Synthetic Methods for Carbohydrates - ACS Publications

6 Synthesis of 2-Amino-2-deoxy-β-D-glucopyranosides

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Properties and Use of 2-Deoxy-2-phthalimidoglycosyl Halides. R. U. LEMIEUX, T. TAKEDA, and Β. Y. CHUNG Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2

The importance of achieving a reliable method for the preparation of 2-amino-2-deoxy-β-glycopyranosides has been commented on in several recent publications (1,2). The importance derives mainly from the natural occurrence of numerous oligo- and polysaccharides which possess this linkage and the chemical synthesis of segments of these structures is of interest to a number of immunochemical and enzymological studies. It is not possible to present in this paper, a c r i t i c a l review of the many approaches developed to meet the challenge of establishing the above-mentioned linkage. However, the most employed reactions have involved either reactions of a protected glycosyl halide with alcohol under Koenigs-Knorr or Helferich conditions which employ heavy metal salts such as silver carbonate and mercuric cyanide as promoters (3-6) or a strong-acid promoted reaction of a 1,2oxazoline derivative of the aminosugar with the alco hol (7-9). Although these approaches have made a v a i l able a large number of desired structures, the stereo chemical control and yields achieved have been highly variable and, in general, rather unsatisfactory. The present research was undertaken in the hope of amel iorating this situation. In principle, a most attractive means for the establishment of a 1,2-trans-glycosidic linkage would be to form a cationic species from a derivative of the sugar with participation of the 2-substituent but with the latter substituent so chosen that i t s engagement does not lead to products other than the desired 1,2trans-β-glycoside. The choice of an imide derivative of the aminosugar appeared promising in this regard since it could be anticipated from the work of Akiya and Osawa (10) that engagement of the imide grouping in charge derealization at the anomeric center would 90

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


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lead only to reactive intermediates. Baker and coworkers (11) prepared 1,3 ,4,6-tetra-(>acetyl-2-deoxy-2-phthalimido-g-D-glucopyranose i n 1954 and observed that treatment of t h i s compound with hy drogen bromide i n a c e t i c acid gave 3 , 4 , 6 - t r i - 0 - a c e t y l 2- deoxy-2-phthalimido-B-D-glucopyranosyl bromide (5) and, indeed, Akiya and Osawa (10) prepared 3-glycosides of simple alcohols from the l a t t e r compound i n high y i e l d using Koenigs-Knorr conditions. At the s t a r t of t h i s i n v e s t i g a t i o n , i t was estab l i s h e d that reaction of e i t h e r 3,4,6-tri-0-acetyl-2deoxy-2-phthalimido-3-D-glucopyranosyl or -β-D-galactopyranosyl bromides with the simple alcohol, 2-propanol, under H e i f e r i c h conditions (12) provided the 3-glycosides i n excellent y i e l d . However, when 2 , 2 , 2 - t r i chloroethanol was used, the main product of the reac t i o n of 5 was the g l y c o s y l cyanide, a w e l l known by product of glycosidation reactions using mercuric cyan ide as promoter. This r e s u l t could be a t t r i b u t e d to the weak n u c l e o p h i l i c i t y of the alcohol which also has a hindered hydroxyl group. For t h i s reason, the promo t i o n of the reaction by the soluble 1:1 complex (13,14) of s i l v e r trifluoromethanesulfonate ( s i l v e r t r i f l a t e ) and 2,4,6-trimethylpyridine ( c o l l i d i n e ) was examined. In the f i r s t e f f o r t to u t i l i z e the s i l v e r t r i f l a t e - c o l l i d i n e complex to promote the reaction of the 3 - bromide (5) with 2,2,2-trichloroethanol, the y i e l d was 60%. However, when greater precaution was taken to exclude water, the y i e l d rose to 89%. Thus i t was apparent that, indeed, the use of the phthalimido pro t e c t i n g group augured well for the development of a generally u s e f u l preparation of 2-amino-2-deoxy-3-Dglucopyranosides. In order to t e s t t h i s hypothesis, i t was decided to attempt the syntheses of three Pje^i o u s l y reported disaccharides;. namely, 3 - D - g l c N A c — — • D-glcNAc (4 JB1, β-D-glcNAc ' > D-glcNAc (1,5), and 3-D-glcNAc—D-gal (6,7). Thus, a comparison of the u t i l i t y of the method with other methods could be achieved under a v a r i e t y of circumstances. The pur pose of t h i s communication i s to present the r e s u l t s obtained and, also, an examination of the chemical pro p e r t i e s of the anomeric 3,4,6-tri-0-acetyl-2-deoxy-2phthalimido-D-glucopyranosyl h a l i d e s . Akiya and Osawa (10) demonstrated that replace ment reactions at the anomeric center of 3,4,6-tri-Oacetyl-2-deoxy-2-phthalimido-D-glucopyranosyl halides provide mainly the 3-anomers. Furthermore, reaction of the l,2-trans-3-bromide was shown not to y i e l d an orthoester under conditions wherein 2,3,4,6-tetra-Oacetyl-D-glucopyranosyl halides do. The marked ob3



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SYNTHETIC METHODS FOR CARBOHYDRATES

s t r u c t i o n to formation of l,2-c£s-a-anomers was as signed to a s t e r i c hindrance a r i s i n g from the phthalimido group. These phenomena appeared worthy of f u r ther i n v e s t i g a t i o n . I t proved r e a d i l y p o s s i b l e to obtain pure samples of both the anomeric forms f o r 3,4,6-tri-0-acetyl-2deoxy-2-phthalimido-D-glucopyranosyl c h l o r i d e , bromide and iodide from the known 1,3,4,6-tetra-0-acetyl-2deoxy-2-phthalimido-B-D-glucopyranose using b a s i c a l l y standard conditions. A l l were c r y s t a l l i n e except the α-bromide which was obtained as a chromatographically pure syrup. This unique a v a i l a b i l i t y of both the ano meric forms f o r a g l y c o s y l halide with the halogen as e i t h e r c h l o r i n e , bromine or iodine prompted a b r i e f k i n e t i c i n v e s t i g a t i o n of the reactions with t e t r a ethylammonium h a l i d e s . Good pseudo f i r s t - o r d e r kine t i c s f o r the anomerization reactions were obtained s t a r t i n g with the ot-anomers. However, the polarimetr i c rates were not cleanly f i r s t - o r d e r s t a r t i n g with the 3-anomers and examination of products i s o l a t e d a f t e r various i n t e r v a l s of time, showed t h i s to r e s u l t from p a r t i a l h y d r o l y s i s of the 3-halide by traces of water which are i n e v i t a b l y present i n the reaction mixtures, a s i t u a t i o n reminiscent of the experience with the anomeric tetra-O-acetyl-D-glucopyranosyl chlorides (15). Thus, i t was apparent that the phthalimido group can p a r t i c i p a t e i n the o v e r a l l reaction and thereby lead to a c a t i o n i c intermediate which has a strong a f f i n i t y f o r water but which, as indicated by the r e s u l t s of Akiya and Osawa (10) and supported by our experience, does not y i e l d a stable orthoester. That some kind of p a r t i c i p a t i o n occurs was also i n d i cated by the d i f f e r e n t routes of the reactions d i s played by the a- and β-bromides (5 and 6) when reac ted with tetraethylammonium c h l o r i d e (0.02 M) i n acet o n i t r i l e . Whereas the reaction of the a-anomer (6) produced an e s s e n t i a l l y quantitative y i e l d (>90%) of the 3 - c h l o r i d e (3) the reaction of the β-bromide (5) proceeded with extensive (near 50%) retention of con f i g u r a t i o n . At a higher c h l o r i d e ion concentration (0.3 Μ ) , the y i e l d of the α-chloride (4) was 80%. The p a r t i c i p a t i o n of a 2-acyloxy group i n a reac t i o n at an anomeric center i s considered to provide anchimeric assistance by providing a s o l v a t i o n - l i k e influence on the formation of an ion-pair and i s mani fested by the collapse of the intermediate ion-pair to the more stable 1,2-acyloxonium s a l t (15). The experimental basis f o r t h i s opinion i s the demonstration by Lemieux and Hayami (15) that whereas the c h l o r i d e - i o n catalyzed anomerization of 1,2-cis-



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93

t e t r a - O - a c e t y l - a - D - g l u c o p y r a n o s y l c h l o r i d e proceeded a t t h e same r a t e as exchange o f c h l o r i d e i o n w i t h t h e environment, the r a t e of i n c o r p o r a t i o n of r a d i o a c t i v e c h l o r i d e i o n s from t h e e n v i r o n m e n t by t h e 1 , 2 - t r a n s - & c h l o r i d e was much g r e a t e r t h a n t h e r a t e o f 3+a a n o m e r i zation. These r e s u l t s seem b e s t i n t e r p r e t e d on t h e b a s i s o f an a t t a c k by c h l o r i d e i o n on an i n t i m a t e i o n p a i r r e s u l t i n g from spontaneous d i s s o c i a t i o n o f t h e C C l bond w i t h p a r t i c i p a t i o n o f t h e r i n g oxygen atom f o r e f f e c t i v e charge d e r e a l i z a t i o n i n the t r a n s i t i o n state. In the case of the 3 - c h l o r i d e , a t t a c k a t the anomeric c e n t e r o f t h e i o n - p a i r by c h l o r i d e i o n was i n c o m p e t i t i o n w i t h t h e n u c l e o p h i l i c a t t a c k by t h e 2 - a c e t o x y group w i t h t h e former r e a c t i o n l e a d i n g t o t h e i o n t r i p l e t intermediate necessary f o r the anomerization and t h e l a t t e r c o u r s e o f r e a c t i o n l e a d i n g t o t h e 1 , 2 a c e t o x o n i u m i o n . On t h i s b a s i s , t h e above-mentioned r e t e n t i o n o f c o n f i g u r a t i o n o b t a i n e d on r e a c t i o n o f t h e 3-bromide (5) w i t h c h l o r i d e i o n may be r a t i o n a l i z e d as i s d i s p l a y e d i n Scheme 1. The most s t a b l e form o f t h e i n t e r m e d i a t e c a t i o n w h i c h a r i s e s from t h e 3-bromide cannot be p r e d i c t e d b u t presumably i s e i t h e r B , C o r D. I f C, the i o n c o u l d , i n the presence of a l c o h o l , p r o v i d e an o r t h o a m i d e p r o d u c t . However, l i k e A k i y a and Osawa (10), we d i d n o t d e t e c t such compounds i n t h e course of t h i s work. I t i s e x p e c t e d , as i n d i c a t e d i n Scheme 1, t h a t t h e s o l v o l y s i s o f t h e 3-bromide p r o ceeds by way o f a b o a t c o n f o r m a t i o n so as t o b e t t e r o r i e n t a p - o r b i t a l o f t h e r i n g oxygen r e l a t i v e t o t h e C - B r bond (16). As mentioned a b o v e , i t was n o t p o s s i b l e t o o b t a i n t h e same v e l o c i t y c o n s t a n t s (k + k ) f o r a n o m e r i z a t i o n s t a r t i n g w i t h t h e 3-anome?s as^were o b t a i n e d f o r α-anomers and t h e d i f f e r e n c e (about 20%) i s a t t r i b u t e d t o c a p t u r e o f t r a c e s o f w a t e r by t h e i n t e r m e d i a t e c a t i o n (B, C o r D i n Scheme 1) formed by s o l v o l y s i s o f t h e 3-anomer. The v a l u e s o b t a i n e d s t a r t i n g w i t h t h e α-anomers a r e c o n s i d e r e d r e l i a b l e and a r e r e p o r t e d u n d e r one s e t o f c o n d i t i o n s i n T a b l e I . As e x p e c t e d , t h e r a t e s o f a n o m e r i z a t i o n were d i r e c t l y p r o p o r t i o n a l t o t h e h a l i d e i o n c o n c e n t r a t i o n (15). These r e s u l t s are considered of i n t e r e s t w i t h regard to h a l i d e - i o n c a t a l y z e d g l y c o s i d a t i o n r e a c t i o n s (16) s i n c e t h e s e show a much g r e a t e r r e a c t i v i t y o f t h e bromides t h a n t h e c h l o r i d e s (700 t i m e s g r e a t e r ) b u t l i t t l e d i f f e r e n c e (about a f a c t o r o f two) between t h e bromides and i o d i d es. These d i f f e r e n c e s a r e even more r e m a r k a b l e when i t i s _ c o n s i d e r e d t h a t the order of n u c l e o p h i l i c i t y i s C I >Br >I under t h e a p r o t i c c o n d i t i o n s u s e d . Indeed, t h e α - i o d i d e (8) was a t t a c k e d about two t i m e s f a s t e r by ft


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SYNTHETIC METHODS

FOR

CARBOHYDRATES


Scheme 1


6.

