This dissertation has been microfilmed exactly as received. M ic 61-912
HANESSIAN, Stephen. DEOXY AND BRANCHED- CHAIN SUGARS.
The Ohio State University, Ph.D., 1960 Chemistry, organic
University Microfilms, Inc., Ann Arbor, Michigan DEOXI AND BRANCHED-CHAIN SUGARS
DISSERTATION
Presented In Partial Fulfillment of the Requirements
for the Degree Doctor of Philosophy in the
Graduate School of The Ohio State
UniTers ity
By
STEPHEN HANESSIAN, B. Sc.
The Ohio State University
I960
Approved by
Adviser Department of Chemls try ACKKOWLEDOMEIT
I would like to dedlaato this dissertation to ay parents.
My particular thanks srs to Profsssor M. L. Velfrom for his latorost and advice throughout this lnvestiga-
tlon#
Ths toehalesl guldsnes given by Ora, F. Shaflsadoh and A. Thompson on many occasions, and ths stimulating dlsousslons with mombars of ths rssoareh group is ac knowledged*
My thanks arc extended to Ora. H. El-Khaden and
M. A. El- Taraboulal of the University of Alexandria,
Alexandria, Egypt, for arousing my interest la the field of carbohydrate ohemlstry, and for encouraging me to further ay studies*
Lastly, I wish to acknowledge the financial assistance given by the Department of Health, Educa tion and Velfare, Public Health Service, national
Institutes of Health (1957-1959, 1960-present) and also the C. F. Kettering Eeseareh Foundation (1959-
1960).
11 TABLE OF CONTENTS fagft INTRODUCTION ...... 1
STATEMENT OF THE PROBLEM ...... 6
HISTORICAL ...... 8
Synthesis of Acyclic Dialdose Derivatives .. 8
Oxidative Methods ...... 8
Reductive Methods ...... 10
Synthesis of Acyclic Dicarbonyl (Aldulose and Diulose)Derivetives ...... 16
Hydrolytic Methods ...... 16
Synthetic Methods ...... 19
Oxidative Methods ...... 21
The Reaction of Carbohydrates with Grignard Reagents ...... 27
Glycosyl Halides ...... 27
Lactones, nclds and Esters ...... 30
Acyclic Aldose and aldulose Derivatives 32
Anhydro Sugars ...... 34-
Synthesis of Unsaturated Sugar Derivatives through Grignard Reactions ...... 36
Synthesis of Terminal Deoxy Hexoses ...... 45
Epimerization Methods ...... 45
Reductive Methods ...... 48
Terminal halo derivatives ...... 48 Terminal unsaturated (didehydro) sugars and glycoseens ...... 51 Terminal anhydro sugars ...... 52 Terminal sulfonyloxy and mercapto derivatives ...... 53
ill Table of Contents (contd.) Page
Oxidative Methods ...... 55
Enzymic Methods ...... 56
The Synthesis of Branched-Chein Sugars ...... 62
The £-Hydroxymethyl Sugars ...... 62
The £-hydroxymethy1 tetroses ...... 62 The £ “hydroxymethyl pentoses ...... 65 The £-hydroxymethyl hexoses ...... 66
The £-Formyl Sugars ...... 67
The £-formyl pentoses ...... 67 Other £-formyl sugars ...... 68
The £-Alkyl and £.-Aryl Sugars ...... 69
Terminal di—,C-substit uted sugars ..... 69 The 3-,0-methyl hexoses ...... 70
DISCUSSION OF hSS'JLTS ...... 75
The Preparation of Dimeric 1,2—Q- is opropvlidene-5-aldehvdo-D-xvlo- 1 . 4-furano-pentodia Idose ...... 75
The Synthesis of 3-_Q—Benzyl-1,2-_Q- isopropylidene-S-aldehydo-D-xylo- l ^ - f urano-pentodialdose (ill) ...... 77
The Synthesis of Monomeric 1,2-.Q- lsopropvlidene-5-aldehvdo-D-xvlo- 1 14-furano—pentodia Idose (V) ...... 80
The Synthesis of D-xvlo-Pentodlaidose (VI) .... 82
The heaction of 3-_0-Benzyl-1 ,2- 0- isopropylide ne-5-aldehydo-D-xylo- 1 .4-furano-pentod ialdose with Me thylmagneaium iodide - The Synthesis of 3-0-Ben zyl-6-deoxy-lr 2-_Q-i s opropylldene- L-ldof uranose ...... 84.
The Assignment of .jtereochemical Configuration to the Grignard i.esction Product ...... 89
iv Table of Contents (contd.) Page
Investigation of the Mother Liquors of the Grignard Product ...... 94
An Explanation for the Apparent Stereospeclficity In the Grignard Reaction ...... 95
The Synthesis of 3-.Q-Bensyl-6-deoxy- L-idose (IX) and soae of Its Derivatives .... 103
The Atteapted Preparation of 6-Deoxy- L-idose ...... 108
An Interpretation of the Results Concerning the Preparation of 6-Deoxy-L-ldoae...... 119
The Synthesis of 6-Deoxy-D-glucose Derivatives ...... 125
The Synthesis of 3-.2~BenByl-6-deoxy- 1 f 2-0-isopropvlldene-D-xvlo-l,4- furano— 5-hexosulose (XXIII ) ...... «... 128
The Carbonyl Reduction of 3-£-Benzyl- 6-deoxy-l, 2-^2-is opr opvlidene-D-xvlo- 1,4-furano-5-hexoaulose with Metal Hydrides ...... 132
An Interpretation of the Results of the Metal Hydride Reductions ...... 135
The Synthesis of 3-.2-B ensyl-1,2-£- isopropylidene-5,5-di-£-methyl-D- xylofuranose (XXIV) ...... 139
The Synthesis of l,2-£-Isopropylidene-5,5- di-£-methyl-D-xylof uranose (XXV) ...... 140
The Acetolysis of 3,5-Di-£-benzoyl- l,2-£—isopropylldene—5 , 5-di-£-methyl- D-xylofur anose (XXVII) ...... 141
The Synthesis of 5,5-Di-£-methyl- D-xylose (XXIX) ...... 144
Soae Crystalline Derivatives of 5, 5-Di-£-jnethyl-D-xylose ...... 146
