I This dissertation has been microfilmed exactly as received 69-11,687
PAREKH, Girlsh Girdhar, 1939- THE REACTION OF VINYL ETHERS WITH CARBO HYDRATES.
The Ohio State University, Ph.D., 1968 Chemistry, organic
University Microfilms, Inc., Ann Arbor, Michigan THE REACTION OF VINYL ETHERS
WITH C/JtDOHYDRATES
DISSERTATION
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University
By Girish Girdhar Parekh, B.So.(Hons.), M.Sc.
*******
The Ohio State University 1968
Approved by
Adviser Department of Chemistry ACKNOWLEDGMENT
I aia grateful to Professor M. L. Wolfrom for suggesting the problem and the advice given throughout the research period.
I wish to acknowledge the helpful suggestions from Dr.
S. S. Bhattacharjeo and the cooperation of other colleagues.
The work was supported by Grant No. 12-14.-100-7652(71), from the U. S. Department of Agriculture, Northern Regional
Research Laboratory, Peoria, Illinois, to The Ohio State Uni versity Research Foundation (Project 1856).
i i VITA
November 11, 1939 ...... Born - Bombay 56, India
i 9 6 0 ...... B.Sc.(Hons.), The University of Bombay, Bombay 1, India
1960-1963 ...... Research Fellow, Institute of Science , Bombay 1, India
1963 ...... M.Sc., The University of Bombay, Bombay 1, India
1963-1964 ...... Research chemist, Lyka Labora to rie s, Bombay 57, India
1964-1968 ...... Research Assistant under Professor M. L. Wolfrom, Department of Chemistry, The Ohio State University, Columbus, Ohio 43210, U.S.A.
ill CONTENTS
Page
ACKHO'ÆiDGKiST...... i i
VITA...... i i i
LIST OF TABLES...... v ii
INTRODUCTION MU STATEMENT OF PROBLEM...... 1
HISTORICAL ...... 11
Vinyl ethers ...... 11
1. Synthesis 2. Reactions 3. Protection of hydroxyl group
Chemical synthesis of l-thioglycosides .... 28
1. Direct acid-catalyzed glyc03i dation 2. Preparation from dithioacetals 3. Synthesis from glycosyl halides 4. Synthesis from l-thioaldosides
DISCUSSION OF RESULTS ...... 45
Part I ...... 45
Part I I ...... 61
EXPERIMENTAL...... 69
Part I ...... 69
Reaction of ethyl vinyl ether with D-galactose diethyl dithioacetal (56^
Reaction of isopropyl vinyl ether with D-galactose diethyl dithioacetal (56)
iv CONTENTS (Continued)
Page
Reaction of ter-butyl vinyl ether •with D-galactose diethyl dithioacetaü. (j^) . . . 71
Desulfurization of 5,6-0-ethylidene D-galactose diethyl dithioacetal (57)
Periodate Oxidation
Periodate oxidation of 5,6-0-ethylidene 1-deoxy-D-galactitol (5S)
Preparation of 6-0-(l-ethoxyethyl)-D- galactose diethyl dithioacetal (6o)
Acid-catalyzed reaction of 6-0-(l-ethoxy- ethyl)-D-galactose diethyl dithioacetal (60)
Partial deiner captai at ion of 5,6-0-ethylidcne- D-galactose diethyl dithioacetal (57)
Synthesis of ethyl 5,6-0-ethylidene-l-thio- a-D-galactofuranoside (62)
Preparation of methyl 6-0-tetrahydro-2H- pyran-2-yl-a-D-glucopyranoside (67)
Conversion of methyl 6-0-tetrahydro-2H- pyran-2-yl-a-D-glucopyranoside to 2,3,4“ tri-0-methyl-N-phenyl-p-D-glucopyranosyl- emine “ • -
Preparation of methyl 6-0-(tetrahydro-2H- pyran-2-yl)-a-D-glucopyranoside from methyl 2,3,4-tri-O-acetyl-a-D-gluco- pyranoside ”
Part I I ...... 82
Synthesis of l,2:3,A-“di-0-benzylidene-6- 0-(l-methoxyphenylethyl)-a-D-galacto- pyranose (tô)
Synthesis of diphcnylmethyl vinyl ether
Synthesis of l,2:3,4-di-0-benzylidono-6-0- (l-diphenylraethoxyethyl)-D-D-galactopyranose (62) CONÏülN'K (Continued)
Page
Reaction of starch viith vinyl e t h e r s ...... 84
Determination of degree of substitution
SU14KMY ...... 88
BIBLIOGRAPHY ...... 91
Vi TABLES
Table No. Page
1. Partial deinercaptalation of 5,6-0- ethylidene--D-galactose diethyl- dithioacetal (^V.) ...... 56
2. Reaction of starch with vinyl ethers ...... ^2
3 . D. S. of starch acetals ...... 55 CHo I ^ /(.. Starch acetals (Starch-O-GHOR)-physical p r o p e r t i e s ......
VI1 INTRODUCTION and STATEMENT OF PROBLEM
In carbohydrate derivatives, it is frequently necessary to protect hydroxyl and amino groups; the methods used to protect these groups are often similar and protective groups used for
one may be applicable to the other. In transformations of sugars,
there are mainly three types of protective groups most commonly
employed; ethers, mixed acetals, and esters. There are a number
of review articles (1-3) •
(1) B. Helferich, Adv. Carbohydrate Chem., 3., 79 (1948).
(2)A. N. DeBelder, ib id .. 20, 219 (1965).
(3) J . F. W. McOraie, Adv. Org. Chem., 2, 216 (1963).
Until recently, alkyl ethers have not found much favor as
protective groups mainly because of the comparatively drastic con
ditions required for their cleavage ( 4). The discovery that methyl
(4) R. L. Burwell, Chem. Rev,, 615 (1954).
ethers can be cleaved under very mild conditions by boron trichloride
or boron tribromide (5) has led to the use of such ethers in the (5) T. G. Bonner, E. J. Bourne, and S. McNally, J . Ghein. Soc., 2929 (i960 ). fie ld of carbohydrates (6). For the f ir s t time Long and coworkers (7)
(6) A. B. Foster, D. Horton, N. Sa].im, M. Stacey, and J . M. Webber, ib id .. 2587 (i960).
(7) M. S. Evans, F. N, Parrish, and L. Long, J r ., Carbohydrate Res., 2, A53 (1967). studied the formation of cyclic acetals of sugars by reactions with ketone dimethyl acetals. The acetal exchange reactions were carried
out with 2,2-dimethoxypropano (2), 2,2-dln’.ethoxy-3,3-dir;iO’bylbutane,
acetophenone dimethyl acetal, and ben%ophcnono dimethyl acetal on methyl o-Ë-glucopy’ranoside (l) , in N,N-dimethylforinaiTiide in the
presence of p,~toluenesulfonic acid as catalyst, whereby the 4,6-
acetals (3,) of the sugar with minor amounts of other products were
isolated. A typical reaction was formulated as an equilibrium
mixture of the two acetals, as shown below. In the case of the
reaction with benzophenone dimethyl acetal, the 4,6-acetal was ob
tained in low yield, which was explained as due to the sterically
hindered axial phenyl group in the resulting methyl 4,6-0-(diphenyl-
methylidene)-c-D-glucopyranoside ( 3). The major product was the
monoacetal, methyl 6-0-(diphenylmethoxymethyl)-a-D-glucopyranoside ( 4), CHgOn OCH
+ ZCH^CH HO \0 OCH, OCH
1 2 1 The monoacetal (A) vjas converted partially into the 4,6-acotal (^)
under acid-cataly sis, as shovin below.
?h
OH OCH OH OCH k
The use of alkyl vinyl ethers to protect hydroxyl or amino
groups has occasionally been done but their potential usefulness
•in the fie ld of carbohydrates has not been investigated. Tchoubar
prepared (8) mixed acetals of simple alkyl vinyl and ethers and
(8) B. Tchoubar, Compt, rend., 237, 1006 (1953).
showed their stability against anionic reagents, Sims and co
workers (9) made use of alkyl vinyl ethers to protect the hydroxyl
(9 ) H. J. Sims, H. B. Parseghian, and P. L. deBenville, J , Org. Chem., 2^, 724 (1958). 4 groups of cyanohydrins in the synthesis of o.-hydroxyguanaiiiines.
Barker and covioikers (lO) prepared acetals of sucrose by the reac-
(lO) S, A, Barker, J . S. Briraacoiribe, J. A. O'aravis, and J. M. Williams, J. Chem, Soc., 3158 (1962). tion of sucrose uith alkyl vinyl ethers under acid catalysis. 3,4-
Dihydro-2H-pyran, a cyclic vinyl ether, has been extensively used in the field of steroids (11) to protect hydrozcyl groups as their
(11) G. Djcrassi, "Steriod Reactions," Holden-Day, In c., San Francisco, (1963), p. 76.
tetrahydropyran-2-yl derivatives. The use of dihydropyran to pro
tect hydroxyl groups in transformations of sugars is quite recent,
Paul f ir s t shewed (12) that dihydropyran reacts with anhydrous
(12) a. Paul, Bull. Soc. Chim., 1, 978 (1934).
methanol under acid catalysis to yield a mixed acetal. Wood and
Kramer (13) extended this reaction to a number of alcohols and phenols,
(13) G. F, Wood and D. Kramer, J . Amer. Chem. Soc., 2246 (1947 ).
They found that the vinyl ether adds to primary, secondary, and
tertiary alcohols in the presence of an acid catalyst. This reac
tion is also found to take place in the presence of acid catalysts
such as hydrochloric acid ( 13), p-toluenesulfonic acid (14), (14) D. Robertson, J . Org, Chem,, 25, 931 (i960). phosphorus oxychloride (15), polyphosphoric acid (l6) , and Air.berlite
(15) G. Greenhough, H. K. Henbest, and E. Jones, J. Chem. Soc., 1190 (1951).
(16) H. Schmid and K. Banholaer, Eelv. Chim. Acta, 37, 1706 (1954 ).
IR-120 (h') resin (l7). The tetrahydropyran-2-yl derivatives are
(17) L. Haynes and J . Plimmer, J . Chem. Soc., 4665 (1956).
also stable toward alkali and anionic reagents and are reasonably
stable in acetic acid solution. They can be easily cleaved by dilute
mineral acid. Baker and Saohdev (18) used dihydropyran to protect
(I8 ) B, R. Baker and H. S. Sachdev, J . Org. Chem., 28. 2132 (1963).
the hydi'oxyl group in 3-0-benzoyl-di-O-isopropylideno-D-m.annitol;
the tetrahydropyran-2-yl derivatives were found to be stable toward
sodium methoxide, cold pyridine hydrochloride, pyridine-chromium
trioxide and also to the displacement reaction conditions.
Angyal and Gero (19) studied the selectivity of the reaction of
(19 ) S. J . Angyal and S. D. Gero, J. Chem. Soc., 5255 (1965) dihydropyran toviard axial and equatorial hydi’oxyl groups in partially acetylated myo-inositoi. They treated 1,4,5,6-tetra-O- acetyl-ioyo-inositol with dihydropyran under acid catalysis with the expectation that preferential pyranylation could take place in the 3-position, that is on the equatorial hydroxyl group. This would have paved the way for the synthesis of 1,2,4,5»6-pGnta-0-
acetyl-myo-inositol, but to their disappointment, they found com
plete nonselectivity for the reaction.
A series- of reactions that interested us most was the reac
tions of alkyl vinyl others (V) with compounds having vicinal groups
such as amino, hydroxyl, or thiol. A few years ago, Shostakovskii
and coworkers (20,21) reported the isolation of l-O-(l-ethoxyethyl)-
(20) M. ?. Shostakovskii, V. V. Zhebrovskii, and M. A. Kedelyansaya, Izvest. Ale ad. Nauk S.S.S.R. Otd. Khirn Nauk, 350 (1955); Bull. Acad. Sci. U.S.S.R., 313 (1955).
(21) M. F. Shotakovskii, A. S. Atavin, and V. V. Zhebrovskii, Izvest. Akad. Nauk S.S.S.R. Otd. Khim Nauk, 539 (1955); Bull. Acad. Sci. U.S.S.R., A77 (1955 ).
2,3"0-ethylideneglycerol (S) and l,2:3,4-di-0-ethylidene pentaerythritol
(10) by the reaction of ethyl vinyl ether (7) with glycerol (6) and
pentaerythritol (2), respectively, under acid catalysis, as shown
below. CH-3 I ^ CHgOH CH2OCKOC2H5
GHOH + CnHcOCH=OH2 —^ GH-0. ' c 0 ^ I OH-CH, CHgOH GHgO
6 7 8 HOCH. CHpOH OCHp CH_ 0, H+ / \ / \ 0 + CpHr-OCH-CHp —5—-> CÎLCH C CHGH_
HOCHg CHgOH OCHg CHgO
2. 2 10
V/atanabe (22) patented the reaction of butoxyethyl vinyl
(22) W. Watanabe, U. S. Patent 2,752,357 (1956); Chem. A bstr., 52-., 4445 (1957).
ether and ethanolarnines in the presence of mercury or silver salts
of organic acids, -whereby 2-methyloxa%olidines were obtained in good
yields. Copenhaver (23) prepared 2-methyl-l,3-oxethiolane by
(23) J . W. Copenhaver, B ritish Patent 6/(2,253 (1950); Chem. Abstr., 4746 (1951).
reaction of methyl vinyl ether and ethylene thioglycol in the presence
of £-toluenesulfonic acid. In our laboratory, the synthesis of
methyl 4,6-0-cthylidene-a-D-glucopyrano3ide (IJ.) has been reported ( 24)
(24) M. L. Wolfrom, Anne B eattie, and S. S. Bhattacharjee, J . Org. Chem., 33., 1067 (1968).
by the reaction of alkyl vinyl ethers with methyl c-D-glucopyranoside,
as shown below. H
H 3 CK R00H-CH2 OCH
OH 11 In the field of starch, considerable work has been done in the preparation of starch derivatives such as esters, ethers, and oxidized starches, but not much work has been done toward the prepara tion and application of starch acetals without crosslinking. The starch acetals known commonly are those produced (25) by the reaction
(25) R. W. Kerr, "Chemistry and Industry of Starch," R. W. Kerr, e d ., Academic Press In c., New York, N. Y ., 2nd e d ., 1950, p. 466. with formaldehyde and low molecular weight aldehydes; these starch derivatives are cross-linked starch acetals. Formaldehyde reacts with starch in aqueous medium to form hemiacetals, which seem to be
stable at pH 6-7, being converted to cross-linked acetals as the pH
is lowered. Recognition of the effect of pH on cross-linking has
led to the development of a series of pregelatinized cold water soluble
starch-formaldehyde compositions prepared under neutral or slightly
alkaline conditions, which are capable of forming w ater-resistant
coatings or adhesi?es when cured under neutral or slightly acid con
ditions (26). A non-cross-linked starch has been prepared in an
(26) E, Meier, Swiss Patent 276,399 (1951). 9 an acid-catalyzed addition reaction viith 3,'^rdibydro-2H-pyran (27).
(27) 0. Weaver, C. Russell, and C. E, R ist, J . Org. Chem., 2#, 2838 (1963).
Low D. S. (degree of substitution) products viere obtained in aqueous solution and were water-soluble. High D. S. products required the use of dimethyl sulfoxide as a solvent; at D. S. values 0.7, 1.1, and 1.5, they became soluble in dioxane chloroform, and benzene, respectively. Reaction of chloromethyl hexyl ether in H,H-dimethyl- forrr.amide containing sodium carbonate also gives (28) non-cross-
(28) M. J . Rosen and I. A, Kaye, U. S. Patent 3,092,618 (1963); B ritish Patent 941,268 (1963); Chem. A bstr., m , 1939 (1964). linked, full acetals.
The principal reasons for undertaking the work described in
Part I of this thesis were as follows.
l~>To study the reaction of alkyl vinyl ethers with a hexose
diethyl di.thioacetal with the objective of protecting the 0-5 and
0-6 hydroxyl groups of the sugar. It was thought plausible that
the reaction of a hexose diethyl dithioacetal with alkyl vinyl ethers
would result in a 1,3-dioxalane derivative by blocking the 0-5 and
0-6 hydroxyl groups, on the basis of the work described earlier.