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2-Amino-2-deoxy^-O-glucopyranosides

LEMiEux E T A L .

tetraethylammonium chloride than by tetraethylammonium bromide. TABLE I


Reactions of 3,4,6-Tri-0-acetyl-2-deoxy-2-phthalimidoD-glucopyranosyl Halides

-OAc^O

N

AcO

X" 1

PhthN

Κ

AcO AcO

OAc

0

v

PhthN

hr

-1

V

h r

rel.

Anomerization X = X X = X X = X =

1

X

1

X

-4

4950

1

0.10

6.9

700

0.22

3.15

1600

—

3.3

0.21

15

—

2.0

0.34

= CI

3.25

1.4 χ 10

= Br

1.22

= I

3.05

= OAc

4.5

Reaction X = I, X

1

= Cl

X = I , X = B r

9.3

For 0.02M solutions at 25°C of the g l y c o s y l halide i n a c e t o n i t r i l e and made 0.02M i n t e t r a e t h y l ammonium halide. An average value f o r the 1-acetates anomerized i n 1:1 a c e t i c a c i d - a c e t i c anhydride, 0.1M i n p e r c h l o r i c a c i d (17). X

4 The H-NMR spectra of compounds 1 to 8 required C^ conformation f o r both the anomeric p a i r s . The doublets f o r the anomeric hydrogens of the α-anomers had spacings i n the range 3.5-4.0 Hz and those f o r the 3-forms near 9.0 Hz. For both forms, the spacings found i n the signals f o r H-3 and H-4 were i n the range 9-11 Hz. In l i n e with t h i s conformation, H-3 f o r an α-form was strongly deshielded (18) by the sz/n-axial halogen as compared to H-3 of the 3-anomer (see Table I I ) . In a l l cases, one of the a c e t y l groups produced


96


TABLE I I H and C N u c l e a r M a g n e t i c Resonance P a r a m e t e r s f o r 3,4,6-Tri-0-acetyl-2-deoxy-2-phthalimido-D-giucop y r a n o s y l Compounds Chemical S h i f t s ( C D C 1 , TMS i n t e r n a l )

Compound Downloaded by UNIV MASSACHUSETTS AMHERST on May 5, 2013 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0039.ch006

3

β-Acetate α-Acetate

(1) (2)

H-l 6.48 6.28

H-3 5.86 6.56

C-l 89.9 90.6

6.20

5.79

85.7

β-Chloride

(3)

α-Chloride

(4)

6.43

6.83

91.4

e-Bromide

(5)

6.43

5.80

78.4

α-Bromide

(6)

6.62

6.67

87.3

3-Iodide

(7)

6.71

5.73

78.2

α-Iodide

(8)

6.97

6.52

75.1

i t s s i g n a l t o e x c e p t i o n a l l y h i g h f i e l d ( 1 . 8 - 1 . 9 ppm). I n d e e d , t h e p l a n e o f t h e p h t h a l i m i d o group would be e x p e c t e d t o be n e a r p e r p e n d i c u l a r t o t h e mean p l a n e o f t h e p y r a n o s e r i n g and t h e r e f o r e have a s p e c i f i c s h i e l d i n g i n f l u e n c e on t h e C-3 a c e t o x y g r o u p . In t h i s o r i e n t a t i o n , t h e c a r b o n y l o f t h e p h t h a l i m i d o group w h i c h i s on t h e α - s i d e o f t h e p y r a n o s e r i n g can e x e r t a s t r o n g non-bonded i n t e r a c t i o n w i t h an a x i a l s u b s t i t u e n t a t C - l . T h a t such an i n t e r a c t i o n does i n f a c t e x i s t i s e v i d e n t from t h e r e l a t i v e c h e m i c a l s h i f t s o f t h e anomeric h y d rogens o f t e t r a a c e t a t e s 1 and 2. As seen from T a b l e I I , t h e s i g n a l f o r t h e β-anomer i s a c t u a l l y 0.2 ppm t o lower f i e l d i n c o n t r a s t , f o r example, to the s i t u a t i o n f o r t h e g l u c o p y r a n o s e p e n t a a c e t a t e s where t h e s i g n a l f o r H - l o f t h e fc-form i s 0.58 ppm t o h i g h e r f i e l d t h a n t h a t o f t h e α-form (18). F o r t h e anomeric 2 - a c e t a m i d o 1,3,4,6-tetra-0-acetyl-2-deoxy-D-glucopyranoses, the s i g n a l f o r H - l o f t h e β-form i s 0.45 ppm t o h i g h e r f i e l d t h a n t h a t o f t h e α-form (19). Strong e l e c t r o s t a t i c s p e c i f i c d e s h i e l d i n g o f t h e anomeric hydrogen o f β - a c e t a t e (1) i s t h e r e f o r e i n d i c a t e d . C l e a r l y , t h e s u b s t i t u t i o n o f t h i s a x i a l hydrogen by a more b u l k y atom must l e a d t o s t r o n g non-bonded i n t e r a c t i o n t h a t would d e s t a b i l i z e t h e m o l e c u l e and i n t h e c a s e o f a n o mers t e n d t o f a v o r t h e β - f o r m . I n d e e d , as seen i n


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Table I, the i n t e r a c t i o n i s powerful enough to counter the anomeric e f f e c t (20) and lead to anomerization e q u i l i b r i a which favor the β-form. Thus, there can be no doubt that the phthalimido group i s well oriented to well shelter the α-side of the pyranose r i n g and, indeed, provide a p a r t i c i p a t i o n i n reactions at the anomeric center. 13 The C-chemical s h i f t s for C - l of compounds 1 to 8 are l i s t e d i n Table I I . I t i s seen that except for the anomeric iodides, the s i g n a l f o r C - l of the a-anomer i s to lower f i e l d than that of the 3-form (21). Reaction of near 1:1 mixture of the a- and 3 bromides (6 and 5) with 2,2,2-trichloroethanol i n the presence of the s i l v e r t r i f l a t e - c o l l i d i n e complex gave only a s l i g h t l y lower y i e l d of the β-glycoside than when pure 3-bromide was used. I t was apparent that the α-bromide may be s l i g h t l y more prone to dehydrobromination. Nevertheless, there appears l i t t l e ad vantage i n using pure 3-bromide instead of a mixture with i t s α-anomer i n these g l y c o s i d a t i o n reactions. Also, the reaction with the 3-chloride (3) gave the same y i e l d as the 3-bromide (5). Indeed, although the g l y c o s i d a t i o n reactions reported herein u t i l i z e d the 3-bromide, i t l i k e l y w i l l prove advantageous to use the 3-chloride i n such reactions i n view of i t s great er s t a b i l i t y on storage. Also, i n the preparations to be reported, the i n i t i a l reaction temperature i s - 3 0 ° . This was mainly as a precautionary measure since v i r t u a l l y the same y i e l d s were obtained at ambient temp eratures for the g l y c o s i d a t i o n of 2,2,2-trichloro ethanol . The reaction of a halide with s i l v e r t r i f l a t e c o l l i d i n e (1:1) i s extremely rapid as indicated by the appearance of p r e c i p i t a t e d s i l v e r h a l i d e . However, t h i s rapid i n i t i a l reaction may lead, even i n the presence of an alcohol, to g l y c o s y l t r i f l a t e which i n turn provides the glycoside since near the same y i e l d of the 2,2,2-trichloroethyl glycoside was obtained, using the 3-bromide as reagent, when the alcohol was added 10 minutes a f t e r the addition of the s i l v e r t r i f l a t e - c o l l i d i n e complex and the formation of s i l v e r bromide was complete as when the alcohol and the pro moter were added at the same time. Reaction of the 3-bromide (5) with 2,2,2-trichloroethanol i n n i t r o methane and using only c o l l i d i n e to n e u t r a l i z e the l i b e r a t e d a c i d gave mainly (-70%) the product of dehydrobromination (9). Thus, the success of the method appears to r e l y on the l i b e r a t i o n over the course of the reaction or a c a t i o n i c intermediate (B, C or D of



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

CARBOHYDRATES

Scheme 1) which has a pronounced tendency to form the 3-glycoside while avoiding elimination of a proton or forming e i t h e r an orthoamide or an orthoacetate. Thus, a highly promising method f o r e s t a b l i s h i n g β-glycosaminide linkages seemed at hand and t h i s promise was well substantiated by the following syntheses. 2,2,2-Trichloroethyl 4,6-0-benzylidene-2-deoxy-2phthalimido-3-D-glucopyranoside (14) was condensed with the 3-bromide (5) i n nitromethane using the s i l ver t r i f l a t e - c o l l i d i n e complex to form compound 15 i n 82% y i e l d . Although care was taken to exclude water from the reaction mixture, a main by-product appeared to be that from the h y d r o l y s i s of 5 ( t i c ) . A small amount of the glycoseen (9) was also formed. The y i e l d obtained i s to be contrasted to the 25% y i e l d reported by Heyns and coworkers (4) i n a s i m i l a r con densation but using mercuric cyanide to promote the glycosidation r e a c t i o n . Using the oxazoline method, Zurabyan and coworkers (8) r e a l i z e d an 81% y i e l d i n forming benzyl 3-0-(2-acetamido-3,4,6-tri-0-acetyl-2deoxy-3-D-glucopyranosyl)-2-acetamido-4,6-0-benzylidene-2-deoxy-3-D-glucopyranoside. Acid hydrolyses to remove the benzylidene and a c e t y l groups of 15 p r o v i ded the diphthalimido glycoside (16) which was treated with hydrazine to form the 2,2,2-trichloroethyl 3-0(2-amino-2-deoxy-3-D-glucopyranosyl)-2-amino-2-deoxy3-D-glucopyranoside (17). The e f f e c t of pH on the C NMR spectrum of 17 i s reported i n Table I I I . 2,2,2-Trichloroethyl 3,6-di-0-acetyl-2-deoxy-2phthalimido-3-D glucopyranoside (21) was prepared from 14 by way of the intermediates 19 and 20. Reaction of 21 with a s l i g h t excess of 5 under usual conditions provided a 51% y i e l d of the desired 3 - l i n k e d disaccharide d e r i v a t i v e 22. The y i e l d was r a i s e d to 68% when a d d i t i o n a l mole equivalents of 5 and the promoter were added a f t e r the i n i t i a l reaction had subsided. I t i s apparent therefore that the hydroxyl group of 21 i s indeed quite unreactive (1). In previous syntheses of the disaccharide (chitobiose) (1,5), very s p e c i a l de r i v a t i v e s of D-glucosamine were prepared i n order to make the 4-hydroxyl more r e a d i l y a v a i l a b l e to the g l y cosidation reaction. In spite of t h i s precaution, the y i e l d s achieved i n the glycosidation reaction were 10% (-35% of the α-linkage) (5) and 36% (8% of the α - l i n k age) (1) using Helferich-type condensations. Thus, the present method i s capable of providing f a r super i o r y i e l d s even when using a type of alcohol which i s notorious for i t s u n r e a c t i v i t y . Although some α-gly coside must form i n our present method none has been detected i n any of the reactions so f a r studied. 13


6.

