Synthetic Methods for Carbohydrates

12 Synthesis of Polyhydroxyalkyl Heterocycles F. GARCIA GONZALEZ and J. FERNANDEZ-BOLAÑOS Universidad de Sevilla, Spain

Downloaded by UNIV OF BATH on July 2, 2016 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0039.ch012

F. J. LOPEZ APARICIO Universidad de Granada, Spain

Aldoses and ketoses react with β-dicarbonyl compounds giving polyhydroxyalkylfurans of type I and II. This reaction has been generalized by García González (1) who showed that the condensation product of D-glucose with ethyl acetoacetate was 3-ethoxycarbonyl-2-methyl-5-(D-arabinotetrahydroxybutyl)furan (I, R = Me; R = OEt) (2,3). 1

2

The reaction was originally carried out by heating the reactants with zinc chloride in a non aqueous medium, however it was also shown that the reaction occurs in aqueous alcohol at room temperature in the presence of metallic salts or hydrochloric acid and even without the addition of any specific catalyst (4). The condensation reaction has been achieved with various dicarbonyl compounds and different sugars since carbon atoms 1 and 2 from the sugar become integrated in the heterocycle the value of n in the polyhydroxyalkyl substituent depends on the sugar chain length. 5-D-arabinotetrahydroxybutyl- and 5-D-lyxotetrahydroxybutyl-furans were obtained from D-glucose (2-8) and D-galactose respectively (9,10). The nature of substituents R and R depends on the dicarbonyl compound. Furans having R = Me, Et, n-Pr, i-Bu, Ph or CH2-COOEt and R = OEt, OMe or Me have been prepared. The pentoses, D-xylose, D- and L-arabinose and D-ribose have been reacted with ethyl acetoacetate and diethyl 3-oxoglutarate to give trihydroxypropylfurans (9,11-14) with D-threo and D- (or L-) erythro configurations. In the same way, the D-glycero-D-gulo-heptose and the D-gly-1

1

2

207

El Khadem; Synthetic Methods for Carbohydrates ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

2


208

SYNTHETIC METHODS FOR CARBOHYDRATES

cero-D-gluco-heptose were reacted with ethyl (methyl) acetoacetate and 2,4-pentanedione (acetylacetone) giving pentahydroxypentyl furans. The reactions have been performed (15,16) in aqueous alco holic solution at 50°during 15 days, and the isolation of the condensation products has been made by chromatography on cellulose columns or by fractional crystalization. D-Fructose and L-Sorbose reacted with ethyl acetoacetate and propionylacetate giving 4-tetrahydroxybutylfurans (II, n = 3). The isolation was effected by extraction of the products of the reac tion with ethyl acetate (17). The acetylation of the polyhydroxy furans was also studied (18). The structure of the condensation products was established by oxidation with periodic acid or sodium metaperiodate. They gave formadehyde, formic acid and 5- (or 4-) formylfurans which could be transformed into other furan deriva tives by the usual synthetic methods. In a previous review (1) the furan derivatives have been tabulated. Polyhydroxyalkylpyrroles• The reaction of 2-amino-2-deoxyaldoses and 1-amino-1-deoxy ketoses, and their l\[-alkyl and N-aryl derivatives, with /3-dicarbonyl compounds was found to give pyrrole derivatives of type III and IV. Pauli and Ludwig (J9) found that when 2-amino-2-deoxy-DHC II CH0H-(CH0H)-C 2

C-CO-R3 II C-R

n

(III)

2

CHoOH-iCHOH)-C II HC

C-CO-R3 II C-R

n

R

1

(IV)

2

R

1

glucose was heated with an excess of j i -dicarbonyl compounds such as ethyl acetoacetate or 2,4-pentanedione, give condensation products that were given the structure of ethyl 2-methyl-5-{D-arabino-tetrahydroxybutyl)-pyrrole-3-carboxylate ( i l l , R = Me, Ri = H, R3 = OEt) and 3-acetyl-2-methyl-5-P-arabino-tetrahydroxybutyl-pyrrole ( i l l , R/j = H, R = Me, R3 = MeJ ! This reaction has been generalized by Garcia Gonzalez, Gomez Sanchez and coworkers (20) by varying the aminoaldoses and the j3 -dicarbonyl compounds. The reaction was conducted in aqueous acetone solution at neutral pH and room temperature. By reacting 2-amino-2-deoxy-D^glucose and its N^alkyl derivatives several 5-(D,-arabinotetrahydroxybutyl)pyrroles have been obtained having Ri = H, Me, Et, n-Pr, η-Bu or CHPh; R = Me, Et, n-Pr, H or CHC00Et and R = OEt, SEt, Me or Ph (21-36). Their structures have been established by degradative oxidations, preparation of derivatives and ultraviolet and infrared absortion spectroscopy. Similarly pyrroles of type IV have been obtained by reacting of 1-amino-l-deoxy-D^fructose and 1-alkyl (aryl)-amino-1-deoxy-D^ fructoses with β -dicarbonyl compounds. Depending on this last 2

2

:

2

2

2

3


12.

GONZALEZ

E T A L .