The search for blocking' the 0-5 and 0-6 hydroxyl groups in a hexose
diethyl dithioacetal was of interest in finding a good method to
synthesize the hexofuranose ring, required for the synthesis of hexo-
furanosyl nucleosides. The partial derr.ercaptalation (29-31) of 10
(29) A. L.. Raymond, Adv. Carbohydrate Chem., 1, 136(19A5).
(30) D« Horton and D. II. Hutson, ib id ., 1^, 131 (I 963 ).
(31) J. W. Green, ibid.. 21._, 112 (I966 ). a hexose diethyl dithioacetal often results in the synthesis of 1- thiohexofuranoside and free sugar or 1-thiohexopyranoside and free sugar. Thus, by blocking the C-5 and C-6 hydroxyl groups, it should be possible to synthesise the required intermediate. This study may
finally lead to the synthesis of the elusive 1-thio-a-D-rnannofurano-
side,
2—To study the selectivity of the reaction of 3,4-dihydro-
2H-pyran between primary and secondary hydroxyl groups.
Part I of this dissertation is concerned with the following
topics.
(a) A study of the reaction of alkyl vinyl others with
^-galactose diethyl dithioacetal.
(b) A study of the reaction of 3,4-dihydro-2H-pyran with methyl c-D-glucopyranoside.
In Part II of this dissertation, the preparation of starch
acetals by the reaction of starch with vinyl ethers has been described,
with the hope that it may provide uses for starch. An ultraviolet
spectrophotometric method to determine the degree of substitution of
the starch acetals has been concomitantly developed. HISTORICAL
Vinyl ethers
1. Synthesis
Alkyl vinyl ethers, CH^^GHOR, have commonly been synthe sized by the methods described below.
(a) Reppe's method.--Renoe (32) prepared a series of
(32) R. Kii'k and D. Othmer, Encyclopedia of Chem. Tech., 11, 649 (1953). vinyl ethers by the reaction of alcohols with acetylene under high pressure at 120-180° in the presence of an alkaline catalyst such
as the hydroxide or alkoxide of an alkali or alkaline earth metal
or the zinc or cadciium salt of an organic acid. Shostakovskii and
coworkers ( 33) prepared aryl vinyl ethers by the reaction of phenols
(33) K. Shostakovskii, A. V. Bogdanova, and G. K. Kraslni- kova, Izvest. Akad. Nauk S.S.S.R. Odt. Khim. Nauk, 339 (1957); Chem. Abstr., 51 , 14,653 (1957 ).
and acetylene in the presence of a base under 15 to 20 atmospheres
pressure, ArOK + HC=CH ~> ArOCH^CHg. Recently vinylation of methyl
a-D-glucopyranoside by acetylene under high pressure has been studied
in aqueous tetrahydrofuran. I t was shown ( 34) that vinylation takes
11 12
(3A) A. J , DeutschiT;sn, J r. and H. W. Kircher, J. /uner. Chem. Soc., 8^, 4070 (1961).
place primarily on the 0-2 hydroxyl group. More recently the prep
aration of 0-vinylstarch has been reported (35) by using similar
(35) J . Berry, A. Deutschnan, and J . Evans, J . Org. Chem., 22, 2619 (1964).
reaction conditions.
/ (b) Transvinylation.—Vinyl ethers sensitive to heat and
alkali can be prepared by the method of Adelman ( 36); vinyl acetate
(36) R. L. Adelman, J. Amer. Chem. Soc., 7,5, 2678 (1953).
is reacted vjith alcohols in the presence of mercuric sulfate at -60
to -10° for one to three hours. By this method good yields of vinyl
ethers are obtained in the case of primary alcohols. Synthesis of
benzyl vinyl ether has been reported (37) by the transvinylation of
(37) W. J. Dejarlais and H. M. Teeter, J. Amer. Oil Chemists’ Soc., 2Z, 556 (1961).
benzyl alcohol with isobutyl vinyl ether in the presence of mercuric
acetate at reflux temperature. The vinyl ether is used in very
large excess so that the equilibrium of the reaction would be in
favor of the benzyl vinyl ether. German patents have mentioned (38) 13
(38) 0. Ernst and W. N. Berndt, German Patent 513,679 (1927); Chem. Abstr., 2%, 1841 (1931); German Patent 525,188 (1928); Chem. Abstr., 2^, 4284 (l93l). the synthesis of phenyl vinyl ether by the reaction of phenol and vinyl chloride or ethylidene dichloride in the presence of a base.
Deutschman and Kircher (34) had reported the reaction of methyl a-D-glucopyranoside with vinyl chloride in the presence of a base
to give the 2-0-vinyl derivative. Recently a good laboratory
method for the preparation of aryl vinyl ethers by the reaction of
phenols viith divinyl mercury has been reported (39).
(39 ) D. Foster and E, Tobler, J. Amor. Chem. Soc., 83 , 851 (1961).
(0) Elimination reaction ( 40) . —Aryl vinyl ethers can also
(40) R. Adam.s, ib id .. 42. 648 (l920) .
be prepared by elimination of hydrogen halide from 2-haloethyl aryl
ethers by sodium hydroxide at high temperature.
2, Reactions
There are many reactions of vinyl ethers of great synthetic
utility. Most of the alkyl vinyl ethers undergo reactions common
to olefinic compounds, as hydrogenation, alcohol addition, halogéna
tion, hydrohalogenation, and the like. The difference is that vinyl
ethers are far more susceptible to electrophilic attack than are 1/, olefins. The high reactivity is due to the presence of an oxygen atom adjacent to an olefinic carbon. Although the elkoxy group is electronegative it shows a strong inesoraeric effect when adja cent to an unsaturated linkage. This niesomeric effect can give rise to rotational isomers in vinyl ethers as shown below. Feeney
“ 0+ = o''** = C ''°"2 -CH- and coworkers ( 4I) studied the nuclear magnetic resonance spectra
(41) J. Feeney, A. Ledwith, and L. H. Sutcliffe, J. Chen. Soc., 2021 ( 1962 ). of closely related alkyl vinyl others. They found that the chemical
shifts of the terminal ethylenic hydrogen atoms were all 0.5—0.75 ppm
higher than the resonance bands of simple olefins, indicating the
reduction in the double bond character in the vinyl grouping. The
coupling constant between geminal hydrogen atoms on the terminal
carbon also decreases from -0.1, -1.2, -1.7, -1.8, -2.2 to -2.7 Ha
in the case of t-butyl, isopropyl, isobutyl, n-butyl, methyl, and
2-chloroethyl vinyl ethers, respectively. Feeney and coworkers ( 4I)
concluded from these observations that the electron density in the
double bond in alkyl vinyl ethers, ROGH^CH^, decreases in the following
order: R = 2-chloroethyl>methyl>isobutyl>iscpropyl-^t-butyl. Infrared
spectra of alkyl vinyl ethers show (42) that the =CH 2 wagging mode of
(42) W. J. Potts and K. A. Nyquist, Spectrochim. Acta, 679 (1959). 15 the vinyl group is louer than that of typical vinyl compounds
(890—910 cm”^), supporting the resonance structures. The =CIl 2 wagging frequency decreases in the sequence t-Bu (824 cm"^) ^ i-Pr (823 cin~^)^Me (810 cm ^) , showing that the degree of resonance increases in the same order.
Alkyl vinyl ethers readily undergo hydrolysis by aqueous
acid (43,44), mercuric salts (45), alumina (46,47), or certain
(43) A. Skrabal and R. Skrabal, Z. Phys. Chem., 181. A449 (1938).
(44) A. Zhaborka and K. Wiemann, Monatsh, 71, 229 (1938).
(45) A. F. Rekashevo and L. A. Kiprianova, Kinetica Kataliz, i, 299 (1964) 5 Chem. Abstr., 61, 4167 (1964).
(46) 0. McKinley, U. S. Patent 2,533,172 (1950); Chem. Abstr., 41, 3407 (1951).
(47) H. J. Hagenmeyer, J r ., and D. C. Anderson, U. S. Patent 2,662,919 (1953); Chem. Abstr., 4i, 367 (1955).
cation exchange resins (48), to form an alkanol and acetaldehyde.
(48 ) M. F. Shostakovskii, A. S. Atavin, B. A. Trofimov, and A. V. Gusarov, Zh. Vses. Khim. Obshchestva Im. D. I. Medeleeva, % 599 (1964); Chem. Abstr., 62, 2701 (1965).
Ledwith and Joods were the f ir s t to undertake the detailed study
of the kinetics and mechanism of acid-catalyzed hydrolysis of alkyl
vinyl ethers to gain insight into the stereospecific polymeriza
tion of vinyl ethers (49). They observed that for a series of alkyl
(49 ) A, Ledwith and H. J . Woods, J . Chem. Soc., (B) 753 (1966 ). 16 vinyl ethers, ROCH^GHg, the specific rate of hydrolysis decreases in the sequence R = t-Bu'’’ i-Pr > Bt^ 1-Bu> Me> 2-chloroethyl. i\3.so with hydrochloric acid as catalyst, the hydrolysis shows features consistent with general acid catalysis. The rate-determining pro cess in all these reactions involves proton addition to the methylene group of the alkyl vinyl ethers. Subsequent hydrolysis of the car bonium ion and hemiacetal is very much faster.
CHg = CKOR + H'*' CH 3 - CHOR H^O V. fast
.OR CH3CHO t ROH ^ CIU - CH + H H+ 'OH fast
Jones and Wood (50) earlier suggested that the slow step
(50) D. K. Jones and N. F. 'food, J . Chem. Soc., 5/+00 (I 96 /+).
involves proton transfer from hydronium ion directly to the methylene
group of the vinyl ether.
+ OH - OR ^ , CH.r.OR " + H 0+ — Ii yH CH^ ^ rate-determining H 1
CH^CHO + ROH + H_0 ^ GH_ - OH - OR + HgO 17
Ledviith and Woods (49) have commented that the above reaction mechanism requires that the electron release to the double bond should fall in the sequence t-Bu>Me in order to explain the ob served relative rates. This rationale is contrary to the conclusions drawn from ir and nm,r study of these compounds. In addition, molec ular models of these ethers suggest that for a ll except methyl vinyl ether, rotational isomers are sterically hindered, especially in the case of isopropyl and t-butyl vinyl ethers. They noted that as the electron release to the double bond fa lls in the sequence
Me>i~Pr> t-Bu, the basicity of the oxygen lone-pair electron in
creases. Consequently they suggested that the transition state for the rate-determining proton transfer involves the oxygen atom.
+ .CH.
HX + CHg ■- CHOR - > CHr ■OR
H'
In this way the observed rate sequence could be explained, especially
the very low reactivity of 2-chloroethyl vinyl ether. For this com- S. pound it is clear that intramolecular or intermolecular dipole-dipole
interaction helps stabilize the polar canonical structure and there
fore reduces the ability of oxygen atom to participate in the
CH, CH ^ 0 CH, 6+ Cl- CH. 18 trails it ion-state formation. More recently, Kresge and Chiangs ( 5I)
(51) A. J. Kresge and Y. Chiangs, J. Chern, Soc., (b) 53 (1967 ). studied the hydrolysis of ethyl vinyl ether and also concluded that it is a general acid-catalyzed reaction.
Other reactions of vinyl ethers of general interest are described below in brief.
Reactions with acetals (52).—Vinyl ethers react with
(52) R. I. Hoaglin and D. H. Hirsch, J. Amer. Chern. Soc., 71, 3468 ( 1949 ). acetals (]^) in diethyl ether in the presence of boron trifluoride to give alkoxy acetals (dj.) as shown below. The alkoxy acetals
R'CH(OCH ) CHCHgCHR' BPj'EtaO RO OCHj
12 11
can react further to polyalkoxy acetals of low to medium
molecular weight. Alkoxy acetals are starting materials for
polyene aldehydes, intermediates for vitamin A ( 53). Thioacetals
(53) B. M. Mikhailov and L. S. Povarov, Izvest. Akad. Nauk 3.S.S.R. otd. Khim. Nauk, 1143 (1963)} Chern. Abstr. , 59, 7564 (1963 ) .
react similarly to give thioalkoxy acetals (54). Normally, under 19
(5A) ■ • M. Mikhailov and G. S. Tor-Sarkisyan, Tr. Konf. Po Vopr. Stroe?: \ : i Reaktsionnoi Sposobnosti Atsetalei, Akad. Nauk Kirg. S.S.R. \n st. Org. Khin., 68 ( 196 I) ; Chern. Abstr. 60, 8065 (1964).
acid cata).ysis, vinyl others undergo self condensation to give polymers. However, Hoaglin and coworkers (55) isolated the dimer (I 4),
(55) R. I. Hoaglin, D. G. Kubler, and A. ÏÏ. Montagna, J . Amer. Chern. Soc., 5460 (l958).
trimer (]^), and tetramer on treatment of vinyl ethers with
boron trifluoride or mercuric acetate. The dimeric products are
acetals of p,v-unsaturated aldehydes, as shown below.
2 CHg = CHOR CH2=GHCH2CH(0R)2
1 (14) CHg^CHOR V BP?
GH2=CHCH2CHCH20HCH2CH(0R)2 GH2=CHCH2GHCH2CH(0R)2
OR OR '^■“cH-=CHOR
16 11
Vinyl ethers also undergo (56) the Friedel-Crafts reaction
(56) V. V. Korshak, K. K. Samlavskaya, and A. I. Gerrshano- vich, J , Gen. chern. (USSR), 16, 1065 (1946).
in the presence of aluminum chloride to give arylalkane and 1,1-
alkoxyaryl ethane. Shotakovskii end couorkers (57) isolated 20
(57) M. F. Shostakovskii, A. V. Bogdanova, and A. N. Vol kov, Invest. Akad. Nauk S.S.S.li. otd, Khim. Naudc, 2224 (1962); Chom, Abstr., 13881 (1963).
l,l-hls(5"methyl"2-fuiyl)ethane (l^.) as one of the major products
formed by reaction of butyl and phenyl vinyl ethers uith 2-methyl-
furan (17) in the presence of en acid cataly st, as shown below.
R00H=CH2 hh-
17 18
Trsnsvinylation.—Transvinylation is an important route
to many other vinyl derivatives. It may be carried out with alcohols
and catalysts such as mercuric acetate (58) and mercuric sulfate (59).
(58) V/. H. Watanabe and L. E. Conlon, J . Amer. Chern. Soc., 7â, 2828 (1957).
(59) R. L. Adelman, ib id .. 77, 1669 (1955).
The reaction is more favorable in cases of allylic or benzylic
alcohols. Nitrogen compounds such as oxazolidinone, pyrrolidone,
and caprolactam can be converted to N-vinyl compounds (60,6l).
(60) W. E. 'dalls, VJ. F. Tousignant, and T. Houtman, J r . , U. S. Patent 2,891,058 (1958); Chern. Abstr., 2359 (i960).
(61) J . Peppel and J. D. vJatkins, U. S. Patent 3 ,019,231 (1962); Chern. Abstr., ^6, 12,748 (1962). 21
However, carbaaole on reaction with vinyl ethers under similar con ditions yields 9-(l-slkoxyethyl)carba%ole (62),
(62) E. E. Sorotkna and A, N. Yushko, U.S.S.R. Patent 176,297 (1965 ); Chern. Abstr., 11,180 (1966).
Reaction with amides. —Vinyl ethers react with amides under
acid catalysis to give addition products. Voronkov reported ( 63)
(63) K. G. Voronkov, J . Gen. Chern. (USSR), 1494 (l9 5 l).
the preparation of 0-alkylated products (^ ) as shown below.