LEMiEux E T A L .


99


The chitobiose d e r i v a t i v e (22) was deacetylated under acid conditions to provide the diphthalimido glycoside (23) which was then converted using hydrazine to 2 , 2 , 2 - t r i c h l o r o e t h y l c h i t o b i o s i d e ( 2 4 ) .

A comparison of the C-NMR t i t r a t i o n curves (22) for the compounds 17 and 24 appears of i n t e r e s t to the subject of conformational preferences about g l y c o s i d i c linkages (20). As seen i n Table I I I , the s h i e l d i n g of C - l of compounds 1 2 , 17 and 24 on protonation of the geminal 2-amino group was 4 . 7 - 5 . 2 ppm, normal 3 s h i f t s (22) f o r t h i s transformation. Normal 3 - s h i f t s (-4.4 ppm) were also observed i n the C - 3 atoms of 17 and 24. These signals could be r e l i a b l y assigned 1


100


from t h e s p e c t r u m f o r t h e s i m p l e g l y c o s i d e 1 2 . How ever, although t h e β - s h i f t f o r C-3 of the c h i t o b i o s e d e r i v a t i v e 24 was n o r m a l , t h a t f o r C - 3 o f t h e 1 ' •> 3 l i n k e d d i s a c c h a r i d e 17 was r e m a r k a b l y h i g h , n a m e l y , 8.6 ppm. T h a t i s , f o r 1 7 , t h e β - s h i f t s o b s e r v e d f o r b o t h C - l and C - 3 o f t h e t e r m i n a l u n i t and C - l were normal b u t t h a t o f t h e a g l y c o n i c C - 3 atom o f t h e n o n - t e r m i n a l u n i t was a b n o r m a l l y h i g h . The two amino groups o f t h e c h i t o b i o s e d e r i v a t i v e 24 a r e e x p e c t e d t o be w e l l s e p a r a t e d a s d i s p l a y e d i n t h e c o n f o r m a t i o n a l f o r m u l a f o r 24 p r e s e n t e d above. Thus, i t i s not s u r p r i s i n g t h a t t h e 3 - s h i f t s o b s e r v e d on p r o t o n a t i o n o f 24 were n o r m a l , l i t t l e i f any c o n f o r m a t i o n a l change o c c u r r i n g on p a s s i n g from t h e f r e e base t o t h e s a l t form. However, c o n s i d e r a t i o n s based on t h e exo-anomeri c e f f e c t and non-bonded i n t e r a c t i o n s (20) would r e q u i r e t h a t t h e l -> 3 l i n k e d d i s a c c h a r i d e 1 7 , i n t h e f r e e base f o r m , has t h e two amino groups i n v e r y c l o s e proximity. T h u s , p r o t o n a t i o n o f t h e amino groups w o u l d be e x p e c t e d t o produce a r e p u l s i o n between groups b o t h a s t h e r e s u l t o f e l e c t r o s t a t i c r e p u l s i o n between t h e c h a r g e d groups and an i n c r e a s e o f t h e e f f e c t i v e volumes o f t h e two groups because o f s t r o n g hydrogen b o n d i n g w i t h t h e w a t e r . T h u s , an a d j u s t m e n t o f t h e c o n f o r m a t i o n o f 17 would be e x p e c t e d , on i t s p a s s i n g from t h e f r e e base t o t h e s a l t f o r m , t h a t would a l l o w a g r e a t e r s e p a r a t i o n between t h e two amino g r o u p s . The abnormal 3 - s h i f t o b s e r v e d f o r t h e a g l y c o n i c C - 3 atom may be c o n s i d e r e d a m a n i f e s t a t i o n o f t h i s c o n f o r m a t i o n a l change. I f so, the fact that the 3 - s h i f t s were n o r m a l f o r t h e o t h e r t h r e e c a r b o n s w h i c h a r e 3 t o an amino group i n 17 would i n f e r t h a t t h e c o n f o r m a t i o n a l change w h i c h o c c u r r e d on p r o t o n a t i o n o f 17 was l a r g e l y r e s t r i c t e d t o a r o t a t i o n about t h e a g l y c o n i c C-3 t o oxygen b o n d , [change i n t h e ψ t o r s i o n a n g l e (20)]. T h i s c o n c l u s i o n would be i n l i n e w i t h t h e e x p e c t a t i o n based on t h e eχο-anomeric effect that the φ t o r s i o n angle tends t o remain constant (exo-anomeric e f f e c t ) (20) and t h e main a d j u s t m e n t t o e s t a b l i s h t h e most s t a b l e c o n f o r m a t i o n about a g l y c o s i d i c l i n k a g e i s by change o f t h e ψ a n g l e . The 2 - a c e t a m i d o - 2 - d e o x y - 3 - D - g a l a c t o p y r a n o s y l group o c c u r s a t t h e 4 - p o s i t i o n o f a D - g a l a c t o p y r a n o s y l group i n c e r t a i n g a n g l i o s i d e s (6,23). T h u s , i t was o f i n t e r e s t t o examine t h e e f f e c t i v e n e s s o f t h e method for the g l y c o s i d a t i o n of the r e a d i l y a v a i l a b l e methyl 2 , 3 , 6 - t r i - O - b e n z o y l - a - D - g a l a c t o p y r a n o s i d e (24). I n d e e d , r e a c t i o n w i t h 5 produced t h e d e s i r e d compound (26) i n e x c e l l e n t y i e l d (79%) and i t i s p l a n n e d t o u s e t h e method i n t h e c o u r s e o f an e f f o r t t o s y n t h e s i z e g a n g -


1

1

1


6.

101

2-Αητίηο-2-ά6θχί^-β-Ό-βΙη€ορι^ταηο8ΐάβ8

LEMiEux E T A L .

13 lioside related structures. The C-NMR spectrum s u b s t a n t i a t e d the s t r u c t u r e of the derived methyl 4-0-(2-amino-2-deoxy-£-D-glucopyranosyl)-a-D-galactopyranoside (27). TABLE I I I


13

C-NMR P a r a m e t e r s To D i s p l a y β - S h i f t s Base Salt a a Compound 12 17 24 12 17 r Δ = 5.2 »

» . 4 . , - ί = ^

C-l

104.3

103.6

C-2

57.0

57.0

76.5

Δ = 4.3 76.6 76.5 72.2 i Λ = 4.5

7 2 ..11

C-3' C-4

24 1

103.3 99.4 98.9 98.1 Δ = 4.7 55.2 57.0 5 6 ..11 56.3 — Δ = 4.4 • a - . . . —— }

72.1

•

1

70.2

69.9

70.0

70.1

69.5

70.4

C-5'

76.0

76.1

75.3

76.9

76.4

75.2

C-6'

61.3

61.0

61.0

60.7

60.4

60.7

Δ = 4.7 103.9 4 56.6

C-l

-

103.6

C-2

-

55.9

C-3

-

85.7

C-4

-

68.2

Δ = 8.6 74 .4 * 78.9

C-5

-

76.1

C-6

-

61.0

It

98.9 Δ = 4.8 55.2

9.9.1 * 55.9

-

77.1 Δ = 4.3 67.2

70.1 * 77.1

76.0

-

76.4

76.3

60.6

-

60.4

60.5

Α

-

a ι

C - l i s denoted C - l f o r convenience of p r e s e n t a t i o n .


102

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

Experimental

A l l s o l v e n t e x t r a c t s were d r i e d over anhydrous sodium s u l f a t e p r i o r to s o l v e n t removal u s i n g a r o t a r y e v a p o r a t o r under the vacuum of a water a s p i r a t o r . The H-HMR s p e c t r a were measured a t 100 MHz ( V a r i a n HA-100) and C-NMR s p e c t r a a t 22.6 MHz (Bruker HFX-90). Un l e s s o t h e r w i s e s t a t e d , d e u t e r i o c h l o r o f o r m was used as a s o l v e n t and i n t e r n a l TMS as a s t a n d a r d . Thin layer chromatograms (TLC) were developed on a s i l i c a g e l G (Ε. Merck A.G., Darmstadt) u s i n g e t h y l a c e t a t e - S k e l l y s o l v e Β or e t h y l a c e t a t e - b e n z e n e and v i s u a l i z e d by s p r a y i n g w i t h 5% s u l f u r i c a c i d i n e t h a n o l f o l l o w e d by h e a t i n g a t 100°. Column chromatography was performed on s i l i c a g e l (CAMAG) or on Woelm Alumina ( n e u t r a l , A c t i v i t y I ) . The g l y c o s i d a t i o n r e a c t i o n s were p e r formed under a dry n i t r o g e n atmosphere. The n i t r o methane, 2 , 2 , 2 - t r i c h l o r o e t h a n o l and 2 , 4 , 6 - t r i m e t h y l p y r i d i n e ( c o l l i d i n e ) were d r i e d and f r e s h l y d i s t i l l e d p r i o r to u s e . A l l s o l i d reactants f o r glycosidation were d r i e d o v e r n i g h t over phosphorus p e n t o x i d e under h i g h vacuum p r i o r t o use. 1,3,4,6-Tetra-0-acetyl-2-deoxy-2-phthalimido-3-Dg l u c o p y r a n o s e (1). D-glucosamine h y d r o c h l o r i d e (21.6 g, 100 mmol) was added to a sodium methoxide s o l u t i o n (prepared from 2.3 g of sodium i n 100 ml of m e t h a n o l ) . A f t e r shaking f o r 10 min, the s e p a r a t e d sodium c h l o r i d e was removed by f i l t r a t i o n and washed w i t h methanol (50 m l ) . The combined f i l t r a t e s were t r e a t e d w i t h f i n e l y ground p h t h a l i c a n h y d r i d e (7.4 g, 50 mmol) and shaken f o r 10 min. T r i e t h y l a m i n e (10.1 g, 100 mmol) was then added and the c l e a r s o l u t i o n was t r e a t e d w i t h p h t h a l i c a n h y d r i d e (8.1 g, 55 mmol). A f t e r shaking f o r 10 min, a c r y s t a l l i n e s o l i d s t a r t e d to p r e c i p i t a t e . The m i x t u r e was then brought to 50° and s t i r r e d f o r 20 min. A f t e r being kept a t 0° f o r 1 h r , the s o l i d (20.5 g) was c o l l e c t e d by f i l t r a t i o n and d r i e d . H-NMR i n d i c a t e d the s o l i d to be the triethylammonium s a l t of 2-(2 -carboxybenzamido)-2-deoxy-D-glucopyranose (25^26). D r y i n g o v e r n i g h t i n a i r r e s u l t e d i n the l o s s of the triethylamine. E v a p o r a t i o n of the f i l t r a t e gave a y e l low s o l i d which was suspended i n d i e t h y l ether (200 ml) and c o l l e c t e d by f i l t r a t i o n . The H-NMR spectrum i n D2O showed t h i s f r a c t i o n to be contaminated w i t h a t r a c e of t h e unreacted glucosamine. The p r o d u c t s were combined (46.5 g) and t r e a t e d w i t h p y r i d i n e (200 ml) and a c e t i c a n h y d r i d e (100 m l ) , at room temperature f o r 16 h r . The s o l u t i o n was poured i n t o i c e - w a t e r and the aqueous m i x t u r e s u b s e q u e n t l y ex t r a c t e d w i t h c h l o r o f o r m (3 χ 100 ml). The combined ex-