Polyhydroxyalkyl

209

Heterocycles

compound the r a d i c a l s introduced i n the furan where as f o l l o w s : R/| = H, η-Bu, C H C 0 0 E t , C H ^ H s , p-CH C6H , P-CH3UC5H4 o r pC2H5UC6H4; R = Me, H or C H C 0 0 E t and R = OEt, S E t , C H o r Me (26, 2 8 , 3 6 , 3 9 ) . More r e c e n t l y the s y n t h e s i s o f p o l y h y d r o x y a l k y l . p y r r o l e s has been extended to t r i h y d r o x y p r o p y l and pentahydroxypentyl p y r r o l e s . The 2 - m e t h y l - 3 - e t h o x y c a r b o n y l - 5 - f D - e r y t h r o t r i h y d r o x y p r o p y l ) p y r r o l e ( I I I , Ri = H, R = Me, R3 = OEt, η = 2 j has been prepared by r e a c t i n g the epimeric p a i r o f 2-amino-2-deoxy-D-arabinose and 2-amino2-deoxy-Dj-ribose with e t h y l acetoacetate ( 4 ϋ ) . The 1-benzyl-2-methyl-3-ethoxycarbonyl-4-L-erythrotrihydroxypropyl and the 1-n-propyl(1-n-butyl, 1-benzyl)-2-methyl—3-ethoxyc a r b o n y l - 4 - D - t h r e o t r i h y d r o x y p r o p y l p y r r o l e s have been obtained by r e a c t i n g the corresponding 1-alkylamino-1-deoxypentuloses with e t h y l acetoacetate ( 4 0 ) . The 2-methyl-3-ethoxycarbonyl-5-D-galact o f P - g l u c o , D-mannol-pentahydroxypentyl-pyrroles are obtained by r e a c t i n g the 2-amino-2-deoxy-D-glycero-j_-manno-heptose, 2 - a m i n o - 2 deoxy-D^glycero-D-gulo-heptose or 2-amino-2-deoxy-D-glycero-D talo -heptose with e t h y l acetoacetate ( 4 l J . The s t r u c t u r e o f a l l these polyhydroxyalkyl p y r r o l e s have been e s t a b l i s h e d by o x i d a t i v e degradation with sodium metaperiodate and o x i d a t i o n o f the corresponding p y r r o l e aldehydes, as well as by p o l a r i m e t r y and UV and IR spectroscopy. P o l y h y d r o x y a l k y l p y r r o l e s have been a l s o obtained by r e a c t i o n of glycosylamines with β - d i c a r b o n y l compounds. Thus β -JD-Glucopyranosylamine ( v ) , N-n-butyl-D-glucosylamine and s e v e r a l ^N-arylD-glucosylamines were found to r e a c t with e t h y l acetoacetate and 2,4-pentanedione i n methanol c o n t a i n i n g c a t a l y t i c amounts o f p i p e r i d i n e g i v i n g e t h y l 2-methyl-4-fD-arabinotetrahydroxybutyl) p y r r o l e - 3 - c a r b o x y l a t e ( V i a ) , 3-ac et yl-2-meth y l - 4 - ( D - a r a b i no te t r a hydroxybutyl) p y r r o l e (Vlb) and N - s u b s t i t u t e d p y r r o l e s (27 3 6 ) • 2

3

2

4

2

3

6

5


2

r

CH 0H 2

CH OH 2

CH C0CH C0R 3

2

^

J

C

\ _ _ r '

H

°M\

(VII) CH 0H- Γ CHOH ) -C 2

C-CO-R

q

II HC V i a , R = OEt

II X N /

'

C-CH

3

ή

b, R = Me r u c

t o s

r

( V I I l ) i J^-ethyl-ID-fructosyl r e a c t e d with e t h y l acetoace-

l a m i n e

In a s i m i l a r way, D " ^ ' y amine and N^-benzyl-D-fructosylamine


210


t a t e and 2 4—pentanedione g i v i n g e t h y l 2-methyl-5-fD-arabinotetrah y d r o x y b u t y l ) p y r r o l e - S - c a r b o x y l a t e ( i X a ) , 3-acetyl-2-methyl-5-(Da r a b i n o t e t r a h y d r o x y b u t y l ) p y r r o l e (iXb) and the corresponding Nsubstituted pyrroles (27,36). #

\


OH

^

Ν Η

2

+

CH C0CH C0-R 3

CH3

2

(VIII)

, II CH 0H-(CH0H)3-C 2

IXa, R = GEt b, R = Me

Y

The y i e l d s o f p y r r o l e compounds produced i n these r e a c t i o n s was found to depend on the glycosylamine used, and v a r i e d from 3-5°/o f o r D-glucosylamine and i t s N - a l k y l d e r i v a t i v e s , to 10-30°/o f o r the l^-alkyl-D^-fructosylamines. The y i e l d s r e f l e c t the a b i l i t y of the glycosylamines to undergo the Amadori rearrangement [20) and support the p r e d i c t i o n (27) t h a t an Amadori rearrangement i s i n v o l v e d i n these r e a c t i o n s . When the r e a c t i o n o f glycosylamines withy3 — d i c a r b o n y l compounds i s c a r r i e d out under milder c o n d i t i o n s the J\[-glycosyl d e r i v a t i v e s of β -amino-Od β -unsaturated e s t e r s o r ketones ( V I l ) may be i s o l a t e d . E t h y l 3-(β -glycopyranosylamino)crotonates have been obtained (42) by a l l o w i n g the glycosylamines o f the common aldohexoses~XD-glucose, ^ - g a l a c t o s e , D-mannose and ^L- rhamnose) t o r e a c t with e t h y l acetoacetate f o r s e v e r a l days. The s t r u c t u r e o f these compounds was determined by chemical and s p e c t r o s c o p i c (UV, IR and PMR) methods. The amino and ethoxycarbonyl groups o f the enamine p o r t i o n were found to be i n c i s c o n f i g u r a t i o n and i n t r a m o l e c u l a r y bonded. The pyranose r i n g s i z e s and anomeric c o n f i g u r a t i o n [β - 4 g - f o r the rhamnose d e r i v a t i v e and / 3 - D - f o r the remaining compounds) were assigned f o r the 0 - a c e t y l d e r i v a t i v e s on the b a s i s o f the chemical s h i f t s and the observed c o u p l i n g constants. The same pyranose s t r u c t u r e s and anomeric con f i g u r a t i o n s have been proposed f o r the parent compounds a f t e r c o n s i d e r i n g the chemical s h i f t s and c o u p l i n g constants o f the anomeric protons ( 4 2 , 4 3 ) . Other intermediate products o f the r e a c t i o n o f glycosylamines with β> - d i c a r b o n y l compounds are the ^N-glycosyl d e r i v a t i v e s o f Ρ-amino- oc9/i -unsaturated ketones obtained by r e a c t i o n o f a l d o 9



12.

GONZALEZ

Polyhydroxyalkyl

E T A L .