v Table of Contents (contd.) L a s *
EXPERIMENTAL ...... 149
The Synthesis of D»xylo-pentodisIdose and Derivatives ...... 149
The Preparation of Dimeric 1,2 laopropvlidane-5-aldahydo-D-XYlo- 1,4“furano-pentodialdoae ...... 149
The Preparation of 3-fl-Banayl-l,2-_Q- laopropylidene-D-glucofuranose (I) ...... 151
The Synthesis of 3-.S2-Benayl-l,2-.fi ls opr opylidene-5,6-bis-,2- (p-nitro- benzoyl)-D-glucofuranose (Tl) ...... 152
The Synthesis of 3-fi-Benzy 1-1,2-.fi- isopropylidene-5-aldehydo-D-xylo- 1.4-furano-pentodlaldoae (III) ...... 153 The Synthesis of 3-fi-Benzyl-l, 2-.fi- lsopropylIdene-5-aldehydo-D-zylo- 1.4-furano-pentodla Idose Semlcarba zone (IV) ...... 156
The Synthesis of 1,2-fi-Isopropylidene- 5-aldehydo-D-xylo-l.4-furano- pent odlaldose (V) ...... 156
The Synthesis of D-xvlo-pentodlaldose (VI). 158
The Synthesis of 6-Deoxy-L-idose and Deriyatives ...... 159
The Synthesis of 3-.fi-Benzyl-6-deoxy- 1 12-fi-is opropylldene-L-idof uranose (VII) .. 159
General description of the Grignard apparatus ...... 159
A. The Grignard Reaction Using Ether as Solvent ...... 160
B. The Grignard Reaction Using Benzene-Ether as Solvent ...... 163
C. The Grignard Reaction Using Tetrahydrofuran as Solvent ...... 164 Normal addition ...... I64 Inverse addition ...... 165 vi Table of Contents (contd.) Page The Synthesis of 3-.2-Benayl-6- de oxy-1,2-£-1 s opr opyll dene-5-j2- methylaulfonyl-L-idofuranose (VIII) ...... 165
The Stereochemical Configuration of the Product from the Grignard Reaction- The Preparation of 6-Deoxy-lf 2-£- isopropylldene-L-ldofuranoae (IX) ...... 166
The Preparation of 3> 5-Di-,Q-acetyl- 6-deoxy-l, 2-£-isopr opylldene-L- idofuranose (X) ...... 168
Investigation of the Mother uiquors from the Grignard Reaction ...... 168
attempted purification ...... 168
Hydrogenolysia of mother liquors ...... 170
4. Grignard Reaction Using Ether as Solvent ...... 170
B. Grignard Reaction Using Benzene-Ether as Solvent ...... 171
C. Grignard Reaction Using Tetrahydrofuran as Solvent ...... 171
The Synthesis of 3-0-Benzyl- 6-deoxy-L-idose (XI) ...... 172
The Synthesis of 3-i)-Benzyl-6-deoxy- L-idose Benzylphenylhydrazone (XII) ...... 173
The Synthesis of 3-<2-Benzyl-6- deoxy-R-idose Phenylosazone (XIII) ...... 174
The Synthesis of Tri-.Q-acetyl-3-.2- benzyl-6-deoxy-L-idose (XIV ) ...... 175
4. Sodium Acetate Method ...... 175
B. 4cetlo Anhydrlde-Pyridine Method ...... 17b
The Synthesis of 1,2,4-Tri-O-acety1- 6-deoxy-L-idose (XV) ...... 177
vii Table of Contents (contd.) Page
The Synthesis of 1,2,3,4**Tetra-.2“ acetyl-6-deoxy-L-idose (XVI) ...... 177
The Syntheala of 3-\Q“Bensyl- 6-deoxy-L-iditol (XVII) ...... 178
The Syntheala of Tetra-£-acetyl- 3-£-ben*yl-L-iditol (XVIII) ...... 179
The Attempted Preparation of 6-Deoxy-L-ldoae ...... 179
A. Resin Hydrolysis of 6-Deoxy- 1,2-£-lsopropylldene-L- idofuranoae (IX) ...... 179
Column Chromatography ...... 180 Paper Chromatography ...... 181
B. Acid Hydrolysis of 6-Deoxy- 1»2-^-iaopropylidene-L- ldofuranose (IX) ...... 184
C. Hydrogenolysis of 3-,fi-B«n*yl- 6-deoxy-L-idose (XI)...... I84
Behavior of the hydrogenolysIs product in acid solution ...... 186
The Synthesis of 6-Deoxy-D- glucose Derivatives ...... 187
The Preparation of 3-5-Benayl-l,2-.Q- lsopropylidene-6— p-tolylsulfonyl- D-glucofuranose (XlT) ...... 187
The Synthesis of 3—D —Benayl—6— deoxy—1,2—.Q—is opropylId ene—D- glucof uranose (XX) ...... 188
The Preparation of 6-Deoxy-l,2-0- isopropylidene-D-glucofuranose (XXI) ...... 189
The Preparation of 3 , 5-Di-J2-acetyl- 6-deoxy-l, 2-,2-isopr opylidene-D- glucof uranose (XXII) ...... 190
viii Table of Contents (contd.) Page
The Synthesis of 3-1fl“B«aiyl-6-deoxy-l,2-<2- isopropylidsne-D-xvlo—1 f 4-furano-5-hexosulose (IIIIl) and its Reduction with Metal Hydrides.. 191
Pyrldlne-Chromium Trloxide Oxidation of 3-i2~B »n*yl-6-deoxy-l,2-fi-isopropylidene- L-idof uranose (VII) ...... 191
Pyridine-Chroaiuo Trioxide Oxidation of 3-£-Bensyl-6-deoxy-l, 2-J2- isopropylidene-D—glucofuranose (XI) ..... 193
The Reduction of 3-,Q-Bensyl—6-deoxy—1,2- O-is opropvlldene-D-xvlo- l,4"furano-5- hexosulose with Metal Hydrides ...... 194
A. Sodium borohydride in 50% aqueous methanol (v/v) ...... 194
B. Sodium borohydride in absolute methanol (at 28°) 195
C. Sodium borohydride in absolute methanol (reflux) ...... 195
D. Sodium borohydride in absolute methanol (inverse addition) ...... 196
E. Potassium borohydride in absolute methanol (at 28°) 196
F. Lithium aluminium hydride in ether (at 35°) 196
G. Lithium aluminium hydride In ether (at 35°, inverse addition) •• 197
Investigation of the Mother Liquors from the Metal Hydride Reductions of 3-j)—Ben ay 1-6—deoxy-1, 2-£-isopropylidene- 4-f urano-5-hexoaulose (XXIII).... 197
Hydrogenolysis and acetylation ...... 198