NH II OCR HH R’coNHo I a* com? « ROCH=CHo ------CHGHg ------CHLCH(OCR'), ' ^ -ROH ^ ^ OR i n 20
Mono-O-acyl amides ( ^ ) were postulated as intermediates. Furukawa
and coworkers ( 64) reported the isolation of N-alkylated products (22)
(64) J . Furukawa, A. Onishi, and T. Tsunuta, J . Org. Chern., gl, 672 (1958).
by reaction of vinyl ethers with benzamide and dicarboxylic acid
amides. Vinyl ethers reacted with only one mole of dicarboxylic
acid amides (23.) to give mono-N-acyl amides (24). The structure
was established by the elimination of alcohols to form the known
N-vinylimides (25,) as shown below. 22
0 II NHCPh 0 PhOONH? « , R O O H = G H p------C H C H g ------> CÎUCH(NH-GPh)2 ^ H+ I j OR 7 21 22
0 G Il II
R00H=CH5 + HiN R' ----- > CH3-CH-N R’ \ / \ / C OR G 1 Il II ^ ' gA 0 0 -ROH II 21 C / \ CHg=GH - N R' \ / G ^ 0
The pyrenylation of amides (65) and purine derivatives (66-63)
(65) A. J. Speziale, K, W. Ratts, and G. J. Karoo, J. Org, Ghera., 26, 4311 (1961).
(66) L. R. Lewis, F. H. Schneider, and R. K. Robins, ib id .. 26, 3837 (1961).
(67) R. K. Robins, E. F. Godefroi, E, L, Taylor, L. R. Lewis, and A. Jackson, J , Amer. Chern. Soc., 81, 2574 (1961).
(68) N. Nagasawa, I, Kimashiro, and T. Takenishi, J. Org. Chern., 11, 2685 (1966). with 3,A-dihydro-2H-pyran in the presence of an acid catalyst has 23 been shown by infrared spectral analysis to give N-(tetrahydro- pyran-2-yl)amides. .All the products show 0=0 bands at 1655-1737 oin”^, one NH stretching band instead of two, and the absence of the amide II band expected of primary aiaide, a ll indicative of a secon dary amide structure. There is also a triplet band characteristic of tetrahydropyran-2-yl structures (at about 1075 cm ^ , 1061 cm"^,
1031 cm"l).
Reactions of vinyl ethers with aromatic amines in the presence of an acid catad.yst gi.ve 2-methylquinoline derivatives (69). A
(69 ) G. T. Pilyugin and 3. P. Cpansenko, J. Gen. chern. (USSR), 27, 1097 ( 1957 ).
representative example is shown below.
ROOH=CHr ~> •OH
26 27
3 . Protection of hydroxyl group
As mentioned in the introduction, 3,4-dihydro-2H-pyran, a
cyclic vinyl ether, has been used for quite some time in the field
of steroids and its application in that area has been extensively
reviewed (11). An obvious disadvantage to the use of the tetrahydro-
pyranyl group for the protection of an optically active alcohol is 24 that i t leads to the introduction of an additional asymmetric carbon center and thus to a mixture of diastereoisomers. In order to avoid this problem, Reese and couorkers (70) prepared 4-methoxy-5,6-dihydro-
(70) 0, B. Reese, R. Saffhill, and J. E. Sulston, J. Amer, Chern. Soc., 8%, 3367 (1967).
2H-pyran (28) which on reaction with an hydroxyl group gave a syr,-metri
cal acetal. Reaction between 3 ',5'“di-0-acetyluridine (22.) and an
excess of 4-methoxy-5,6-dihydro-2H-pyran (28) in the presence of p.-
toluenesulfonic acid, followed by treatment with methanolio ammonia
gave the required uridine 2'-acetal (j30) in very good yield. OCH- HOŒI2 AcOCB Uracil Uracil
Recently Cohen and Steele investigated (71) the vinyl thio-
(71) L. A. Cohen and J. A. Steele, J . Crg. Chern., 3I, 2333 (1966).
ethers, such as 3,4-dihydro-2H-thiopyran 2,3-dihydrothiophene as
means to protect a hydroxyl group. These vinyl thioethers were
found to form adducts with alcohols. The 5’-O-acetylthymidine (31)
was allowed to react with the dihydrothiophene under acid catalysis
to give the adduct (j2). The protective group on the adduct (32)
could be removed by aqueous silver n itra te solution, to return the
acetyl derivative (31). AcOCH2 Thymine AcOCH. 'hymine
Dihydrothiophene OH
In the synthesis of C-3' — G-5' internucleotide linkages,
Khorana and coworkers (72,73) found that the use of a protected
(72) M. Smith, D. H. Rammler, I . H. Goldberg, and H. G. Khorana, J . Am. Chern. Soc., 430 (1962). (73) D. H. Rammler and H. G. Khorana, ib id .. 84. 3112 (1962) ribonucleoside bearing an acyl group on the C-2' hydroxyl group was not practical since the acyl groups were found to have a tendency to migrate from C-2' hydroxyl to C-3' hydroxyl group. The problem was solved by protecting the C-2' hydroxyl group by the tetrahydropyranyl group. Uridine 3',5'-cyclic phosphate (33) was treated with dihydro- pyran under acid catalysis to give the tetrahydropyranyl derivative
(M) > which on subsequent hydrolysis with an alkali resulted in 2'-
0-(tetrahydropyran-2-yl)uridine 3*-phosphate ( 3^) and 5 '-phosphate
(2â) • The 3'- and 5'-phosphate derivatives were found to be good
starting materials for the internucleotide syntheses. OCR 0 0 % Uracil 0 Uracil DHP B a ( O H ) / / 0 0 OTHP
HOCH2 0 ^ Uracil ’O-POCH2 Uracil
OTHP OTHP 16 26
The C“3* — C-5’ linked dinucleotides were also synthesized by condensation of the tetrahydropyranyl derivatives (^) with
2* ,3'“di-O-benzocyluridine, N^,0^ ,0^*-tribenzoylcytidine, and pi O I N,N,0' ,0 . -tetrabenzoyladenosine (38) in the presence of N,N- dicyclohexylcarbodiiraide. Subsequently, protective groups were removed to give the dinucleotides (^ ) as shown below.
THPOCH HOCH R = Uracil = N-acetyladenino + R* = N-benzoyl- cytesine = uracil Ph. CO 0=P-0 OTHP 00-Ph = N,N-dibenzoyl- adenine 0"
1) DOG 2) NH3 3) H3O+
HOCH, R = Uracil = Adenine R* = Uracil = Cytosine 0 Og'Ph = Adenine
0 -
OH OH 27
An early reference on the use of alkyl vinyl ethers in carbo hydrate chemistry is a short note (?/+) by Chaldek and Srart,
(VA) S, Chaldek and J , Smrt, Chern, Ind., 1719 (1964).
Reaction of 5'-0-acetyluridine 3'-phosphate ( 40) with ethyl vinyl ether
in the presence of hydrochloric acid gave 5*-O-acetyl-2'-0-(l-ethoxy-
ethyl)uridine 3 '-phosphate (41). fhe 2*-O-(l-ethoxyethyl) group could
be easily removed quantitatively in two hours with % acetic acid at
20°. This contrasts with the 2'-0-tetrahydropyranyl group, which under
the same conditions could be removed to the extent of only 37%. The
pyridinium salt of ^ was condensed with 2 * ,3 '-0-ethoxymethyleneuri-
dine (42) in the presence of N,N-dicyclohexylcarbodiimide to give,
a fte r removal of protective groups, urid y ly l-(3 '-5 ')u rid in e (^2)>
shown below.
A0OÇH2 Uracil AcOCH Uracil
(H0)2P-0 OCHOEt CH^
HOCH2 Ov- Uracil HOCH2 ^ 0 . Uracil
61 1) DCC ;^ 2 0 - Px— 0 OH 0 0 2) H+0 ^ Ov Uracil
OH OH 28
Chemical synthesis of 1-thioglycosides
A number of preparative methods for 1-thioglycosides have been developed and modified during the last four decades.
The methods of synthetic value as well as of theoretical interest
are described below.
1. Direct acid-catalyzed glycosidation
The reaction between carbonyl compounds and alcohols in
the presence of an acid catalyst is a reversible reaction and can
proceed via hemiacetals, to mixed full acetal-s, or symmetrical
full acetals. In the sugar series, the mutarotation reaction of
an aldose represents an equilibrium between the free carbonyl
(aldehyde) form and the hemiacetal (intramolecubrly cyclized)
forms. The acid-catalyzed glycosidation reaction takes the process
a stage further, to give a mixed full acetal (glycoside). In the
acid-catalyzed glycosidation reaction with alcohols, the reaction
halts at this stage and thus constitutes a valuable synthetic route
to glycosides. However when a sugar is treated with a thiol in
the presence of a strong acid (mercaptalation), two molecules of
thiol usually react with one molecule of sugar and acyclic dithio-
acetal results. This makes the procedure unsatisfactory as a general
method for the preparation of 1-thioglycosides. However, conditions
have been found where, in individual instances, 1-thioglycosides may
be isolated. The dithioacetals, which are rapidly formed at 0°, 29 may be isolated in high yields if the acid is rapidly neutroli%ed
(75,76). Hoviever, for longer reaction times or higher temperatures
(75) M. L. Wolfrora, M. R. Newlin, and E. E. Stahly, J . Amer. Chern. Soc., A-379 (l9 3 l).
(76) M. L. Wolfrom and F. B. Moody, ib id ., 62, 3465 (1940 ) .
or if the dithioacetal is put back into the system, a subsequent
slower reaction takes place to give (77,78) a mixture of products
(77) E. Pacsu and E. J. Wilson, Jr., ibid. . 61, 1930 (1939 ) . (78) P. Brigl, K. Gronemeier, and H. Schulz, Ber., 12^ 1052 (1939 ).
from which fair yields of 1-thioglycosides may be obtainable. In
the cases investigated, the 1-thioglycosides found have been pyrano-
sides. Treatment of D-mannose with ethanethiol and concentrated
hydrochloric acid for 16 hours at room temperature gave a fair
y ield of the ethyl 1-thio-a- and p-D-mannopyranoside, isolated as
the tetraacetates (79), with no dithioacetal detected, whereas a
(79 ) J . Fried and D. E. Walz, J . Amer. Chern. Soc., 71, 140 (1949).
reaction time of five minutes gave only the diethyl dithioacetal
in very good yield (80). Ethyl 1-thio-c-D-glu.copyranoside was
(80) P. A. Levene and G. M. Meyer, J. Biol. Chern., 74, 695 (1927 ). 30 isolated in lovi yield (78) by the p^rcaptelation reaction with
ethanethiol. A paper chromatographic study of the mercaptalation
reaction with D-glucose, D-galactose, and D-mannose confirmed (81)
(81) M. L. i/olfrom, D. Horton, and H. G. Garg, J, Org. Chern., 28^ 1569 (19&3).
that almost complete conversion to the dithioacetal occurred within
five minutes. However, after several hours, an equilibrium was set
up in which two 1-thioglycosides, probably anoir.eric pyranosides, the
dithioacetal, and the free aldose were present. The 1-thioglyco-
pyranoside was particularly favored with the D-mannose structure.
2-Acetamido-2-deoxy-D-glucose is converted into the diethyl dithio
acetal in very good yield by mercaptalation (82) at 0°, but at
(82) M. L. Wolfrom and K. Anno, J . Amer. Chern. Soc., 7A, 6150 (1952).
room temperature a mixture of products was obtained (63) , including
(83 ) L. Hough and M. I. Taha, J . Chern. Soc., 20^2 (1956).
the dithioacetal, starting material, and 2-amino-2-deoxy-D-glucose
hydrochloride together with the anomeric ethyl 2-acetamido-2-
deoxy-l-thio-c- and p-D-glucopyranosides (the ji-D anomer was the
major product)* Mercaptolysis of the dithioacetal or of either
1-thiopyranoside gave a mixture containing all three of these com
pounds. It is possible that participation, through an oxazolidinium 31 ion, of the acetaiaido group adjacent to the C-1, influences the
reaction and accounts for the preferential formation of the p-g
anomer of the 1-thioglycoside. It also seems that under mercaptala
tion conditions, the dithioacetal formation is a fast, kinetically
controlled reaction, followed in turn by a slower reaction, which
at equilibrium gives a distribution of products, including the free
aldose, the thioglycoside and the dithioacetal, according to their
thermodynamic s ta b ilitie s in the system. It was shown by Pacsu
and Wilson (84,85) that hydrolysis of D-glucose diethyl dithioacetal
(84) E. Pacsu and E. J . Wilson, J r . , J . Amer. Chem. Soc., 61, 1450 (1939).
(85) E. Pacsu, "Methods in Carbohydrate Chemistry," R, L. Whistler and M. L. Wolfrom, eds.. Academic Press In c ., New York, N. Y ., 1963, Vol. 2, p. 354.
in O.OIN acid at 100° proceeds stepwise via the sequence D-glucose
diethyl dithioacetal ------> ethyl 1-thio-a-D-glucofuranooide ----->
ethyl 1-thio-p-D-glucofuranoside ------) ethyl 1-thio-a- and p-D-
glucopyranoside.
Mercaptalation of ester derivatives of the sugars may lead
to 1-thioglycosides, and the course of the reaction is strongly
dependent upon the ability of a suitably located ester group to
form a closed-ion intermediate by neighboring group participation.
Wolfrom and Thompson (86) had shown that p-D-fructose pentaacetate
(86) M. L. Wolfrom and A. Thompson, J , Amer. Chem. Soc. 16, 880 (1934). 32 undergoes mercaptalation •with ethanetiol and zinc chloride to give
ethyl 1-thio-p-D-fructoside tetraacetate. Later Leraieux end Brice
(87) showed that zinc chloride-catalyzed mercaptalation of penta-0-
(87) R. U. Leraieux and C. Brice, Can. J . Chem., 21) 109 (1955).
acetyl-p-D-glucopyranose gives a very good yield of ethyl tetra-0-
acetyl-l-thio-p-D-glucopyranoside. Under the same conditions, the
a-D anomer yields starting material, but with prolonged reaction
times a small amount of p-D anomer can be isolated. The D-galactose
derivative reacts analogously. The steric course of the reaction
can be rationalized by neighboring group participation as shown below.
GHOAc
OAc EtSH ütSH'ZnClg \ CAc fast OAc AcO AcO \ | ^ 1+1 00=0 o:c. 'CBU CH-
GHgQAc GHgOAc
EtSH.ZnGlg OAc OAc slow AcO AcO OAc OAc 33
In the case of the a-D anomer such neighboring group p a rtic i pation is not possible end this explains the low yield of the product,
Mercaptolysis of either c- or p-D-inannose pentaacetate gives ethyl tetra-O-acetyl-l-thlo-a-D-mannopyranoslde.
2. Preparation from dithioacetals
Schneider and Sepp showed (88) that treatment of an aqueous
(88) W. Schneider and J . Sepp, Ber., 2054 (1916).
solution of one mole of D-glucose diethyl dithioacetal with one mole
of mercuric chloride (demcrcaptalatlon) at room temperature, with
addition of base, gives an ethyl 1-thlo-D-glucoslde. Other alkyl
1-thio-D-glucosides wore sim ilarly prepared (89). Green and Pacsu (90)
(89) W. Schneider, J. Sepp, and 0. Stlehler, Ibid.. 51, 220 (1918).
(90 ) J . W. Green £ind E. Pacsu, J. Amer. Chem. Soc., 59, 1205 (1937 ).
modified the method by using yellow mercuric oxide to neutralize
the hydrochloric acid as It was formed, and they favored the a-D-
furanoslde structure for the resulting ethyl 1-thlo-D-glucoslde on
the basis of Its optical rotatory value and its ease of acid hydroly
sis. This conclusion was verified ( 9 I) for this derivative by
(91 ) M. L. Wolfrom, S. W. Walsbrot, D. 1. Weisblat, and A. Thompson, I b id .. 66. 2063 (1944). 34. periodate oxidation. The 2-acetarcido analog of D-glucose diethyl dithioacetal gave 2-acetamido-2-deoxy“l-thio--a-D-glucofuranoside by this procedure ( 92 ).
(92 ) M. L. Wolfrora, 3. M. Olin, and W. J . Polglase, ib id .. 72, 1724 (1950 ).
The route is a good general procedure for the preparation
of 1-thioglycosides. Early attempts to prepare 1-thioglycosides by
partial domercaptaiation of D-galactose diethyl dithioacetal (88,89)
or L-arabinose diethyl dithioacetal (93) were unsuccessful. The
(93 ) J. W. Green and E, Pacsu, ib id .. 60. (1938).
chromatographic study (94) of deraercaptalation of D-galactose diethyl
(94 ) M. L. Wolfrom, Z. Yosizawa, and B. 0. Juliano, J . Org. Ghera., 24, 1529 (1959 ).
dithioacetal indicated that only half of it was converted into
1-thiogalactofuranoside (sirup). The remainder was converted into
D-galactose. Partial deraercaptalation (95) of 2-acetamido-2-deoxy-
(95 ) M. L. Wolfrom and Z. Yosizawa, J. Arcer. Ghera. Soc., 81, 3474 ( 1959 ).
