University of the Pacific Scholarly Commons
University of the Pacific Theses and Dissertations Graduate School
1974
Synthesis and reactions of p-Nitrobenzyl 4,6-0-benzylidene-2,3-di-0-methoxymethyl-β-D-glucopyranoside
Ray Douglas Carpenter University of the Pacific
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Recommended Citation Carpenter, Ray Douglas. (1974). Synthesis and reactions of p-Nitrobenzyl 4,6-0-benzylidene-2,3-di-0-methoxymethyl-β-D-glucopyranoside. University of the Pacific, Thesis. https://scholarlycommons.pacific.edu/uop_etds/1836
This Thesis is brought to you for free and open access by the Graduate School at Scholarly Commons. It has been accepted for inclusion in University of the Pacific Theses and Dissertations by an authorized administrator of Scholarly Commons. For more information, please contact [email protected]. SYN'l'lillSIS AND REACTIONS OP p-NI'l'ROBENZYL 4, 6-0-BENZY.LIDENE-2, 3-DT-0-IVfETHOXYIVJEl'HYL·-{J -·!2_--·GLUCOPYHANOSIDE
A THESIS
PRESENTED TO
THE FACUL'J~Y OF THE GRADUATE SCHOOL
UNIVERSITY OF THE PACIFIC
IN P ARriAL FULFILLMFNr
OB' rrrlE f\EQUIREMEN'l'S FDR TBE DEGHEE
l'~'T1\STER OP SCIENC'E
by
Ray Douglas Carpente1~ DEDICATION
This work is dedicated to Dr. Paul H. Gross without whose encouragerrent, advice, and unfailing enthusiasm it would never have been possible.
It is also dedicated to my loving wife Bonnie who managed to bear my irregular hot~s and three o'clock in the morning inspirations.
Thanks are also due to Daniel Robinson, Terry Tompkins, and Ram Babu whose experiences and criticisms really made this work a group effort. TABLE OF CONTENTS
CHAPIER PAGE
I. Jl\ITRODUCTION • • • • • . l
II. METHODS AND DISCUSSION • • 8 III. EXPERIMENTAL PROCEDURE • • ...... 16 Tetra-0-acetyl-G{-D-glucopyranosyl bromide (II) • . .. 17 = p-Nitrobenzyl tetra-0-acetyl-/3 -!2_-glucopyranoside (III) • • .18 p-Nitrobenzy1-/3 -R-g1ucopyranoside (TV) .19 Method (a). • . . • . . • • ...... 19 Method (b) . • • . . • ...... 19 p-Nitrobenzyl 4,6-0-benzylidene-P-£-g1ucopyranoside (V) ••• 20 Trimethylsily1 Azide • 20 p-Nitrobenzyl l!, 6--0-benzylidene-2, 3-di-O-trimethylsi1yl- /3 -·£-glueopyranoc-;ide (VI) • • . . • . • • • • • . • • . . • 21 p-Nitrobenzy 1 4, 6·-0-benzylidene-2, 3-di-0-methoxymethyl- /3 -!?_-glucopyranoside (VII) • • • • • . • • • 21
Method (a) .. 21 . Method (b) ·22 p-Aminobenzyl 4,6-0-benzy1idene-2,3-di-O-methoxymethyl- O -~glucopyranoside (VIII) • • • • • • • • • • • • • .23 4, 6-0-Benzylidene-2, 3-di-~0-methoxymethyl- (3 -~-glucopyranose (X) • • • • • • • . • • • • • • • • • • • • • • • • • • .. 23 p-Nitrobenzyl 2, 3-di-0-methoxymethyl-!3 -D-·glucopyrano- side (IX) • • • • • • • • • • • • • • •-. • • • • • • 21.1
..· .IV. SUMMARY • • • 25 .·~ BIBLIOGRAPHY • 26 FIGURE PAGE
1.1 Haworth projection, specifically blocked D-glucose deriva- tive with a free hydroxyl on the anorreric carbon (C-1) l
2.1 Formula Chart, Preparation of p-Nitrobenzyl 4,6-0- benzylidene- (3 -D-glucopyranoside (V) ...... 9
2.2 Formula Chart, Preparation of p-Nitrobenzyl 4,6-0-benzylidene- 2, 3-di-0-methoxymethyl-{3 -£-glucopyranos:Lde (VII) ll
2.3 Formula Chart, Preparation of 4,6-0-Benzylidene-2,3-di-0- methoxyrnethyl-/3 -!?_-glucopyranose (X) ...... 13
2.4 Formula Chart, Preparation of p-Nitrobenzyl fo-D~ glucopyranoside (IV) ...... =. . . . 15 5.1 Infrared Spectra of p-Nitrobenzyl tetra-0-acetyl-/3 -D- glucopyranoside (III) ...... ~ . 27 5.2 Infrared Spectra of p-Nitrobenzyl-/3 -D-glucopyranoside (IV) . 29 = 5. 3 Infrared Spectra of p-Nitrobenzyl L! ,6-0-benzylidene-/3 -!2;- . glucopyranoside (V) ...... 31
5. 4 Infrared Spectra of p-Nitrobenzyl 4, 6-0-benzylidene-·2, 3-di-0- trimethylsilyl-/3 -£-glucopyranoside (VI) ...... 33
5.5 Infrared Spectra of p-Nitrobenzyl 4,6-0-benzylidene-2,3-di~O methoxyrnethyl-/3 -D-glucopyranoside (VII) ...... 35
5. 6 Infrared Spectra of. p-Aminobenzyl 4, 6-0-benzylidene-2, 3-·di-·0- methoxymethyl-/3 -!2:-glucopyranoside (VIII) ...... 3'7
5. 7 Infrared Spectra of p-Nitrobenzyl 2,3-di-0--methoxynethyl-[3---D- glucopyranoside (IX) ...... =-:' .39
5.8 Infrared Spectra of 4,6-0-Benzylidene-2,3-di-0-methoxyrrethyl- /3 -£-glucopyranose (X) ...... 41 JNII'RODUCTION
The purpose of this work was the preparation of specifically blocked !2_-glucose derivatives with a free hydroxyl group on the anomeric carbon
(C-1) (Fig. 1.1).