ix Table of Contents (contd.) Pegs
The Syntheala of 5,5-Di-fi-methyl-D- xylose and some of Its Derivatives ...... 199
The Synthesis of 3-fi-Benayl-l,2-fi- isopropylidene-5,5-di-fi-methyl-D- xylofuranose (XXIV) ...... 199
The Synthesis of 1,2-fi-Isopropylidene- 5.5-dl-fi-methyl-D-xylofuranose (XXV) ...... 200
The Attempted Synthesis of 3,5-Di-fi- aoetyl-l,2-fi-ieopropylidene-5,5-di-fi- methyl-D-xylofuranose (XXVI) ...... 201
The Synthesis of 3,5-Di-fi-benzoyl- 1> 2-fi-isopropylidene-5,5-di-fi-methyl- D-xylof uranose (XXVII) ...... 202
The Synthesis of 1,2-Di-fi-acetyl- 3.5-di-fi-benzoyl-5,5-di-fi-methyl- D-xylofuranose (XXVIII) ...... 203
The Synthesis of 5,5-0i-fi-methyl- D-xylose (XXIX) ...... T ...... 203
A. Acid Hydrolysis of 1,2-fi- Is opropylidene-5,5-di-fi- methyl-D-xylofuranose (XXV) ...... 203
B. iiesin Hydrolysis of 1,2-fi- Ia opropylidene-5,5-di-fi-methyl- D-xylofuranose (XXV) ...... 2 04
The Synthesis of 5,5-Di-fi-methyl-D- xyloae Phenylosazone (XXX) ...... 206
The Synthesis of 5,5-Di-fi-methyl-D- xylose Fhenylosotrlazole (XXXI) ...... 206
The Synthesis of 5,5-di-fi-methyl-D- xylose Benzylphenylhydrazone (XXXII) ..... 207
SUMMARY ...... 2 09
BIBLIOGRAPHY ...... 213
AUTOBIOGRAPHY ...... 216
x LIST OF TABLES
Table Ziifl.
1. The Synthetic Acyclic Dialdosea ...... 14
2. The Synthetic Dicarbonyl Sugara ...... 25
3. The Reactions of Carbohydrates with Grignard Reagents ...... 39
4. The Synthetic 6— Deoxy-hexoses ...... 58
5. The Branched-Chain Aldoses ...... 72
6. The R Values of the Sugar Components from the Hydrolysis of 6-deoxy-l,2-£-isopropyli- dene-L-idofuranose (IX) and the Hydrogen— olysis of 3—.fi-Benzyl-6-deoxy-L-idose (XI).. 115
7. The Color Reactions of the Component Sugars ...... 117
8. The Reduction of 3-,Q-Benayl-6-deoxy- 1 T2-0-iaoproPYlidene-D-XTlo-l.A-furano- 5-hexosulose with Metal Hydrides ...... 134
xl LIST OP FIGURES
T l W fflEtt 1. Infrared Absorption Speetrua of 3-£-Bensyl-l,2-£-ia opropylidene- 5—aide hy d o—D-xylo—1,A-furano- pentodlaldose ...... 79
2 . Infrared Absorption Speetrua of 1 .2-Q-IsoDroPTlidone-5~aldohydo- D-rrlo-1.A-furano-pentodialdoae ...... 7 9
3* Infrared Absorption Speetrua of 3-,fi-Bensyl-6-d e oxy-1, 2 -£- isopropylldene-L-idofuranose ...... 38
A* Infrared Absorption Speetrua of 6 -Deoxy-1 ,2 -£-l*°propylidene- L-idofuranose ...... 6 8
5* Infrared Absorption Speetrua of 3-Q-Bensyl-6-deoxy-1$2 isopropylidene-D-xiXa-1,A- furano-5 -hexosulose ...... 1 3 1
xii INTRODUCTION
Today, oftor almost a century of continuous lntaraat
In the flald, it is atill diffioult to dafina carbohy drates, with exactitude. in oversimpliflad and ganaral dafinition would parhapa eonaidar tha earbohydrataa aa polyhydroxy earbonyl compounds and thair condensation products.
Carbohydrates have bean known to man (l) probably
(l) For tha detailed description of tha history of the osrbohydratea, see the following referenoeat
E. 0, won Llppmann, "Gesehichte das Zuakera," 2nd ad.,
Berlin, 1938; "Bailstain*s Handbuch dar organlschan
Chamia," Vol. 31, Springer, Berlin, 1938; N. Daarr,
"History of Sugar," Chapman and Hall, London, 1949—50. since tha sense of taste was acquired. Tha sweat taste of a large number of naturally occurring carbohydrate substances of which honey was probably the most familiar to man, aroused the desire to find new sweetening agents.
Raisins, honey and many fruits ware known to contain material that crystallised under certain conditions, is time progressed, it was found that tha acid treatment of certain naturally occurring substances, such as starch and cellulose, also produced a sweet sugar which later
1 was given the name glucose by Dumas In 1838, end of dextrose by Kekule In 1866. When the pioneering work
of Emil Fischer was extended to the carbohydrate field, he revived the name glucose for this aubatance. The first configurational formula for D-(+)-glucose, previously shown to be slx-oarbon polyhydroxy aldehyde
(l), was nsde by Fischer in two publications (2).
(2) E. Fischer, 2 £ , 2683 (1891).
The formula of glucose was reprasented as a straight
six-carbon chain polyhydroxy compound bearing an alde hyde group and corresponding to the formula
Although this original formulation was later modified
to the Fischer-Tollens formula and finally to the cyclic Haworth formula, one still Is urged in »ume cases to consider the open chain aldehyde form. I--- HCO HCOH i i CHOH HCOH HCOH i i HOCH HOCH I i H,OH HCOH HC ---- i t HCOH HCOH H OH I i c h 2o h CH2 0H
Fischer formula Fisoher-Tollena Haworth formula formula
The aldehyde form of sugars may be important particularly when the sugar is in solution (3). An 3
(3) For example, 9-rlbose ii believed to exist in aqueous solution to sn appreciable extact (10-305&) in
the aldehyde form; S. M. Cantor and Q. P. Penlston, J.