13

1

1


6.

LEMiEux E T A L .

103

2-Α™ΐηο-2-άβοχΐ}-β-Ό-βΙηοορΐ}ταηο8ΐ(Ιβ8

t r a c t s were washed successively with cold water, 3% h y d r o c h l o r i c a c i d , saturated sodium bicarbonate s o l u t i o n and w a t e r . Solvent removal l e f t a yellow foam w h i c h was d i s s o l v e d i n d i e t h y l ether (500 ml) and treated with c h a r c o a l . C o n c e n t r a t i o n to a volume of 150 m l and s t o r a g e overnight a t 0° gave a c o l o r l e s s s o l i d (39.1 g, 82% y i e l d ) . The H - N M R s p e c t r u m of the product showed i t to be a 2:1 m i x t u r e of 3and a-anomers. A 3:1 m i x t u r e of t h e β- and α - a n o m e r s was ob t a i n e d on r e a c t i o n of the t r i e t h y l a m i n e s a l t with sod ium a c e t a t e and a c e t i c a n h y d r i d e a t 100° for 1 h r . However, the product was d a r k r e d and d i f f i c u l t to de c o l o r i z e . The pure 3-anomer ( 1 5 - 2 0 g) c a n be obtained by c r y s t a l l i z a t i o n from e t h a n o l and r e e r y s t a l l i z a t i o n from e t h y l acetate, mp 9 0 - 9 4 ° [ l i t . 199-200° (11) , 9 1 - 9 4 ° f:Z0J] , [a]g2 + 65.5° (ο, 1 i n chloroform). The •^H-NMR s p e c t r u m w a s i n g e n e r a l a c c o r d with that repor t e d by H o r t o n and c o w o r k e r s (19).


1

1,3,4,6-Tetra-0-acetyl-2-deoxy-2-phthalimido-a-gglucopyranose ( 2 ) . A sample (6.6 g) of 2 - ( 2 - c a r b o x y 1

benzamido)-2-deoxy-ot-D-glucopyranose w h i c h had the same p h y s i c a l constants as r e p o r t e d i n the l i t e r a t u r e was obtained by f r a c t i o n a l c r y s t a l l i z a t i o n of a p r e p a r a t i o n of the 3-anomer f o l l o w i n g the procedure reported by Hirano (25). A c e t y l a t i o n of the m a t e r i a l as described b y H i r a n o (25) provided a 51% c r u d e y i e l d of a product w i t h mp 1 1 6 - 1 1 6 . 5 ° a n d [ a ] +114° (chloroform). A f t e r two r e c r y s t a l l i z a t i o n s f r o m m e t h a n o l , t h e mp w a s 126127° and [a]^ +119.2° (c 1, i n chloroform). Hirano (25) h a s r e p o r t e d mp 1 3 1 ° , [a]jjj + 98° whereas Akiya and Osawa (10) reported mp 1 2 4 - 1 2 6 ° , [a]g + 116.1°. T h e NMR s p e c t r a (see Table II) were i n agreement with the assigned s t r u c t u r e . 2

2

2

6

5

3,4,6-Tri-0-acetyl-2-deoxy-2-phthalimido-a-g-glucopyranosyl C h l o r i d e (4). T h i s compound was prepared

from the 3-bromide (5, to be d e s c r i b e d below) under k i n e t i c conditions using the procedure of Lemieux and Hayami (15). Compound 5 (1.03 g) was d i s s o l v e d i n dry a c e t o n i t r i l e (10 ml) w h i c h c o n t a i n e d tetraethylammonium c h l o r ide (0.50 g). A f t e r 5 hr at room t e m p e r a t u r e , the p r o d u c t was i s o l a t e d i n t h e u s u a l manner and was r e c r y s t a l l i z e d from d i e t h y l e t h e r - S k e l l y s o l v e Β to a f f o r d an 80% y i e l d (0.72 g) of m a t e r i a l , mp 1 7 4 - 1 7 5 ° , [ C L ] ^ + 122.2° (c, 0.88 i n a c e t o n i t r i l e ) (see Table I I ) . Anal. C a l c d . for C 2 Ν, 3.09; C l , 7.80. Found: C l , 7.78. The 3-anomer (3) (see 3-tetraacetate (1) using al 2

0

H

0 C,

N

0

9 53.13; C

1

:

C

' H,

52.93; 4.59;

H, Ν,

4.44; 3.39;

Table II) was p r e p a r e d from uminum c h l o r i d e as described


104

SYNTHETIC

by A k i y a agreed.

and

Osawa

and

(10)

the

METHODS

p h y s i c a l

FOR

CARBOHYDRATES

constants


3,4,6-Tri-0-acetyl-2-deoxy-2-phthalimido-3-Q-glucopyranosyl Bromide ( 5 ) . A s o l u t i o n o f t h e β - a c e t a t e 3 (9.54 g, 20 m m o l ) and a c e t i c a n h y d r i d e (5 m l ) i n a saturated hydrogen bromide s o l u t i o n of g l a c i a l a c e t i c acid (30 ml) was k e p t a t room t e m p e r a t u r e f o r 24 h r . A f t e r d i l u t i o n with chloroform (200 ml) and c h i l l i n g with ice, the s o l u t i o n was washed w i t h c o l d w a t e r (3 times) and s a t u r a t e d sodium bicarbonate s o l u t i o n . S o l vent removal a f t e r d r y i n g l e f t a foamy s o l i d w h i c h was c r y s t a l l i z e d from d i e t h y l ether (7.77 g, 78% y i e l d of a c o l o r l e s s s o l i d , s e e T a b l e I I ) , m p 122-123°, [α]ρ + 57.3° ( c , 1 i n c h l o r o f o r m ) . L i t . m p 120-121° (11).

3.4.5- Tri-0-acetyl-2-deoxy-2-phthalimido-a-g-glucopyranosyl Bromide ( 6 ) . T h e m o t h e r l i q u o r s f r o m t h e above p r e p a r a t i o n of compound 5 were evaporated to d r y n e s s and the r e s i d u e a p p l i e d to a s i l i c a gel column for chromatography using benzene-diethyl ether (1:1) as d e v e l o p i n g phase. Four f r a c t i o n s were separated. T h e s e c o n d f r a c t i o n t o b e e l u t e d w a s t h e ( 3 - f o r m 5. The t h i r d f r a c t i o n r e s i s t e d c r y s t a l l i z a t i o n b u t NMR s p e c tra r e q u i r e d a h i g h s t a t e of p u r i t y . 1

3

yls), 123.9

C-4,

C-NMR:

169.0, 169.9, 170.4 (3 a c e t y l c a r b o n p h t h a l o y l c a r b o n y l s ) , 134.5, 131.4 a n d (aromatic), 87.3 ( C - l ) , 72.6, 69.1, 67.8 (C-3,

167.3 C-5),

(2

61.1

(C-6),

56.4

(C-2),

20.6

(3

acetyl

methyls). H-NMR: δ 7.80 (m, H - l ) ; 6.52 (q, 9, 11 H - 4 ) ; 4.35 ( q , 4, 11 H z , 1

Hz,

4, p h t h a l i m i d o ) , 6.97 (d, 4 H z , H - 3 ) ; 5.18 (q, 9, 10 H z , H - 2 ) ; 4.2 ( m , H - 5 , H-6 a n d (s, 0-acetyl).

H - 6 ) ; 2.10, 2.08, 1.88 3.4.6- Tri-0-acetyl-2-deoxy-2-phthalimido-3-g-glucopyranosyl Iodide (7). A s o l u t i o n o f h y d r o g e n i o d i d e 1

in acetic a c i d was p r e p a r e d by a d d i t i o n of acetic a n hydride (14 ml) t o 47% hydroiodic a c i d (3 m l ) a t 0° i n a n i t r o g e n atmosphere. C o m p o u n d 1 (15.0 g) was added, t h e s o l u t i o n was s t i r r e d for 1 hr at room temperature and then poured into i c e - w a t e r . The c h l o r o f o r m ex t r a c t was f i r s t n e u t r a l i z e d with saturated aqueous sod ium b i c a r b o n a t e and t h e n w i t h aqueous sodium t h i o s u l f a t e p r i o r to d r y i n g over sodium s u l f a t e . The c h l o r o f o r m s o l u t i o n was e v a p o r a t e d to an o i l y r e s i d u e which c r y s t a l l i z e d from d i e t h y l ether. The from

y i e l d

ether

tot]

+ 38.2° H-NMR: H - l ) ; 5.73 1

Hz,

4.68

(t,

10

was

r a i s e d

50%, the

mp

91-92°.

m e l t i n g

point

R e c r y s t a l l i z a t i o n to

94-94.5°

(β, 1 in chloroform). 6 7.83 ( m , 4, p h t h a l i m i d o ) , 6.71 (q, 9, 10 H z , H - 3 ) ; 5.26 ( t , 10

H z , H - 2 ) ; 4.24

(m,H-6 a n d H-6 ); f

(dec.), (d, Hz,

3.94


10

H-4);

6.

LEMiEux E T A L .