H,OH
OR R ; blocking group Figure 1.1
Such corrpounds should provide routes to monosaccharide derivatives with reactive :r;.ep;ative groups such as chloro or bromo on that carbon. These compounds could then be used for oligosaccharide synthesis. To contribute to the knowledge of the structure of a particular oligo- saccharide, the method for its preparation 1nust be such that the reaction takes place between ill10WD positions on the reacting saccharides, as otherwise several structural isomers.are possible. The restriction of the reaction to predeterm:i.ned positions is accornplished by blocking all the hydroxyl groups except those between which the condensation is to occur. A blocking ~~oup is used to trclllsforrn a reactive group 16 on an organic molecule into a relatively stable group. Miyai outlines the following requirements for a useful blocking group: 2
1. 'Ihe blocked compound should be prepared in high yield in
a simple manner.
2. The reaction between the blocking agent and the group to be
blocked must be selective and stereospecific.
3. The chemical properties of the blocking group must be such
that it can be removed again selectively without altering
the rest of the molecule.
4. 'Ihe blocking group must not intermolecularly or intramolecularly
participate in any reaction at the reactive sites.
In carbohydrates the dominant functional group is the hydroxyl group; even the carbonyl function, by forming a hemiacetyl, produces a hydroxyl. The most widely used blocking groups for hydroxyl groups ax'e ether and ester groups. The work in our laboratory has, for a long time, centered al'ound benzyl glycos1des. In 1957, JVIcCloskey15 reviewed the chemistr-y of benzyl ethers and benzyl glycosides. Benzyl ethers of sugars are of value as synthetic intermediates because the benzyl blocking group can be removed under mild conditions by hydro- genolysis according to the following equation: (Pd) c H cH 0R + H >- c H cH + HOR 6 5 2 2 6 5 3
Steric factors seem to play an important role in these hydrogenolyses. 2 In 1951, Ballou, Roseman, and Link reported that the relative rates of hydrogenolysis of anomeric benzyl glycopyranosides are quite different.
With Q-glucose derivatives, the {3 -!?_-glucoside was cleaved in three minutes, but the cC -P.:-glucoside required eight hours under comparable 3
conditions. ~:his difference has been linked to the stereochemistry of the groups on C-1 and C-2. In the {3 anomer, the groups are trans, while in the ct. anomer the groups are cis . Steric or neighboring group effects are thus probably responsible for the observed difference in rates. The availability of methods for the preparation of certain of these benzyl ethers in high yield and their relatively inert nature in general, has made them especially useful. It is of particular value to the sugar chemist that the benzyl aglycon can be removed without reduction of the sugar hemiacetal function. Chiu prepared benzyl 6 glycosides which also contained a 4,6-0-benzylidene blocking group.
When hydrogenolysis of the benzyl group was atten~ted for these compounds a mixture of products,' some of which showed cleavage of the 4,6-0- benzylidene group, was obtained.
Due to the partial success of the benzyl glycoside protective 6 group, Chiu prepared p·--n:i.trobenzyl glycosides in an effort to find
a blocking group. that could be more selectively removed.
The p-n:i.trobenzyJ. ester group has been used many times for the 18 synthesis of biologically active polypeptides.17 Schwarz and Arakawa
used p-nitrobenzyl esters in the synthesis of peptides which also
contained carbobenzoxy bloc.king groups. When ordinary benzyl ester blocking groups were used, the required selective cleavage of the
carbobenzoxy group with HBr in glaei.aJ. acet:l.c acid was not always
assured. They found no free peptide cD.rboxylic groups, however, when
they used p-n:Ltrobenzyl esters. This finding indicates increased acid
stability for p-nitrobenzyl groups. On the other hand, p-nitrobenzyloxy 11
carbonyl groups can be removed with great ease by catalytic hydrogena.t:lon. It was even possible to remove this blocking group from a cysteine ,peptide. 3 Normally, the poisoning of the catalyst by sulfur containing substrates precludes such a hydrogenolytic removal. Since they are similar to benzyl glycosides, p-nitrobenzyl glycosides usually crystallize well. The aglycon can be removed under very mild conditions, not only by acid, but also by hydrogenation. p-Nitrobenzyl ethers are hydrogenated much faster than ordinary benzyl ethers.6 Thus, selective removal in the presence of other benzyl or benzylidene groups is feasible. The p-·nitrobenzyl blocking group appears to meet all of the requirements listed above. Commonly used acetyl blocking groups were thought to be unsatis- factory for the blocking of the hydroxyl groups on C-2 and C-3 of our D-glucose derivatives because of their alkali lability. It had also been found that acetyl groups at C-2 participate in nucleophilic displacements at the glycosidic carbon with the intermediate formation of acetoxonium ions. 20 The final products will often retain the ring structure between C-1 and C-2, for example in orthoester type corrpounds. Wulff and Rohle20 observed that the ability of pyranosyl halide esters to undergo such neighbouring group reactions, with formation of cyclic ortho esters, was strongly dependent upon the relative stereo- chemistry c:md conforrnation of the leaving group at the glycosidic carbon. Reactivity of the leaving group at C-1 is also influenced by the blocking groups at C-2 or C-6. Fletcher ru1d Inch9 produced the. 5