Heterocycles

211

sylamines with 2,4-pentanedione, 1-phenyl-1,3-butanedione and benzoylacetaldehyde (45). The r e a c t i o n o f ketohexosylamines with e t h y l acetoacetate and 2,4-pentanedione proceeds (42,44) r e a d i l y to y i e l d the correspon ding 5-tetrahydroxybutylpyrroles i n s t e a d o f the _N-ketohexosyl de r i v a t i v e s o f type X. In the r e a c t i o n o f 2-amino-2-deoxy-D-glucose with 2,4-pentane dione an intermediate, 2-deoxy-2-[2-(4-oxo-2-pentenyl)aminoJ-Dglucose has been i s o l a t e d (32). The y i e l d was high when the r e a c t i o n was performed i n anhydro basic media. This enamine c y c l i z e d r e a d i l y i n t o the 5-arabinotetrahydroxybutylpyrrole when i t was kept i n aqueous s o l u t i o n a t room temperature f o r s e v e r a l days. The 2-amino-2-deoxy-D^glucose a l s o reacted (34) with benzoylacet aldehyde and 1-phenyl-1,3-butanedione i n methanol i n the presence o f t r i e t h y l a m i n e y i e l d i n g 2-deoxy-2-[l-(3-oxo-3-phenyl-1-propenyl) amino3-D-glucose and 2-deoxy-2-£l-methyl-1(3-oxo-3-phenyl-1-propenyl)aminoj -β-glucose. The former compound could be obtained i n high y i e l d by merely t r e a t i n g an aqueous s o l u t i o n o f the amino su gar with benzoylacetaldehyde a t room temperature. The s t r u c t u r e of these compounds has been s t a b l i s h e d by studying t h e i r chemical and s p e c t r o s c o p i c p r o p e r t i e s (45). Heating o f these enamines i n aqueous ethanol, o r a mixture o f t r i e t h y l a m i n e and methanol, r e s u l t e d i n c y c l i s a t i o n to the t e t r a h y d r o x y b u t y l p y r r o l e s (45). Another enamine, 2-deoxy-2-£( 1,2-dimethoxycarbonylvinyl)aminoJ-Dglucose (Xl) has been obtained (46) i n almost q u a n t i t a t i v e y i e l d by r e a c t i o n o f 2-amino-2-deoxy- ^3-Q-glucopyranose with the dime t h y l a c e t y l e n e d i c a r b o x i l a t e . Heating the adduct (Xl) with water, or s l i g h t l y basic s o l u t i o n , a f f o r d e d 3-methoxycarbonyl-5-(D-arabinotetrahydroxybutyl)-2-pyrrole c a r b o x y l i c a c i d ( X I l ) .

Η ρ OH

HC

C-C00CH

3

II

II

CH 0H-(CHGH)3-e

C-CQOH

3

X

NH I

N ή

D-^OOC-C^H-COOCHa

XII

XI Polydydroxyalkyl-1,5,6,7-tetrahydroindol-4-ones. The r e a c t i o n o f amino-sugars with fh - d i c a r b o n y l compounds has been a l s o extended to cyclohexane-1,3-diones (47,48). The primary products o f the r e a c t i o n o f 2 - a m i n o - 2 - d e o x y - y 5 - S r 9 l P y with cyclohexane-1,3-diones i n aqueous s o l u t i o n a t room tempera ture are enamine (XIIl), which c y c l i z e spontaneously to give 1,5, 6,7-tetrahydro-2-(D-arabino-tetrahydroxybutyl)indol-4-ones (Xiv), Both products are obtained as mixtures that can be separated by f r a c t i o n a l c r y s t a l i z a t i o n o r by chromatography on a c e l l u l o s e column ( y i e l d s 25-40%). UCD


ranose

212

S Y N T H E T I C M E T H O D S FOR

Xllla, R b, R


1

1

R = H = H, R = 0

2

Me

HOCH I HCOH I HCOH I CH 0H 2

CARBOHYDRATES

Xla, R = R = H b, R/j =H, R = Me c, R/| = R = Me 1

2

2

2

S i m i l a r y , the 1-amino-1-deoxy-D-fructose r e a c t s (48) with cyclohexane-1,3-diones to give enamines XV and t e t r a h y d r o x y b u t y l tetrahydroindolones XVI. Ketose enamines XV are more s t a b l e than the i s o m e r i c aldose d e r i v a t i v e s XIII and are obtained i n higher y i e l d s (ca. 70%). In a d d i t i o n , enamines X H I a and XVa are more s t a b l e than t h e i r homologous compounds X H I b and XVb. Apparently the i n t r o d u c t i o n of a methyl group i n t o the enamine system i n c r e a s e s the s u s s e p t i b i l i t y to c y c l i z a t i o n . The f a i l u r e to o b t a i n enamines s i m i l a r to XIII and XV derived from dimedone may be a t t r i b u t e d to t h i s f a c t . A l s o , the r e a c t i o n o f 1-benzylamino1-deoxy-D-fructose with cyclohexane-1,3-dione gave only compound XVId, and no intermediate could be i s o l a t e d or detected chromatographically.

CHn-NH-^X

CH 0H-(CH0H) ^ 2

3

c=o I

HOCH I

HCOH I HCOH I 2

XVa, R = R = Η b, R/, = H . R = 1

XVIa, R = b, R/j = R/, = d R/j = R 1

CH 0H 2

2

c #

Me

f

2

R = R = R = = H, 2

3

2

R = Η H, R = Me Me, R = Η R = CH Ph 3

d

3

3

2

Enamines XIII and XV c y c l i z e to t e t r a h y d r o x y b u t y l i n d o l - 4 ones XIV and XVI i n high y i e l d s by heating i n water. In the case o f the 2-amino-2-deoxy-D-glucose d e r i v a t i v e small amounts (ca. 9°/o) o f 1 , 5 , 6 , 7 - t e t r a h y d r o i n d o l - 4 - o n e s which lacked the p o l y o l chain were a l s o obtained at a n e u t r a l pH. I f the r e a c t i o n was performed a t pH 9 - 1 0 the y i e l d o f these secondary products i n c r e a s e d up to 30%. The other enamines XV c y c l i z e d without l o o s i n g the tetrahydroxybutyl c h a i n . A l l s t r u c t u r e s have been s t a b l i s h e d by degradative o x i d a t i o n s and UV, IR and NMR spectros copy.


12.

GONZALEZ

ET

Polyhydwxyalkyl

AL.