D-galactose diethyl dithioacetal gave the 1-thio-ct-D-furanoside,
aldose, and small amounts of the 1-thio-p-D-pyranoside and the
1-thio-p-D-furanoside. k typical partial deraercaptalation reaction
has been formulated as follows. 35
CH(SEt), CHSEt I <- I CHOH CHOH I CHOH O.SHgClg + O.SHgO ^ CHOH + O.SHgO I 5> J CHOH CHO — I I + C].HgSEt CHOH CHOH 1 I GHgOH CHgOH
The chromatographic study of the partial demercaptalotion of p-iaannose diethyl dithioacetal and D-xylose diethyl dithioacetal revealed that even with 0.5 mole of mercuric chloride, there re su lts a complete demercaptalation to the free sugar, Zinner and coworkers (96) proposed that since the 1-thioglycoside is the half-
(96 ) H. Zinner, A. Koine, and H. Niji.r., Ber., 22.) 2705 (i960).
Vl way stage in the sequence aldose diethyl dithiioacotal
1-thioglycoside V2 aldose, its yield must depend on the relative rates V]_ and Vg of the two reactions. With D-glucose and D-ribose
the 1-thioglycoside is the major product, whereas with
D-galactose and D-lyxose and are of the same order, the yields
of 1-thioglycosides are lower. With D-mannose and D-xylose,
and the free sugar is the only product.
A number of pathways for the formation of aldofuranosides
(A6) and l-thioaldofuranosides ( 47) from dithioacetals are shown
on the following page, as suggested by Green ( 3I ) . Pathway A-C leads
to the aldofurenoside through an acyclic monothioacetal ( 4I ) ; the 36 ^OR HC HC(OR), ^SEt I ' HCOH HCOH I 1 CHOH (ROH) CHOH
H OH H - OH
Y Y
61
A(ROH)
OR HC(S%t)s I HCOH 1 CHOH OH H — —- OH 66
Ï
65 SEt H,OH OH
E (H pO )
OH / HC N CHO SEt I HCOH HCOH (Y = CHgOH, 1 CHOH = -CHOH CHOH I H^O H OH CHpOH) H OH Y Y
61 37 la tte r can also afford the diacetal ( ^ ) by pathway B. Pathway D leads directly from the dithioacetal to the 1-thioaldofuranoside.
A th ird pathway, E-F, in aqueous solution, leads to the free sugar
(A9). Pathway C* and F’ show alternative formations of the aldo- furanoside ( 46) and the free sugar (42.) j respectively, starting from the 1-thioaldofuranoside (47).
Pacsu proposed (97) the possibility of an acyclic intermediate,
(97 ) E. Pacsu, J. Amer. Chem. Soc., 60, 2277 (1938); 61, 1671 (1939 ).
a monothioacetal ( 48 ), in the formation of aldofuranosides and 1-
thioaldofuranosides. This suggestion was based on the isolation of
acetals as minor products. Wolfrom and coworkers (98), starting
(98 ) M. L. Wolfrom, D. I. Weisblat, and A. R. Hanze, ib id .. 66, 2065 (1944).
with such a monothioacetal,prepared from unrelated systems, showed
that such a pathway is valid for D-galactose. A very high yield
of ethyl p-D-galactofuranoside was obtained from D-galactose diethyl
dithioacetal; the yield was higher than that obtained (90) directly
from the dithioacetal. For D-glucose, the formation of ethyl 1-thio-
o-D-glucopyranoside from S-ethyl-O-methyl monothioacetal was not
demonstrated. Instead, a 95% yield of methyl p-D-glucofuranoside
was obtained, again showing that pathway C had been followed. It
may be pointed out that the conversion of the monothioacetal into
the l-thiafiuanoside is improbable since it involves the preferential 38 displacement of an alkoxy group instead of an ethylthio group (a better leaving group) . Pathviay C has been indicated for the ethyl
and benzyl 1-thio-a-D-glucofuranosides by Green and Pacsu (90).
These compounds were converted in ethanol at 70° into a nonreducing
sirup, ethyl D-glucofuranoside. In one instance, Wolfrora and
Groebke reported (30) the isolation of ethyl l-thio-a-D-raannopyrano-
side in moderate yield by paxtial deraercaptalation of g-raannose di
ethyl dithioacetal.
There is no adequate explanation as to why path A or E is
observed with some sugars (D-galactose, D-mannose, D- or L-arabinose,
D-xylose and D-lyxose) while for others (D-glucose and D-ribose),
path D is observed. ' The 0-2 hydroxyl group has been shown to have
an effect in the case of D-glucose. The 1-thio-o-D-glucofuranoside
is readily formed from the dithioacetal, but 2-deoxy-D-arabino-hexose
dithioacetal gives only free sugar and unconverted dithioacetal
under the same conditions. In methanol, the methyl 2-deoxy-D-
arabino-hexofuranosides are readily formed from the dithioacetal,
in contrast to the behavior of the D-glucose dithioacetal. It is
not yet known whether pathway D-G' or pathway A-C is being observed
for the 2-deoxy-D-arabino-hexose system.
Work by Capon and Thaker (99) on the formation of aldo-
(99) B. Capon and D. Thaker, i b i d .. 87, 4199 (1965).
furanosides from the corresponding acyclic dialkyl acetals in aqueous
acid has suggested that the C-4 hydroxyl group of the D-glucose 39 derivative is much more nucleophilic than that of the D-galactose derivative and that both of these groups are able to compete suc cessfully with water present as a solvent. Thus, ring closure to the furanoside occurs in preference to the formation of the free sugar. This concept might be extended to the dialkyl dithioacetals.
For D-glucose dialkyl dithioacetals, the C-A hydroxyl group success
fully displaces a thioalkyl group at C-1 in competition with the
solvent (either alcohol or water) and the resulting product is a
l-thio-D-glucofuranosidc. With D-galactose and D-mannose deriva
tiv e s, the C-y^ hydroxyl group is , presumably, a weaker nucleophile
than the solvent, and cannot compete successfully with the solvent.
This results in the free sugar and a low yield of 1-thio-D-galacto-
furanoside and no 1-thio-D-mannofuranoside, respectively.
All the major products obtained by cyclization of the dithio
acetal in partial demercaptalation have a cis relationship of the
alkyl thio group and the hydroxyl (or 2-acetamido-2-deoxy) group at
0-2. A Corresponding effect has been noted for the 1-thioaldo-
pyranosides. Ethyl 2-acetamido-3,A,6-tri-0-acetyl-2-deoxy-l-thio-
a-D-glucopyranoside is resistant to the action of mercuric chloride
in hot, neutral methanol solution, whereas the p-D anomer is readily
converted into the p-D-glucopyranoside (83). Again, ethyl 1-thio-
p-D-mannopyranoside has been shown (79) to be resistan t to the action
of mercuric chloride in methanol. Both of these nonreactive 1-thio-
aldopyranosides have th is cis relationship. Conversely, whereas
dithioacetals of D-ribose afford the 1-thio-D-ribofuranosides 40 readily, those of Z-deoxy-D-erybhro-pentoso do not, but give (98) instead, the free sugar and unchanged dithioacetal.
The favored formation of (cis-1 ,2) -1-thioaldofuranoside is more difficult to explain. There seems at present no real ade quate explanation.
3. Synthesis from glycosyl halides
The first 1-thioglycoside to be recorded, phenyl 1-thio-p-
D-glucopyranoside, vias prepared by condensation of per-O-acyl glycosyl halide with a salt of a thiol (lOO), This reaction has
(100) Fischer and K. Delbruck, Ber., ^2, 1476 (1909). been used as a general synthetic method for acetylated alkyl and
aryl 1-thioglycosides (88,95,101-107). The high nucleophilicity
(101) C. B. Purves, J . /aner. Chem. Soc., 3619 (1929).
(102) 'J. T. Haskins, R. M. Hann, and C. S. Hudson, ib id .. 62, 1668 (1947).
(103) ü). K, Montgomery, N. K. Richtmyer, and C. S. Hudson, J . Org. Chem., 31, 301 (1946).
(104) L. Monti and G. Franchi, Ann. chim. (Rome), 936 (1962).
(105) B. Helferich, H. Grünewald, and ?. Lsngenhoff, Ber., 86, 873 ( 1953 ).
(106) B. Helferich and D. Tlirk, ib id .. 82, 2215 (1956); B. Helferich, D. Turk, and ?. Stoeber, ibid. . 89. 2220 (1956).
(107) J. Stanek, K. Malkovsky, M. Novak, and D. Petricek, Chem. Listy, 21, 1556 (1957); Collection Czech. Chem. Commun., 2J_, 336 (1958). 41 of sulfur facilitates the reaction particularly with aryl thiols
and it caji be conducted in acetone, in methanol or even in acetone—
water. Modification of older procedures have resulted in improved
yields and numerous examples of alkyl and aryl 1-thioglycosides have
been described. The 1-thioglycosidcs synthesized from glycosyl
halides possess the same ring structure as their glycosyl halide
precursors. In the D-glucose, D-galactose, D-ribose, and D-xylose
series, the products formed have the p~D configuration and the reac
tion presumably proceeds from the stable a-D-glycosyl halide by way
of a closed-ion intermediate, with participation of the C-2 acetoxy
group, to give the observed 1,2-trans related products. Although
the glycosyl halides usually react by a unimolecular process, the
high nucleophilicity of sulfur may, in certain cases, cause this
reaction to become bimolecular. The reaction between tetra-0-methyl-
û-D-glucopyranosyl chloride and thiophenolate anion in 1-propanol
has been shown to obey second order kinetics (108) and it probably
(108) A. J. Rhind-Tutt and C. A. Vernon, J . Chem. Soc., 4637 (1960).
constitutes a direct, bimolecular displacement of chloride ion with
inversion. The D-mannose analog, surprisingly, gives no 1-thio
glycoside in this reaction. 42
4., Synthesis from l-thioaldoses
A practical alternative synthesis of acetylated 1-thio- p-D-glucopyranosides, especially valuable when appropriate thiols
are not available, is S-alkylation of tetra-O-acetyl-l-thio-p-g-
glucopyranoside with alkyl bromides or iodides (109,HO). A series
(109) W. Schneider, R. Gille, and K. Eisfeld, Ber., 12U (1928).
(n o ) M. Cerny and J . Pao&k, Chem. Listy, j2 , 2090 (1958); Collection Czech. Chem. Commun., 2566 (1959).
of alkyl tetra-O-acetyl-l-thlo-p-D-glucopyranosides has been pre
pared in this way. One such reaction is shown as follows.
SH RBr______^ OAc + KgCO^ or NaOn AcO AcO OAc
iQ
Recently Stanek and coworkers ( ill) reported a b etter
(ill) J. Stanek, M. Sindlerova, and K. Cerny, Collection Czech. Chem. Commun., 297 (1965).
method to prepare l-thioaldopyranosides. The method involved a
modification of older procedures (100-109). Tri-O-acetyl-p-D-
xylopyranosyl thiouronium bromide ( j^ ) , prepared by the reaction A3 of tri-0-acetyl-û.-D->:ylopyranosyl bromide ( ^ ) and thiourea, on reductive cleavage by potassium pyrosulfite end subsequent
S-alkylation by a modified procedure (112) gave alkyl tri-0-
(112) K. Serny and J . Pacak, ib id ., 26. 208A (1961); M. Cerny, J. Stanek, and J . Pacalr, Monatsch, 2A, 290 (1963). acetyl-l-thio-p-D-xylopyranoside ($A). The desired 1-thioaldo- pyranoside (55) was obtained by subsequent deactylation of 5A. as shown on page
^ 0 / \ j '■“ '2 - > , O.A c AC..
OAc OAc
i l 44
1) Reduc::/c cleavafre i l OAc 2) S-e.lkylf.tion AcO ÔAc
Deacetylation
OH HO
OH
i l DISCUSSION OF RESULTS
Part I
As mentioned in the Historical Section (75-Ho) , there are quite a few methods to synthesize some 1-thiohexofuranosides but a general method is lacking. Often the yields of 1-thiohexofuranosides ob tained by p artia l demercaptalation of hexose diethyl d ithioacetals, are not good. In case of D-galactose diethyl dithioocotal the 1-thio-
furanoside as well as the free sugar is obtained. g-Mannose diethyl
dithioacetal gives the l-thiopyranoside and the free sugar on partial
demercaptalation. Our effort was thus directed to finding a suit
able blocking group to protect the C-5 and C-6 hydroxyl groups in
D-galactose diethyl dithioacetal. This could lead to improved yields
of the 1-thiofuranoside on subsequent partial demercaptalation of
the 5,6-blocked dithioacetal.
Several years ago (23), isolation of 2-methyl-1,3-oxathiolane
was reported by the reaction of methyl vinyl ether and ethylene
thioglycol in the presence of £-toluenesulfonic acid. Watanabe
synthesized (22) 2-methyloxazolidines by reaction of butoxyethyl
vinyl ether and ethanolsmines in the presence of mercuric benzoate.
Later Shostakovskii and coworkers (20,21) isolated l-O-(l-ethoxyethyl)'
2,3”0-ethylidene glycerol and 1,2;3,4-di-O-ethylidene pentaerythritol
as the major products in the reaction of ethyl vinyl ether with
45 46 glycerol and pentaerythritol, respectively, under acid catalysis.
These resu lts led us to investigate the reaction of alkyl vinyl ethers with D-galactose diethyl dithioacetal.
Reaction of alkyl vinyl ethers with D-galactose diethyl dithioacetal.—Equimolar quantities of D-galactose diethyl dithio acetal (^) and alkyl vinyl ether (7) were brought into reaction in R,R"dimethylformacide solution in the presence of £-toluene- sulfonic acid as catalyst at room temperature. On workup of the reaction mixture and removal of the starting material, a sirup was obtained, which was found to be mainly a iriixture of two products, by thin-layer chromatography. From this sirup, the major product
(R£=0.74) crystallized out partially on the addition of ether—
petroleum ether (b.p. 30-60°). The remainder of the major product
in the sirup was isolated by partition chromatography. The elemental
analysis of these major products, isolated by reaction with alkyl
vinyl ethers (ethyl vinyl ether, isopropyl vinyl ether, and tert-
butyl vinyl ether), corresponded to a mono-O-ethylidene derivative
of D-galactose diethyl dithioacetal. The physical data such as
melting point, optical rotation. Infrared spectrum, and X-ray
powder diffraction data obtained for each of the mono-O-ethylidene
derivatives were identical.
The structure of the mono-O-ethylidene derivative was
proved to be 5,6-0-ethylidene-D-galactose diethyl dithioacetal (57)
by periodate oxidation studies. 47
CH(S3t)_ GH(SEt) • I HCOH HCOH I I HOCH HOOH • + ROCH = CHg - 5> I HOCH HOOH I I HCOH H C -0 I I CH-CH CH^OH H gC -O
^ 52 a=02H -;(CH igCH-; (CH^i^C-.
Periodate oxidation.--A standard method for the determination of v ic in a l glycol groups in organic compounds is th e oxidation of a weighed sample by a known amount of periodate followed by a volum etric
(113) or a spectrophotometric (II4) determination of the excess
(113) J . M. Bobbitt, Adv. Carbohydrate Chem., 11, 1 (1956).
(114) J. S. Dixon and D. Lipkin, Anal. Chem., 26, 1092 (1954) . periodate. It is well known that the presence of an ethylthio
group in a molecule results in excess uptake of the periodate than
that required for the Malaprade type of oxidation, and the propor
tion may vary widely with concentration of oxidant and other experi
mental conditions (115,116). The reasons for this are still obscure.
(115) S. Okui, Yakugaku 2kisshi, 7^, 1262 ( I 965) .
(116) L. Hough and M. I. Taha, J. Chem. Soc., 3994 (1957). 48
Oxidation of the mono-O-ethylidene-D-galactose diethyl dithioacetal indeed resulted in excess uptake of the periodate.