(3 -nEthyl glycoside from 2-acetamido-1-0-acetyl-3,4,6-tri-0-benzyl·-
2-deoxy-/3 -~-glucopyranose by boiling it in nEthanol. The acetyl function is converted to the free acid. However, 2-acetamido-tetra-
0-acetyl-2-deoxy-B-~-glucopyranoside, with an ester function at C-6, is stable under these methanolysis conditions, indicating a less reactive 1-0-acetyl group. In these cases the ester function at C-1 is trans to the aceta- mido group at C-2 . When no nucleophilic displacement occurs, however, acyl migrations involving C--1 and C-2 are often linked to a cis- configuration of the involved groups. Nonnal, otherwise unblocked, 1-0-acylaldoses having a trans relationshi.p between the ester group at C-1 and an hydroxyl group at C-2 are comparatively stable substances, while the corresponding cis corrvounds readily undergo rearrangement, the acyl group mlgraUng to C-2. It was noted that whi.le the acylaldoses which are benzylated at C-6 undergo rearrangement, those which were acylated at C-6 did not.9 Inorder to exclude all participations by C-2 substituents, a new nonparticipating blocking group, that was stable to alkali, was necessary for blocking the hydroxyl groups at C-2 ~:md C-3. 11 In 1909 Hoering and Baum reported and patented a synthetic procedu~e for the methoxymethylation of the phenolic hyrn~oxyl group of salicylaldehyde jn 33% yield from the sodium salt. A better pro cedure was found by LaForge13 in 19 33. When he treated the sodiwn salt of salicylaldehyde with chloromethyl methyl ether in dry toluene, he obtained a 93% yield of the nEthmwmethyl derivative; Stern, English, and Cassidy19 found the methoxymethyl group to be ideal for 6
the blocking of phenolic hydroxyl groups in the production of poly- vinyl phenols, since the methoxymethyl gt:>oup ls stable in the presence of organometallics but much less stable to acid than other ether blocking 1 groups. M.A. Abdel-Rahman, ~t al. used the methoxymethyl group in the preparation of morphine analogues. More recently, Corey7 has used it in the preparation of prostaglandins.
The methoxy!l'Bthyl blocking group appears to be synthetically useful to sugar chemists because of its relatively mild introduction ani removal conditions. It also appears to fulfill all the require-
!l'Bnts for useful blocking groups, outlined nbove. It was thought, and subsequently found, that ·the methoxymethyl gr>oup might be introduced via a trimethyl silylated intermediate. SilyJ.a:Cion as an auxiliary
1 method of organic synthesis was reviewed by B:lrkofer an.d Ritter. ~ The term silylation il3 used to denote the lntJ:'oduetion o.f triorganosilyl moieties, espedally the trimethyl species, into organic compounds. 4
It has been shown that hydroxyl groups can be· silylated with trimethylsilyl 12 azide , and acidic or basic reaction conditions typical .for other
, silylation reagents could be avoided. The trlorganosilyl moiety in organic compounds can either be replaced wl t:.h other functional groups or may be used as a protective group in orga.n:Lc synthesis. Trimethylsilyl groups are sensitive to acid and base, and. arc; also typically removed by hot alcohols or water. Thus, the derived cornpovnds in this work should have no acyl or. other groups at C-;~ or C-·6 whlch can interfer with reaction at C-1. The ft.ndings of Pletchor and Inch9, that show the influence of the C-·6 substituent on r•es.c.tl.vity of C-1 groups. have 7
10 already been discussed. Frechet and Schuerch have postulated that the acyl at C-6 interfers primarily due to orbital overlap of the carbonyl function with the ring oxygen in the transition state. This decreases the electron donation stabiliz~tion of a carbonium ion at
C-1 by the ring oxygen. Also, Frechet and Schuerch found that the fraction of anomeric glucosides produced in oligosaccharide synthesis varied from over 90% o( to over 90% ~ depending on the nature of the C-6 group.10 Such influence or interference was to be excluded in this work by the use of a benzylidene group, linking e-Ll and C-6.
The following chemical properties were predicted and desired for the title compound, or for compounds derived from it. The 4,6-0- benzylidene group should exclude C-6 from participation. The p-nitro- benzyl group :Jhould be se1ecti.ve1y removable by catalytic hydrogenation leaving the 4,6-Q.-bem!:ylidene group intact. The m=thoxymethyl group should exclude C-2 from participation. IVETHODS AND DISCUSSION OF RESULTS
In order to show that the p-nitrobenzyl blocking group can be selectively hydrogenated in the presence of a 4,6-0-benzylidene group for nonnitrogenous glucose derivatives, a number of precursors had to be prepared, starting from £-glucose. Tetra-0-acetyl-(i( -£-glucopyranosyl bromide (II) (Figure 2 .1) was prepared by acetylation of anhydrous £-glucose with acetic anhydFlde in the presence of perchloric acid. The mixture of the pentaacetates j_n glacial acetic acid solution, without isolation, was treated with red phosphorous and bromine to generate hydrogen bromide in situ and to give compound (II) .14 The (3 -anomer of compound (II) was not present in the final p:•oduct. p-Nitrobenzyl tetra-0-acetyl-/3 -£-glucopyranoside (III) was prepared by treatment of compound (II) with p-nitrobenzyl alcohol in the presence of mercuric cyanide and mercuric trifluoroacetate .
