l glucose formation

7/23/2019 L Glucose Formation

1/4

L Glucose.A convenient synthesis from D glucose

WALTER . S ZA R EK , EOR GE . H AY ,D O L A T R A I. V Y A S , ' D W A R D. ISON,

A N D

L U C J A N

. J .

H R O N O W S K I

Cnrbohycirnte Recent-ch Irlstrtlrte ntlci Depdr-rtl~at~tf Chemistry Q u ee tl s U n i v e ~ s i t ~ .itzg~totz,Otlr., Catlncin

K7L

3N6

Received August 3 1983

WALTER

A. SZAREK,EORGE . HA Y.

DOLATRAI

.

VYAS,

E D W A R D

. ISON, and L U C JA N . J .

H R O N O W S K I .an.

J.

Chem. 62, 671 (1984).

L-Glucosehas been synthesized from D-glucoseby

a convenient

method involving methyl

2.3-0-isopropyl idene-K~-gulo-

furanosiduronic acid (6 ) as a key intermediate. Compound 6 was converted into L-g lucono-l 5-lactonc (8 ), which, by

a

selective reduction, afforded L-glucose (9 ).

WALTER . S ZAR EK,EORGE . HAY,DOLATR AI

. V Y A S,

E D W A R D. ISON t LUCJAN

J .

HRONO\VSKI.an. J . Chem.

62, 671 (1984).

On a

synthCtisC de f a ~ o n onvenable le L-gluc ose

i

partir du D-glucosepar une mCthode faisant appel I'intermCdiaire de

I'acide mCthyle 2 3-0-isopropylidene-P-D-gulofuranosiduronique6) . On a transforme le composC 6 en L-glucono-lactone- ,5

(8 ), qui conduit par

la

suite au L-glucose (9 ) par une rtduction sClective.

[Traduit par le journal]

ntroduction

The natural sugars occur with an enormous predomination of

one of the enantiomeric configurations, the other being rare or

purely artificial. There is, at present, a growing interest in the

study of the less-common enantiomers of the carbohydrates

because of their potential organoleptic, and other biochemical,

properties (1).

It has been known for more than a quarter of a century that

the L -isomer of certain hexos es elicits a taste similar to, and

frequently as intense as, the D-isomer

2).

Although there have

been claim s that L-gluco se occurs as a com pon ent of certain

complex carbohydrates (3), the evidence is inconclusive as yet.

Moreover, most studies of the metabolism of L-glucose by

microorganism s have indicated that it is not metabolized (4 ); an

enzy me catalyzing the ox idation of L-glucose has been isolated

from cell- free extracts of

Pseudomoizns caryophylii

I F 0

1

3694

(5). These data suggested that certain of the enantiomers of

naturally occurring sugars may be safe, effective, non-nutritive

sweeteners.

Th e synthesis of L,L-sucrose P-L-fructofuranosyl a-L-g luco-

pyranoside) in this laboratory (6) permitted this hypothesis to

be assessed. The compound was found to be not only indistin-

guishable in taste from natural sucrose ( 6) but also resistant to

hydrolysis catalyzed by the sucrase of the jejunal brush border

mem brane of the hamster (7 ). These ob servations indicated that

L-sugars may be useful as non-caloric or low caloric sweet-

eners. The need for an improved method for the synthesis of

L-glucose stimulated the investigation reported below.

The first reported chemical syn thesis of L-glucose was that of

Fischer

(8)

who prepared the compound from L-arabinose by a

Kiliani synthesis. Since then each of Richtmyer and Hudson

9)

and ~ o w a10) has published a synthesis of L-glucose starting

from D-g lucose by way of a chain extension and subs equent

degradation. In addition, Takahata

et a/

(1 1) produced racemic

glucose in low yield from a complex reaction of ethylene car-

bonate, tetrachloromethane, and sodium cyanide. However,

none of these procedures has gained the relatively extensive

application achieved by that of Sowden and Fischer (12) who

prepared L-glu cose from L-arabino se by conden sation w ith ni-

trom ethan e, hydrolysis of.the l -deox y- -nitroalditols, and sep-

Present address: Bristol Laboratories, Syracuse,

NY

13201,

U.S.A.

HCO

I

\ Cwe

tJ2c0

HCOHp e

MQ2

HzCOH

p

HCOH C

Me2

CO2H

aration of the L-m annose and L-glucose so produ ced. T h

present paper describes a new synthesis of L-glucose from

D-glucose which d oes not invo lve chain extension.