213

Heterocycles


Reaction mechanisms: During the r e a c t i o n o f yj-dicarbonylcompounds with aldoses and with 2-amino-(2-alkylamino or 2-arylamino)-2-deoxyaldoses two molecules of water are e l i m i n a t e d and a heteroaromatic pentacycle, furan or p y r r o l e , i s formed. Although t h i s analogy may l e a d one to suggest a s i m i l a r r e a c t i o n mechanism f o r both r e a c t i o n s , i t must be kept i n mind that r e p l a c i n g an amino group by a hydroxyl group may produce enough change i n r e a c t i v i t y to l e a d to a d i f f e r e n t r e a c t i o n route. In agreement with t h i s i s the f a c t that i n the case o f 2-amino-(or 2-alkylamino)-2-deoxyaldoses, i t has been p o s s i b l e to i s o l a t e the intermediate 2-enamines, which can be transformed i n t o the p o l y h y d r o x y a l k y l - p y r r o l e s (45,46), but i n the case o f aldose d e r i v a t i v e s no s i m i l a r intermediates have been detected. The formation of p o l y h y d r o x y a l k y l f u r a n s . No systematic i n v e s t i g a t i o n of r e a c t i o n mechanism has been c a r r i e d out f o r the condensation of aldoses and y î - d i c a r b o n y l compounds. One d i f f i c u l t y i s the deep s t r u c t u r a l change that i s i n v o l v e d i n the r e a c t i o n which a f f e c t e s a multitude of bonds. T h i s suggests t h a t the r e a c t i o n does not proceed by a concerted process and t h a t s e v e r a l r e a c t i o n intermediates are formed which have not been detected a t present. The complexity o f the problem can be seen i f we r e a l i z e that the two r e a c t a n t s can e x i s t i n s e v e r a l i n t e r c o n v e r t i b l e forms. Thus the sugar may e x i s t i n aldehydic (even s o l v a t e d ) , anomeric and e n e d i o l i c forms, and the dicarbonylcompound i n the k e t o - and enol-forms. The p a r t i c i p a t i o n of e n e d i o l i c forms can c e r t a i n l y be discarded s i n c e the r e a c t i o n of D-glucose with ^/3-dicarbonyl compounds y i e l d s 5-polyhydroxyalkylfurans I while D-fructose y i e l d s the isomer with the polyhydroxyalkylated s u b s t i t u e n t i n p o s i t i o n - 4 , I I , XVII ( J 7 ) . The r e a c t i o n i s p o s s i b l e , not only with aldohexoses and a l d o pentoses, which can e x i s t as pyranoses or furanoses, but a l s o with D-glyceraldehyde i n which the hemiacetal forms are l e s s s t a b l e (15]_. In a d d i t i o n , the r e a c t i o n has been c a r r i e d out with simple ûtf-hydroxyaldehydes or ot-hydroxyketones f15)[17). CH=0 I CH 0H 2

+

CH C0CH CG0Et 3

2

^

HC || HC

C-COOEt || C-CH 3

In the case o f hydroxyketones the p a r t i c i p a t i o n o f a c y c l i c form i s not very probable owing to the higher s t a b i l i t y of the ketonic carbonyl group. I t i s t h e r e f o r e reasonable to suppose t h a t the f r e e a l d e h y d i c form o f the aldose i s t a k i n g part i n the r e a c t i o n . I t may be supposed that t h i s form, i n the presence of an a c t i v e methylene


214


group, can undergo an a l d o l i c type a d d i t i o n as the f i r s t step A) i n the r e a c t i o n : CH=G

CH C0R 2

HC-OH

C0R

CH(0H)-CH-C0R

2

3

p

V > HC-OH

A/|

CO-R3

R/|

V

CH(GH)—C-C0R2

I


R

(XIX)

n

I

C) fast

\

R

fastD)X

À

(XVII) fast

CH(UH)—CH-C0R

H 0

1

2

H

HC C

C

II

_

•

1

C-CGF C

0

R

2

2

I ^

0 H

(XVIII)

II

FU-C

^ C - R T v

0'

(XX) Step A) i s s i m i l a r to other n u c l e o p h y l i c a t t a c k s on the c a r bonyl form o f monosaccharides and resembles c l o s e l y the f i r s t step i n Knoevenagel type r e a c t i o n s o f aldehydes with a c t i v e methylene groups. I t i s probably r e v e r s i b l e and slower than the subsequent steps: B) formation o f the hemiacetal; C ) : formation o f the c o n j u gated système 0 - C = C - C = 0 , and D): a r o m a t i z a t i o n . None the intermedias i n t h i s hypothetic scheme has been detected. Nevert h e l e s s , a s i m i l a r r e a c t i o n with a previous blocked hydroxyl i n C-2 has been s t u d i e d (49), t o e l i m i n a t e step Β and subsequent s t e p s . O-Isopropylidene-D-glyceraldehyde was r e a c t e d with e t h y l acetoacetate (or with 2,4-pentanedione) y i e l d i n g the unsaturated products XXIIa and XXIIb. With e t h y l acetoacetate the a l d o l type product XXI could be i s o l a t e d , which corresponds t o intermediate XVII i n the r e a c t i o n o f the unprotected D-Glyceraldehyde. When the p r o t e c t i n g group was removed i n XXI by a c i d h y d r o l i s i s , the furan d e r i v a t i v e XXV was r e a d i l y formed. T h i s r e s u l t demostrates the great tendency o f the a l d o l type product XXIII to c y c l i 2 e to furan by a double dehydration. The h y d r o l y s i s o f the i s o p r o p y l i d e n e group appears to be much slower than the c y c l a t i o n . The gradual f a d i n g o f the PMR s i g n a l s corresponding to product XXI can be observed (5ϋ) a t the time, s e v e r a l new s i g n a l s appear belonging to acetone and to the furan compound XXV. No other s i g n a l s were observed t h a t could be a s c r i b e d t o the hypothetic intermedia XVIII and XIX. When the H y d r o l y s i s was c a r r i e d out i n the presence o f periodate ions two molecules o f oxidant were consumed and one mole o f formic a c i d was formed, as expected from an intermediate such as XXIII (50). The a d d i t i o n A' without the use o f any c a t a l y s t can be observed by PMR. I t appears to be a r e v e r s i b l e process. In our e a r l y experiments (49) we found that on a c i d h y d r o l y s i s compound XXII do not g i v e furan d e r i v a t i v e s . a


12.

GONZALEZ ET

CH=0

Polyhydwxyalkyl

AL.