Attempts to find the uptake of periodate to cleave vicinal glycol groups in the mono-O-ethylidene derivative by using D-galactose diethyl dithioacetal as the control, were also unsuccessful. The uptake of periodate in cases of mono-0-ebhylidene D-galactose di ethyl dithioacetal and D-ga3.actose diethyl dithioacetal varied with the i n i t i a l amount of sodium m etaperiodate so lu tio n added to the sample and the rates of oxidation were also different. In order to overcome this problem, the ethylidene derivative was desulfurized
to 1-deoxy-mono-O-ethylidene-D-galactitol by Raney nickel (W2 cata
lyst) in 95^ ethanol under reflux.
The desulfurized product, 1-deoxy-mono-O-ethylidene-D-
galactitol, on oxidation by sodium metaperiodate in a phosphate
buffer (pH 6.9) consumed two moles of periodate within half an hour.
There was no further consumption of periodate for an additional six
hours, as shown in the follow ing graph.
(moles)
Time (hr) 49
By periodate oxidation on a preparative scale, acetaldehyde vias isolated as its 2,4-dinitrophenylhydra%one in quantitative yield, from the distillate of the reaction mixture. The sirup obtained from the reaction mixture was hydi’olyzed with an aqueous acid solution. The sirup obtained after hydrolysis was identified
as D-glyceraldehyde (j^) by preparing the diinedone derivative.
These results conclusively show that the 1-deoxy-mono-O-ethylidene-
D-galactitol and mono-O-ethylidene-D-galactose diethyl dithioacetal
are l-deoxy-5,6-0-ethylidene-D-galactitol (j58) and 5,6-0-ethylidene-
D-galactose diethyl dithioacetal (^/), respectively.
CH(Sdt), CH3 I HCOH HCOH I Desulfurization ' HOCH ------HOCH I I HOCH HOCH I I HC-0 HC-0 » ^CH-CH, • ^CH-CH. H2C-O HgC-O^ ^
2 10- 4 pH 6-7
CHO CHO I I + CH3CHO H3O+ HCOH HC-0. + HCOgH I ' CH-CH. CHgOH H^C-O-"
12 50
The n&ss spectrum of 5,6-0-ethylidene-D-galaotose diethyl dithioacetal (57) confirmed these results. It showed a similar fragmentation pattern to those of hexose dithioacetals reported by DeJongh (117). The molecular ion peak at c/e 312 has an
(117) D. C. DeJongh, J. Org. Chem., 30, 1563 (1965). intensity of 13%, relative to that of the base peak at m/e 135 resulting from the cleavage at C-1—C-2 with charge retention on the dithioacetal carbon atom C-1, where it is stabilized by two sulfur atoms. The peak at m/e 87 having the relative intensity of 58% could be accounted for by cleavage between C-4—C-5 with charge re te n tio n on the C-5 as shown below.
+ HG===0
HgC -— - 0 ^ m/e 87
Reaction pathways.—It is noteworthy that yields of 5,6-0-
ethylidene-D-galactose diethyl dithioacetal (37) improved on
reaction of D-galactose diethyl dithioacetal (36) with ethyl vinyl
ether, isopropyl vinyl ether to teit-butvl vinyl ether (see Experi
mental) . In order to rationalize the increase in yield from ethyl
vinyl ether to teit-butyl vinyl ether and to understand the reaction
pathways, a more detailed study of the reaction between ethyl vinyl
ether and D-galactose diethyl dithioacetal (36) was undertaken.
The other major product (R^=0.65) of the reaction was isolated by
preparative thin-layer chromatography. The elemental analysis of 51 the crystalline product was in agreement with that of mono-Q-
(l-ethoxyethyl)-D-galactose diethyl dithioacetal. The product was considered most likely to be the 6-acetal, on the basis of the previous findings from this laboratory (2/+) on the reaction of alkyl vinyl ethers and methyl a-D-glucopyranoside under acid cataly
sis. It was found that acyclic vinyl ethers first react to give the
6-acetal, which undergoes further reaction to yield,methyl 4,6-0-
ethylidone-a-D-glucopyranoside.
In order to prove the structure of the monoacetal, 6-0-
(l-ethoxyetbyl)-D-galactose diethyl dithioacetal was synthesized
by the following route.
2,3,4,5-Tetra-O-acetyl-D-galactose diethyl dithioacetal was
prepared by the method of Wolfrom and coworkers ( l l 8 ) . The p o sitio n
(118) M. L. Wolfrom, J. L, Quinn, and 0. 0. Christman, J. Amer. Chem. Soc., 714 (1935).
of th e fre e hydroxyl group in th is compound was considered u n certain ,
since Leraieux and Bauer had reported (119) that the tetra-O^acetyl
(119) R. U. Lemieux and H. ?. Bauer, Can. J. Chem., 32, 362 ( 1 9 5 4 ) .
derivative of D-glucose diethyl dithioacetal, prepared by the
similar method had no free hydroxyl group on the C-6. This con
c lu sio n was based on m éthylation stu d ies on th is compound, which
indicated that it acts as if an hydroxyl group is available for reac
tion on C-2 or C-4. The nuclear magnetic resonance spectra of the 52 tetva-0-acetyl-D-galactose diethyl dithioacetal in deuterated dimethyl sulfoxide on 100 MHz instrument showed that the free hydroxyl group is on C-6. The chemical shift of methylene protons on 0-6 was at 3.720 , a triplet Hz; £,_oH“
5.8 Hz), which became a doublet ^=5 * § Hz, when the spectrum was recorded in deuterated dimethyl sulfoxide and traces of water..
The acetyl derivative, on reaction with equimolar amount of ethyl vinyl ether at low temperature under acid catalysis, yielded, after deacetylation, 6-0-(l-ethoxyethyl)-D-galactose
diethy] dithioacetal (^ ). Melting point and mobility on thin-
layer chromatography were identical with those of mono-0-(l-
ethoxyethyl)-D-galactose diethyl dithioacetal. Infrared spectra
were similar and the mixed melting point was undepressed. The
x-ray powder diffraction data were also identical.
The 6-acetal ( ^ ) , under acid catalysis underwent further
reaction to give the ethylidene derivative (5?) and D-galactose
diethyl dithioacetal (^) and unconverted starting material. The
progress of the reaction was followed by thin-layer chromatography.
This particular acid-catalyzed reaction shows intermediacy of the
6-acetal in the formation of 5,6-0-ethylidene-D-galactose diethyl
dithioacetal (^) in the reaction of alkyl vinyl ethers and the
dithioacetal (^6), On the basis of these results the following
mechanism and pathway for the reaction is proposed.
In the Course of the reaction, first, 6-0-(l-ethoxyethyl)-
B-galactose diethyl dithioacetal (^) is formed, which rapidly 53 undergoes further reaction to form the carbonium ion (^) on elimina tion of a molecule of an alcohol (a slow step). The carbonium ion then rapidly reacts with the adjacent hydroxyl group to give the ethylidene derivative (57)» The mechanism proposed also explains the increase in yield of 52 on reaction of D-galactose diethyl di thioacetal with ethyl to tert-butyl vinyl ether. The increasing
steric requirement of the R group in the 6-acetal (^) facilitates the formation of the carbonium ion (^) in the slow step and can
account for the increase in yield of 57« That the formation of car
bonium ion is the slow step in the hydrolysis of acetals has been
proved by many workers (120). The alcohols formed during the reac-
(120) S. H. Cordes, Progress Phys. Org. Chem., 1 (1967).
tion are ethanol, 2-propanol, and tert-butyl alcohol in the case of
ethyl, isopropyl, and tert-butyl vinyl ether, respectively. The secon
dary and tertiary alcohols are less reactive toward vinyl ethers than
are primary alcohols and thus in the case of isopropyl vinyl ether and
tert-butyl vinyl ether, the overall yield of the reaction is higher.
CH(SEt)2 HCOH HOCH 56 + a0CH=CHg ------HOCH 7 HCOH ihpO — CH-OR I CH_
60 54
60
H"
CH(S3t), GH(SEt)2 I HCOH HCOH I I HOCH HOCH . ' I HOCH HOCH I I HCOH HCOH I I H CHg ~ 0 “ CH-OH CHgO-CH 7 OR H b'H- CHo CH.
60a 60b -ROH
CH(SEt). i6 + CHjCHOR I HCOH I -H^ HOCH t ROCH=CHr HOCH I HC-OH I ^ + CHg - 0 - CH I CH,
-H'' 61 55
Formation of D-galactose diethyl dithioacetal (^) in the acid-
catalyzed reaction of the 6-acetal (^) is explained by protonation
of the oxygen adjacent to the C-6, to form 60a and subsequent
cleavage of the bond as indicated in 60a.
Partial demercaptalation of 5.6-0-ethylidene-D-galactose
diethyl dithioacetal (57).—5,6-0-dthylidene-D-galactose diethyl
dithioacetal (^ ) vias partially demercaptalated by mercuric
chloride and mercuric oxide in aqueous acetone to ethyl 5,6-0-
ethylidene l-thio-n-D-galactofurenoside (62). The reaction was
studied by using various amounts of mercuric chloride and mercuric
oxide and temperatures varying from 25 to 60°. The reaction was
also studied in a aprotic solvent, K,K-dimsthylformamide; herein
the reaction was slow and the formation of the free sugar could
not be prevented. The progress of the reaction was followed by
thin-layer chromatography. The best results were obtained when
only 0.3 molar equivalent of mercuric chloride and 5 molar equi
valents of mercuric oxide were used in aqueous acetone medium.
The experimental results obtained by using various amounts of
mercuric chloride and mercuric oxide at 35-40°, are tabulated
in Table 1, Initial experiments on the use of mercuric chloride
and cadmium carbonate instead of mercuric oxide for the partial
demercaptalation of 5,6-0-ethylidene-D-galactose diethyl dithio
acetal did not give good results, and hence a further study of
this reaction, using cadmium carbonate was discontinued.
The oi-D anomeric configuration for the ethylthio group 56
TABLE 1
PARTIAL DEMERCAPTALATION CE 5,6-0-ETHYLIDENE-
D-GALAGTOSE DIETHYL DITHIOACETAL (^7)
M ercuric M ercuric Y ield £ % oxide â ch lo rid e B. 5 1 - 62 ^ 63 - of ^
2 0.5 - m vs ^ 2 0
2 0.5 - m s -25
2.5 0.3 w 8 m 40-50
5 0.3 vw vs mw 70-75
5 0.1 m 8 vw 40
5 : 0.3 8 m m -20
2.5 ^ 0.5 m mw m -20
2.5 1 .0 w vw 8 >10
— Molar equivalent ( s), — 5,6-0-Sthylidene-D-galactose diethyl dithioacetal (57).., Rf=0.74 Ethyl 5,6-0-ethylidene-l-thio-a-D-galaotofuranoside (62) R^^O. 69 ~ 5,6-0-Ethylidene-D-galactofuranose ( ^ ) ...... R^=0.24-. — Visual estimation from tic spots. — N,N-dimethylformair.ide as the solvent. “ The re a c tio n m ixture at 55°.
was indicated by the synthesis of ethyl 5,6-0-ethylidene-l-thio-c-
5-galactofuranoside (^) by reaction of isopropyl vinyl ether and
ethyl-l-thio-a-D-galactofuranoside (^ ) , prepared according to the
method of Wolfrom and coworkers (121). The physical constants 57
(l2l) M. L. Wolfrom, P. McWain, R. Pagnucco, and A. Thomp son, J. Org. Chem,, 2£, (l964).
such as melting point, infrared spectra, nuclear magnetic resonance
spectra and x-ray powder diffraction data were identical.
0 Hgcia HgO OH \1 ______/ SC2H5 T OH OH 0 \ CH-CH. CH-CH
62 61
.(CH3)2CH0GH=CH.
OH
OH
The s p e c ific ro ta tio n of the two compounds were s lig h tly d iffe re n t
+69.2°, of the product obtained from 1? and +76.2° of
the product obtained from ethyl l-thio-a-B-galactofuranoside (64)),
due to the difference in proportions of two diastereoisomers resulting 58 from the creation of additional asymmetric center on carbon atom in the ethylidene group. The difference in proportions of two di astereoisom ers in the two compounds was in d icated by gas—liq u id chromatography of their trim ethylsilyl derivatives. No attempt was made to determine the specific rotations of the two diastereoisomers.
Although the yield of ethyl 5,6-0-ethylidene-l-thio-c-D- galactofuranoside (62) was more than 70^ (as shown by tic ) by partial demercaptalation of 5,6-0-ethylidene-D-galactose diethyl
dithioacetal (57). only yi% of the pure crystalline product was ob
ta in e d on is o la tio n by p a r titio n chromatography. Wolfrom and
coworkers (94) had reported 43^ yield of ethyl 1-thio-a-D-galacto-
furanoside (as its tetraacetate) by partial demercaptalation of
D-galactose diethyl dithioacetal. Several attempts to repeat this
work were not successful. The chromatographic examination of the
re a c tio n m ixture in d ic a te d the form ation of a small amount of eth y l
l-thio-a-S-galactofuranoside and D-galactose was isolated in 80-85% y ie ld .
Reaction of 3.4-dihydro-2H-pyran with methyl-c-D-glucopyrano-
side.—As mentioned in the Historical Section, vinyl etheis react
with primary, secondary, and also tertiary alcohols. Concurrently
with this work. Dr. S, Bhattacharjee and Dr. Anne Beattie (24),
formerly of this laboratory, attempted to study the selectivity of
reaction of alkyl vinyl ethers with primary and secondary hydroxyl
groups in methyl a-D-glucopyranoside. They isolated methyl 6-0-
(l-alkoxyethyl)-a-D-glucopyranoside (^) and methyl 4,6-0-ethylidene-
a-D-glucopyranoside (12). The ethylidene derivative (l2) was shown 59 to be formed by elimination of an alcohol molecule from the 6-acetal
(65) in the presence of an acid c a ta ly s t, as shown below. H OR I CH3-CHOCH2 CH^-CK0CH2
OCIL N
h i
OGH 0CH2 /
OH CH OGH OGH OH OH 77
It was thought that this latter process should not occur
with a cyclic vinyl ether such as 3,4“dihydro-2^-pyran and this
reagent might be preferred for such a preferential or selective
re a c tio n .
In the present work, equimolar quantities of methyl a-D-
glucopyranoside (1) and 3,4-dihydro-2H-pyran (^ ) were brought into
reaction, in N,N-dimethylformamide solution and under catalysis by
£-toluenesulfonic acid, for different reaction periods at room
temperature. After removal of the starting materials, the crude 60 reaction product was fractionated by preparative thin-layer chromatography. The major component, obtained (reaction period
4 hr) in a yield of 58^6 of the crude reaction product, was identified as methyl 6- 0-tetrahydro-2H -p y ra n -2-yl-a-D-gluco- pyranoside (67) on the basis of the following observations. On méthylation and subsequent hydrolysis the above compound gave
2 , 3 , 4 -tri-O-methyl-D-glucose identified by conversion to the known
2,3,4"tri-0-methyl-N-phenyl-p-D-glucopyranosylamine; this major
component was chromatographically identical with a compound obtained
from methyl 2 , 3 , 4 -tri-O-acetyl-a-D-gluoopyranoside by its reaction
w it h 3 , 4 -d ih y d r o -2H pyran followed by deacetylation. In some
experiments a portion (251^) of the sirupy reaction product crystal
lized. The low yield of crystals was probably due to the sirup
being a mixture of diastereoisomers since the acetal carbon (as shown
below) is asymmetric. It is accordingly established that
CHgOH
OH OCR.
OH 66 OH
3,4-dihydro-2H-pyran, reacts preferentially with the C-6 primary
hydroxyl group of methyl a-D-glucopyranoside. However, the reaction
is not as selective as is the tritylation reaction (122).
(122) B. Helferich and J. Becker, Ann., AAO. 1 (1924). 61
Part II
Starch acetals, most commonly known are those prepared by the reaction of starch with aldehydes. The starch acetals formed
in this manner are cross-linked, Rist and coworkers (27) prepared
starch acetals by the reaction of 3,4-dihydro-2H-pyran and wheat
starch in the presence of hydrochloric acid as the catalyst. The
objective was to prepare starch acetals without generating water
or forming crosslinks. Starch acetals ranging from D. S. (degree
of substitution) 0.1 to 2.6 were prepared.