.A. large excess of p-nitrobenzyl alcohol was found disadvantageous for this preparation due to the difficulty of separating the p-nitro benzyl glycoside (III) from the excess p-nitrobenzyl alcohol. The relative cunounts used, in fact, were nearly equirnolar. Compout1d (III) was then de_;aeetylated with dilutepotassium pydroxide in dioxane and methanol to give p·-nitrobenzyl (3 -£-gluco
pyranm>ide (IV). This compound vms extremely difficult to crystallize
in the presenee of water and i.t was important to use anhydrous ethanol for the :ceerysta11ization. ("'H r.A . ~ Y· jV c 1'/ \' CH20Ao I .' !- - . _/") HOCH2 ~\-h!Q I J 'U~ ,-'jl'i -? ;/\\. ;---<, ~ OCHzw N02 nf,,..y.--.'-' . H ff"'t-,i) ~ - OA.c b- J... - B... j"..... '' ? 1 ~r I - OAc ..,...... li ·m.· KOH w
<;H20H ocH 2-o~o2 , CH2r'\ \=( N0 2 1 . PhCHOt-io ZnCl2 v:r·w ' J[_ \ TIZ
Fig-ire 2.1 \0
Prepa:"ation of p-Nitrobenzyl 4 ;6-0-b€mzylidene-{.rJ;-glucopyra.'1.oside~ (V) 10
p-Ni.trobenzyl 4,6-0-benzyli.den-/.3 -)2:-glucopyranoside (V) (Figure 2.1) was prepared by stirring compound (IV) with anhydrous zinc chlori.de 8 and benzaldehyde. Care had to be taken to exclude all water. The yi.eld was poor• i.n the presence of water because the reaction is reversible.
For that reason zi.nc chloride was freshly fused, and was carefully sti.rred as it cooled in order to granulate the mass.
The presence of the acid sensiti.ve benzylidene group and of the base sensitive p-nitrobenzyl group precluded the use of the cormnon trimethylsilylation mlxtures5 for the preparation of compound (VI)
(Figure 2. 2) . Trimethylsilyl azide was prepared by refluxing tri. methylsilyl chloride with dry sodium azide. (Both the chloride and the azide cc-u.me severe headaches when inhaled even in mlnute amounts and it is ir;Iperative that this reaction be carried out in an efficient hood. ) 'l'he trimethy1si.lyl azide was directly distilled into the reaction vessel with compound (V) and ref'luxed to give p-nitrobenzyl
4 ,6-0-benzylidene-2, 3-di-0-trimethylsilyl-/3 -P;-glucopyranoside (VI) .
Excess trirnethylsilyl azide was distilled at normal pressure first to reclaim it, and then under vacuum to remove all unreacted traces.
Compound (VI) was found to be 0table in water suspension but when boiled with very dilute base it was de-silylated to compound (V).
p-Nitrobenzyl 1-1 ,6-0-benzylidene-2, 3-di-0-methoxymethyl-(.3 -1?: glucopyranoside (VII) wa.s formed by heating compound (V) with chloro- methyl methyl ether, and dii.sopropyl ethyl arnine to absorb the hydro- chloric acid produced. Dimethylformamide, used as the reaction solvent, .. '
2 /ocH OCHz·O'' .\ NO . / j I OCH~NO2'>=f- 2 -- 2 PhCH
:' I . Si fviE ... N"' t> \ 0 I OH }[_ :ill C;c~ . ?De~ CtCH20CH 3 ;.r
~ /O?Hz Ph~ c------'< MEM =CH 20CH 3 CH 2-oN02 OMEM . J ----/1 -1' OMEM "SZll \
Figure 2.2
\ . Preparation of p-Nitrobenzyl 4, 6.:.0-benZIJlidene-2, 3-di-0-metnozymethyl~-Q-glucopyranoside (VII) 1--' 1--'
... 12
appears to act as a catalyst ln the reactlon and lt was necessary to keep all reagents and compounds formed in solutlon. It was :Lmportant to test the product for acid. If any mineral acid was present the product had to be washed with d1lute sodlum bicarbonate solution before recrystallization to prevent removal of the 4,6-0-benzylidene group.
Compound (VII) (Figure 2. 2) was also prepared by refluxing compound
(VI) in an oil bath at 40°C with chloromethyl methyl ether in dimethyl- formarnide at reduced pressure. The trjJnethylsilylchloride produced by the reaction was removed as it was formed and did not cause cleavage of the 4,6-0-benzylidene blocking group. Refluxing at atmospheric pressure was accompanied by decomposition of Inaterial and the purification of products was extremely difficult.
The corrpletely blocked compound (VII) was reacted in a varlety of ways to determine the conditions for selective removal of the blocking gr0ups. The selective removal of the benzylidene group or of the p-nitrobenzyl group was possible from ·compound (VII) (Figure 2. 3).
V.Jhen con-pound (VII) was hydrogenated i:t1 dioxane ln the presence of palladium on charcoal, the nitro group was quantitatively and specifically converted to an amino group, and compound (VIII) was obtained. However, when aqueous methanol was used as solvent for the hydrogenation of compound (VII), the aglycon was quantitatively removed and compound (X) was obtained. Alternatively, compound (VIII) could be hydrogenated to give (X) in aqueous methanol. The products of the hydrogenations from (VII) to (VIII) and from (VII) to (X) were obtained in almost quant:Ltative yield. However, the yield of (X) ·..... ' ~OyHz . · OCH / r--11 1H ~~2 1 ~ PhCH /, ~ QC' >{/ · '\>-Nr0 / CH 2\=(NH2 \ V · · "'.~' n2 \={ 2 H2 PhCH b~~~M ~ . Pd/C e> \ I lI . D l 0 '~l\ ,-,.A !1\\j p- C. 0 U.·•M 1EM •, OMEM w ... 1ZI[ I H Pd_/C · 2 IMEOH/ H20 ..