(m,

H-5); 2.12,2.04, 1.86 ( s , O - a c e t y l ) . 3,4,6-Tri-0-acetyl-2-deoxy-2-phthalimido-a-g-gluc o p y r a n o s y l I o d i d e ( 8 ) . The mother l i q u o r from t h e c r y s t a l l i z a t i o n of 7 was l e f t a t room temperature. A f t er two days, a compound, mp 89.5-90°, [α]β +131.3° (c, 0.58 i n a c e t o n i t r i l e ) c r y s t a l l i z e d . The y i e l d was 15% (2.6 g ) . S i n c e the NMR s p e c t r a (see T a b l e I I ) i n d i c a t e d h i g h p u r i t y and, l i k e 7, the product was q u i t e u n s t a b l e , no f u r t h e r p u r i f i c a t i o n was attempted. H-NMR: 6 7 .80 (m, 4, p h t h a l i m i d o ) ; 6.97 (d, 4Hz, H - l ) ; 6.52 ( q , 10, 8 Hz, H-3); 5.18 ( t , 8 Hz, H-4); 4.35 (q, 4, 10 Hz, H-2); 4.60-4.10 (m, 3, H-5, H-6 and H - 6 ) ; 2.10, 2.08, 1.88 ( s , O - a c e t y l ) . 3,4,6-Tri-O-acetyl-l,2-dideoxy-2-phthalimido-gα:rα&^nσ-hex-l-enopyranose (9) . A s o l u t i o n o f the brom i d e 5 (996 mg, 2 mmol), 2 , 2 , 2 - t r i c h l o r o e t h a n o l (330 mg, 2 mmol) and 2 , 4 , 6 - t r i m e t h y l p y r i d i n e (254 mg, 2.1 mmol) i n nitromethane (20 ml) was s t i r r e d a t 90° f o r 48 h r . The s o l u t i o n was d i l u t e d w i t h c h l o r o f o r m (50 ml) and washed w i t h c o l d water and c o l d 10% h y d r o c h l o r i c a c i d . E v a p o r a t i o n of the s o l v e n t gave a syrup which was passed through a s h o r t alumina column u s i n g e t h y l a c e t a t e - d i e t h y l ether (1:1). Treatment of the e l u e n t w i t h c h a r c o a l , e v a p o r a t i o n and c r y s t a l l i z a t i o n from d i e t h y l e t h e r gave a c o l o r l e s s s o l i d (585 mg, 70% y i e l d ) , mp 117-118°, [ α ] £ - 34.2° {a, 0.5 i n c h l o r o form) . H-NMR: δ 7.98-7.68 (m, 4, p h t h a l i m i d o ) ; 6.78 ( s , H - l ) ; 5.61 ( d , 4 Hz, H-3); 5.32 ( t , 4 Hz, H-4); 4.664.25 (m, 3, H-5 and H-6); 2.16, 2.13, 1.94 ( s , O-ace tyl). Anal. C a l c d . f o r C H I Q N O : C,57.55; H, 4.59; N, 3.36. Found: C, 57 . 52 ; Η, 4 . 57 ; Ν, 3.29. 2,2,2-Trichloroethyl 3,4,6-Tri-0-acetyl-2-deoxy2 - p h t h a l i m i d o - p - D - g l u c o p y r a n o s i d e (10). A s o l u t i o n of the 3-bromide 5 7 9 . 9 6 g, 20 mmol) i n n i t r o m e t h a n e (20 ml) was added dropwise to a c o o l e d (-30°) s o l u t i o n of 2 , 2 , 2 - t r i c h l o r o e t h a n o l (3.30 g, 22 mmol), s i l v e r t r i f l a t e (5.66 g, 22 mmol) and c o l l i d i n e (2.66 g, 22 mmol) i n nitromethane (20 m l ) . A f t e r s t i r r i n g a t -30° f o r 2 hr and d i l u t i o n w i t h c h l o r o f o r m (100 m l ) , t h e s o l i d was removed by f i l t r a t i o n and washed w i t h c h l o r o form (20 m l ) . The combined f i l t r a t e s were washed w i t h c o l d water, 3% h y d r o c h l o r i c a c i d and water and d r i e d . S o l v e n t removal l e f t a y e l l o w foam which was passed through a s h o r t alumina column u s i n g d i e t h y l e t h e r e t h y l acetate (1:1). Treatment w i t h c h a r c o a l , s o l v e n t removal and c r y s t a l l i z a t i o n from d i e t h y l e t h e r gave a c o l o r l e s s s o l i d (9.74 g, 86% based on 5 ) , mp 176-177°, [a]£ + 4.4° (β, 0.5 i n c h l o r o f o r m ) . 1


105

1

4

1

2

0

q

3


106


H-NMR:

6

7.95-7.65

(m,

4,

p h t h a l i m i d o ) ;

10 H z , H - 3 ) ; 5 . 6 0 ( d , 8 H z , H - l ) ; 5 . 1 9 ( t , 10 2.12, 2.04, 1.88 (s, O - a c e t y l ) ; 4.52-3.82 (m, ing p r o t o n s ) . Anal. C a l c d . f o r Ν, 2.47; C l , 18.77. 2.34; C l , 18.84.

C22H22 OioCl3: C, Found: C , 46 . 6 8 ; N


2,2,2-Trichloroethyl glucopyranoside ( 1 1 ) . A

5.92

( t ,

H z , H-4); 6 remain

46.62; H , 3.91; H , 3 . 9 7 ; Ν,

2-Deoxy-2-phthalimido-

s o l u t i o n of the t r i a c e t a t e 10 (7.93 g, 15 mmol) i n acetone (200 m l ) , water (100 ml) and cone, h y d r o c h l o r i c a c i d (40 ml) was s t i r r e d a t 70° for 3 h r . Removal of acetone l e f t a white suspension w h i c h was e x t r a c t e d w i t h e t h y l acetate (3 χ 100 m l ) . The combined e x t r a c t s were washed w i t h cold water, saturated sodium bicarbonate s o l u t i o n and water and d r i e d . Solvent removal and r e e r y s t a l l i z a t i o n from benzene-ethyl acetate (20:1) gave a c o l o r l e s s s o l i d (6.0 g, 91% y i e l d ) , mp 2 2 4 - 2 2 5 ° , [α]£° - 37.6° (e, 0.5 in acetone). iH-NMR ( a c e t o n e - d ) : δ 7.86 (s, 4, p h t h a l i m i d o ) ; 5.46 (d, 8 H z , H - l ) ; 4.31 (d, 5 H z , 2, CHoCCl-); 4.72 (d, 5 H z , 1, O H , D 0 e x c h a n g e a b l e ) ; 2.80 (d, 3 H z , 2, O H , D2O exchangeable); 4.80-3.45 (m, 6 r e m a i n i n g p r o tons) . 13C-NMR ( a c e t o n e - d ) : 99.9 ( C - l ) , 97.4 ( C C l o ) , 81.1 ( C H ) , 77.9 (C-5), 72.4 (C-3), 71.8 (C-4), 62.5 (C-6), 57.7 (C-2). Anal. C a l c d . f o r C-, Η N0 C l ο : C, 43.61; H , 3.66; Ν, 3.18; C l , 24.14. Found: C, 43.70; H , 3 . 6 5 ; N , 2.93; CI, 24.00. 6

2

6

2

6

Ί

2,2,2-Trichloroethyl ranoside ( 1 2 ) . A s o l u t i o n

fi

7

2-Amino-2-deoxy-3-Q-glucopy-

of the p h t h a l i m i d o compound 11 (2.20 g, 5 mmol) a n d 87% h y d r a z i n e h y d r a t e (1.0 g) in 95% e t h a n o l (50 m l ) was r e f l u x e d f o r 4 h r . The p r e c i p i t a t e was removed by f i l t r a t i o n and washed w i t h ethanol (10 m l ) . S o l v e n t removal l e f t a pale y e l l o w s o l i d which was a p p l i e d to an ion-exchange r e s i n (Dowex l x , hydroxide form) column and eluted w i t h water. F r e e z e - d r y i n g l e f t a c o l o r l e s s s o l i d w h i c h was d r i e d over P2O5 u n d e r h i g h v a c u u m ( 1 . 3 5 g , 8 7 % y i e l d ) , m p 167-168°, [a]£° - 44.2° (c 0.5 i n w a t e r ) . I H - N M R (ΓΓ20) : 6 5 .12 (d, 8 H z , H - l ) ; 4.88 (d, 5 H z , 2 , CH2CCI3); 4 . 4 6 - 3 . 0 4 (m, 6 r e m a i n i n g p r o t o n s ) . The C-NMR i s reported i n Table I I I . Anal. C a l c d . f o r C0H1ANOCCIO: C, 30.94; H , 4.54; Ν, 4 . 5 1 ; C l , 34.25. Found: C, 31.18; H , 4 . 5 4 ; Ν, 4 . 3 3 ; C l , 34.07. y

1

3

2,2,2-Trichloroethyl copyranoside ( 1 3 ) . A s o l

(1.25 g) methanol

2-Acetamido-2-deoxy-3-g-glu-

u t i o n of t h e amino compound and a c e t i c anhydride (6 m l ) i n 50% aqueous (20 ml) was s t i r r e d a t room t e m p e r a t u r e f o r


12 2

6.

107

2-Α™ϊηο-2-άβοχψβ-τ)-$ηοορψαηού(ΙβΒ

LEMiEux E T A L .

hr. Solvent removal and d r y i n g over P2O5 gave a c o l o r less s o l i d w h i c h was r e e r y s t a l l i z e d from benzene-ace tone (2:1) (1.34 g, 9 6 % y i e l d ) , mp 1 7 1 - 1 7 2 ° , [a]* 35.7° (tf, 0.6 i n w a t e r ) , (lit.(27) 170-171°). H-NMR ( D 0 ) : 6 5.24 (d, 8 Hz, H - l ) ; 4.83 (d, 5 Hz, CH2CCI3); 2.45 (s, tf-acetyl), 4.45-3.80 (m, 6 r e maining protons). 13C-NMR (D20): 102.9 ( C - l ) , 96.5 (CClo) , 80.9 (CH ), 76.4 (C-5), 73.7 (C-3), 70.3 (C-4), 61.2 (C-6), 55.8 (C-2). Anal. C a l c d . for 0, H , N0 Clo : C, 3 4 . 0 5 ; H, 4.57; Ν, 3.97; C l , 30.16. F o u n d : C, 3 4 . 4 6 ; H, 4.65; Ν, 4.21; C l , 29.77. 0

D

2

J

2


Λ

n

fi

fi

2,2,2-Trichloroethyl 4,6-0-Benzylidene-2-deoxy-2phthalimido-3-D-glucopyranoside (14). A s o l u t i o n of

the hydroxy compound 11 (6.61 g, 15 m m o l ) , α,α-dimethoxytoluene (9.10 g, 60 mmol) and p-toluenesulfonic acid ( 1 0 0 mg) i n f r e s h l y d i s t i l l e d a c e t o n i t r i l e (200 ml) was s t i r r e d at room t e m p e r a t u r e for 12 h r . T r e a t ment w i t h t r i e t h y l a m i n e (1 m l ) and s o l v e n t removal l e f t a s t i c k y s o l i d w h i c h was d i s s o l v e d i n chloroform (100 ml) and washed w i t h c o l d water and s a t u r a t e d sod ium b i c a r b o n a t e s o l u t i o n . Solvent removal a f t e r d r y ing, and c r y s t a l l i z a t i o n from e t h y l a c e t a t e - S k e l l y s o l v e Β gave a c o l o r l e s s s o l i d w h i c h was r e e r y s t a l l i z e d from 2-propanol (7.37 g, 9 3 % y i e l d ) , mp 1 9 6 - 1 9 7 ° , [α]£° 47.2° (c, 0.5 i n chloroform). H-NMR: δ 7.89-7.24 (m, 9, b e n z y l and p h t a l i m i d o ) ; 5.58 (s, 1, b e n z y l i d e n e ) ; 5.50 (d, 8 Hz, H - l ) ; 4.72-4.50 (m, 1, H-2); 2.98 (d, 3 H z , OH, D2O exchange a b l e ) ; 4.44-3.50 (m, 7 remaining protons). Anal. C a l c d . for C23H20NO7CI3: C, 52.24; H, 3.81; N, 2.65; C I , 20.11. F o u n d : C, 5 2 . 3 3 ; H, 3.85; N, 2.38; CI, 20.25.