CHoCOR

!

CH(OH)-CHCOR

ι

+

HC—0 t

C0CH

ν

HC—0

3

COCH:

CH 0

2

CH=

=C—COR

HC—0

COCH3

I

Ip

CH 0

215

Heterocycles

>

CH 0 « XXIIa, R=Me J CH b, R=OEt

2

2

XXI

3

CH(0H)-CHC0R

-C-COR

HC-

I

H0H C-C 2

^.C-CH

x

0

CH 0H

XXV

2

I

χ

χ

ι

Ι

Ι

2

R-CO-C-

I

CHo

II

c—0 CH 0

Il

CH3CO-CH I

CH

COCH3

I

COR


I

HC-OH 3

H 0

CH

2

>

XXIV

I

CH -C

2

3

*

CO I

CH 0H 2

XXVIII

R-CO-O CH

CH 0

NH

J

^C-COR C H "

HC-OH

I CH 0 2

2

CH 0H 2

XXXIII, R = OEt XXXIV, R = OMe

XXXV

With 2,4-pentanedione i t was necessary to add a few drops o f concentrated h y d r o c h l o r i c a c i d as a c a t a l y s t . 2-Hydroxy-4-(D-1,2dihydroxyethyl)-5-methyl-6-acetyl-3,4-dihydropyrimidine XXXV was i s o l a t e d . The i s o p r o p y l i d e n e group having been hydrolysed i n the a c i d i c medium. In the second type o f s y n t h e s i s e t h y l t r a n s - 4 , 5 - 0 - i s o p r o p y l idene-4,5-dihydroxy-D-pent-2-enoate XXXVI, described above, and urea were used. The r e a c t i o n product i s o l a t e d was 4 - ( O - i s o p r o p y l idene-D-1,2-dihydroxyethyl)-5,6-dihydro u r a c i l . Acid hydrolysis a f f o r d e d the pyrimidine d e r i v a t i v e XXXVII with the f r e e hydroxyls groups· The O-isopropylidene d e r i v a t i v e XXXVIII having a β - k e t o e s t e r group and a polyhydroxyalkyl chain was obtained by the r e a c t i o n of O-isopropylidene-D-glyceraldehyde with methyl diazoacetate. I t forms a copper s a l t and i t s b a s i c h y d r o l y s i s followed by decarboxylation produced j0-isopropylidene-3,4-dihydroxybutan-2one. These / 3 - k e t o - e s t e r XXXVIII has been used i n the t h i r d


218

SYNTHETIC

,NH

X

5

CO ι

COOEt

F O R CARBOHYDRATES

^NH CO co

NH x

CO

x

CO

I

I

NH HC I HC—0 I CH 0

METHODS

X

^CH

I

ι

x

2

I

HC-OH

>

CH 0H 2

CH 0

2

CH

CH

X

CH I HC—Ο

>

I

NH

2

2

I XXXVII

XXXVI


method o f s y n t h e s i s f o l l o i n g the scheme: (58) N CH-C00R

NH

CH C00R

2

ι

2

CH=0

—

CH3S-C HC—0

I

HC—0

'CO

CH3S-C

NH

C=0 ι

+

X

NH-glucopyrano)imidazolidin-2-one (XLV, R = Ph; X = • ) . The s y n t h e s i s o f s i m i l a r compounds (XLV, R = a r y l , X = 0, S) s t a r t i n g from 1,3,4,6 -tetra-O-acetyl^-amino^-deoxy-^-DT-glucopyranose has been achie ved (74-7". The l a t t e r was converted i n t o the 2 - a r y l u r e i d o or 2a r y l t h i o u r e i d o d e r i v a t i v e s , and then deacetylated with ammonia i n methanol and c y c l i z e d . L a t e r , however, a f u r a n o i d s t r u c t u r e (XLVI, R = a r y l ) f o r the sugar moiety o f these compound has been e s t a b l i s h e d by PMR and periodate o x i d a t i o n (75) and a l s o by o x i d a t i o n with l e a d t e t r a acetate (76,77). Recently, the s t r u c t u r e o f 1-alkyl ( a r y l )-4,5-( 1,2-J^glucofur a n o ) - i m i d a z o l i d i n e - 2 - t h i o n e s (XLVI, R = Me, CH2 = CH - 0 Η , Ph, 4-ClCsH4, 4-BrC5H4; X = S) has been confirmed by X-ray c r y s t a l l o graphic methods. (78-82). Compounds with the b i c y c l e glucofuranoimidazoline-2-thione s t r u c t u r e (XLVI, R = Me, Et, C H ( C H ) , CH3(CH ) , (CH ) CH, CH = CH - C H Ph, 4-CH C H , 4-CH 0C H , 4-C H 0C H , C H ) can be isomerized (72,83,84) to a c y c l i c i m i d a z o l i n e t h i o n e XXXIX by heating with a c e t i c a c i d . Some o f these compounds have been obtained by r e a c t i n g D-glucosamine with the corresponding a l k y l i s o t h i o c y a n a t e i n ethanol and a c e t i c a c i d (72). The i m i d a z o l i n e d e r i v a t i v e s XXXIX have been a l s o obtained by r e a c t i n g 1-alkyl(aryl)amino-1-deoxy-fruetoses with ammonium(potassium)thiocyanate i n the presence o f a c i d s . (7^,85). S i m i l a r l y , the s y n t h e s i s o f 1 - a l k y l ( a r y l ) - 4 - D - a r a b i n o t e t r a h y d r o x y b u t y l i m i d a zoline-2-ones (XL, R = a l k y l , a r y l ) by r e a c t i o n o f 1 - a l k y l ( a r y l ) amino-1-deoxy-jD-frutoses with i s o c y a n i c a c i d has been reported (85,87). 3-Alkyl(aryl)-4-D-arabinotetrahydroxybutylimidazoline-2thiones (XXXIX, R = H; R = H, Me, Ph, 4-fer-C H ) have been ob t a i n e d by r e a c t i o n o f 1-amino-1-deoxy-D-fructose with a l k y l ( a r y l ) i s o t h i o c y a n a t e s . The compound having'Ri = Η and R2 = Me has been a l s o prepared by r e a c t i n g 2-deoxy-2-methylamino-D-glucose hydro c h l o r i d e with potassium thiocyanate (88). The s y n t h e s i s o f 1 - a r y l - 3 - a l k y l ( a r y l ) - 4 - D - a r a b i n o t e t r a h y d r o x y . b u t y l i m i d a z o l i n e - 2 - t h i o n e s (XXXIX, R/j = a r y l ; R = a l k y l (aryl)) by r e a c t i o n o f 1-arylamino-1-deoxy-D_fructose with a l k y l ( a r y l ) i s o t h i o c y a n a t e s have been reported (89). The thione group was removed by r e d u c t i v e desulphuration or protected by a l k y l a t i o n with benzyl c h l o r i d e g i v i n g the corresponding 1 f 3 ) - a l k y l ( r y l ) 4-D-arabinotetrahydroxybutylimidazoles ( 9 0 , 9 l J and 2-benzylthio d e r i v a t i v e s (7Ί,83,88). Oxidative degradation o f the p o l y o l chain (92) a f f o r d e d formyl imidazol d e r i v a t i v e s (93,94).