Results and discussion

The synthesis of L-glucose from D-glucose that is describe

in this paper involv es the intermediacy of a D-gluco se deriva

tive and is an attractive one from the point of view of both th

operational simplicity and the low costs of reagents.

The acid-catalysed conversion of 1 nto

2

is a facile, routin

method (13) which afforded the required intermediate com

pound (Scheme 1) in satisfactory yield. The synthesis the

required the oxidation of

2

and treatment of the resultant prod

uct with acetic anhydride in pyridine to afford the en01 acetat

3 followed by reduction of 3 to give 1,2:5,6-di-0-iso

propylidene-a-D-gulofuranose

(4 ) . Although 2 could be ox

idized to 1,2

5 6-di-0-isopropylidene-a-D-ribo-hexofura

3-ulose hydrate in 95 yield using dimethylsu lfoxide and ace

tic anhydride

(14),

the reduction of 3 which was prepared fro

the oxidation product ( l5 ), was inhibited, presumably by trace

of dimethylsulfoxide or dimethylsulfide which would poiso

the catalyst. Consequently, the ulose hydrate was prkpare

from

2

by catalytic oxidation (16) using a ruthenium tetraoxid

catalyst (17 ), a method which gave only minor side product

c om pound

3

could be reduced quantitatively to 3-0-ac ety

1,2

5 6-di-0-isopropylidene-a-D-gulofuranose

y the metho


2/4

672 CAN.

I.

CHEM. \

of Lemieux and Stick (18) using a palladium-on-carbon cata-

lyst, and the product was deacetylated to afford

4.

Treatment

of compound

3

with sodium borohydride gave lower yields as

a result of a comp eting , base-catalyzed @-elimin ation which

afforded 4,5-unsaturated compo unds (15, 19). Even in buffer-

ed reaction solutions only moderate yields of product (4) were

obtainable using sodium borohydride.

The acid-catalyzed hydrolysis of

4

to give 1 ,2-0-isopropyli-

dene-a-D-gulofuranose was

investigated.

The influence of

structure on the relatlve ease of hydrolysis of acetal rings has

been well documented (20) and the conditions for the selective

removal of the 5,6-0-iso prop yliden e group of such compound s

as 2 (2 ) , and the 1,2

:

5,6-di-0-isopropylidene acetals of

L-idose (22) and D-allose (23), have been defined. Brimacom be

et al.

(24 ) have reported that the use of 70% acetic acid for the

selective hydrolysis of 3-acetamido-3-deoxy- 1,2 5,6 -di- 0-is o-

propylidene-a-D-gulofuranose

gave the desired pro duct, name-

ly 3-acetamido-3-deoxy- 2-0-isopropylidene-a-D-gulofuran-

ose, but that it was mixed with both the starting compound and

the free acetamido sugar. Similarly, it has been reported (25)

that selective deacetalation of 1,2

5 6-di-0-isopropylidene-

a-D-g ulofu rano se could not be achieved, but that the corre-

sponding 3-0-benzyl derivative could be converted into

3-0-benzyl- 2-0-isopropylidene-a-D-gulofuranose n 55%

yield by treatment with aqueous acetic acid in 1,4-dioxan e. The

rationalization of these data is, at present, inadequate.

A

range

of acidic conditions was explored in an attempt to effect the

conversion of 4 into 1 , 2 - 0 ~ i s o ~ r o ~ ~ l i d e n e - ~ - ~ u l o f u r a n o s e ,

but in each case the major product was the free sugar.

Th e high-yield conversion of D-glucose into methyl 2,3 -0 -

isopropylidene-P-D-gulofuranoside 5) had been shown (26) to

proceed through the intermediacy of methyl 2,3:5,6-di-0-

isopropylidene-P-D-gulofuranoside. his selectivity in hydro-

lysis was noted (27) also in the preparation of methyl 2,3-0-

isopropylidene-a-D-mannofuranoside

from methyl 2,3

:

5,6-

di 0 isopropylidene a D mannofuranoside

owever, methyl

2,3

:

5 6-di-0-isopropylidene-@-D-mannofuranoside

as much

more sensitive to acid and selective hydrolysis was unattainab le

(27). In the present work, the reaction of

4

with methanol,

2,2-dimethoxypropane, acetone, and hydrochloric acid pro-

duced 5 in high yield.

Th e catalytic oxidation of 5 to 6 was effected by the method

of Perlin

et al.