Am. Chen. Soo.r £2, 2113 (1940)j W. G. Overend, A. R.
Peaoocke and J. B. Smith, Chen. & Ind. (London), 113
(1957). equilibrium may be set up which in its simplest form,
and depending on the particular sugar, may Involve two
or more oyolic structures and the aldehydo or aldehydrol
structure.
Fer reasons pertaining to the reactivity and chemi
cal bonding through hemlacetal linkages, sugars in the
true aldehyde form are not found as such in nature and
have been sought for synthetically. The logloal approach
has been to prevent the particular sugar from acquiring a cyclic (hemlacetal) structure, by suitable blocking
techniques.
The synthesis of acyclic aldose (aldehydo derivatives) has been useful for the better understanding of the optical proparties of sugars, and in some cases they have served as synthetic intermediates.
Another class of sugars exists in a higher state of
oxidation, the dicarbonyl sugars. Of these the dialde hydes and the keto aldehydes are the most common; much 4 leaa ia known about thaaa aubataneea and thalr rcietlona, than ia known about tha nonofunetional eonpounda. Tha free dicarbonyl augara ara qulta unatable, yat oryatallina apeclmena, generally cyeliied, have baan reported in a few lnataneaa. In vary fav oceaaiona have thaaa dicar— banyl augar dorivatlvea baan uaad in tha aynthaaia of highar augara. Thia claaa of eonpounda oould ba vary lntaraeting intarnadiatea for tha aynthaaia of tarninal daoxy augara or branched-chaIn augara. The foraar group
of oonpounda haa baan known in nature and nany effective
syntheaea have baan reported, which nainly modify eartain groupa within a augar compound of fixed oarbon akeleton.
Tha occurrence of deoxy augara in nature ia quite common.
Another elaaa of augara, bearing carbon aubatltuenta
(uaually of amall ohaln length) attached to the main
backbone, have found aoma diatrlbution in nature (A).
(4) Shafiaadah, Advaacaa in Carbohydrate Cham.
11, 263 (1956).
Theaa ara an intaraatlng claaa of oompounda, tha
chenlatry of which haa not baan widely investigated.
Even though moat of tha naturally ooourring branched-
chain augara ara not atructurally complex, vary faw
have baan aynthaaiaad. Moat of them bear a tertiary 5 hydroxyl group or a derivative thereof. Little ia kaova eoaeeraiag the origin of theae deoxy and branehed-ehaln augara; their detection and iaelation from natural products require a constant search for newer and nore effective nethoda for their synthesis. STATEMENT OF THE PROBLEM
The object of this inveatigatlon haa baan tha
synthesis of naw dioarbonyl augar derivatives of tha dialdose and alduleaa tjpaay in which one of tha car bonyl gronpa ia unmasked (Formulae III ana XXIII), and tha reaction of thaaa eonpounda with organometallle raaganta to produce new terminal da0 x7 and branched- ehaln augara.
Tha dialdose derivative was S7 nthaalaad fron a aultablj blocked D—glucose derivative by glycol— olaaving raaganta, and waa transformed into new oonponnds of tha same type, by tha progressiva re moval of tha blocking groups. Tha aldulose derivative was synthesised by the oxidation of a secondary hydroxyl group at C-5 in a suitably blocked 6 -deoxy-(L-ldo or
D-gluco) derivative.
In the condensation of methylmagneslum iodide with the dialdose derivative, only one of the two possible products waa formed, and this was the 6 -de oxy-L-ld o
Isomer (VII). The synthesis of the other possible
Isomer, a 6 -deoxy-D-glucose derivative (XX) had to be independently effected by the hydride reduction of the corresponding 6 -p-tolylaulfonyloxy derivative. In the case of the aldulose derivative, the condensation product wa> of tha branched-ahain type, namely, a
5,5-di-£-methyl-D-xylo8e derivative (IIIV). Thaaa oryatalline condensation produots wara transformed to several maw compoumds of tha same respective
^ypaa, by tha progressive removal of tha blooking groups. A mechanism haa baan proposad to interpret tha reaction of tha dlaldosa derivative with methyl- nagnoaiun iodida and tha raaotlon of tha alduloaa derivative with metal hydrides. HISTORICAL
Sm U i i Ii of Aoyolle P t i l d w PerlTatlvea
Oxidative Methods
Prebably the first dialdehyde sugar derivative waa raportad by Flseher and Appal (5). Thay traatad
(5) H. 0. L. Flaehar and H. Appal, Hall. Calm.
▲ALU, 1?, 157A (1936).
3,A-fi-isopropylidaaa-P-aannitol with laad tatraaeatata and obtainad 2 .3-0-lsooropylldona-dl-aldehvdo-L-throo- tatrodialdoaa as a sirup.
Latar Fiaahar and Dangaehat (6) aynthaaisad tatra-
(6) Cerda Dangaahat and H. 0. L. Fiaahar,
Matnrwiaaoneahaftan. 27, 756 (1939).
0-acetyl-dl-aldehvdo-D-aalaato-hoxodlaidosa by tha oxidation of a tetra-,Q-aoetyl-eyelphexane-l, 2-diol, a ooupound obtainad from eonduritol. Whan aondurltol, a tatrahydroxyayalohaxana, was transformed to tha hexa- acatata, and tha latter nildly saponified, a different tetra-£-aeetyl-eyolohexane-l,2-dlol waa obtainad which whan oxidised gave tetra-O-aoetyl-dl-aldohydo-D-allo- hexodlaldose (6). 9
Tha first dlaldahyds sugar dsrlTatlra in ths psntsss i«ri«a was rspsrtsd hj Iwadars (7). Thus,
(7) K. Iwadars, Bttll,. .C.htt*. .JtpU, 16, 40
(1941). oxidation of 1,2-£-iaopropylldana-I>-glucofuranoae with lsad tstraaestats gars 1.2-fl-laopropylidana-»5-aldshTdo-
P-iTltt«.lrl-fttrano-Dsntodlildofls. Ths ascond such psntodialdoas was rsportsd by Iwadars (8) in ths sans
(8) I. Iwadars, AfcLd*, (1941). ysar. Oxidation of 2,3-£~l*0Pr0P7ll4aaa~D-nannoaa with lsad tstrasostats gavs 2,3-£-laopropylldsna-di- ildihyds-D-lTio-pantodiildoas as a sirup. In ths sans manner, oxidation of 2,3-„Q-l,,opropylidsna-l-nannoas affsrdsd 2.3-0—iaopropylidans-dl-aldahydo—1-I t x q — psntodialdoas (9). Thua, of ths four posslbls panto*
(9) 1. Iwadars, ibid.P JL7, 372 (1942). dlaldosss, thrss haYs aotaslly bssn synthsalisd and orystallins dsriratiTsa obtainad.