2,2,2-Trichloroethyl 3-0-(3,4,6-Tri-0-acetyl-2deoxy-2-phthalimido-(S-D-glucopyranosyl)-4,6-O-benzylidene-2-deoxy-2-phthalimido-3-g-glucopyranoside (15).

A s o l u t i o n of the (S-bromide 5 (800 mg, 1.5 mmol) i n nitromethane (5 m l ) was a d d e d to a cooled (-30°) s o l u t i o n of the 3-hydroxy compound 14 (670 mg, 1.27 mmol), s i l v e r t r i f l a t e (385 mg, 1.5 mmol) and c o l l i d i n e (182 mg, 1.5 mmol) i n nitromethane (10 m l ) . A f t e r s t i r r i n g at -30° for 3 h r , then at room t e m p e r a t u r e for 1 h r , the m i x t u r e was d i l u t e d w i t h c h l o r o f o r m (50 m l ) . The s o l i d was removed by f i l t r a t i o n and washed w i t h chloro form (20 m l ) . The combined f i l t r a t e s were washed suc c e s s i v e l y with cold water, 3% h y d r o c h l o r i c a c i d and wa t e r . Solvent removal l e f t a yellow foam w h i c h was ap p l i e d to a s i l i c a g e l column and e l u t e d w i t h e t h y l ace t a t e - S k e l l y s o l v e Β ( 1 : 1 ) . Solvent removal and c r y s t a l l i z a t i o n from d i e t h y l ether gave a c o l o r l e s s s o l i d (980


108


mg, (Cj

82% y i e 0.5 i n H-NMR: i d o ) ; 5.60 5.49 (d, 8 Hz, H - 4 ' ) ; a c e t y l ) ; 4.

l d based on 1 4 ) , mp 1 6 7 - 1 6 8 ° , [a]g 0.6 c h l o r o f o r m ) . δ 7.76-7.28 (m, 1 3 , b e n z y l a n d 2 p h t h a l (s, 1, b e n z y l i d e n e ) ; 5.52 (t, 10 H z , H - 3 H z , H - l ) ; 5.24 (d, 8 Hz, H - l ) ; 5.07 (t, 4.96 (q, 9 Hz, H - 3 ) ; 2.02, 1.92, 1.71 (s, 45-3.50 (m, 11 r e m a i n i n g p r o t o n s ) . u

f

1


Anal. C a l c d . for N, 2.96; C I , 11.24. CI, 11.11.

0 Η Ν Found: 4

3

3

9

2

° i m ) ; 10 0-

0 0 1 : C,54.59; H, 4.15; C, 53.99; H, 4.06; N , 2.88; 1

6

3

2,2,2-Trichloroethyl 3-0-(2-Deoxy-2-phthalimido-3D-glucopyranosyl)-2-deoxy-2-phthalimido-3-D-glucopyranoside ( 1 6 ) . A s o l u t i o n of compound 15 (550 mg, 0.58 mmol) i n 10% t r i f l u o r o a c e t i c a c i d (90%) i n d i c h l o r o m e thane (10 ml) was s t i r r e d for 10 m i n a t room tempera t u r e . Solvent removal l e f t an o i l w h i c h was d i s s o l v e d i n a m i x t u r e of acetone (20 m l ) , w a t e r (10 ml) and cone, h y d r o c h l o r i c a c i d (4 m l ) . The s o l u t i o n was s t i r r e d at 70° for 3 h r . E v a p o r a t i o n of acetone gave a suspension w h i c h was c o l l e c t e d by f i l t r a t i o n and washed w i t h cold water. R e c r y s t a l l i z a t i o n from a c e t o n e - e t h y l acetate gave a c o l o r l e s s s o l i d ( 4 0 0 m g , 94% y i e l d ) , m p , 263.5264°, [a]g - 0.86° (c, 0.35 i n acetone). 3

!H-NMR ( a c e t o n e - d j : δ 8.0-7.10 (m, 8, p h t h a l i m i do); 5.23, 5.21 (d, 8 H z , H - l and H - l ) ; 4.72-4.38 (m, H-2 and H - 2 ) . !3c-NMR ( a c e t o n e - d j : 99.4 ( C - l , C - l ) , 97.1 (CC1 ), 82.3 (CH ), 80?5 (C-3), 78.3, 77.9 (C-5, C - 5 ) , 72.1 ( C - 3 ) , 71.4 ( C - 4 ) , 70.7 (C-4), 62.0 (C-6, C - 6 ) , 57.9 (C-2), 55.6 ( C - 2 ) . Anal. C a l c d . for C o H N O i 0 C I 0 : C, 4 9 . 2 3 ; H, 3.99; N, 3.83. Found: C , 4 9 T 4 8 ; H7 4.02 ; Ν , 3.75. 1

1

f

3

f

2

1

f

f

f

n

9

q

?

2,2,2-Trichloroethyl 2-Amino-2-deoxy-3-0-(2-amino2-deoxy-3-D-glucopyranosyl)-β-g-glucopyranoside ( 1 7 ) .

A s o l u t i o n of the p h t 85% h y d r a z i n e h y d r a t e r e f l u x e d for 2 hr and s o l i d was removed by ethanol (5 m l ) . The to a foam w h i c h was d p l i e d to a column of F r e e z e - d r y i n g of the m g , 8 8 % y i e l d ) , mp 2 0 0 . 2 5 - i n w a t e r ) .

h a l i m i d o compound 16 (366 mg), and (2 m l ) i n 95% e t h a n o l (20 ml) was the s o l u t i o n cooled to 0°. The f i l t r a t i o n and washed w i t h cold combined f i l t r a t e s were evaporated i s s o l v e d i n water (10 ml) and ap Dowex 1x8 r e s i n (hydroxide form). e l u e n t gave a c o l o r l e s s s o l i d (208 2-204° ( d e c ) , [α]£ - 33.6° (c, 5

H-NMR ( D 0 ) : δ 5.22, 5.19 (d, 8 Hz, H - l and The ^C-NMR i s r e p o r t e d i n T a b l e I I I . Anal. C a l c d . for C H N 0 C l o : C, 35.65; H , 5.94. Found: C, 3 5 . 8 2 ; H, 5.23; N, 5.78. 2

1

N,

4

2

5

2

9

H - l ) . f

5.34;

2,2,2-Trichloroethyl 2-Acetamido-2-deoxy-3-0-(2acetamido-2-deoxy-3-D-glucopyranosyl)-3-D-glucopyranoside ( 1 8 ) . A s o l u t i o n of t h e a m i n o c o m p o u n d 17 (161


mg,

6.

0.34 with s t i r r l e f t treat mesh, f i l t r ( d e c

mmol) i n 50% a q u e o u s m e t h a n o l ( 1 0 m l ) w a s t r e a t e d acetic a n h y d r i d e (1.0 ml) and t h e s o l u t i o n was e d f o r 2 h r a t room t e m p e r a t u r e . Solvent removal a foam w h i c h was d i s s o l v e d i n w a t e r (10 ml) and ed with Ion R e t a r d a t i o n Resin, AG 11A8 (50-100 B i o - R a d ) . F i l t r a t i o n and f r e e z e - d r y i n g of the a t e g a v e a s o l i d ( 1 7 0 m g , 9 0 % y i e l d ) , mp 222-224° ) , [a]g - 26.6° (c, 0.5 i n water). H-NMR(D 0): δ 5.12 (d, 8 H z , H - l ) ; 4.92 (d, 8 H - l ) ; 2 . 3 3 , 2 .39 (s, tf-acetyl) . 5

1

Hz,

2

f

C-NMR (D 0): 103.9 ( C - l (C-3), 7 5 . 8 , 75.5 ( C - 5 , C - 5 ) , 68.6 ( C - 4 ' ) , 60.7 ( C - 6 , C - 6 ) , Anal. Calcd. for C H αΝ 0 5.26; N , 5.04. Found: C, 38.54 1


109

2-Α™ϊηο-2-άβοχψβ-τ>-φιοορνταηούάβ$

LEMiEux E T A L .

3

2

1

f

n

ft

2

2

Ί

) , 101.3 ( C - l ) , 81.5 73.3 ( C - 3 ) , 69.9 (C-4), 5 5 . 7 , 54.3 ( C - 2 , C - 2 ) . -, C l o : C , 3 8 . 9 0 ; H , ; Η , 5 . 2 6 ; Ν, 5 . 2 3 . 1

f

1

2,2,2-Trichloroethyl 3-0-Acetyl-4,6-O-benzylidene2-deoxy-2-phthalimido-3-g-glucopyranoside (19). A c e t i c a n h y d r i d e (8 m l ) w a s a d d e d t o a c o o l e d s o l u t i o n of t h e 3 - h y d r o x y compound 14 ( 3 . 7 0 g) i n d r y p y r i d i n e (16 m l ) . The s o l u t i o n was kept o v e r n i g h t a t room tem perature and poured into crushed i c e . C o l l e c t i o n of the separated s o l i d by f i l t r a t i o n and r e e r y s t a l l i z a t i o n from ethyl a c e t a t e - e t h a n o l (1:4) gave a c o l o r l e s s s o l i d ( 3 . 5 8 g , 9 0 % y i e l d ) , mp 2 0 8 ° " , [a]^° - 29.8° (ο, 0.5 i n chloroform). H-NMR: δ 7.90-722 (m, 9, b e n z y l and p h t h a l i m i d o ) ; 6.00 (t, 9 H z , H - 3 ) ; 5.64 (d, 8 H z , H - l ) ; 5.53 (s, 1, b e n z y l i d e n e ) ; 1.90 (s, 0 - a c e t y l ) ; 4.52-3.64 (m, 7 remaining protons). 1

Anal. Calcd. f o r C H N 0 C 1 : C, Ν, 2 . 4 5 ; C l , 1 8 . 6 3 . Found: C , 52 . 8 9 ; 2.31; C I , 18.72. 2