2

3

2

2#

3

q

6

4

2

3

2

2

6

4

2

3

2

5

6

3

6

2

4

1 0

?

4

2

a

Anhydro-polyhydroxyalkylheterocycles. One o f the most c h a r a c t e r i s t i c chemical p r o p e r t i e s o f the polyhydroxyalkylheterocycles i s t h a t they can be e a s i l y dehydra-


12.

GONZALEZ

Polyhydroxyalkyl

E T AL.

221

Heterocycles

ted g i v i n g C-glycosides o f h e t e r o c y c l e s . A study about t h i s r e a c t i o n was undertook by G a r c i a Gonzalez and coworkers Q , 9 5 , 9 6 ) who e s t a b l i s h e d the s t r u c t u r e o f 2-(1,4-anhydro-tetrahydroxybutyl)furans f o r the dehydration pro ducts o f 2-(D-arabinotetrahydroxybutyl)furans ( I , Ri = CH C00H, 2

Me;

R

2

= 0Me7 OEt, OH or Me).

HC ψ Η Η (Ι CH -C—C—C-C J ÙH OH j

C-C0-R

II

0 ν HC H y 1 || CH -C—C—C-C ÙHÙHn *

2

C-R/j

2

Il

2

C-R η

2

XLVII Downloaded by UNIV OF BATH on July 2, 2016 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0039.ch012

C-C0-R

I

XLVIII

L a t e r , Gomez Sanchez and Rodriguez have demostrated the conf i g u r a t i o n a t C-1'. An a c i d c a t a l y z e d dehydration o f 2-fD-arabino tetrahydroxybutyl)furans i s a r e v e r s i b l e process (97-99) which proceeds p r e f e r e n t i a l y with i n v e r s i o n o f the c o n f i g u r a t i o n a t C-1' y i e l d i n g the thermodynamically more s t a b l e 2-f1,4-anhydro-D-ribotetrahydroxybutyl)furans XLVII and, to a much s m o l l e r extent the D-arabino isomer XLVIII. An unequivocal proof that supports t h i s s t r u c t u r e i s the s y n t h e s i s o f XLVIII by r e a c t i o n o f 3,6-anhydroD-glucose with a c e t o a c e t i c e s t e r s (98). Oxidation o f these anhydro compounds with p e r i o d i c a c i d gave dialdehydes which c r y s t a l i zed as monohydrates and were formulated as hemialdals (99-101). In a s i m i l a r way, 2-(D-arabinotetrahydroxybutyl)pyrroles ( I I I , R = H, R = Me, R = Me; R = H, R = Me, R = OEt; R = Et, n-C H9, R = Me, R = Me) and 3-(D-arabinotetrahydroxytutyl) p y r r o l e s (IV, R/| = n-C Hg, R = Me, R = OEtJ l o s e a molecule o f water g i v i n g the corresponding 1*,4'-anhydro d e r i v a t i v e s IL and L (102, 103, 32). 1

2

4

3

2

1

4

H

2

3

1

3

4

2

HC η Ι)

C-C0-R ||

CH -Ç—Ç—C-C

C-CH

2

L

ÔH OH

| »

3

N R

x

3

2

H H fj CH -C—Ç—C-C

C-C0-R

2

I

OH ÔH

I

0

I || J

HC

C-CH

b, R

1

= H, R

2

= Me

2

= OEt

c, R/| = E t , R

2

g

L, R

1

1

= n-C H , R2 = OEt 4

g

= Me

d, R/j = n-C H , R 4

3

1

R ILa, R/j = H, R

2

|l

2

= Me

An anhydropentahydroxypentylpyrrole has r e c e n t l y been i s o l a ted from the r e a c t i o n o f the 2-amino-2-deoxy-D-glycero-D-guloheptose with e t h y l acetoacetate, that has been formulated as 2-methyl-3-ethoxycarbonyl-5-(oc - or A — D - a r a b i n o f u r a n o s y l ) p y rrole '


222


The structure of these compounds are supported by oxidation with sodium metaperiodate, polarimetric measurements, UV and IR spectroscopy. HC II

HOCHo^C)


V OH

C^

C-COOEt II C-CHQ

(LI)

The 4~D-arabinotetrahydroxybutyl-imidazoline-2-thione can be easily dehydrated by heating its aqueous solution (1 °/o) for six hours under pressure (rv/ 2 Kg/cm^) giving the 4-(ji -D-erythrofuranosyl)imidazoline-2-thione (104) LII.

•H OH LII Recently, the synthesis of 1-halogenophenyl-4-[Q( -D-erythrofuranosyl)imidazoline-2-thiones LUI (R = 4-CIC5H4, 4-BrC6H4, or 3,4^Cl2CgH3) by treatment of the 1-halogenophenyl-4,5-(cis1,2-D-glucofuranosyl)imidazolidine-2-thiones XLVI, (X = Sj with trifluoroacetic acid has been also reported (105). The structures of these compounds have been established by preparation of derivatives, oxidative estimation with periodate, UV spectroscopy and X-ray crystallografic methods (106,107). Literature Cited. 1 2 3 4

García González, F., Advan. Carbohyd. Chem., (1956) 11, 97. West, E. S., J. Biol. Chem., (1927) 74, 561. García González, F., Anales Fís. Quím., (1934) 32B, 815. García González, F., López Aparicio, F. J. and Vázquez Roncero, Α., An. real soc. españ. Fís. Quím. (1949) 45 B, 1539.