Ballon and Fiaehsr (10) synthsaissd ths first
(10) C. E. Ballou and H. 0. L. Flaohsr, J. i n . Chon. Sso.. 75, 3673 (1953). 10 dl-ild«ltfio-P-»ittttO<»hi»odlildoit derivative. Oxidation ef dl-£-laopropylldene*D-laoaitol with lead tetraaoetate
Cave cryatalline 2 r 3 ti. 5-dl-O-laopropylldana-dl-aldahvdo-
D-jyUUUt-hexodlaldeee. The free augar waa anorpheua but gave a eryatalline dimethyl dlglyoealde (11).
(11) C. I. Ballou and H. 0. L. Flaeher, Ibid..
75, 4695 (1953).
Sehaffer and labell (12) were able to eryetalllse
(12) R. Schaffer and H. S. labell, Reaearoh
Matl. Bur. Standarda. 56, 191 (1956). the prevloualy obtained 1.2-Q-laoproPTlidono-5-aldohvdo-
D-xvle-1.4-furano-pontodlaldoaa (7), In the anhydroua and hemlhydrate forma. In the aubaequent year, the compound waa ahown to be a dimer and lta atruoture waa elucidated (13).
(13) R. Sehaffer and H. S. labell, J. An. Chen.
1?, 3364 (1957).
Reductive Mothoda I
The flrat dlaldehydo hexodlaldose derivative, totra-Q-acetyl-dl-aldahydo-D-aalacto-hcxodlaldoao, waa reported la 1930 (14) and waa cited by Michael (15), 11
• - (14) V. Uaaelaaan, Dias. (F. Kbgl, preceptor),
Gottingen, 1930.
(15) F. Michael, A ^ . , £96, 77 (1932). bat experlaental details war* given. A general
nethod for tho synthesis of dlaldehydo augar derivatives
froa tho oorroapoadiug aeld ehlorldoa vaa also pointod
out bp Mleheel (16).
(16) F. Mlohoel, "Choalo dar Zueker uad Poly-
saeeharld,” Akadenlsohes Verlagageaellaohaft, Lelpslg,
1939, p. 163.
Volfroa and UaAln (17) oouplotod Mlohool'a
(17) M. L. Volfroa and K. Usdln, J. Am. Chou, fill., 75, 4318 (1953).
citation (15) whan they proparad tetra-fl»aoetyl-di-
aldahTdo-D-galaoto-hexodlaldoaa by tho roductioa of
tetra*£-aeetyl-D-galaetaric aeld diohlorldo with palladiua
on-barlun sulfato catalyst. Tha saaa pethod waa appliod
In tha synthesis of ponta-0-aaotyl..di-aldahvdo-neao-
(glrcaro-guloi-hoptodlaldose froa tho eorroaponding
aeld ohlorida. This waa tha first raoordad oxaaplo
of this typo of aubstanoo in tha aldohaptoaa aarloa. 12
Th* first dialdehydo flueos* deriratlT* was
*ynth*sls*d by Macdonald aid Fi**h*r (18). Thus th*
(18) D. C. Msodon*Id sad H. 0. L, Fl*eh*r, Ibid. r
78, 5025 (1956). eoadsasstioa of 1 .2»Q-lsoDropTlid*n*-5-ald*hrdo«-D-
,ZXlft-l,.4~f urano-p*ntodlaldos* (7) with nltroaethan* sad th* s*par*tioa of th* isoaors gar* 1,2-£-lsopropyl- id*n*-6—d*oxy-6-sltro-»D-glueoforaaos* whleh was anbj*ot*d to th* I*f r*aotloa to glT* dl-aldahvdB»D-gluQo-h*io- dialdos* (aot isolated), id*atlfi*d as Its eryatallla* bls(di*thyl dithloao*tal)• Th* saa* ooapouad was ob- tala*d la 10% yl*ld froa tho controlled sodlna borohydrld* r*d«otioa of D-glueuronolaeton*.
Th* first eryatallla* fr** dlald*hydo hoxodialdo** was r*o*atly d*sorib*d by Fi G. Fisoh*r and Sohaldt (19).
(19) F. G. Flaehor and H. Sohaldt, Chea. B*r.r
93, 658 (1960).
Th* reduction of D-gluoaronolaetona with sodlna aaalgaa gar* a alxtur* whleh was separated by paper ohrouatog- raphy. Aaoag th* produots was dl-*ld*hTdo-D-glneo— hoxodlaldose (80%), which eryatallls*d as th* aonohydrat*.
It Is Interesting to point out that this ooapouad showed ao oarboayl band in its infrared speetrua, aor in Its ultrarlolot absorption speotrun la water. Vbllo tho authors (19) havo represented tho sugar la tho "dl- furanese* fora, tho possibility of a soptanoso rlag or othor combinations of hoalaootal struoturos should not bo exeluded.
