) and potassium thiobenzoate under reflux for 3 h, then cooled, filtered,

(4.5 g) in dry acetone (180 mL) to dryness. The

was heated residue

was partitioned

between

dried and concentrated, 85X), talc.:

m.p. 140-142”,

water

and concentrated

and dichloromethane,

and the residue was recrystallised [GI], + 35” (c 0.9, chloroform)

the organic

from ethanol

(Found:

phase

was

to give 2 (8.4 g,

C, 43.5; H, 4.8. C,,H,,O,,S

C, 43.5; H, 4.9%).

5,6-Dideo,~y-5,6-epithio-l,2-O-isopropylidene-3-O-methanesulphony/-~-L-idofuranose (3). ~ Sodium methoxide [from sodium (0.8 g)] in methanol (16 mL) was added slowly to a stirred mixture

was poured

solution

of 2 (8.2 g) in dichloromethane

into water

(100 mL), the organic

(82 mL). After

layer was separated,

15 min, the dried,

and

~-THIO-L-IDO~EDERIVATIVES

127

Eluted second was 1,2,3,4,6-penta-O-acetyl-5-thio-@-L-idopyranose (12; 0.13 g, 44X), m.p. 94-100” (from ethanol), [a], + 51’ (C 0.8, chloroform); 1it.lm.p. 9&92”, [r], +41”,andm.p.

1033104”,

[a], +76”(Found:

C,47.1;H,

5.4. C,,H2,0,,Scalc.:

C47.3;

H, 5.5%).

3,6-anhydro-5-thio-cr-L-tafopyranoside (16). - A solution of 5 (0.25 g) in cont. hydrochloric acid (0.5 mL) was heated under

Methyl

(5 mL) that contained

methanol

reflux for 3 h, then neutralised residue

(PbCO,),

in ethyl acetate-methanol

filtered,

was passed

and concentrated.

through

A solution

a short column

of the

of silica gel and

then concentrated to give 16 (22 mg, 16%), m.p. 148-150” (from ethyl acetate chloroform), [a], -88” (c 0.4, methanol) (Found: C, 43.7; H, 6.3. C,H,20,S talc.: 43.7; H, 6.3%). The diacetate 1.1, chloroform)

(17) of 16 had m.p. 11 l-1 12” (from di-isopropyl

(Found:

C, 47.7; H, 5.8. C,,H,,O,S

or C,

ether), [cI], - 84” (c

talc.:

C, 47.8; H, 5.8%). Methyl 2,3:4,6-di-O-isopropylidene-5-thi-~-L-idopyranoside (18). - A mixture

of 8 (80 mg) and toluene-p-sulphonic acid (60 mg) in acetone (5 mL) and 2,2-dimethoxypropane (1 mL) was stirred at 20” for 45 min, then neutralised (NaCO,), and concentrated, organic

the residue

layer was dried

petroleum)

was partitioned

between

and concentrated.

of the residue

yielded

[aID - 171” (c 0.8, chloroform)

dichloromethane

Column

18 (93 mg, 84%), m.p. 9697’ (Found:

and water, and the (I:2 ether-light

chromatography

(from light petroleum),

C, 53.6; H, 7.6. C,,H,,O,S

talc.:

C, 53.8; H,

7.6%). of methyl 5-thio-p-L-idopyranoside

Acetalation was treated sulphonic

with

acetone

acid as described

mL) and pyridine subjected methyl

and

above.

(1 mL). After

to column

(7). ~ The P-glycoside

2,2_dimethoxypropane The product

was acetylated

15 h, the solvents

chromatography.

in the presence

Elution

C,,H,20,S

talc.:

Elution

Eluted

with

1:2 ether-light

Mass spectrum:

petroleum

17%1), m.p.

C, 53.0; H, 7.2.

then gave syrupy

methyl 2,6-di-O-ace(21; 24 mg, 15%), [a], + 81” (c 1.O,

next was methyl

m/z 334.1077 (C,,H,20,S

talc. m/z 334.1086

for Mf).

4,6-di-O-acetyI-2,3-O-isopropylidene-5-thio-P-L-idopy-

ranoside (20; 27 mg, 17%), isolated spectrum: m/z 334.1082. Eluted

gave

C, 53.8; H, 7.6%).

tyl-3,4-O-isopropylidene-5-thio-~-L-idopyranoside chloroform).

(Found:

was

petroleum

(19; 23 mg,

[a], + 73” (c 0.8, chloroform)

(1

and the residue

I:4 ether-light

2,3:4,6-di-O-isopropylidene-5-thio-P-L-idopyranoside

112-l 14” (from light petroleum),

with acetic anhydride

were evaporated with

7 (100 mg) of toluene-p-

last was the tetra-acetate

as a syrup,

[cx], + 117” (c 1.5, chloroform).

Mass

9 (20 mg, 11O/o),m.p. 91-92” (see above). A crude sample of 11 [obtained from

Acetafation of 5-thio-L-idose (II). -

diacetal 6 (0.50 g)] was stirred with acetone, 2,2_dimethoxypropane, sulphonic acid as described above. Column chromatography (ether) yielded

6 (0.22 g, 44%) as the major

product

with m.p. and mixture

the

and toluene-pof the product m.p. 102~104”.

-

r!

n

-f

I,,

c

:-

r

>

-

=

_..

-

-

c-,

r-, _

t -_

‘i,

-

;

-

r -

% -