5

2

2,2,2-Trichloroethyl limido-B-D-glucopyranoside

2

8

3

52.60; H , 3.88; H , 3.97; N ,

3-0-Acetyl-2-deoxy-2-phtha-

(20). A s o l u t i o n of the above b e n z y l i d e n e compound 19 ( 2 . 8 5 g) i n 60% a q u e o u s a c e t i c a c i d (150 ml) was s t i r r e d a t 100° f o r 30 m i n . Solvent removal l e f t a y e l l o w s o l i d w h i c h was s l i g h t l y contaminated by the s t a r t i n g compound. The crude mix t u r e was a p p l i e d to a s i l i c a - g e l column and e l u t e d with ethyl acetate-benzene. Solvent removal of the second f r a c t i o n gave a c o l o r l e s s s o l i d ( 2 . 1 5 g , 89% y i e l d ) , mp 1 9 0 - 1 9 1 ° , [a]^° - 29.2° (c , 1 i n acetone). H-NMR ( a c e t o n e - d ) : δ 7.86 (s, 4, p h t h a l i m i d o ) ; 5.70 ( t , 10 H z , H - 3 ) ; 5.67 (d, 8 H z , H - l ) ; 4.88 (d, 5 Hz, 1, OH, D 0 e x c h a n g e a b l e ) ; 4.36 (d, 4 H z , 2, CH2CCI3); 2.91 ( s , 1, OH, D 0 e x c h a n g e a b l e ) ; 1.86 (s, 0 - a c e t y l ) ; 4.50-3.55 (m, 5 r e m a i n i n g protons). Anal. Calcd. for C Η 0NO0CI0: C, 44.79; H , 3.74; N, 2.90; C I , 22.03. Found: C, 44.93; H , 3.82; N , 2.81; C I , 22.06. 6

2

2

n 8

η


110



2,2,2-Trichloroethyl 3,6-Di-0-acetyl-2-deoxy-2phthalimido-3-g-glucopyranoside (21). A c e t i c anhydride ( 0 . 3 0 6 g , 3 mmol) was added to a cooled s o l u t i o n of compound 20 ( 1 . 4 6 6 g , 3 mmol) i n d r y p y r i d i n e (4 m l ) . After s t i r r i n g a t room t e m p e r a t u r e f o r 2 h r , t h e s o l u t i o n was c o o l e d t o 0° a n d t r e a t e d w i t h m e t h a n o l (5 m l ) . Solvent removal l e f t a foamy s o l i d w h i c h was shown to be a m i x t u r e o f 1 0 , 2 0 , a n d 21 b y T L C . T h e c r u d e m i x t u r e was a p p l i e d t o a s i l i c a g e l column and eluted with benzene-ethyl acetate (4:1). Solvent removal of the second f r a c t i o n gave a c o l o r l e s s s o l i d (0.86 g, 54.5% y i e l d ) , mp 1 3 9 - 1 4 0 ° [a]^ -36.7° (c, 0.9 i n chloroform).

exchangeable); 2.16, 1.96 7 remaining protons).

(s,

0 - a c e t y l ) ;

Anal. C a l c d . f o r C o H o 9 N, 2.67; C I , 20.27. Found: C, 2.70; C I , 20.11. N

2

0

c

2

4.55-3.60

(m,

3 > 45.78; H , 3.84; 45.83; H , 3.94; N ,

l

:

c

2,2,2-Trichloroethyl 4-0-(3,4,6-Tri-0-acetyl-2deoxy-2-phthalimido-£-D-glucopyranosyl)-3,6-di-Oacetyl-2-deoxy-2-phthaIimido-3-D-glucopyranosidë ( 2 2 ) . A s o l u t i o n o f t h e β - b r o m i d e 5 ( 1 . 1 0 g , 22 mmol) i n nitromethane (15 m l ) was added to a cooled (-30°) s o l u t i o n of the 4-hydroxy compound 21 ( 1 . 0 5 g , 2 . 0 mmol) and c o l l i d i n e (266 m g , 2 . 2 mmol) i n nitromethane (15 m l ) . A f t e r s t i r r i n g a t - 3 0 ° f o r 4 h r , 1 mmol each of 5, the s i l v e r s a l t and c o l l i d i n e were added. The m i x t u r e was s t i r r e d f o r an a d d i t i o n a l 2 hr a t -30° and then l e f t overnight a t room t e m p e r a t u r e . Chloroform (50 m l ) was added a n d t h e s o l i d s were removed by f i l t r a t i o n and washed w i t h chloroform (20 m l ) . The com bined f i l t r a t e s were washed w i t h cold w a t e r , 3% h y d r o c h l o r i c acid and water and d r i e d . Solvent removal l e f t a y e l l o w foam w h i c h was a p p l i e d to a s i l i c a g e l column and e l u t e d w i t h b e n z e n e - e t h y l acetate (4:1). Removal of the solvent from the second f r a c t i o n and c r y s t a l l i z a t i o n from d i e t h y l ether gave a c o l o r l e s s s o l i d (1.28 g, 68% y i e l d b a s e d o n 2 1 ) , mp 1 3 3 - 1 3 4 ° , [α]£ +1.6° (ο 0.5 i n chloroform). H-NMR: δ 8.0-7.62 (m, 8, 2 p h t h a l i m i d o ) ; 5.87 (q, 9 H z , H - 3 ) ; 5 . 7 4 ( t , 10 H z , H - 3 ) ; 5.51 (d, 8 H z , H - l ) ; 5.48 (d, 8 H z , H - l ) ; 5 . 1 5 ( t , 10 H z , H - 4 ) ; 2.11, 2 . 0 1 , 1.99, 1.94, 1.84 (s, 0 - a c e t y l ) ; 4.60-3.62 (m, 11 r e m a i n i n g p r o t o n s ) . Anal. C a l c d . f o r 0 Η Ν 0 0 1 : C, 51.00; H , 4.17; Ν, 2 . 9 7 ; C l , 1 1 . 2 9 . Found: C, 50.85; H , 4.27; Ν, 3.10; C l , 11.36. 4

9

1

1

f

4

0

1

3

9

2

1

8

3


6.

111

2'Αχηιηο-2'άβοχψβ-τ>-φιοο'ρψαηούάβ8

LEMIEUX ET AL.

2,2,2-Trichloroethyl 2-Deoxy-2-phthalimido-4-0-(2deoxy-2-phthalimido-β-Q-glucopyranosyl)-£-|)-gluco-~ pyranoside (23). A s o l u t i o n o f t h e c o m p o u n d 2 2 ( 3 4 6 mg, 0.5 mmol) i n a m i x t u r e of acetone (20 m l ) , water (10 ml) and cone, h y d r o c h l o r i c a c i d (4 m l ) was s t i r r e d at 70° for 6 h r . E v a p o r a t i o n of acetone l e f t a white s u s p e n s i o n w h i c h was c o l l e c t e d by f i l t r a t i o n and washed with water. R e c r y s t a l l i z a t i o n from e t h y l a c e t a t e benzene gave a c o l o r l e s s s o l i d ( 2 2 0 m g , 82% y i e l d ) , mp 221-223° ( d e c ) , [a]£ -20.8° {β, 0.25 i n acetone). 5

H-NMR (acetone-d ): δ 7.88, 7.86 (m, 8, 2 p h t h a l i m i d o ) ; 5.38, 5.36 (d, 8 Hz, H - l , H - l ) ; 5.862.80 ( m , r e m a i n i n g 19 protons). C-NMR (acetone-d ): 100.6, 100.4 ( C - l , C - l ) , 81.5 (C-4), 78.4 ( C - 5 ) , 76.6 (C-5), 72.8, 72.5 (C-3, C - 3 ) , 70.7 ( C - 4 ) , 62.8, 61.7 (C-6, C - 6 ) , 58.5, 57.1 (C-2, C - 2 ) .


1

6

1

1

3

1

6

1

1

1

1

1

Anal. Ν,

3.99;

Calcd. for C 3.83. Found:

3

H C, 0

2

N 0 C 1 : C, 49.23; H, 49.84; H, 4.12; Ν, 3.54.

9

2

1

3

3

2,2,2-Trichloroethyl 2-Amino-2-deoxy-4-0-(2-amino2-deoxy-(3-D~glucopyranosyl) -3-Q-glucopyranoside (24) . C o m p o u n d 2 4 , mp 1 6 0 - 1 6 2 ° ( d e c ) , [a]g water), w a s o b t a i n e d i n 87% y i e l d from the method used for the p r e p a r a t i o n of H-NMR (D 0): δ 5.26 (d, 8 Hz, H Hz, H - l ) : 4.69 (d, 3.5 H z , 2, C H C C 1 4

1

2

f

N,

The Anal. 5.94.

2

3

-7.8° (ο, 2 i n compound 23 by the compound 17. - l ) ; 5.02 (d, 8 ) .

1 C-NMR i s reported i n Table I I I . Calcd. for C ^ H ^ N ^ g C ^ : C , 35 . 65 ; Found: C, 35.63; H, 5.17; N, 5.99. 3

H,

5.34;

2,2,2-Trichloroethyl 2-Acetamido-2-deoxy-4-0-(2acetamido-2-deoxy-3-D-glucopyranosyl)-3-g-glucopyranoside ( 2 5 ) . C o m p o u n d 2 5 , mp 2 1 8 - 2 1 9 ° ( d e c ) , [a]]} -22.4° (c 0.25 i n w a t e r ) , was y i e l d from compound 24 b y t h e m e t h o d p a r a t i o n of the compound 18. 3

y

H-NMR (D 0): δ H - l ) ; 2.22, 2.18 1

Hz,

2

f

4.98 (d, 8 Hz, (s, N - a c e t y l ) .

prepared used for H - l ) ;

i n 80% the p r e

4.74

(d,

8

C-NMR (D 0): 102.8, 102.0 ( C - l , C - l ' ) , 79.8 (C-4), 76.3 ( C - 5 ) , 75.0 (C-5), 74.2, 73.8 (C-3, C - 3 ) , 72.4 ( C - 4 ) , 61.0, 60.6 (C-6, C - 6 ) , 56.0, 55.1 (C-2, C-2 ) . Anal. Calcd. for C H N 0 C 1 : C, 38.90; H, 5.26; Ν, 5.04. Found: C , 38 . 3 5 ; H , 5 . 2 0 ; Ν, 5.12. 1

3

2

1

T

1

?

f

1

8

2

9

2

1

1

3

Methyl 4 - 0 - ( 3 , 4 , 6 - T r i - 0 - a c e t y l - 2 - d e o x y - 2 - p h t h a l i mido-3-D-glucopyranosyl)-2,3,6-tri-O-benzoyl-a-Dgalactopyranoside ( 2 6 ) . A s o l u t i o n of the β-bromide 5 (1.99 g, 4 mmol) i n n i t r o m e t h a n e (10 cooled (-30°) s o l u t i o n of m e t h y l 2 , 3 D-galactopyranoside (24) , mp 1 3 5 . 5 ° , in chloroform), (1.52 g, 3 mmol), s i l

ml) was added to a , 6 - t r i - 0 - b e n z o y 1 - a [a]g -120° (c, 1 v e r t r i f l a t e 2


112


(1.03

g,

4

mmol),

nitromethane and

at

room

d i l u t e d by

(20

chloroform

(70

m l ) .

and washed

f i l t r a t e s a c i d

foam

was

d i e t h y l


153-154°,

passed

f

) ;

5.47

4

1.93,

protons)

N,

1.52.

f o r

the

m i x t u r e

was

The

s o l i d

w i t h a

short

(c,

i n

The

3%

l e f t

hr

removed

w a t e r ,

a

3

m l ) . a

alumina

gave

i n

was

Solvent

ether

1

mmol)

(20

cold

a c e t a t e .

d i e t h y l

(q,

12

(m,

9

h y

y e l l o w

column

removal

s o l i d ,

c h l o r o f o r m ) , 19,

H z , H - 3

H z , H - 2 ) ; (d,

(s,

and

mp

2.19

g

(79%

2

f

3

benzoyl

) ;

5.19

5.52 (d,

4

1

8 H z ,

H z , H - 3 ) ;

H z , H - l ) ; 3.31

0 - a c e t y l ) ;

and

(d,

4 . 6 7 - 3 . 5 0

(s,

3,

(m,

7

4.97 0 C H

3

) ;

r e m a i n

. C a l c d .