CK,OH CH .OH
HCOH HCOH 0 0 CH HOCH
HC HCOH 0 HCOH HCOH
CH.OIi w (pH, OH dl-fursnoso soptanoso ring ring
Tho synthetic aeyelle dlsldoso derlTatlYos arc listed In Tsblo 1. Table 1
The Synthetic Acyclic Dlaldoaee
Sugar or derivative M.P. r % J i References
Tetroses 2,3-,fl-l8opropyl idene-di- aldehydo-D-threq-tetrodla1dose a lrup +26.6° _ +5.2 (EtOH)
Pentoses
D-xvl9-Pentodlaldose^ sirup
1,2-ii-1 s opr opyl 1 d e ne - 5-liialalfi- D-xvly-lf A-furano-pantodlaidosa airup +20*3° (EtOH) 7,20,21
(Anhydrous dimer) 182-184* -25.9° (H20) ° 12,22
D-lvxo-Pentodiald oae ^ sirup +5° (H20) c 8
L-lyxo-Pentodlaldoae ^ airup -17° (H20 ) c 9
Hexoses
Tetra-O-acatyl-di-aldehvdo- D-galacto-hexodlaidoae 184 (dec.) 6,14,15,17
Tetra-O-acetyl-di-aldehydo- D-allo-hexodialdoae 164° (dec.) 6
Tetra-O-acetyl-dl-aldehydo-DL-ldo- hexodialdose bis (phenylhydrazone) 154° (dec.) 23
D-manno-Hexodialdosa amorphous +47.7° (H20) 10 Table 1 (contlnutd)
2,3* 4,5-Di-2-iaopropylidene-di- ^ aldshydo-D-nanno-hexodialdose 125-132° -21.6° (MeOH) 10
D-elueo-Hexodialdoset (aonohvdrat#) 80-83° 45.5° (H20) 19 flaBlaaag
Penta-0-scetyl-di-aldahYdo-«e8o- (fflTeero-eulo)-hantodialdoae 133-134° 17
a Polyaeriaes to a glass (24 hr.), b Not isolated. c Equilibrium value. ^ Deeoaposes on standing (2 weeks).
(20) J. M. Groahelntz and H. 0. u. Fischer, Ail. Chen. Soc.f 22, 1476 (1948).
(21) J. C. Sovden, U O d . , 2 1 , 5496 (1951).
(22) V. Brocca and A. Dansi, Ann. Chla.. (Home), 120 (1954).
(23) Gerda Dangachat, Naturwisgenschaftenf 22, 146 (1942). 16
Syntheala of Acyclic Dlcarbonyl (Alduloae and Diitloae) PtrlTitlTii
Since acyclic dialose derivatives war* dlacusaad separately, this section will comprise the alduloaa
(aldehydo-keto) and diuloaa (dikato) sugara and their derivatives. In the former group, the oaonea are In a olaaa by themselves and will not be discussed hare as they are unrelated to thla work. A detailed account of the oaonea haa recently been published (24)*
(24) S. Bayne and J. A. Fewster, Advances In
£ixb9taflr«tf,, 1 1 , (1956).
Hydrolytic Methods
In the first of a aeries of papers entitled "New
Dlcarbonyl Sugara," Helferich and Hlmmen (25) reported
(25) B. Helferich and E. Hlmmen, Bar.. 62 f 2136
(1929). the synthesis of crystalline 6-daoxy-.D~XYlo-5-hexosulofla
(6-deoxy-5-kato-izlucose r isorhamnonose ) . Thus methyl
D-xylo-hexopyranoss-5-eenlda waa treated with dilute acid to give an unlsolated D-xvlo-5-.hexosaen. which tautomerlzed to the 5-keto compound. 17 1— HC0C1, HCOH CHO CHO i J i i t HCOH HC HCOH HCOH t i H30* i i HOCH HOCH HOCH HOCH t i « t HCOH HCOH HCOH HCOH i i i C- C COH C-0 ■ ■ • I CH, CH, GH„ CH?
Similarly the a eld hydrolysis of 1,2 t3,4-di<-£- lsanraoylldana-I— arabina-haxonrranoaa-5-aan. gavt 6-daoxy.
L-arablno-5-haxasulosa f5-kato-fueosa. fueanoss) as a sirup.
Bradaraok (26) raportad anothar synthasis of 6-dsoxy.
(26) H. Bradaraok, fitt., 6^, 959 (1930).
D-xylo-5-haxoauloaa r In conjunction vlth tha proof of structure of tha dlsaooharlda trahaloaa. Tha lattar was oonrarted through a sarlaa of ataps to tha bis (5- haxosaan) and traatad vlth aold to give 6-daoxt-D-xt!o*
5-hexosulose as a sirup.
In tha saeond pa par of tha sarlas, Halferioh and
Bigalov (27) rapoitad tha synthasis of a nav oxidation
(27) B. Halfarioh and H. M. Bigalov, Z. Physiol.
Ghan.. 200. 263 (1931). product of glucosa. Treatment of nathyl 2,3,6-trl-£- It acetyl-p-D-jULL2-hexopyr*noae-5-eenide with lead tetra acetate added two acetoxy groups to the double bond and gave the crystalline penta-jQ-acetyl derivative. Water was capable of transforming this compound Into 2,3,4,6- tatra-O-acstvl-D-xvlo—5-hexosulose. Saponification and hydrolysis of either acetates afforded D-xvlo-hexoauloae
(5-keto-gluooae) as a yellow sirup,
Mlcheel (15) reported the synthesis of a l,4~diketo sugar, 1 r6-dideoxT-D-threo-2.5—hexodluloae. by the acid hydrolysis of the corresponding terminally unaaturated di-£-methylane derivative. The ether linkages are believed to be 2,3*4,5 (16,28).
(28) W. G. M. Jones and L. F. Wiggins, J. Chem.
, 364 (1944).
Several crystalline derivatives of 6-de oxv-D-xvlo-
5-hexosulose were reported by Ohle and Deplanque (29).
(29) H. Ohle and R. Deplanque, per.r 66r 12 (1933).
The acid hydrolysis of 1,2:3,5-di-£-isopropylidene-D- xvlo-hexofuranose-5-ean afforded the crystalline 1,2-
Q-lsopropylidene-6-deoxv-D-xvlo—5-hexo3ulose,
A second dlketo sugar was announced by Mlcheel (30)
(30) F. Mlcheel and K. Horn, Ann.f 515. 1 (1934). 19
1 a 1934. 1 previously obtained intermediate (28) was traatad with laad tatraaaatata to yield tha correspond ing tetra-fi-acetyl dsrlntlva, which ah hydrolysis gave l,6 -di-fi-acetyl-D-ifcuii-2 ,5-hexodiuloae (ljb-di-fi- acctvl-g-kato-frnctose ).
Synthetic Mathoda
la a number of instances, condaaaation raaotioaa batwaan suitably bloekad carbohydrate derivatives aad otbar reagenta have given oarboajl derivatives. Thia kind of approach haa not had extensive application.
la early attempt waa aada by Fischer and Ippal (3) whan 2 r 3-0-laonropylldane-dl-aldahyde-D-thrsp-tetro- dlaldoaa waa raaetad with dlasoaathana. They elalaad tha laolatlon of a liquid aabataaca and preanaed it to be a dikatona by ita analysis, but ita properties ware not investigated.