/0~ PhCH ... \ 0 i i OMEM \ X
Figure 2.3
I-' w Preparation of 4,6-0- BenvJlidene-2)3-di-O-methoxymet~yli3-Q-glucopyranose- (X) .\ ... 14
from (VIII) was somewhat diminished and the tlc analysis showed some slower moving material corresponding to de-0-benzylidenation. Rotational data suggest that compound (X) was obtained in the original
~ -configuration. vJhen compound (VII) (Figure 2. 4) was treated with trif'luoroacetic acid in benzene the 4,6-0-benzylidene group was selectively removed to yield compound (IX). Treatment of' compound (VII) with methanol, acidified with acetyl chloride, removes both the methoxymethyl groups and the 4,6-0-benzylidene group to regenerate compound (IV). ~OCH 2 PhCH ~CH 2 1_ ~ N02 1i> ~CHz-oN~ 2 .. ' 0 . . . ~?MEM \f . . CF3COOH l I · O~vlEM · · :szrr IX
eli CH~COCt .?Coc; ....
•' ~ }/\\_ CHzw-N02
FiE;Ure 2.4
Preparation of p-Nitrobenzyl ~-R-glucopyra.'1oside (IV) !-' \ ..l1 EXPERIMENTAL SEGriON
Melting points were taken in a 'l'homas-Hoover melting point apparatus model No. 6404H. All melting points reported herein are uncorrected. Optical rotations were measured at the sodium D line with an O.C. Rudolph and Sons) Inc., model No. 956 Polarimeter. The homogeneity of all corr~ounds synthesized was determined by thin layer chromatography using a mixture of two parts Silica Gel G (Merck) with one part Silica Gel GF (Merck), the plates being activated by heating at 140°C for three hours. The plates were developed with a variety of solvents stutable to produce Rf values between 0.2 and 0.7.
The compounds were detected by extinction of the untraviolet fluorescence of a zinc-~silicate indicator and also by subsequent spraying with sulfuric acid ( 10-15%) - methanol and heating about 20. minutes at 140° C. The microanalyses were performed by Microanalytisches Laboratorium Beller)
West Germany. Infrared spectra were taken with a Perkin-Elmer 337 spectrophotometer using potassium bromide pellets made with a Wilk
"mini press". 17
~etra-0-acetyl-~,D-glucopyranosyl Bromide (II).- Acetic anhydride
(1200 ml, 12.1 mol) was cooled to 0°C and 60% perchloric acid (7.2 ml) was added. The solution was warmed to 20°C and anhydrous !.?_-glucose (I)
(300 g, 1.67 mol) was added with stirring at such a rate as to keep the temperature at 30-40°C. The homogenous mixture was cooled to
20°C, and treated with red phosphorous (90 g). Bromine (540 g, 174 ml), and subsequently water ( 108 ml) were added dropwise, the temperature being kept below 20°C. The mixture was sitrred at room temperature for 2 hr. Chloroform (900 ml) was added and the mixture was filtered.
The filtrate was poured on cracked ice and water (2000 ml) with stirring.
The chloroform layer was separated, was washed with water (1500 ml) and saturated. sodiwn bicarbonate solution ( 1500 ml) , was stirred for
10 min with dry siliclc acid (30 g). The mixture was then filtered and the filtra:ce concentrated. Anhydrous diethyl ether (1200 ml) was added and the compound precipitated by addition of petroleum ether.
The product was recrystalUzed from diethyl ether and petroleum ether to give II (605 g, 96%); mp 88-89°C, [dl]~0 + 198 (C=2, chloroform) 14 (literatLq>e mp 89°C). 18
p-·Nitrobenz;yl tetra-0-acetyl-.@..:::,E-glucopyranoside (III). -
'roluene ( 350 ml) was distilled from p-·nitrobenzyl alcohol ( 80 g, 0. 52
. mol) and mercuric cyanide (120 g, 0.48 mol) until only a small amount
of the toluene (10 ml) was left. To the cooled mixture, compound II
(183 g, 0.5 mol), acetonitrile(30 ml), nitromethane (30 ml), and mercuric
trifluoracetate ( 0. 3 g) were added. 'l'he mixture was shaken for 211 hr
and poured into water (LIOO ml) and diisopropyl ether ( 500 ml), with
stirring. The mixture was shaken for 24 hr and filtered to give a
first crop of III. From the filtrate, the diisopropyl ether layer
was separated, washed with water, and evaporated to dryness . The
residue was extracted with methylene chloride (220 ml). The first
crop was dissolved in the extract and isopropanol (350 ml) was added.
The solution vms then concentrated in vacuo until crystallization
began and remained at room temperature, overnight, to complete crys-
tallization. The product was filtered and washed with diethyl ether
(200 ml) to remove the small amount of p-nitrobenzyl alcohol remaining
in the bulk of the product. Evaporation of the filtrate and subsequent
recrystallizations of precipitates from isopropanol gave further
crops of III to give the total yield of III (174 g, 72%); mp 134-135°C,
20 [cC ]~ ·- 36° (C=l, pyridine).
An~l· Calcd for H N (i-183)1): C, 52.18; H, 5.22; N, 2.90 c21 25o12 Pound : C, 52.40; H, 5.19; N, 2.88. 19
p-Nitrobel~l-~1-@ -D-glucopyranoside (IV): (Method a) - Co!Tq)ound III
(25 g, 0.0517 mol) was dissolved in dioxane (100 ml) and methanol (50 ml).