Anal.

through

4.73

1.80

-30°

C o n c e n t r a t i o n

8.12-7.12

(q,

4

g a l a c t o p y r a n o s i d e ) .

5.80

H z , H - 4 ) ;

2.03, ing

the δ

-••H-NMR:

(t,

+no°

on

p h t h a l i m i d o ) ; H - l

from

g, at

chloroform

washed

e t h e r - e t h y l

[a]22

based

were

h r ,

w i t h

and water.

c r y s t a l l i z a t i o n y i e l d

(0.48

s t i r r i n g 1

w i t h

which

A f t e r f o r

d r o c h l o r i c using

c o l l i d i n e

temperature

f i l t r a t i o n

combined

and m l ) .

f o r

Found:

C ^ H ^ N O - ^ :

C,

62.61;

H ,

C,

5.02;

62.40; N ,

H ,

4 . 9 1 ;

1.58.

Methyl 4 - 0 - ( 2 - A m i n o - 2 - d e o x y - 3 - D - g l u c o p y r a n o s y l ) a-D-galactopyranoside ( 2 7 ) . A s o l u t i o n of the d i s a c c h a r i d e

26

(40

m l ) ,

ml)

was

(1.02

water the

acetate

(2

χ

at

70°

f o r

3

s t i c k y

r e s i d u e

50

and

ml)

bonate

s o l u t i o n .

t i o n

of

t h i s

r e l f u x e d a

the

by

e t h a n o l 1

(302

) ;

1

3

100.0,

61.5

( C - 6

3.94.

w i t h

a

a

The

which

was

A ml)

was

was

evaporated

of

Dowex

1x8

F r e e z e - d r y i n g

c r y s t a l l i z e d 210-212°

mg)

s o l u

a n d 85%

(10

was

b i c a r

(890

s o l i d

column

w a t e r . mp

s o l i d

product

f i l t r a t e to

were

compound.

0 ° .

of

e t h y l

sodium

e t h a n o l

u s i n g

(d,

OCH3);

r e m a i n i n g

from

( d e c ) ,

of 98%

[ α ] £

( C - l

7 0 . 6 , 1

70.1

) ,

and

68.9 70.1

5 7 . 5 ,

( C - 4

f

2

H z , H - l ) ; 4.86

2.96

( t ,

8

H z ,

(d,

8

H - 2 ' ) ;

5.0

(C-5),

56.9

) ,

r e s p e c t i v e l y ) :

(C-2),

7 0 . 4 , 6 1 . 5 ,

( C - 2 ) ,

7 6 . 5 ,

f

7 6 . 5 ,

76.4

69.7 60.9

( C - 5 ' ) ,

(C-3), (C-6),

72.6 6 1 . 5 ,

) . C a l c d .

Found:

4

p r o t o n s ) .

pH 9.5 6 9 . 2 ,

(C-4),

1

the

5.15

3,

0 ,

(C-I),

7 0 . 4 ,

and

95% to

a p p l i e d

δ

(s,

2

l e f t

(8

removal

w a t e r ) .

11 ( D

100.1

) , Anal.

N,

(m,

79.1

105.0,

cooled

acetone a c i d

e x t r a c t s

c o n t a i n i n g i n

of

the

s a t u r a t e d

removal

77% y i e l d ) ,

i n 2

C-NMR

combined

ml)

foam

(D 0):

99.9

78.9,

a

A f t e r

d e a c e t y l a t e d

form)

3.70

4.60-3.56

1

was

m i x t u r e

e x t r a c t e d

cold

group

and

mg,

0.5

H-NMR ?

a

(3.0

hr

gave

(c,

H - l

( C - 3

3

(hydroxide

+102°

be

benzoyl

which

eluent

Hz,

to

a

h y d r o c h l o r i c

h r . was

the and

Solvent

f i l t r a t i o n

syrup

r e s i n

water

hydrate f o r

removed to

cold

appeared

i n

cone,

w i t h

h y d r a z i n e

mmol) and

washed which

1.1 ml)

s t i r r e d

acetone,

g,

(20

f o r C,

C

1

3

H

43.32;

2

5

N 0 H ,

1

0

:

C,

6 . 9 6 ;

43.94; N ,

H ,

3 . 9 0 .


7.09;


6. LEMiEux ET AL.

2-Ατηΐηο-2-άβοχί^-β'Ό^Ιη€ορί^ΐαηο8ΐάβ8

113

Methyl 4-0-(2-Acetamido-2-deoxy-g-D-glucopyranos y l ) - α - g - g a l a c t o p y r a n o s i d e (28). The compound, mp 160162° ( d e c ) , [a]g5 +83.3 (c, 0.5 in water), was obtained in 94% yield from compound 27 by the method used for the preparation of the compound 18. 1 H-NMR (D 2 0): 6 5.12 (d, 2.5 Hz, H-l); 4.94 (d, 8 Hz, H - l 1 ) ; 3.72 (s, 0CH 3 ); 2.38 (s, N-acetyl). 13 C-NMR (D 2 0): 102.2 ( C - l ? ) , 99.5 (C-l), 77.2 (C-4), 75.6 (C-5 f ), 73.9 (C-3'), 70.9 (C-5), 70.2 (C-3), 69.4 (C-2), 68.5 (C-4 1 ), 61.0 (C-6, C-6 f ), 55.8 (C-2 f ). Anal. Calcd. for C 1 5 H 2 7 N 0 1 1 : C, 45.34; H, 6.85; N, 3.53. Found: C, 44.98; H, 6.80; Ν, 4.02. Acknowledgements The authors are indebted to the National Research Council of Canada for grants-in-aid of this research to R. U. Lemieux (A-172). The NMR and microanalyses were provided by the service laboratories of this Department. Abstract The chemical properties of the anomeric t r i - 0 acetyl-2-deoxy-2-phthalimido-D-glucopyranosyl halides were examined. With the halogen C1, Br and I, the anomerization equilibrium constants are 3.2, 1.2 and 3.0, respectively, in accord with earlier evidence (S. Akiya and T. Osawa, 1960) for destabilization of the α-forms by the phthalimido group. The α-anomers undergo replacement of the halogen with inversion whereas extensive retention of configuration occurs using the β-forms and therefore a cationic inter mediate is indicated. Reaction of the β - h a l i d e s with 2-propanol in nitromethane containing mercuric cyanide provided the β - g l y c o s i d e s in high yield. However, with 2,2,2-trichloroethanol, glycosyl cyanide formation was extensive. Using silver triflate-collidine (1:1) as the halogen acceptor, 2,2,2-trichloroethyl t r i - 0 acetyl-2-deoxy-2-phthalimido-β-D-glucopyranoside was formed in 86% yield. Under these conditions, the t r i 0-acetyl-2-deoxy-2-phthalimido-β-g-glucopyranosyl derivatives of 2,2,2-trichloroethyl 4,6-0-benzylidene2- deoxy-2-phthalimido-3-g-glucopyranoside, 2,2,2trichloroethyl 3,6-di-0-acetyl-2-deoxy-2-phthalimidoβ- D-glucopyranoside and methyl 2,3,6-tri-0-benzoyl-αg-galactopyranoside were synthesized in 82, 68 and 79% yields, respectively.


114


Literature 1. 2. 3.


4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

Cited

Schmitt, F. and Sinaÿ, P., Carbohyd. Res., (1973), 29, 99. Wulff, G. and Röhle, G., Angew. Chemie, Internat. Edit., (1974), 13, 157. Meyer zu Reckendorf, W. and Wassiliadou-Micheli, Ν., Chem. Ber., (1970), 103, 1792. Heyns, K., Harrison, R. and Paulsen, H., Chem. Ber., (1967), 100, 271. Heyns, Κ., Propp, Κ., Harrison, R. and Paulsen, H . , Chem. Ber., (1967), 100, 2655. Shapiro, D., Acher, A. J. and Rachaman, E. S., J . Org. Chem., (1967), 32, 3767. Matta, K. L., Johnson, E. A. and Barlow, J . J., Carbohyd. Res., (1973), 26, 215. Zurabyan, S. E . , Antonenko, T. S. and Khorlin, A. Ya., Carbohyd. Res., (1970), 15, 21. Jacquinet, J . - C . and Sinaÿ, P., Carbohyd. Res., (1976), 46, 138. Akiya, S. and Osawa, T., Chem. Pharm. Bull. (Tokyo), (1960), 8, 583. Baker, R. B., Joseph, J . P., Schaub, R. E. and Williams, J. H . , J. Org. Chem., (1954), 19, 1786. Helferich, B. and Zirner, J., Chem. Ber., (1962), 95, 2604. Igarashi, K., Irisawa, J . and Honma, T., Carbohyd. Res., (1975), 39, 213. Kronzer, F. J. and Schuerch, C., Carbohyd. Res., (1973), 27, 379. Lemieux, R. U. and Hayami, J., Can. J. Chem., (1965), 43, 2162. Lemieux, R. U., Hendriks, Κ. B., Stick, R. V. and James, Κ., J . Am. Chem. Soc., (1975), 97, 4056. Lemieux, R. U. and Chu, Ν. J., Abstr. of Papers, Am. Chem. Soc., (1958), 133, 31N. Lemieux, R. U. and Stevens, J. D., Can. J. Chem., (1965), 43, 2059. Horton, D., Hughes, J . B., Jewell, J . S., Philips, K. D. and Turner, W. N., J. Org. Chem., (1967), 32, 1073. Lemieux, R. U. and Koto, S., Tetrahedron, (1974), 30, 1933. Bundle, D. R. and Lemieux, R. U., Methods in Carbohydrate Chemistry, (1976), VII, 79. Lemieux, R. U. and Koto, S., Abstr. of Papers, Am. Chem. Soc., (1973), 165, Medi 022. McKibbin, J . Μ., "The Carbohydrates Chemistry and Biochemistry," Vol IIB, p. 711, Editors, Pigman, W. and Horton, D., Academic Press, New York (1970).


6. LEMIEUX ET AL.

2-Amino-2-deoxy-β-D-glucopyranosides

115


24. Reist, Ε. J., Spencer, R. R., Calkins, D. F., Baker, B. R. and Goodman, L., J. Org. Chem., (1965), 30, 2312. 25. Inouye, Y . , Onodera, K., Kitaoka, S. and Hirano, S., J. Am. Chem. Soc., (1956), 78, 4722. 26. Hirano, S., Carbohyd. Res., (1971), 16, 229. 27. Lemieux, R. U. and Driguez, H . , J. Am. Chem. Soc., (1975), 97, 4063.


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