In extensive study of tha reaction of Grlgnard reagents on a variety of carbohydrate earboxylle deriva tives was initiated by Ohle and Hacht (31). Treatment
(31) B. Ohle and 0. Heoht, A*®., 4J*1, 233 (1930).
ef 2,3i4.5-dl-0-laoprODTlldana-D-arabino-2,6 -pyrane- hexulosoaio acid vlth aathylmagnaaium iodide, gave l-daoxy-3,4*5, 6-di-fi-isepropylidene-D-,®g®®®-2,3— haxodiulo-3»7-pyranoaa. 20
Ghla and Danbargla (3 2 ) than axtandad tha raaetian
(32) H. Ohio and C. Danbargla, ifcli, 481, 2 53
(1930). to hazuronle a olds. Tha raaation of 1,2 1 3,4-di-j2- laoprapylldana-D-galacturonlo aold vlth various Grlgnard raagants affordad airapy tarninal daoxy-D-valacto-6 - hoptosuloaa darlvativaa.
Tha raaetlon of aldahydo aagar darivatlvas vlth diasonathana waa ravivad by Wolfron and eoworkara (33).
(33) M. L. Wolfron, S. W. Walabrot and R. L.
Brown, ^ gh«U,,£gfi«> 6A> 2329 (1942).
Thna tha raaotlon of 2,3t4|$*tatr«-j}-aa«tyl-fi-galaotarlo aold dlchlorlda with diasonathana gava tha aorraapondlng dlasonathyl darlvatlva, vhleh on traatnant vlth aaatlo aeld gava 1.3.4.5.6.8-haxa-Q-acatyl-P-valaoto-2.7- octodluloaa. Tha aana dlasonathyl katona was latar raaotad vlth hydroiodle aold to glva tha now 3,4,5,6- tatra-O-acatTl-1,8-didaoxy-D-valacto-2 r7-oetodloloaa (34).
(34) M. L. Wolfron, S. M. Olln and E. F. Evano,
Ibid.. 6 6 , 206 (1966). 21
Oxidative Mithodi
With the objective of understanding tha oxidative transfornatloas of various sugars In vlvof nany ohanlsts bars studlad tha aetioa of baotarla on tha sugars.
Tery raeantly a rapart on tha production of a new crystalline diaarboayl sugar, namely D-lvxo-5-hcxo- sulosa (6-aldahvdo-D-fructosa). by tha action of
Acotobactar saboiTdana on eaao sugar solutions has boon published (35)*
(35) a. Veidenhagen and G. Bernsse, Ansew. Chan..
72, 109 (I9 6 0 ).
There has not bean much variety in tha type of ehemleal oxidations reported in tha literature.
An early attenpt by Craws, Hart and Everett (36)
(36) L. T, Craws, J. P. Hart and M. H. Everett,
J. 4.. Ch..- S.B.. 62, 491 (1940).
deserlbed tha oxidation of lavogluoosan (1 ,6 -anhTdro-p-
D-glucopyranosa) with bronlne and tha isolation of a crystalline subatanaa to which they assigned tha tenta tive structure of 1.6 -anhvdro-D-xylo-5-haxoauloao
(katolavoglucosan). 22
la recent f u r l Liadberg and coworkera (37) have
(37) B. Liadbarg and 0. Thaaadar, A eta Cham.
Seaad-. J, 1870 (195A). aaad ehramlaa aalta aa azidialag ageate; treatment of
■ethyl p-D-glucopyraaoalde with potaaalaa diehroaata la ozallo aeld aolatloa waa ahova to product oryatal- llaa methyl p-D-£Xkl-3 -hexoaulo-l,5 -pyran©alde aloag with aoaa alrupy methyl 6 -aldahvds-p-D-aluae-hexo« dlaldo-1 ,5 -pyraaoalda In law ylelda.
Later, Thaaadar (38) uaad ehromlum trloxlda la
(38) 0 . Thaaadar, JJild., 11, 1557 (1957). aoetone la aa attempt to obtala Improved ylelda In the oxidation of tha anomerle methyl 6 -£-trltyl-D-glUGopy- ranoaldaa. Low ylelda of 2-hexoauloae, 3 -hexosuloae, i-hexoaoloae and 6 -aldahydo-hezodlaldoae derivatives ware laolatad and aaparatad by chromatography,
Aaaaraaoa and Thaaadar (39) oxidised methyl
(39) A. Aaaaraaoa and 0. Thaaadar, Ibid.. 12,
1507 (1958).
A,6 -£-ethylldene-p-D-glucopyranoside with chromium trl oxlda la acetone aad Isolated tha methyl glycoaldea of 23
2 -haxoauloaa and 3 -haxonuloan dariratlvaa, together with othar oxidation prodmata.
Tha uaa of tha fallow aoaplax fornad bj ehroaiu triaxlda 1 m pyridina, for tha oxidation of primary or aaoamdary hydroxyl group a In aeld-tanaitl'va aanpounda haa baan danonatratad raaantly (40). Thla raagant haa
(40) G. I. Fooa, G. K. Arth, R. S. Baylar and
1. £. Saratt, J. An. Chan. Soa. . J75. 422 (1953). baan raportad In tha aarbohydrata lltaratura in only tRraa inatanaaa.
Sugihara and luan (41) haTa aueeaaafully utlllsad
(41) J. M. Sugihara and G. U. Tuan, ibid., _79,
5780 (1957). thla raagant in tha oxidation of 4~£-bansoyl-l,2»5,6— di— iaopropjlldano-D-nannitol and obtainad 4-jfc-hansoyl-
1,2:5 r6-dl-0-iaopropylldana*D*arablno-3~haxuloaa in eryatalllna atata.
Folkara and oovorkara (42) ha t o obtainad aathyl
(42) S. Walton, J. 0. Rodin, C. B. Stanner, F. V.
Holly and K. Folkara, ibid.r BO, 5168 (1958). 24
6-de0X7-2,3-,2-iaopropylidone-L-iiiji-l,4-furano-5- hexoauloslde as a airup from the oxidation of methyl
2,3-U-isopropylidene-L-rha nnof uranoside .
Othar workara (43) are believed to be presently
(43) Personal communication, Dr. G. G. S.
Dutton, University of British Columbia, Vancouver,
B . C ., Canada. utilising the chromium trioxide-pyridlne reagent.