With a similar objective in mind, we undertook a study of
the reaction of vinyl ethers, differing in polar and steric charac
ter, with starch followed by a further study of some of the properties
of the starch acetals obtained.
Among the vinyl ethers (Table 2) selected for the present
study, benzyl, diphenylmethyl, and phenyl vinyl ethers were not
available commercially and were, therefore, prepared in the labora
tory. l,2:3,4-Di-0-benzylidene-6-0-(l-methoxyphenylethyl)-c-B-
galactopyranose (^ ) and l,2:3,A-di-0-benzylidene-6-0-(l-diphenyl-
methoxyethyl)-G-D-galactopyranose { ^ ) were prepared by the reaction
of l,2;3,'4“di-0-benzylidene-a-D“galactopyranose with benzyl vinyl
ether and diphenylmethyl vinyl ether, respectively, under acid
c a ta ly s is .
By treating corn starch, dissolved in dimethyl sulfoxide,
with vinyl ethers in the presence of p-toluenesulfonic acid at room 62 TABLE 2
REACTION G? STARCH vJITH VINYL ETHERS
S ta r c h - OH + ROCH = CH. S ta r c h - 0 CHOR CH3
Moles of Reac. Reac. Y ield a D. S. vinyl eth. tem p., tim e, wt. Based Gravi Spectro- a per 162 g oc hr on m etric photoraet sta rc h ^ 0 method method
Methyl 0 20° 2 100 --- 2.0 20 0.50 100 0.11 0.10 0.09 2.0 20 2.5 119 0.60 -- 2.0 20 72 119 0.50 0.69 0.48 8.0 20 0.33 100 0.10 0.20 0.16 8.0 20 0.50 100 0.50 0.30 0.16 8.0 20 0.9 132 1.40 1.30 - 8.0 20 1.75 150 2.70 2.50 2.48 8.0 20 2 170 2.8 2.65 -
Benzyl 1.0 25° 6 100 0.04 _ 2.0 25 6 150 0.58 - - 3.0 25 6 168 0.78 -- A.O 25 3 190 1.65 - - 6.0 25 2 190 1.72 - -
Diphenyl- 1.0 25° 24 100 0.20 methyl 2.0 25 24 110 0.70 - - 4.0 25 3 120 1.05 - -■ 6.0 25 2 120 1.22 - -
Phenyl 0 50° 48 98 _ 1 30 24 100 0 -- 2 30 24 100 0.04 - - 4 50 48 100 0.07 -- 8 50 48 100 0.19 -- 12 50 48 105 0.54 - -
5 Expressed in gram per 100 g of starch. 63 temperature, products of various D. S. were obtained as shown in
Table 2, Methyl vinyl ether reacted to the extent of D. S. 2.8, while phenyl vinyl ether was found to be rather unreactive. Even
at higher temperatures and longer reaction periods, it reacted only
to the extent of D. S. 0.54. It was not possible to obtain very
high D. S. products by the reaction of benzyl and diphenyl vinyl
ethers because of the appearance of color (probably due to polymeri
zation of the vinyl ether) on longer reaction periods. In the case
of phenyl vinyl ether, on longer reaction periods or higher tempera
tures, there was no development of color in the reaction, but the
reaction product separated from dimethyl sulfoxide solution as a gel,
indicating the formation of a cross-linked starch acetal. The
product of D. S. 0.54 vias insoluble in any organic solvent.
Various methods for the isolation of the starch acetals were
studied. For methyl and phenyl vinyl ether it was preferable to
isolate low and intermediate D. S. products by dialysis of the
neutralized (sodium hydrogen carbonate) reaction mixture with sub
sequent freeze-drying. This procedure was not suitable with starch
products obtained from benzyl and diphenylmethyl vinyl ether because
of the fact that gummy insoluble (in water) products were obtained.
Ammonium hydi’oxide was then found to be a better neutralizing agent
than sodium hydrogen carbonate since it is difficult to eliminate
the latter from gummy materials. Drastic drying conditions led to
completely or partially insoluble products in most cases. This
could be due to hornification or due to the formation of some cross
links. It was found essential to dry the freeze-dried product 64 finally over potassium hydroxide under reduced pressure at 60°. The solubility of the starch acetals, being thus dependent on the process of isolation,or drying, was examined in a number of solvents. In
general, low D. S. products were hydrophilic; even more hydrophilic
than the starch. The high D. S. products from methyl vinyl ether
were organophilic. Some of the high D, S. starch acetals obtained
by the reaction of benzyl vinyl ether and diphenylmethyl vinyl
ether, were partially soluble in organic solvents and the remainder
of the insoluble product was in the form of a gel. This could be
due either to crosslinking or to some other physical modification.
Carbon analysis was not always a good method for ascertaining
the degree of substitution, especially for low D. S. material. To
verify the D. S. calculated on the basis of carbon analysis,
alternative methods were utilized for the starch acetals obtained
by the reaction of methyl vinyl ether and starch.
Also the high D. S. starch acetals, prepared by Dr. 3. S,
Bhattacharjee (formerly of this laboratory), by the reaction of
various alkyl vinyl ethers with amylose and amylopectin were estimated
spectrophotometrically. The comparative results of estimation of
D. S. on the basis of percent carbon, gravimetric method and
spectrophotometric methods is tabulated in Table 3. These involved
hydrolysis of the acetals to acetaldehyde which could be estimated
gravimetrically by preparing its 2,4-dinitrophenylhydrazone or
spectrophotometrically (123) by preparing its bisulfite complex,
(123) M. C. Bowman, M. Beroza, and F. Acree, Jr., Anal. Chem., 21, 1053 (l96l). 65
TABLE 3
D.S. OF STARCH ACETALS
D. S. M aterial Vinyl ether Based on Gravimetric Spectroph. % 0 method method,
Amylose Methyl vinyl 2.69 2.50 2.73 eth er
Ethyl vinyl 1.46 1.32 1.65 e th e r
Isobutyl vinyl 1.98 1.72 1.45 e th e r
Amylopectin Methyl vinyl 2.20 1.90 2.23 e th e r 66
Intrinsic viscosities as shown in Table 4» indicate that there had been no significant depolymerization during the reaction.
Blank runs of the reaction (without addition of the vinyl ethers) under identical reaction conditions and workup of the reaction, followed by d ia ly sis and freeze-d ry in g , showed th a t th ere was no appreciable loss of weight of the starch. This also indicated that there was no significant degradation of starch. Since low
D. S. products, other than those prepared from phenyl vinyl ether, did not show high viscosities compared to that of the starch used, formation of crosslinks by alkoxyl exchange (124) did not take place
(124) M. 0. Weaver, J. A. Martens, C. E. Russell, and C. E. Rist, unpublished results.
during their preparation or isolation. Methoxyl contents of some
of the acetals, as given in the Expe: rimental Section, also do not
support alkoxyl exchange. The diffe rence in intrinsic viscosities
of some starch acetals in different solvents may be due p a rtly to
changes in the molecular conformations of the polymers (125).
(125) V. S. R. Rao and J. P. Foster, Biopolymers, 1, 527 (1963).
The acetals prepared by the reaction of alkyl vinyl ethers
w ith a monosaccharide were shown (74) to be more e a s ily hydrolyzed
than were those prepared by the reaction of 3,4“dihydro-2H-pyran.
Although no systematic investigation has yet been made to ascertain
the relative stabilities of the starch acetals originating from 67
TABLE 4 ÇH3 Starch Acetals (Starch-O-CH-OR) - Physical Properties
I n tr in s ic PMT - Physical form, v isc o sity R D. S. OC s o lu b ility in N KOH
S tarch - >295° 0.87
Methyl 0.11 >295° Powder, soluble in water 0.95 0,6 205-210 Powder, soluble in N KOH 0.98 1.4 140 Powder, soluble in acetone 0.51 0 . 60k 2.7 99-104 Powder, soluble in acetone. dioxane 0.79f 2.8 95-104 Powder, soluble in dioxane. acetone, benzene 0.70É
Benzyl 0.04 >295° Powder, partly soluble in dioxane 0.58 178-180 Powder, soluble in dioxane 0.58 0.78 67-70 Powder, partly soluble in dioxane - 1.65 42-47 Sticky powder, partly sol uble in dioxane - 1.72 35-45 Gum, partly soluble in dioxane -
Diphenyl 0.20 245-250° Powder, soluble in dioxane w ■ methyl 0.70 150-160 Powder, partly soluble in dioxane - 1.05 62-70 Powder, partly soluble in dioxane - 1.22 - Gum, partly soluble in dioxane, chloroform -
Phenyl 0 > 295° Powder, soluble in water » 0.07 > 295 Powder, soluble in water - 0.19 > 295 Powder, insoluble in water and common organic so lv en ts - 0.54 > 295 Powder, swells in ether -
8. “ Polymer melt temperature ^ In acetone. £ In dioxane. É In benzene. 68 methyl vinyl ether and the tetrahydropyran-2-yl derivatives (126)
(126) Prepared in this laboratory by Dr. S. S. Bhat- ta o h a rje e . of starch, a few preliminary observations suggest that the former acetals are less stable toward residual catalyst acidity. The stability of starch acetals was improved by careful removal of acid catalyst during the workup of the reaction and by the addition of a small amount of sodium hydrogen carbonate to the starch acetals,
It is noteworthy that with increase in D. S. the PMT
(polymer melt temperature) of the starch acetals decreases as shown in Table 4. EXPERIMENTAL (l27)
P art X
(127) Melting points were determined with a Thomas-Hoover apparatus. Specific rotations were determined in a 2-dm polarimeter tube. Infrared spectra were measured by a Perkin-Elmer Infrared spectrometer. Hmr spectra were recorded with a Varian A-60 spectrom eter. Nmr spectra recorded with Varian A-lOO spectrometer were taken by John H. Lauterbach. Mass spectrum was recorded with the MS-9 spectrometer by C, R. Weisenberger. X-ray powder diffraction data give interplanar spacings in angstroms for Cuka radiation. Relative intensities were estimated visually: s, strong; m, moderate; w, weak; v, very. Parenthetical numerals indicate the order of the most intense lines; 1, most intense. Ascending thin-layer chromâtog- graphy was effected on 0.25-1.25 mm layers of Silica Gel G. (S. Merck, Darmstadt, Germany), activated at 110°, using the solvent system chloroform-acetone (1:1 v/v) with indication by iodine vapor (preparative) or sulfuric acid. Partition chromatography was effected by a column of silica gel (60-200, Grace Davison Chemical), using the solvent system chloroform—acetone (4:1 v/v). Paper chromatography was effected on i/hatman Mo. 1 paper in the solvent systems 1-butanol— ethanol—water (4:1:5 v/v). Tetramethylsilyl derivatives were prepared according to the method described by 0. L. Sweeley, R. Bent- ly, M. Makita, and W. W. Veils, J. Amer. Ghem. Soc., 2497 (1963). Gas—liquid chromatography was carried out by the &ckman GC-5 instrument. The column packing contained 15^ SE-52 silicon gum rubber (obtained from VJilkens Instrument and Research, Inc.) sup ported on Chromosorb-V, mesh 8O/IOO (obtained from Johns Manville Products Co.), Microanalytical determinations were made by V. N. Rond, Unless otherwise mentioned, solvents were evaporated under reduced pressure (water aspirator) below 35°.
Reaction of ethyl vinyl ether with D-galactose diethyl
dithioacetel (56).—D-Galactose diethyl dithioacetal (^ , 10.6 g.
0.0375 mole) was dissolved in dry N,N-dimethylformamide (40 ml.) Ethyl
vinyl ether (2.7 g, 0.0375 mole) was added followed by a catalytic
amount of ^-toluenesulfonic acid (lOO mg). The reaction mixture
69 70 was shaken for 2.5 hr at room temperature. Sodium carbonate (l g)
Vlas added to the reaction mixture and the mixture was shaken for
0.5 hr. The solvent was evaporated and after addition of chloroform to the residue, it was left overnight in the refrigerator. The small amount of starting material that separated was filtered from the chloroform solution. The sirup obtained on removal of chloro form consisted of two major components in the ratio 3:2, as indicated b y t i c (Rp=0.74 and 0.6 5 , respectively). On partition chromatog raphy two products were obtained from the sirup. The major product
(Rp=0.7A) was recrystallized from ethanol—petroleum ether (b.p. 30-
600), mp 122°, y i e l d 2.7 g , 23%. +71.3° ( c 1 .3 8 , chloroform);
i r : 2.83 (-0H), 3.40 (C-H), 6.91, 7.10, 7.26, 7.36, 7.47, 7.86,
8.05, 8.66, 9.05, 9.26, 9.5, 9.75, 9.9, 10.2, 11.36, 11.65, 11.97,
and 13.05 X-ray powder diffraction data; 11.47 s ( l ) , 6.87 vw ,
5.86 8 (3), 4.92 m, 4.66 m, 4.36 s (2 ), 4 . I 0 m, 3.69 w, 3.57 w,
3.43 VI, 3.29 w, 3.20 m, 3.07 w, 2.90 w, 2.75 m, 2.62 m, 2.57 m,
2.51 m, 2.22 m.
Anal. Galcd. for GigHgyOgS^: C, 46.I6; H, 7.69; S, 20.51.
Found: G, 45.96; H, 7.84; S, 20.20.
The minor product (Rf=0.65) was further purified by prepara
tive tic separation and was crystallized with difficulty from
chloroform—petroleum ether (b.p. 3 0 -6 0°), yield 300 mg, 2%.
+63.6° (chloroform); ir: 2.91 (O-H), 3.4 (C-H), 6.95,
7.25, 7.50, 7.90, 8.80, 9.15, 9.40, 9.80, 10.80, 11.30, 13.0 and
13.30p.m; X-ray powder diffraction data: 13.67 s (l), 11.39 m,
8.18 vw, 6.83 m, 5.24 w, 4.89 s (2), 4.6O m, 4.26 m, 4.09 m, 3.88 m, 3.70 s (3), 3.50 m, 3.21 m, 3.06 w, 2.82 w. 71
Anal. Galcd. for C, 46.92; H, 8.37; S, 17.87.
Found: C, 46.78; H, 8.09; S, 17.60
Reaction of isopropyl vinyl ether with D-gelactose diethyl dithioacetal (56).—D-Qalactose diethyl dithioacetal (^ , 10.6 g
0.0375 mole) was brought into reaction with isopropyl vinyl ether
(3.25 g, 0.0375 mole) under identical conditions as used for the reaction with ethyl vinyl ether. The sirup obtained after the workup of the reaction, crystallized partially on addition of ether— petroleum ether (b.p. 30-60^). The product showed identical mobil ity on tic to that of the product (R£=0.?4) obtained by reaction of the dithioacetal (^) and ethyl vinyl ether. The product was recrystallized from ethanol—petroleum ether (b.p. 30-60°) mp 122-23°, yield 1.8 g. From the remainder of the sirup, additional 3 g of this product was isolated by partition chromatography. The total yield was 41^. [a]^Q +71.7° (0 1,3, chloroform); ir: 2.83 (-0H),
3.40 (C-H), 6.91, 7.10, 7.26, 7.36, 7.47, 7.86, 8.05, 8.66, 9.05,
9.25, 9.5, 9.75, 9.9, 10.2, 11.36, 11.65, 11.97, and 13.05 pm; X-ray
powder diffraction data: 11.44 s (l), 6.91 vw, 5.86 s (3), 5.09 m,
4.69 m, 4.38 s (2), 3.94 m, 3.71 w, 3.60 w, 3.45 w, 3.33 vw,
3.20 w, 3.08 m, 2.94 w, 2.77 m, 2.62 w, 2.52 w.
Anal. Galcd. for C, 46.16; H, 7.69; 8, 20.51. Found:
C, 46.26; R, 7.60; S, 20.43.