N-Potassium ;,~d.eoxide (225 ml) was added slowly with stirring for 5 h:b at room te!Tq)erature . The clear solution was concentrated in vacuo
to 250 ml and cooled to 0°C. The pH was then adjusted to 4. 0 with 5-N hydrochloric acid. Crystals were filtered and washed with cold water, and the filtrate was evaporated to dryness in vacuo and extracted with hot isopropanol. The extract was concentrated and cooled and gave an additional crop of crystals. Crops were combined and re-
crystallized from absolute ethanol to give IV (15.6 g, 96%); ITq) 160-161°C 220 40 (C=l, pyridine). [~]D - Anal. Calcd for c13H170gN (315.43): C, 49.52; H, 5.43; N, 4.44 Folmd : C, 49.52; H, 5.50; N, 4.56.
12::_Nitrobenzy~ -D-glucopyranoside (IV): (Method b) - Co!Tq)ound VII
(0.05 g, 0.0001 mol) was dissolved in methanol (2.0 ml) and acetyl
chloride (0.10 ml) was added. The solution was stirred at room te!Tq)erature for 15 mL11 and evaporated to dryness in, vacuo. The remaining solid
was recrystallized from absolute ~thanol to give IV (0.026, 82%);
Melting points, rrLi.xed melting po:lnt, and tlc analysis showed the product to be identical with material prepared, as described before. 20
p-Nitrobenz;yl L~ ,6-0-benzylidene-@ -D-glucopyranoside (V): - Compound IV (20.0 g, 0.0635 mol) was dried over phosphorous pentoxide in ~acuo at 100°C for 24 hr and added to a mixture of anhydrous zinc chloride (16.0 g), benzaldehyde (75 ml, 0.636 mol), and absolute diethyl ether (180 ml). The mixture was stirred for 12 hr at room temperature. Saturated aqueous armnonium chloride ( 5. 0 ml) , diisopropyl ether (300 ml), and cracked ice (150 g) were added and the mixture was shaken for 6 hr. The three phase system was filtered and the filtercake was blended with water and filtered. The solids were recrystallized from dioxane, by addition of diisopropyl ether, to give V (20.4 g, 40 80.3%); mp 173.5-174.5°0, [oCJ63· - 67 (C=l, pyridine).
Anal. Calcd for c20H21o8N ( 403.4): c, 59 ~54; H, 5.25; N, 3.48 Found: c, 59.15; H, 5.84; N, 3.03.
~ri_l_!l~thylsilyl A~ide: Sodiwn azide (15 g, 0.023 mol), bis(2- ethoxyethyl) ether (10 ml) and trimethylsilyl chloride (30 g, 0.28 mol) were heated at 85° for 30 hr. The mixture was distilled and the fraction boiling at 93-97° was collected and redistilled to give trimethylsilylazide (22 g, 83%); bp 93-94°C. (literature5 bp 95°). 21
p-Nitrobenzyl 4,6-0-benzylidene-2,3-di-0-trimethylsilyl-@-D~ g1ucopyranoside (VI): - Compound V (8.5 g, 0.0212 mol) was ref1uxed in trimethylsilyl azide (85 ml) for 24 hr. Excess trimethylsilyl azide was distilled off under reduced pressure. Methylcyclohexane
( 10 ml) was added to the remaining syrup and removed by distillation in vacuo. Heptane ( 10 ml) was added to the syrup and the resulting solution was kept at 0° . After 24 hr, crystals were collected to 23 0° give VI (11.07 g, 96%); mp l20-l2l°C, [C(,]D · -51.7 (C=l, toluene).
Anal. Calcd for c H o si N (547.8): C, 57.00; H, 6.81; O, 23.3'1; 26 37 8 2 N, 2.56; Si, 10.25- Found: C, 56.97; H, 6.86; N, 2.75.
p-N i trobenz;y~ 6-0-benzy lidene-2, 3-di-0-methoxymethyl-(3-D glucopyrSJ!lOSide (VII):- (Method a) Compound V (2.0 g, 0.005 mol) was dissolved in dimethylformamide (10 ml). Ethyldiisopr~pyl amine
( 4 ml) and chloromethyl methyl ether ( 4 ml) were added and the reaction vessel was sealed. The solution was kept at room temperature for
20 min and then heated to 85°C for 10 min. The mixture was poured onto cracked ice (300 g) and stirred until all ice had dissolved.
The precipitate was filtered and recrystallized from ethanol and
10 water (1:1) to give VII (2.31 g, 95%); mp l00.5-l0l.5°C, [0:.]~ - 65.2° (C=l, pyridine).
Anal. Calcd for c H o N ( 1-191. 5): C, 58.65; H, 5 .94; O, 32.55; 24 29 10 N, 2.85 FOUi'1d: c, 58.'79; H, 5.81; N, 2.86. 22
p-Nitrobenzyl__i,.6-0-benz_ylidene-2_, 3-·di-0-methoxymethyl-/3 -D glucopyranoside (VII): (Method b) -Compound VI (2.75 g, 0.005 mol) was dissolved in dirrethyl-formamide (25 ml) and chlororrethyl methyl ether (2.5 ml) was added. The solution was then refluxed in vacuo at 40°C for 90 min. The mixture was poured onto cracked ice (250 g) and stirred until the ice had dissolved. The precipitate was filtered, washed with saturated potassium bicarbonate solution, and recrystallized from ethanol and water ( l: l) to give VII ( 2. 20 g, 89.2%); mp, 101. 0-lOL 5° C, [o(]D21° - 65.0° (C=l, pyridene). Melting points, mixed melting point, tlc, and ir-spectra were identical for the compound produced by both rrethods. 23
p-Aminobenzyl lj, 6-0-benzylidene-2, 3-di-0-metho:xyrrethyl-@ -D-: glucopyranoside (VIII): - Corrpound VII (0.2 g, 0.0004 mol) was dis solved in dioxane (25 ml) and 10% palladium on charcoal (0.2 g) was added. The mixture was hydrogenated (1 at, 10 min) at room terrperature and then filtered. 1Dhe filtrate was evaporated to dryness in vacuo.