12. GONZALEZ ET AL. Polyhydroxyalkyl Heterocycles 5 García González, F. and López Aparicio, F. J., An. Fís. Quím., (1945) 41B, 846; Ibid., (1947) 43B, 279. 6 Széki, T. and Laszló, Eva., Ber., (1940) 73, 924. 7 García González, F. and Sequeiros, C., An. Fís. Quím., (1945) 41B, 1479. 8 Jones, J. K. N., J. Chem. Soc., (1945) 116. 9 López Aparicio, F. J., Enriquez, R. and García González, F., An. Fís. Quím., (1950) 46B, 655. 10 García González, F., López Aparicio, F. J. and Ortíz Rizo, M., An. real soc. españ. Fís. Quím., (1957) 53B, 303. 11 Stiefel Román, V. and López Aparicio, F. J., Ibid., (1954) 50B, 207. 12 García González, F., Fernández-Bolaños, J. and Pérez de Guzmán, A. M., Ibid., (1964) 60B, 339. 13 García González, F., Fernández-Bolaños, J. and Martín Lomas, M., Ibid., (1965) 61B, 1035. 14 García González, F., Fernández-Bolaños, J. and Maestro Durán M., Ibid., (1966) 62B, 467. 15 García González, F., Enríquez, R., Rodríguez, J. and López Aparicio, F. J., Ibid., (1954) 50B, 311. 16 García González, F. and Rodríguez, Α., An. Quím., in press. 17 García González, F., Lopez Aparicio, F. J. and Sânchez-Laulhè, F., An. real Soc. españ. Fís. Quím., (1954) 50B, 407. 18 Gómez Sánchez, Α., Rodríguez Roldán, Α., López Artiguez, M. and García González, F., An. Fís. Quím., (1968) 64, 1007 19 Pauly, H. and Ludwig, Ε., Z. Physiol. Chem., (1922) 121, 170 20 García González, F. and Gómez Sánchez, Α., Advan. Carbohyd. Chem., (1965) 20, 303. 21 García González, F., An. Fís. Quím., (1934) 32, 815. 22 García González, F. and Trujillo Torres, R., Ibid., (1935) 33,566. 23 Müller, A. and Varga, I., Ber., (1939) 72, 1993. 24 Ollero, A. and de Castro Brzezicki, R., An. Fís. Quím., (1945) 41, 868. 25 García González, F. and de Castro Brzezicki, R., An. real soc. españ. Fís. Quím., (1950) 46B, 68. 26 García González, F., Gómez Sánchez, A and Gasch Gómez, J., Ibid., (1958) 54B, 513, 519. 27 Gómez Sánchez, A. and Gasch Gómez, J., Ibid., (1958) 54B, 753. 28 Gómez Sánchez, Α., Rey Romero, L. and García González, F., Ibid., (1964) 60B, 505. 29 Fernández-Jiménez, J. and Ollero, Α., Ibid., (1948) 44B, 133 30 Ollero Gómez, A. and Fernández Jiménez, J . , An. Fís. Quím., (1945) 41, 1165. 31 Boyer, R and Furth, O., Biochem. Z., (1935) 282, 242. 32 García González, F., Gómez Sánchez, A. and Goñi de Rey, M., Carbohyd. Res., (1965) 1, 261. 33 García González, F., Fernández-Bolaños, J. and Alcudia, F., An. Quím., (1971) 67, 383.


223


224


34 García González, F., Gómez Guillen, H. and Scheidegger, U., Carbohyd. Res., (1967) 3, 486. 35 García González, F., Fernández-Bolaños, J and Martín Jimnez de la Plata, G., (unpublished results). 36 García González, F., Gasch Gómez, J., Bello Gutierrez, J. and Gómez Sánchez, Α., An. real soc. españ. Fís. Quím. (1961) 57B, 383. 37 García González, F., Gómez Sánchez, Α., Gómez Guillén, M. and Tena Aldave, M. An. Quím., (1971) 67, 389. 38 García González, F., Fernández-Bolaños, J. and Alducia, F., Ibid., (1972) 68, 571. 39 García González, F., Gómez Sánchez, A. and Goñi de Rey, M. An. real soc. españ. Fís. Quím., (1964) 60B, 579. 40 García González, F., Fernández-Bolaños, J. and Muñoz Guerra, S., (unpublished results). 41 García González, F., Fernández-Bolaños, J. and Galbis Pérez, J . , An. Quím., (1974) 70, 1082. 42 Gómez Sánchez, A. and Velasco del Pino, J . , Carbohyd. Res., (1966) 421. 43 Gómez Sánchez, A. and Velasco del Pino, J., Ibid., (1969) 9, 335. 44 Gómez Sánchez, Α., Velasco del Pino, J. and Scheidegger, U., An. real soc. espan. Fís. Quím., (1966) 62B, 487. 45 Gómez Sánchez, Α., Tena Aldave, M., Velasco del Pino, J. and Scheidegger, U., Carbohyd. Res., (1969) 10, 19. 46 Gómez Sánchez, Α., Gómez Guillén, M., Pando Ramos, E. and Cert Ventulá, Α., Ibid., (1974) 35, 39. 47 García González, F., Gómez Sánchez, A. and Gómez Guillén, M. An. real soc. españ. Fís. Quím., (1966) 62B, 471. 48 Gómez Sánchez, Α., Toledano, E. and Gomez Guillén, M., J. Chem. Soc. Perkin I, (1974) 1237. 49 López Aparicio, F. J., Yruela, M. and García González, F., An. real soc. españ. Fís. Quím., (1958) 54B, 705. 50 López Aparicio, F. J. and López Herrera, F. J., unpublished results. 51 López Aparicio, F. J., López Heprera, F. J. and Sanchez Ballesteros, J . , (unpublished results). 52 Alonso Cermeno, F., González Nogal, A. M. and López Aparicio, F. J., An. Quím.,(1972) 68, 285, 293. 53 Zinner, H., Wittemburg, E. and Rembarz, G., Ber., (1959) 92, 1614. 54 López Aparicio, F. J. and López Herrera, F. J., An. Quím., (in press). 55 Kochetkov, Ν. K. and Dmitriev, Β. A., Chem. Ind. (London) (1963) 115. 56 López Aparicio, F. J., Gómez Guillén, M. and Izquierdo, I., An. Quím., (in press). 57 López Aparicio, F. J., Izquierdo, I. and Portal, M. (unpublished results). 58 López Aparicio, F. J., López Herrera, F. J. and Valpuesta,