Reaction of tert.-butvl vinvl ether with D-galactose diethyl
dithioacetal.--D-Galactose diethyl dithioacetal (^ , 10.6 g, 0.0375
mole) was brought into reaction with tert-butyl vinyl ether (3.75 g,
0.0375 mole) under identical conditions as used for the reaction 72 with ethyl and isopropyl vinyl ether. The major reaction product
isolated was recrystallized from ethanol—petroleum ether (b.p.
30-60°), mp 123°, total yield 6.7 g (56%), +74.2° (c 1.3,
chloroform); ir: 2.83 (-0H), 3.40 (C-H), 6.91, 7.10, 7.26,
7.36, 7.47, 7.86, 8.05, 8.66, 9.05, 9.25, 9.5, 9.75, 9.9, 10.2,
11.36, 11,65, 11.97, and 13.05 p.m; X-ray powder diffraction data:
11.62 8 (1), 6.85 vw, 5.86 s (3), 4.91 m, 4.69 m, 4.37 s (2),
3.92 m, 3.71 w, 3.58 w, 3.45 w, 3.32 vw, 3.22 w, 3.09 m, 3.00 w,
2.91 m, 2.76 m, 2.61 m, 2.57 m, 2.52 m, 2.22 w; mass sp e c tra l data:
m/e Ions m/e Ions
3 1 2 107 CH^CHgSfe-SH
233 M-CgH^S'-HgO y H(^ OH 105 189 f CHpO\ HCOH ... t OH = Ox 87 I ^CH-CH^j relative 177 M-135 ^ 2 " ° p e n a l t y
171 189-HgO CH-S-CH OH , re la tiv e in - 159 I77-H2O tensity, 55%
135 G&(SG2H^)2, intensity 100%
117 HOG&-GH ÇHp , re la tiv e 0^ ^0 intensity 8% F CH^
The relative intensities of the rest of the mass units recorded
above ranged between 10-15%.
Anal. Galcd. for G^2%4^5^2' °» 46.16; H, 7.69; S, 20.51 Found: G, 46.12; H, 7.94; S, 20.21. 73
Desulfurization of 5.6-0-ethylidene-D-galactose diethyl dithioacetal (57).—To a solution of 5,6-0-ethylidene-D-galactose diethyl dithioacetal (^ , 2 g) in 95^ ethanol (250 ml) , Raney nickel (30 g) was added and refluxed for 5 hr. The Raney nickel was filtered and extracted with hot ethanol. On evaporation of the solvent from combined filtrate and extract, a crystalline product
(58) was obtained which was recrystallized from ethanol—petroleum ether,; yield 870 mg (64$), mp 141-42° [a]^° -13.7° (o 1.0, ethanol); X-ray powder diffraction data: 10.97 s, 6.88 vw (3),
5.53 vw, 4.99 m, 4.71 s, 4.44 vs (1), 4.34 vs (2), 4.I4 m, 3.63 w,
3.47 m, 3.33 s, 3.21 m, 3.03 m, 2.87 s, 2.63 vw, 2.55 w, 2.46 m,
2.42 w, and 2.30 m.
Anal. Galcd. for C, 50.00; H, 8.33; Found: G, 50.05;
H, 8 .42.
Periodate oxidation.—In each case, sodium metaperiodate
solution (0.06M, 10 ml) was added to the compound (20-25 mg,
accurately weighed) in a buffered solution of pH 6.9 (phosphate
buffer, 10 ml) and the solution made up to 25 ml with water and
stored in the dark. A blank was worked concurrently. At intervals,
samples (2 ml) were transferred into a buffer solution (pH 6.9;
25 ml) and 20$ potassium iodide solution (l ml) and the liberated
iodine titrated (starch indicator) with O.OIN sodium-thiosulfate
so lu tio n . 74
Results of the periodate oxidation yere as follows:
Uptake of 10 (in moles) 4 10 20 min min 1.5 hr 1 hr 2 hr 4 hr 6 hr 9 hr
D-Galactose 5.1 5.1 5.18 5.6 5.6 5.8 “ diethyl dithio acetal (56)
5,6-0-Ethyli- 2.5 2.65 2.65 2.75 2.75 3.10 dene-D- g alactose diethyl dithio acetal (57) l-Deoxy-5,6-0- 1.9 2.0 2.0 2.0 2.0 2.0 2.0 ethylidene-D- galactitolw ~
Periodate oxidation of l-deoxy-5.6-0-ethvlidene-D-galactitol
(58).—To the solution of l".deoxy-5,6-0-ethylidene-D-galactitol
(58. 1.92 g, 0.01 mole) was added sodium metaperiodate (4.2 g, 0.021
mole) in water (lOO ml). The solution was maintained at pH 6-7 by
addition of sodium hydroxide solution (l N) and kept at room tempera
ture in the dark. After 2 hr, the solution was distilled at room
temperature under reduced pressure; the distillate was collected
into a cooled saturated solution of 2,4“dinitrophenylhydrazine in
2 N hydrochloric acid. The yellow precipitate obtained was filtered
and recrystallized from ethanol, yield 1.9 g (91%), mp 146°, identi
cal with that of the 2,6-dinitrophenylhydrazone of acetaldehyde.
The resid u e was e x tracted with chloroform . A siru p was obtained on
removal of the solvent from the dried ex'tract (sodium sulfate),
The siru p was then tre a te d w ith d ilu te s u lfu ric acid (0.05 N, 10 ml) 75 and kept overnight at room temperature. After removing the acid, the solution was evaporated to dryness. The dimedone derivative was ob tained from the sirupy residue by the standard method, mp 196°,
[a]^g +207 (a 1.2, ethanol); mp 198° and [o.]^^ +210 (ethanol) lit.
(128) for the dimedone derivative of D-glyceraldehyde. } : ______(128) A, S. B erlin and C. B rice, Can, J . Ghem,, 24» 85 (1956).
Preparation of 6-0-(l-ethoxyethyl)-D-galactose diethyl dithio
acetal (to).—2,3,4,5-Totra-O-acetyl-D-galactose diethyl dithioacetal
was prepared by th e method of Wolfrom and coworkers ( l l 8) ; mp 97°.
The nmr (Me2S0-d^) was recorded by Vai'ian-HAIOO and chemical s h if ts
were assigned by spin decoupling. 1.54 & ( t , J=7 Hz, -SGHgCHj), 1.52 &
( t , J = 7 Hz, -SG H gC H ) 2 .3 5 -2 .4 6 (4-OCOGH^), 2.85-3.16 (m, ^(SCI^CH^)^) ,
3.72 6 (t, ^=5.8 Hz, ^^=5.8 Hz, -GH^OH; it became a doublet in
the presence of HgO), 4.23 6 (d, 2~8 Hz, GH(8825^)2, 5.51-5.3 ^
(m, H-5 and -GH2OH), 5.5 6 (g, 2=8 Hz, J 2 3=2.5 Hz, H-2) , 5.66 6
(a, i 3^^=8 Hz, J^^5=2.5 Hz, H-4) , 6.0 6 (g J^^^=8 Hz, ^ ^ 2 .5 Hz, H-3).
To the solution of the tetra-O-acetyl derivative (2 g) in
chloroform (20 ml) was added ethyl vinyl ether (0.5 g), followed
by the addition of p-toluenesulfonic acid (lO mg). The reaction
mixture was kept below 10° for 15 min. After washing the reaction
mixture with sodium hydrogen carbonate solution, the organic layer
was dried (sodium sulfate) and evaporated to a sirup. The ir of
the sirup showed the absence of the free hydroxyl group. The sirup
dissolved in methanol (lO ml) was treated with 0.5 N sodium
methoxide solution (l ml) and kept overnight below 5°. It was 76 finally neutralized by Ambcrlite IR 120(H^) resin. After removal of the resin, the solution was evaporated. The product obtained was recrystallized from chloroform—petroleum ether (b.p. 30-60°), mp,
113°; yield 400 mg (25%). Ir: 2.90 (-0H), 3.37 (C-H), 6.92,
7.25, 7.50, 7.85, 8.75, 9.15, 9.40, 9.80, 10.75, 11.25, 11.6, 13.00, and 13.3 p-m. X-ray powder diffraction data: 13.67 s (l), 11.39 m,
8.18 vw, 6.83 m, 5.24 w, 4.89 s (2), 4.60 m, 4.26 m, 4.09 m, 3.88 m,
3.70 s (3), 3.50 m, 3.21 w, 3.06 w, and 2.82 w.
Anal. Galcd. for C^^H^QO^Sg: G, 46.92; H, 8.37; S, 17.87.
Found: G, 47.14; H, 8.53; S, 17.63.
Acid catalyzed reaction of 6-0-(l-ethoxvethvl)-D-galactose diethyl dithioacetal (6o).—To the solution of 6-acetal (60, 50 mg) in methylene dichloride (50 ml), was added p-toluenesulfonic acid
(3 mg). The reaction was followed by tic. After 1.5 hr, there were only traces of the 6-acetal (6o) detected (Rf=0.65) but two
o ther major compounds were p resen t (R^=0.74 and Rp=0). These two
compounds were found to be 5,6-0-ethylidene-p-galactose diethyl
dithioacetal and D-galactose diethyl dithioacetal, respectively,
by tic comparison with authentic samples.
Partial demercaptalation of 5.6-0-ethylidene-D-fralactose
diethvldithioacetal (57).—5,6-0-Ethylidene-D-galactose diethyl
dithioacetal (57., 1.40 g, 0.0045 mole) was dissolved in a solution
of acetone (15 ml) and water (20 ml) by warming on a water b ath .
The solution was brought to 35° and freshly prepared yellow mer
curic oxide (4.8 g, 0.0225 mole) was added. To this heterogeneous
mixture, mercuric chloride (406 mg, 0.0015 mole), dissolved in 77 water (lO ml), was added dropwise, while stirring at 35°. The
reaction mixture was stirred for 24. hr at 35°. After this period
th ere was a very sm all amount of the s ta r tin g m ateria l l e f t in the
reaction mixture as indicated by tic. Pyridine (20 ml) was added
and the reaction mixture was kept below 10° for several hours.
The mixture was filtered and washed with acetone and water. The
combined filtrate was evaporated in the presence of sodium carbonate.
The residue was extracted with ethyl acetate. The extract was fil
tered over Celite and dried sodium sulfate. The sirup obtained
after removal of the solvent from the extract was a mixture of two
components along with little unconverted starting material. The
major component (Rf=0.69) was separated by partition chromatography.
The compound obtained was recrystallized from ether—petroleum ether
(b.p. 30-60°), mp 80-81°. The gas chromatography of the trimethyl-
silyl derivative indicated it to be a mixture of diastereoisomers
approximately in the ratio 9:1. As the two peaks wore not completely
resolved it was not possible to find the exact ratio. Yield 9.81 g
(37%), [o]^Q +69.2° (o 1.26, chloroform), ir; ^max 2.90 (OH) , 3.43
(C-H), 6.90, 7.04, 7.90, 8.23, 8.68, 9.08, 9.28, 9.8-10 (broad band),
10.25, 10.74, 11.00, 11.70, 12.93, 13.3, and 13.7 ^im; nmr (CDGI3);
1.2-1.53 Ô (m, -CH2-CH3 , CH-CH^), 2.756 (a , J=7 Hz, -SGHgCHj),
3.506 and 4.O8 Ô (2, “OH; signals disappeared in the presence
of DgO), 3.85-4.5 6 (m, H-1, H-2, H-3, H-4, H-5, and CH-CH^),
5.3-5.5 6 (mij C-6 methylene protons); X-ray powder diffraction
data; 10.21 s (3), 8.39 w, 5.15 s, 4.64 vs (2), 3.89 m, 3.65 vs (l), - 78
3.50 m, 3.29 s , 3.13 vi, 2.99 w, 2.87 s , 2.60 m, 2.54 m, 2.47 m,
2.33 VI, 2.29 vj, 2.17 m, 2.05 m, 1.97 m.
Anal. Calcd. for S: C, 48.00; H, 7.20; S, 12.80.
Found: C, 47.77; H, 7.39; S, 12.94.
Synthesis of ethyl 5.6-0-ethylidene-l-thio-c-D-galacto- furanoalde (62) by reaction of isooropyl vinyl ether and ethyl-1- thio-a-D"g8lactofuranoside (64).—Ethyl l-thio-a-D-galactofuranoside
(64. 2.2 g , 0.01 m ole), prepared according to th e method of Wolfrom
and coworkers (l2l ) , was dissolved in N,N-dimethylformamide (8 ml).
To this solution was added isopropyl vinyl ether (0.8 g, 0.01 mole)
followed by the addition of £-toluenesulfonic acid (40 mg). The
reaction mi±Lure was shaken for 2.5 hr. After neutralizing the
acid with sodium carbonate, the solvent was evaporated. The sirup
obtained showed one major spot (Rf=0.69) on tic. The major product
was isolated in crystalline form by partition chromatography. It was
recrystallized from ether—petroleum ether (b.p. 30-60°), mp 81°.
The gas chromatography of the trimethylsilyl derivative indicated
to be a mixture of diastereoisomers approximately in the ratio 13:1.
As the two peaks were not completely resolved, it was not possible
to find the exact ratio. Yield 0.60 g (27^), +76.6° (c 0.84,
chloroform), ir: 4^Br 2,93 (oH), 3.43 (C-H), 6.90, 7.04, 7.90,
8.23, 8.68, 9.08, 9.28, 9.8-10 (broad band), 10.25, 10.74, 11.00,
11.70, 12.90, 13.30, and 13.70 ;im; nmr (CDCl^): 1.2-1.53& (m, GHg-CH^
CH-CH^), 2 .7 5 66(g J=7 Hz, -S-CH^-GH ) , 3.48 6 and 4.055(2 - OH;
signals disappeared in the presence of D2O), 3.85-4.55 (m, H-1, H-2,
H-3, H-4, H-5, and CH-CH^) and 5.3-5.5 6(m, 0-6 methylene protons); 79
X-ray povider diffraction data; 10.32 s (3), 7.30 v, 5.18 m, 4.61 vs
(2), 3.88 vj, 3.70 vs (l), 3.47 m, 3.29 s, 3.10 vw, 2.99 w, 2.87 s,
2,60 m, 2.63 m, 2.46 m, 2.33 w, 2.28 w, 2.17 m, 2.04 w, 1.96 m.
Anal. Calcd. for G^QH^gO.S: C, 48.00; H, 7.20; S, 12.80.
Found: C, 48.26; H, 7.08; S, 12.85.
Preparation of methyl 6-0-(tetrehvdro-2H-pvran-2-yl^-a-
D-glucopyranoside (67),—Methyl c-D-glucopyranoside (lO g) was dissolved in dry N,N-dimethylfoi’inairiide (250 ml). To this solution was added 3,4-dihydro-2H-pyran (5.0 g, 1:1.1 molar ratio) and £- toluenesulfonic acid (lOO mg). The mixture was stirred in a closed
fla sk fo r 4 hr a t room tem perature. The acid was n e u tra liz e d w ith
aqueous ammonia. The sirup obtained on removal of N,N-dimethylforma-
mide was thoroughly mixed with chloroform and unchanged methyl
a-D-glucopyranoside separated. The chloroform solution was concen
trated to a sirup (3.8 g) which showed one major spot along with
several minor spots by tic. The major reaction product was isolated
as a sirup by preparative tic, yield 2.2 g. A portion (25%) of this
sirup (probably a mixture of diastereoisomers) crystallized with
difficulty from ethyl acetate; mp 170°, [a]^p +40° (0 1.0, chloro
form); X-ray powder diffraction data; 13.81 s (3), 7.29 m, 6.75 m,
6.13 w, 5.62 vs (1), 5.27 vs (2), 4.54 s, 4.09 m, 3.97 m, 3.74 m,
3.47 w, 3.28 vw, 3.19 w, 3.03 s, 2.89 w, 2.83 w, 2.69 w, 2.50 m,
2.43 w, 2.35 w, and 2.29 w.