1Dhe remaining solid was recrystallized from methylcyclohexane to give
20 compound VIII (0.18 g, 96%); mp 132.5-133.5°C, [oCJ~ - 26.6° (C=l, pyridine)
AnaL Calcd for c24H31ogN (461.5): C, 62.455; H, 6.772; O, 27.735; N, 3.035 Found: C, 62.45; H, 6.65; N, 3.17.
!!_,. 6-0-Benzylidene-2, 3-di-0-metho~ethyl- (3-D-glucopyranose (X) : -
Compound VII (1.0 g, 0.002Iml) was dissolved in methanol (100ml).
10% Palladium on charcoal (2.0 g), slurried with water (8 ml), was added to the methanol solution. The mixture was hydrogenated ( 2 at,
1 hr) at room temperature and was filtered. The filtrate was evaporated to. dryness ~n vacuo. The remaining solid was recrystallized from a sm.all amount of methylene chloride, with addition of methyl cyclohexane, to give, after 48 hr, compound X (0.66 g, 91%); mp 146.5°C [oC]D22° - 40.2°, ( C=l, chloroform)
Anal. Calcd for c17H24o8 (356.40): c, 57.29; H, 6.78; o, 35.92 Found : C, 57.10; H, 6.76. p-Nitrobenzyl 2, 3-di-0-methoxyrrethyl-@ -D-glucopyranoside (IX): -
Compound VII (0.50 g, 0.001 mol) was dissolved in benzene (20 ml) and trifluoracetic acid (0.10 ml) was added. rrhe solution was stirred at room temperature for 18 hr. A chromatographic column (inner diameter
16 mm, length 150 rnm) was prepared from a slurry of silicagel a60 (12 g) in benzene. The solution was poured into the column, and benzene eluted a small amount of compound VII and benzaldehyde. Methanol and benzene (1:49) eluted a light yellow band. The eluate was evaporated and the remaining solid was recrystallized from ethyl ether and hexane (1:9) to give IX (0.33 g, 80.5%); mp 95-96°C, ' 20° [oC]D - 71.8° (C=l, chloroforrn).
Anal. Calcd for H N (403.1U): C. 50.62; H, 6.25; 0, 39.66; c17 25o10 N, 3.4'(
Found: C, 50.65; H., 6.25; N, ·3.48. SUMMARY
The overall yield of the title cor~ound, p-nitrobenzyl 4,6-0- benzylidene-2, 3-cli-0-methoxymethyl-f3 -£-glucopyranose VII, from D glucose was 46%. The various blocking groups could be selectively removed. The p-nitrobenzyl blocking group on C-1 proved to be removable by hydrogenation with retention of the Ll ,6-0-benzylidene blocking group. By stirring co~ound VII overnight in benzene with a trace of trifluoroacetic acid, the 4,6-0-benzylidene group was found to be removable with retention of the methoxymethyl groups on C-2 and C-3.
Alternatively, by treating compound VII with one equivalent of acetyl chloride in methanol for five minutes, both the 4,6-0-benzylidene group and the methoxymethyl groups could be removed together.
All of the corr:poLmds prepared in this work are easily crystallized.
No syrups or oils were encou;·1tered, probably due to the p-nitrobenzyl and 4,6-0-benzylidene groups which were used. The experimental yields range·from 72% to 96%. The easy introduction and removal of the p-nitrobenzyl and methoxymethyl protective groups make them excellent prospects for use in oligosaccharide synthesis. BIBLIOGRAPHY
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2. C.E. Ballou, S. Roseman, and K.P. Link, J. Am. Chern. Soc., 73, 1140 (1951). -
3. C. Berse, R. Boucher, and L. Pich~, ~· Org. Chern., 22, 805 (1957). 4. L. Birkofer and A. Ritter, Agnew. Chern. Intern. Ed., Eng.,.!!_, 417 (1965).
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llL R.U. Lemieux, Meth. Carbohydr. Chern., Vol. II, 221 (1963). 15. C .M. IVIcClosky, Adv. Carbohydr. Chern., g 137 (1957). 16. K. Ivllyai, Dissertation, University of the Paciflc (1968).