(28), using a platinum-on-carbon catalyst in an

aqueous reaction medium at 50C. The pH of the reaction

solution was monitored continuously and maintained at 7.5 by

the addition of small increments of sodium hydrogen carbonate

until a stoichiometric quantity had been utilized. Compound

was isolated in 9 yield as its sodium salt, and characterized

by conversion (29) into its dicyclohexylammonium salt and

into L-glucono-1 4-lactone. The lactone was obtained by the

conversion of 6 into barium D-guluronate, which was con-

verted, using sodium borohydride, into L-gluconic acid, the

lactonization of which afforded the product. Perry and Hu-

lyalkar (30) have established a gas-liquid chromatog raphic

technique for the unambiguous characterization of glycono-

1,4-lactones. The sample of L-glucono-1 4-lactone prepared

from 6 exhibited a retention tim e identical to that of an authen -

tic reference sample, obtained by way of acid-catalyzed hydro-

lysis of alginic acid (3

,

but clearly distinguishable from those

of authentic samples of

D-galactono-l 4-lactone

-glucono-

1,5-lactone, D-gulono- ,4-lacto ne, and D-mannono- 1,4-

lactone (32).

The synthesis now required the preparation of L-glucono-

CHO

6

COH

HCOH

I

HOjH OH OH

1,5-lactone (8) (Scheme 2) . Thus, methyl 2,3-0-isopr

idene-P-D-gulofuranosiduronic cid (6) was subjected

acid-catalyzed hydrolysis, and the resultant product

7

reduced by hydrogenation over Raney nickel; from the pr

solution, crystalline L-glucono-1 5-lactone ( 8) was obtain

the method of crystallization described by Isbell and Frush

for the D-enantiomer of 8. Catalytic reduction of 8 b

method of Glattfeld and Schimpff (34) afforded L-gluco

only in low yield. Consequently, the method of Wolfrom

Thom pson (35), using sodium borohydride, was employe

a high yield of 9 was obtained. The product 9 had a me

point in agreemen t with that of D-glucose and exhibite

expected specific rotation; the ir and 'Hmr spectra were

tinguishable from those of D-glucose. Thus, the conversi

D-glucose into L-glucose has been achieved in an unoptim

overall yield of 12%.

Experimental

Melting points were determined on a Fisher-Johns apparatu

are uncorrected. Optical rotations were measured with a Pe

Elmer model 141 automatic polarimeter at 23 + 3C. Infrared s

were recorded with a Beckman Acculab 6 or a Perkin-Elmer

spectrophotometer. The 'Hmr spectra were recorded on a B

HX-60 (6 0 MHz) or a Bruker CXP -200 (200 MHz) spectromete

tetramethylsilane (TM S) as the internal standard; chemical shi

are given in ppm downfield from TMS. Thin-layer chromatog

(tlc) was performed using Merck plates precoated with silica

F-254 in the following solvent systems (v/v): (A) ethyl ace

benzene, 1: 1; (B) ethyl acetate; C) I-propanol ethyl ace

water, 3 : 1 : 1. The developed plates were dried and com poun

cated by heating the plates at 50C after they had been spraye

10% aqueous sulfuric acid containing 1% cerium sulfate and

molybdic acid.

I

2 :5 6-Di-0-isopropylidene-a-D-glucofrose

2)

The acetalation of anhydrous

1

(200 g) by the method of S

(13) produced

2

(160 g, 55% ), mp 108- 110C;

{a ,

13.6 (

CHCI,) (lit. (13, 21) m p 110- 11 1C, {a , 3.5 (CHCl,)).

3-0-Acetyl-1,2 :5 6-di-0-isopropylidene-a-D-erythro-hex-

3-enofuranose

3)

The oxidation of 2 (10 g) with ruthenium tetraoxide in the pr

of potassium periodate (17) gave

1 2:5 6-di-0-isopropylide

ribo-hexofuranos-3-ulose

hydrate (13) (9.5 g), mp 109- 110C

+ 3 9 S0 (c 1.5, CHC1,). The last named compound (6.1 g) wa

verted into (15) (5.2 g, 75%), mp 62-63 C,

{a ,

32.7

CHCl,), by treatment with pyridine and acetic anhyd ride as des

by Meyer zu Reckendorf (15).

1 , 2

:5 6-Di-O-isopropylidene-a-~-gulofura1~0e

4 )

The reduction of (4.2 g) by the action of 5% palladium-on-

in a hydrogen atmosphere (room temperature, atmospheric pre

(1 8) afforded 3-0-acetyl- l , 2

5 6-di-0-isopropylidene-a-D-

anose (36) (4.2 g), m p 72-74 C,

+6 6S 0 (c 1.5, CHCI,),

sample of which was deace tylated by stirring with Am berlite IR

anion-exchang e resin (OH- form) (18) for 40 h at room temp e

(-20C) to give aquan titative yield (2.5 g) of 4 (15), mp 103-

{a , 9.8 (c 2.0, CHCI,).