An^. Galcd. for C, 51.79; H, 7.91. Found;
C, 52.10; H, 7.72. 80
Conversion of methyl 6-0-(tetrahydro-2H-pyran-2-yl)-c-D- glucopyranoside to 2,3,A -tri-0-methyl-N-phenyl-g-D-glucopyranosyl- amine.—Methyl 6-0-(tetrahydro-2H-pyran-2-yl)-a-D-glucopyranoside
(67. sirup, 2 g) was dissolved in methyl iodide (10 ml) and silver oxide (10 g) was added. The mixture was shaken for 24 hr at room temperature (or alternatively refluxed for the same time), filtered and concentrated to a sirup. The méthylation procedure was repeated
(2-3 times) until the resulting sirup showed no hydroxyl absorption in its infrared spectrum. The methylated product was hydrolyzed with 1 N sulfuric acid for 10 hr under reflux. The evaporation of
the neutralized barium carbonate solution afforded a sirup (1.8 g)
which was homogeneous by paper chromatography. A portion (200 mg)
of the above sirup was dissolved in methanol (10 ml) followed by
the addition of freshly distilled aniline (lOO mg) and refluxed for
3 hr. On evaporation, the product crystallized and was recrystal
lized from methanol, yield 150 mg, mp 145-46° undepressed on admixture
with authentic (129) 2,3,4-tri-O-methyl-N-phenyl-p-D-glucopyranosyl-
(129) Obtained through the courtesy of S, Kirkwood, Uni versity of Minnesota, St. Paul.
amine. The X-ray powder diffraction data (I30) were identical with
(130) M. L. Wolfrom, A, Thompson, and A. M, Brownstein, J. Amer, Ghem, S o c,, 80, 2015 (1958),
those of a known specimen, [a] ^ -100° (c 1,0, ethanol), lit, (I3I) -103° (ethanol). 81
(131) J. D. Geerdes, B. A, Lewis, and F. Smith, ibid., 79. 4209 (1957).
Preparation of methyl 6-0-(tetrahydro-2H-pyran-2-yl)-a-D- glucopyranoside from methyl 2,3,4~tri-0-aoetyl-a-D-glucopyranoside.—
Methyl 2,3,4-tri-O-acetyl-a-D-glucopyranoside (200 mg) prepared according to the method of Helferich and coworkers (132), was dis-
(132) B. Helferich, H. Bredereck, and A. Schneidmllller, Ann., 458. I l l (1927) .
solved in diethyl ether (lO ml) to which p-toluenesulfonic acid
(10 mg) and 3,4-dihydro-2H-pyran (0.5 ml) were added. The mixture
- was stirred for 30 min and the completion of the reaction was indi
cated by tic. After being neutralized with sodium carbonate and
filtered, the filtrate was concentrated to a sirup and dried. This
sirup (210 mg) was dissolved in methanol (10 ml) to which was added
0.5 N sodium methoxide solution (l ml). The mixture was kept at
room temperature for 45 min with occasional shaking. After being
treated with Amberlite IH-120 (H ), the methanolic solution was con
centrated to a sirup which was chromatographically (thin-layer)
Identical to that of the major reaction product obtained by the
reaction of methyl a-g-gluoopyranoside with 3,4-dihydro-2H-pyran as described above. 82
Part II (133)
(133) Corn starch (Pearl type), furnished by the Northern Regional Research Laboratory, U. Department of Agriculture, Peoria, Illinois, was dried at 110 for 8 hr and then at 65 , under reduced pressure over calcium chloride and potassium hydroxide, for another 20 hr, to obtain a moisture content of 0.2 to 0.5%. Reagent grade dimethyl sulfoxide (anhydrous), dried over a molecular sieve, was used. Intrinsic viscosities were determined at 28° with Oswald-Gannon-Fenske No, 100 viscometers. Samples were dissolved in N potassium hydroxide solution, acetone, or other organic sol vents depending on the solubility. Samples (between 0.100 to 0.200 g) were dissolved in 50 ml of the suitable solvent and lower concentrations were obtained by dilution. Polymer melt tempera tures (PMT) were recorded on a Fischer Scientific melting point apparatus. Samples were sandwiched between microscope cover glasses and heated at maximum rate to near the melting range. The temperature at which the sample was soft enough to flow when the upper cover slip was pressed down with a spatula is given as the PMT. A Beckman DU Spectrophotom eter was used fo r determ ining the D.S. of starch acetals by the spectrophotometric method.
Synthesis of l,2;3,4--di-0-benzlyidene-6-0-(l-methoxy- phenylethyl)-a-D-galactopyranose (68).—l,2;3,4“Di-0-benzylidene-a-
D-galactopyranose (0.4-76 g, 0.0012 mole) prepared according to the
method of Pacak and 6erny (134) was taken in benzene (15 ml). To
(134) J • ]^oak and K. Cerny, Collection Czech. Chem. Commun., 28, 541 (1963).
this was added benzyl vinyl ether (O.4OO g, 0.003 mole) prepared
by transvinylation of benzyl alcohol (37), followed by the addition
of E.-toluenesulfonic acid (20 mg). The reaction mixture was shaken
for 15 min, when it became homogeneous. After being allowed to
stand at room temperature for 1 hr, the acid was neutralized with
sodium hydrogen carbonate aqueous solution and washed with water. 83
On removal of benzene under reduced pressure, the sirup showed no hydroxyl group as indicated by ir. On tic (Silica Gel G solvent— chloroform:petroleum ether (b.p. 30-60°) in a ratio of 7:3 v/v).
One major sp o tv ith a tra c e amount of another component could be observed after double development. The major component was iso lated by preparative tic. It was recrystallized from ethanol; yield 0.156 g, mp 105°, -86.2° (c 1.0, chloroform); %-ray powder diffraction data (127): 14.26 m, 10.53 s (l), 6.33 m,
5.72 s, 5.03 s (3), 4.78 m, 4.65 m, 4.46 s (2), 4.21 w, 4.02 w,
3.93 s, 3.53, 3.38 w, 3.24 w, 3.14 m, 3.05 w, 2.93 w, 2.76 w,
2.57 w, 2.44 w, and 2.32 w.
Anal. Galcd. for 71.01; H, 6.12. Found:
C, 70.66; H, 6.34.
Synthesis of diphenvlmethyl vinvl ether.—The modified
method (37) of vinylation of alcohol by acetylene was used. Diphenyl-
carbinol (25 g) was taken in a tube and melted on an oil bath. To
this was added potassium hydroxide (2 g) dissolved in methanol. The
m ixture was heated to 185-195° and acetylene was passed fo r 90 min
when a blue-orange color developed the reaction mixture was cooled.
Benzene was added to the cooled reaction mixture and the insoluble
precipitate was filtered off. Benzene was evaporated from the fil
trate and the residual oil was distilled under reduced pressure.
The fraction collected at 116°/1.5 mm showed no hydroxyl group as
indicated by ir; yield 15 g (60.8^); mp -24°; n^g 1.5703;
JO = C, , 4.15 Ô (a i, Hz, =2 Hz, HJ , (AgCHO-^ K ' 84
4 . 4 5 6 ( a Ja,o=15 Hz, ^ = 2 Hz, 5 . 9 3 5 ( s ,
6.58 ^ (a J”a,b , =7 Hz, J ~a,o =15 Hz, H a), 7.41 & (s 10, benzene p ro to n s),
Anal. Calcd. for 0, 85.71; H, 5.67. Found:
0 , 85.90; H, 6.80.
Synthesis of l,2:3,4-di-0-benzylldene-6-0-(l-diphenyl-
methoxyethyl)-a-D-galactopyranose (69).—1,2:3,4-Di-Q-benzylldene-
e-D-galactopyranose (0.24 g, 0.00062 mole) was taken in benzene
(15 ml) to which diphenylmethyl vinyl ether (0.31 g, 0.002 mole)
and p-toluenesulfonic acid (lO mg) were added successively. The
reaction mixture was shaken occasionally and the progress of the
reaction was followed by tic (chloroform: hexane in a ratio of 7:3
v/v). The reaction was almost complete after 2 hr. The product
was separated from unreacted vinyl ether and diphenylcarbinol by
preparative tic. The product obtained was recrystallized from ethanol
mp 136°; yield 0.100 g (28%), [a]^^ -28° (c 1.0, chloroform);
ir did not indicate presence of any hydroxyl group; X-ray powder
diffraction data (127): 15.64 w, 12.19 s, 9.61 s, 8.47 m, 7.25 w,
5.93 s, 5.59 s, 5.15 vs (1), 4.99 vw, 4.81 vs, 4.53 vs (3), 4.20 vs
(2), 3.86 w, 3.50 m, 3.36 w, 3.43 m, 3.06 w, 2.96 w.
Anal. Galcd. for G» 74.16; H, 6.00.
Found: 0, 74.40; H, 6.21.
Reaction of starch with vinvl ethers.—Corn starch (5 g)
was gelatinized in dimethyl sulfoxide (125 ml) by stirring at 95°
for 1 hr in a stoppered flask. The mixture was then cooled to
the desired temperature (see Table 2) and p-toluenesulfonic acid 85
(0.200 g) vjas added followed by the addition of vinyl ether. Stir ring was continued magnetically throughout the reaction period. In the case of the reaction with methyl vinyl ether, products of low
D. S. were precipitated by pouring the reaction mixture into methanol
containing a small aniount of sodium hydroxide. The precipitate was
washed thoroughly with methanol by stirring in a Wai’ing Blendor,
filtered, and washed again. In the case of the other vinyl ethers,
the low D. S. products were obtained by pouring the reaction mix
ture into dilute ammonium hydroxide solution. The solution was
freeze^dried after being dialyzed.
Products of high D. S. were precipitated by pouring the reac
tion mixture into water containing sodium hydrogen carbonate (:iust -
slightly more than required for neutralization) or into dilute
ammonium hydroxide solution. The precipitate or gummy solid was
washed thoroughly with water and then dried (potassium hydroxide)
under reduced pressure. The dry product was washed several times
with ether to remove adhering unreacted vinyl ether.
Finally, all the products were dried (over calcium chloride
and potassium hydroxide) under reduced pressure at 60°.
Analyses of methoxyl content of starch acetals of D. S. l.A,
and 2.7, obtained by the reaction of methyl vinyl ether were as
follow s.
(1) Anal, calcd. for D. S. 1.4: 17.8^, OCH^, Found:
1 8 .7 % , OCH3 .
(2) Anal, calcd. for D. S. 2.7: 26.2% , OCH^. Found:
2 6 .8 % , OCH3 . 86
Determination of degree of substitution.—Gravimetric method. A small quantity (O.l to 0.2 g) of the sample was placed in a 50-ml reaction flask to which 10^ sulfuric acid (20 ml) was added, the mixture was refluxed for 30 min, and then distilled into a saturated solution of 2,4"dinitrophenylhydrazine in 2 N hydrochloric acid. The all-glass apparatus described by Giang and Schecter (135) ,
(135) P. A. Giang and M. S. S checter, J . Agr. Food Chem., 6 , 845 (1958). permitting refluxing and distillation without transfer, was used in
this determination.
The crystalline acetaldehyde 2,4-dinitrophenylhydrazone
was transferred quantitatively to a sintered-glass funnel, washed
successively with dilute hydrochloric acid, and water, dried, and
weighed. From th e amount of hydrazone th e D. S. of th e sta rc h a c e ta ls
were calculated by using the following formula.
Wt. of DNP d e riv . x 162 D. S. = 224 X wt. of the sample - mol. wt of vinyl ether X wt. of DNP deriv.
Spectrophotom etric method. The sample (O.OlO to 0.050 g)
was hydrolyzed as in the previous method and the acetaldehyde
formed was distilled into a cooled 2% sodium bisulfite solution (50 ml),
The bisulfite solution was diluted to 100 ml by 2% sodium bisulfite
solution. An amount of 5 ml of this solution was diluted to 50 ml
with distilled water. To 1 ml of this mixture was added, with
swirling, 8 ml of cold sulfuric acid—cupric sulfate reagent in a 87 test tube partly immersed in an ice bath. The p-phenylphenol reagent (0.2 ml) was added in a similar manner. These reagents
■were prepared as described by Giang and Smith (136) . The tube
(136) P. A. Giang and P. F. Smith, J . Agr. Food Ghem., 4 , 623 (1956). was removed from the ice bath and allowed to stand in the dark at room temperature for 1 hr. The tube was heated in a water bath
at 100° for 90 sec, then returned to the dark for 30 min to adjust
to room temperature. With distilled water in the reference cell,
the absorbance of the violet color was determined at 572 nm. A
blank was worked co ncurrently.
These methods were standardized by using crystalline 4,6-0-
ethylidene-D-glucopyranose and methyl 4,6-0-ethylidene-2,3-0-oxydi-
ethylidene-a-D-glucopyranoside which were prepared according to
literature methods (137,138). The comparative results obtained are
(137) R. Baker and D. L. MacDonald, J. Amer. Chem. Soc., 2301 (I960) .
(138) H. Appel, W. N. Haworth, S. G. Cox, and F. J. Llewellyn, J. Chem. Soc., 793 (1938).
tabulated in Table 2. The D. S, of the starch acetals were calculated
by using the following formula,
162 X wt, of acetaldehyde D. S, — 44 X wt. of sample - Mol. wt. of vinyl/ether x wt. of acetaldehyde SUMMARY
P art I
1. A mono-O-ethylidene derivative of D-galactose diethyl dithioacetal vias obtained by reaction of D-galactose diethyl di thioacetal and alkyl vinyl ethers (ethyl, isopropyl, and tert- butyl vinyl ether) under acid catalysis.
2. The ethylidene d eriv ativ e was shown to be 5,6-0- ethylidene-D-galactose diethyl dithioacetal by periodate oxidation studies. The ethylidene derivative was desulfurized by Raney nickel. The periodate oxidation of the desulfurized product
showed it to be l-deoxy-5,6-0-ethylidene-D-galactitol.
3. The mass spectrum of 5,6-0-ethylidene-D-galactose
diethyl dithioacetal also confirmed its structure.
4-. The reaction pathway for the formation of 5,6-0-ethyli
dene-D-galactose diethyl dithioacetal was shown to be as follows.
Alkyl vinyl ethers first react with D-galactose diethyl dithioacetal
to give 6-0-(l-alkoxyethyl)-D-galactose diethyl dithioacetal, which
undergoes further rearrangement on elimination of a molecule of
alcohol under acid catalysis to give the 5,6-0-ethylidene derivative,
5. Partial demercaptalation of 5,6-0-ethylidene-D-
galactose diethyl dithioacetal was studied by mercuric chloride
and mercuric oxide in aqueous medium and also in N.N-dimethvl-
formamide. 88 89
6. Ethyl 5,6-0-ethylidene-l-thio-a-D-galactofuranoside was synthesized by partial demercaptalation of the ethylidene deriva
tiv e in aqueous medium. The anomeric configuration was shown to be
a-D by the synthesis of the same compound on reaction of isopropyl
vinyl ether and ethyl-l-thio-a-D-galactofuranoside under acid
c a ta ly s is .
7. The selectivity of reaction of 3,A-dihydro-2H-pyran be
tween primary and secondary hydroxyl groups in. methyl a-D-gluco
pyranoside was studied. It was found that this reaction is not as
selective as the tritylation reaction but the dihydropyran does
react preferentally with primary hydroxyl groups.
8. Methyl 6-0-(tetrahydro-2H-pyran-2-yl)-a-D-glucopyranoside
was synthesized by the reaction of methyl a-D-glucopyranoside with
dihydropyran. The structure was proved by méthylation studies.
P art I I
1. Benzyl vinyl ether diphenyl vinyl ether, and phenyl
vinyl ether, required to prepare starch acetals, were synthesized.
2. 1,2:3,A-Di-0-benzylidene-6-0-(l-methoxyphenylethyl)-a-
D-galactopyranose and 1,2:3,4-di-0-benzylidene-6-0-(l-diphenyl-
methoxyethyl)-a-D-galactopyranose were synthesized by the reaction
of 1,2:3,<4.-di-0-benzylidene-D-galactopyranose with benzyl vinyl
ether and diphenylmethyl vinyl ether, respectively, under acid
c a ta ly s is .
3. Starch acetals of various degrees of substitution were
prepared by the reaction of corn starch with methyl vinyl ether. 90 benzyl vinyl ether, diphenylmethyl vinyl ether, and phenyl vinyl ether, under acid catalysis.
4. A method for determining the degree of substitution of the starch acetals, so prepared, -was established. The method was based on the gravimetric or spectrophotometric assay of the acetaldehyde liberated from them by acid hydrolysis. BIBLIOGRAPHY
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