12. GONZALEZ ET AL. 59 60 61 62 63 64 65


66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86

Polyhydroxyalkyl Heterocycles

225

M., unpublished results. Neuberg, C. and Wolff, H., Ber., (1901) 34, 3840. Steudel, H., Z. Physiol. Chem., (1901) 33, 223; Ibid., (1902) 34, 352. Ishifuku, K., J. Pharm. Soc., Japan (1928) 48, 584. García González, F. and Fernández-Bolaños, J., An. real soc. espan. Fís. Quím., (1948) 44B, 233; Ibid., (1949) 45B, 1527. García González, F. and Fernández-Bolaños, J., Ibid., (1949) 45B, 1531. Fernández-Bolaños, J., Ruíz Cruz, J. and García González, F., Ibid., (1950) 46B, 501. Fernández-Bolaños, J., Ruîz Cruz, J. and García González, F., Ibid., (1951) 47B, 737. García González, F., Fernández-Bolaños, J. and Menéndez, M., Ibid., (1964) 60B, 653. Fernández-Bolaños, J. and Menéndez, M., Ibid., (1966) 62B, 1005. García González, F., Fernández-Bolaños, J. and Ruíz Cruz, J., Ibid., (1951) 47B, 299. García González, F., Fernández-Bolaños, J. and Paneque, Α., Las Ciencias (Madrid), (1959) 29, 189. García González, F., Fernández-Bolaños, J. and Paneque, Α., An. real soc. españ. Fís. Quím., (1961) 57B, 379. Fernández-Bolaños, J., García González, F., Gasch, J. and Menéndez, M.,Tetrahedron, (1963) 19, 1883. Kruger, F. and Rudy, H., Ann., (1963) 669, 146. Micheel, F. and Lengsfeld, W., Chem. Ber., (1959) 89, 1246. Morel, Ch. J., Helv. Chim. Acta, (1961) 44, 403. Fritz, H., Morel, Ch. J. and Wacker, O., Helv. Chim. Acta, (1968) 51, 569. Fernández-Bolaños, J. and Viguera, J. M., unpublished work. García González, F., Fernández-Bolaños, J. and Pradera de Fuentes, M. Α., An. Quím., (1974) 70, 57. Jiménez-Garay, R., López Castro, A. and Márquez, R., Acta Cryst., (1974) B30, 180. Jiménez-Garay, R., Vega, R. and López Castro, Α., Crystal. Struct. Comm., (in press). Jiménez-Garay, R., López Castro, A. and Márquez, R., Acta Cryst., (in press). García Gea, M., Hernández, V. and Moreno, E . , Cryst. Struct. Comm., (in press). Hernández, V., Vega, R. and López-Castro, Α., Acta Crysta., (in press). Garcîa González, F., Fernández-Bolaños, J. and Heredia, Α., An. real soc. españ. Fís. Quím., (1966) 62B, 999. García González, F., Menéndez, M., Ariza, F. and Alvarez González, C., Ibid., (1968) 648, 407. Huber, G., Schier, O. and Druey, J., Helv. Chim. Acta, (1960) 43, 713; 1787. Druey, J. and Huber, G., Helv. Chim. Acta, (1957) 40, 342.


226



87 88

Fernández-Bolaños, J. and Viguera, J., An. Quím., in press. García González, F., Fernández-Bolaños, J. and Fuentes, J., Carbohyd. Res., (1972) 22, 436. 89 García González, F., Fernández-Bolaños, J., Fuentes, J. and Pradera, Μ. Α., Carbohyd. Res., (1973) 26, 427. 90 Fernández-Bolaños, J., Martin Lomas, M., Martinez Ruiz, D. and Pradera, Μ. Α., An. real soc. españ. Fís. Quím., (1968) 64B, 203. 91 Fernández-Bolaños, J. and Fuentes Mota, J., An. Quím., (1972) 68, 1053. 92 Fernández-Bolaños, J., Heredia, A. and Sáenz de Buruaga, J., An. Quím., (1973) 69, 933. 93 Fernández-Bolaños, J. and Martínez Ruíz, D., An. real soc. españ. Fís. Quím., (1968) 64B, 423. 94 Fernández-Bolaños, J., Martinez Ruíz, D. and Menéndez, M., An. Quím., (1974) 70, 94. 95 García González, F. and Sequeiros, C., Ibid., (1945) 41B, 1463. 96 García Gonzalez, F., López Aparicio, F. J. and Vázquez, Α., An. real soc. españ. Fís. Quím., (1948) 44B, 243. 97 López Aparicio, F. J. and Vázquez Roncero, Α., Ibid., (1949) 45, 1577. 98 Gómez Sánchez, A. and Rodríguez Roldán, Α., An. Quím., (1972) 68, 609. 99 Gómez Sánchez, A. and Rodríguez Roldán, Α., Carbohyd. Res., (1972) 22, 53. 100 García González, F., López Aparicio, F. J. and Vázquez Ron cero, Α., An. real soc. españ. Fís. Quím., (1948) 44, 243. 101 López Aparicio, F. J. and Piazza, C., Ibid., (1956) 52B, 723. 102 García González, F. and Castro Brzezicki, R.,An. real Soc. espan. Fís. Quím., (1950) 46B, 73. 103 García González, F., López Aparicio, F. J. and Ortíz, M:, Ibid., (1956) 52B, 717. 104 Fernández-Bolaños, J., Repetto, M., Fuentes, J. and Martin M. J., An. Quím., (1973) 69, 771. 105 Fernández-Bolaños, J. and Fuentes, J., Ibid., (1976) 72, 79. 106 Pérez-Garrido, S., López-Castro, A. and Márquez, R., An. Fís., (1973) 69, 179. 107 Pérez-Garrido, S., Conde, A. and Márquez, R., Acta Cryst., (1974) B30, 2348.


Synthetic Methods for Carbohydrates

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