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I ..; • ! r : ~- I , 1 • _ , , , , : I , 1 ~ ~ i _ . 1 . ! __ : , . ! 1 , _; 1 J 1. : ~ ; . 1 • 1 i , . 1 1 1 1 1 I : 1--i·-J-.::: :- :.:r.1 ·! 1 · L ·.:; I ; i :_I != i -l.-i _: T; 1 ; l ·j. l ~= 1-.-1 ; 1·~--1 1 1 _r : j=-!-_ !_..J_ - ! --: : ·! LJ._ j · j-i--'...::..:__:i...::.:L..! __ Pt...::.!..._L-1--H-r.:.:1 .. :.--l--t.-LL)-:.::..+-.!-i ' 1 • ~~-J_-_ _Ll±_.._._,_t-~-·- 1 ..:._-_,_~ ___ J_~~-~---·-;_;._-: ___ _ 00t....i_ I :. I i I i 1 i ! !.....Ll_! ! I : I : 1 ; I i ! I I i 1 i i : I i ·1 i I ! I ! l i j ! ! i I I I : i ' i ! i l '-"0 4000 3500 3000 2500 2000 1500 FREQL'Et--;CY (O\·') IR Spectra of w p-Nitrobenzyl 4 _,6-0-benzylidene-2_,3-di-0-trirr.ethylsilyl-l3 -D-glucopyranoside (Iii) w 34 ...... "-..../~ (!) '0 •rl rJl H~ :>:, §• () ;j hb I c:rn <:.!1 I rl,.,._..... r-l •rl rJl rl if .., CH .)..) 0 ~ ~1 v cd .;4 >- f-~ ~=-~ u .j..) .p z () I "J ::> (l) 0 (j ~2. I "J rl) •rl u.·" '0 rr:: I H (Y) ("\)" I (\) ~ ·-o(1.) ·r--1 rl :>:, N ~ (!) f 0 I \.0 ..... •:::t· .-l :>:, N ~ (!) .g H .p •rl '7 Ip, 35 ~~ 0 Cc?, ~~ s:~ :?) S?) Ct? ~ o () ···- ~ . ' ' "' ,_ 0 _...... H 0 0 !;! 1.() '..J "(<13 .,-~ (/) 0 § ~-·:>, P~ 0 C) 0, ;::3 0 rl l() ; : I : ~ . ! i i I "' I .. I I ! . l : ' ! l l ! i ! i . ! 0 'f· <"t rr11 I:Q ..~·:~ I c rl f..::: » '.,._) .p.c. -:·: .. .:, .. <11 c,_, &l, 0 ~ C> ; 0 0 ~() ~ \U .c..p 0l )- >-l u .J..) z C) ill ~J I ::> Q) 0 (j o, I [)) •r-1 '"u. 'd "' I ~ ('f')... C\J I 0 Q) ~~ 0 rJ 0 '0 (Y) ·r-1 I I ' ; I ! : ~ i j i ; ! . I . :; I :--- i ; ! . . . I . I . ,--j ~ L'l -g ::~~~D~:~~J=:+L_f-, :-~ =1:_~~<-~~::C~_:cJ~;--; i_iE~~:T~J::J-- (J-: 3_~[ r.:~ 1 -:J V;'· I) 1 ...... ,~ : ,....,.no , .. 0 ,~, . 0 · .,. ,\,\~C~Ci·-lS 1...... 0 -v?n . Q..1 . ...L.....;.v --: r. 1..• 1... ' 1 __• _I __! I I --'--'----'--.L..-·j-----·--__1_._._-__l__ I __L_j ! SJ I I _l__,_::._I._L..!__J ,,J I : I . . ' I . . 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I ·- ... : . ~~=- :.~L.: j:_ t,.~~-i_ *~5t\ :\-.+~\i~_~>---tr-_: \i I____ t1.-H-~~~~t~i~~ .. b--_~t-_ 1l ~ i~~! _~:~~~~_;_t£1----~-~~-~~~-:~.:~~ ~-\ ~--~ -~J) ~ -... l • ! l(i ! l I ' : f_ ' \ 1 ! • ' • I 1 j ~ : ! ' l ' ' ' l I ; i 1 :jtf=f;!t~~~i;Jf,~~~if~l~})b:;JI·l-~_~-:~~~~~0if·~-J--:~-~ 1300 1200 1100 1000 . 900 800 700 600 500 400 f~::ou:t..:CY ~CM·l) IR Spectra of l.J.) p-Nitrobenzyl 4,6-0-ber~ylidene-2,3-di-0-rrethoxymethyl-p-Q-~lucopyranoside (VII) 0'\ 3'7 ..--,. H H ..__.,~ ~ •rl {/) 0 fil H :>:. 0. 0 C) ~ bO 911I (!).. I rl 1"'.p G) G-1 s:, ;, 0 x u 0 cU ..c.: >- ::.~ .p u .p z () UJ ~- :::> (i) ,. a 0 \U Ji• I u.'" •r-l rr.: '0 H rh 0.l"' I G) s:: ~ •r-l rl :>:. N s:: G) f 0 I \.0... 0 -":.1" 0 1.0 rl ("") :;:., Ns:: (j) ·d8 ~0.. 38 , " .' >u u;z :?- 0 "' "-•"' 39 0 0 0 0 0 0 00 0 8 ~ {±i~~-=!;:::j;~~~~·~.~~~~: ;~-:~~=~~:-::;~,2j~~~i~~~] j·-1---·------j-·--.---·-l-·~-·-··-·-·-····L~-- .. ---T· --- .. 1··--- ., ...... -----"'"1 ~ Jlf~~j~~::.J~~-t~~J~~~~~~;~i~! ~ _,...... _, ,-]:TTl -.~--·-q---'-----J-:-' ___ --. --:--r;--:- ---i-- --;-~---~- -·------·;-·: T- ~ H ~; :~~=~~~-- ·{~~j~!.----~~r~-~-~2J~-~- J~~~:...: +j:~~~~-;-~-~l~-) ::~-l~H~~;-~~ ~~ '---' ----1·. · · , §· C) ;j r-l bO ~'n 0 .., CH '!L -:;: 0 I 0 u r-l l() «l :>> c'-1 >- H u .p .c:.p 7.: C) UJ ,...... :X~ H •-A ~) '0 •rl {/) 0 ~ H :>. §· C) ;:j rl bO I r:-711 rH '!!.. :, 0 I u r-l (l"j :>, >- H u .p .p..c:: z C) UJ 0) . a:::> UJ J5• ,.,~' (¥. u.. 0 r-< ~ .J-:l~-· 1•ill 0 ;aI I (Y')... N rl ::: ... s:::t:-~ <]) fJ ..p::.i ,•rl.. ,. "rp, -... ~ ...... '...... ::..:: "-' (]) {j) 0 cu~~ H ::>, !2... 0 C) :3 ~0 I 9" '"\1. I rl ::>, G-; ,C! 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