3/4

SZ ARE K ET AL . 6

Melhyl

2,3-O-isoprop ~lidet1e-P-~-g1tIqfitrat1oside

5)

A solution containing 4 (500 mg) in 2.2-dirnethoxypropane (1.6

mL ), acetone (1.35 mL ), methanol (1.3 5 mL ), and concentrated hy-

drochloric acid (0.04 mL), was heated at reflux temperature for 2 h

(26). The solution was cooled to room temperature, diluted with water

(4 mL), and the organic solvents were removed under reduced pres-

sure at 3SC. A white precipitate formed in the residual aqueo us phase;

this was dissolved by the addition of methanol (4 mL). Thin-layer

chromatography of this solution revealed the presence of a new com-

ponent (Rc 0.89, solvent A), but no

4

(R, 0.58, solvent A) was de-

tectable. Concentrated hydrochloric acid (1 mL) was added and the

formation of product (R' 0.2, solvent A) was monitored by tlc (-3 h

at room temperature). 'The solution was neutralized with aqueous

sodium hydrogen carbonate, concentrated to -5 mL , and extracted

with chloroform (3 X 5 mL). The aqueous layer was saturated with

sodium chloride and extracted with chloroform (3 X 5 mL). The

combined extracts were dried (anhydrous sodium sulfate) and evapo-

rated to a syrup from which there were obtained 340 mg (76%) of

crystalline 5 (26), mp 77-79C (from CHC1,- hexane); {a), -82.8

(c 1 .2 , CHjOH).

Meflzyl

2,3-O-isopropylidene-~~-gulo~tranosiclt1ic

c id 6)

To an aqueous solution (500 mL) of 5 (9.3 g) was added 10%

platinum-on-carbon (0.9 g). A pH electrode was immersed in the

mixture and a stream of oxygen w as passed through the liquid at a rate

sufficient to keep the catalyst uniformly suspended. The reaction

mixture was held at 55-60C, and the pH maintained at 7. 5 by the

addition, as required, of solid sodium hydrogen carbonate (2.19 g,

total). After 5 h,

4

was not detectable by tlc (R, 0.51 , solvent

B) ,

but

a new compound (Rr 0. 50 , solvent C) was observed. Evaporation of

the reaction solutio n, after filtration, afforded 9 .8 g (91% ) of 6 (sodi-

um salt), {a), -82.5 (c 1.5, HzO); v (KBr): 1590 (COO

-

m - ' ;

'Hmr (60 MHz, DMSO-(I6) 6: 1.3 and .5 (s 's , 6H, CM e2), 3.3 (s ,

3H, OMe), 3.6-4.2 (4H, H-4, H-5, 2 OH'S), 4.5 (d, I H,

JZ .?

6 Hz,

H-2), 4 .7 (dd, lH ,

J .

2.5 HZ, H-3) , 4 .9 (s , IH, H -I) .

Compound

6

(sodium salt) decomposed before melting and was

further characterized by treatment with dicyclohexylamine as de-

scribed by Zissis el al. (29) to give 6 (dicyclohexylammonium salt),

mp 158- 159C; {a) -45.9 ( c 0.5, HlO); v ; (KBr): 3400 (OH ),

1620, 1540 (COO--) cm -'; 'Hmr (60 MHz, CDCI,) 6: 1.2 and 1.4

(s 's , 6H, CMez), 1.4-2.3 (22H, cyclohexyl protons), 1.5 (s , 3H,

OM e), 4.7 (s, IH, H-I ). Anal. calcd. for C22H3707: C 51.7 7, H 5.62;

found: C 52.01, H 5.66.

A solution of 6 (sodium salt) (650 mg) in water (5 mL) was heated

on a steam bath for 3 h with Amberlite IR-120 cation-exchange resin

(H + form) (5 m L). The resin was removed by filtration.

he-filtrate

was neutralized with barium carbonate and evaporated to give the

barium salt (540 mg) of D-guluron ic acid

7)

as a light-yellow solid,

{q), -24.7' (c 2.0, HzO); v (KBr): 1595 (COO-) cm-'. 'The

barium salt was converted, using sodium borohydride, into L-gluconic

acid, w hich was then identified in the form of L-gluco no-l ,4-lactone

by gas-liquid chromatog raphy (see ref. 32) as described by Perry and

Hulyalkar (30).

Acidification of a cold (


4/4

674

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l glucose formation

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