The synthetic alduloses and diuloses and their derivatives are compiled in Table 2. The Synthetic Dicarbonyl Sugars cn X Cfa Q fl +> o 0 • a ► 3 O fa fa V 00 e» *CJ t —t « « 3 o 0 o O o —' '— >0 0 0 0 CM op a o (M CM P CM UP f-H CM CP trv Q p w 33 H rH \T\ rH o X S 7 0 « a O I at 0 N 3 o CM 1 1 1 1 1 i 1 1 i0 1 0 i i 1 • * -0 Q -0 H » rH CM Ol 3 •H P H CP rHH t ■HO lrHOl Ol H 1 h « O # n ►» O rnl o o fl rH H 0 fa «P | O ►»0 0 Pa . 1 P. I 1 fa 1 1 ? a O —' "— 0 (M o O o o rH fat Xt O 33 O i— 1 O' rH trv rH o O 0 0 a 3 1 f*P • 0 rH *H **H TJ o1I 1 •o >-3* 33 CMfl 1 Of 0 •H «T3 p 1 op +» H K 0 K a 1 0 O fat z? >» H O P, 0 Pa O H 3 H I 1 1 0 1trv 1 33 a Oo Ol o| aa O o --—’V CM 33 CM rH X O '4- -H 0 « 0 fa 3 HI H O Pa 1 1 * 0 CM u\ .-3 •H rH rH a 33 WP 0 u 0 0 o o 0 fa 3 0 0 0 K ►a O fa 0 a H 3 0 o o p 1 1 1 i 1 . 0 tf\ a ja 0 CP •H -41 H 0 0 H S. a O fa 0 3 3 0 1 1 1 CM cp ft3 Ol O *H rH 721 rH Pa t f TJ0 -sf T30 ►t 0 • « *■ 0 faPa 0 Pa fa rH C3 I - O O IT i a K O 1 1 t 1 o t 1.H ' - 0 o o ' 0 00 vr\ O 33 O rH CM CM ja — (*> arH rH 0 fa 3 P. H a I 1 CP » ft rH 0 CM | 1 ^ TJO •H0 0)rH I H o H ►a 0 0 0 rH fa 1 o ►» 0 CD 0 0 O H H H •* « o P trv 1-P 1 O 1 3 1 - Ol *. o o c CM O O 33 O H C*PCM 3 fa Q. n r~ CM fa 3 O no Pa O o '— --— a. O o o 0 t"- 0CM rH 00 O rH rH 33 o CM f— 1 CP o o O rH "* o <0 n t 1 ' — --— a -— •a 0 0 0 «o CM CM H 333 33 33 33 33 HrH rH rH rH o r O trv 3 rH a o 0 0 0 K o 0 3 a >» 1 1 1 1 1 1 CM i 25 * ro-D 33« 33 rHO tTa cx x -t-> CP rH rH ft Q ^ ►» 0 O K m 0 K 0 i 1 1 1 1*o aa o 00 00 00 C*- CM o O op op ch fa m 0 • CM 1 *fc , Table 2 (continued)
Methyl D-XYlo-4-hexoaulo-l,5- pyranoside 120-121° -47° (H20) 38,39
P-lYXQ-5-Hexosuloae ^ 158° -86.6° (H20) 35
3 ,7-Anhydro-l,2-.Q-isopr opylidene- c 6-deoxy-7,7-dl-C-aethYl-D-xylo- 1,4-furano-5-heptoauloae 116-117° +99.4° (CHC13) 29
Biulosea
lf6-Dideoxv-D-threo-2f 5-hexodiulose 77° +106° (H20) 15,30
D-x y Io-2 ,5-Hexodiulose sirup -29.7° (H20) 30
1,6-Dl-Q-a cetyl-D-xYlo-2,5- hexodlulose 75° +79.4° (EtAc) 30
1,3,4, 5,6,8-Hexa-,2-acetyl-D- aralacto-2f 7-octodlulose 193-195° 33 (dec.)
3,4, 5,6-Tetra-£-acetyl-l,8- dideoxv-D-eala cto-2r7-oetodlulose 204-206° 34
• ,c Structure tentatively assigned. b Product of bacterial oxidation.
(44) J. K. N. Jones, Fourth Int. Congr. Biochem., Vienna, 1958, p, 89. 27
Tha Baaotion of CtrbohydrtUi with StUa«4 i m « t t
filymul Btlldti Tha aarllast attanpt to raaat a Grignard raagant
with a oarbohydrata aubatanoa waa nada by Paal and
H&rnstaln (4-5), who elalnad that tha raaetion of
(45) C. Paal and F. H&rastalnf *i£., _3?» 1 3 6 1 (1906).
tatra-£~aoatyl-D-glueopyranoayl bronida or p-D-gluooaa
pantaaoatata with phanylnagnaalun broalda produoad
solaly aathyl dlphenylearblnol, by raaotion on tha
aeatata groups.
Flaehar and Haas (4 6 a) aa wall aa othara (4 6 b),
(4 6 ) (a) I. Fiaohar and K. Has a, Bar., 4 J, 912
(1912); (b) N. Fr&aohl, J. Zallnar and H. Zak, Monatah..
15, 25 (1930).
alao elalnad tha fornatlon of an addition product whan
tha abora nantlonad raaetion was run. Vatar raganaratad
tha sugar eonpound, whila traatnant with nathanol
followad by daaeatylatlon gars nathyl f-D-glucopyranosida.
Othar aoylglyeoayl halldaa aaanad to bahava ainllarly.
An azplanatlon had to ba proridad for tha laek of 28 eondenaatlon, aince tha nature of tha halogen aton la
thaaa oonpounda ahould raflaet high reactivity.
Hurd and Banner (47) relnveatigated thaaa raaotlona
(47) C. D. Hard and tf. A. Bonner, J. An. Chan.
± 2, 1972 (1 9 4 5 ).
and found that a large exeeaa of tha Grignard reagent
had to be uaad. Thua tha reaction of tetra-£-acetyl- p-D-glueopyranoayl chloride with twelve nolea of
phenylnagnealun bronlde afforded after appropriate
aeparatioaa, tetra-g-aoetyl-1,5-anhydro-l-i-phenyl-D-
gluoltol.
Jereniaa and Maokenaie (46) further invalidated
(46) C. G. Jereniaa and C. A. Hackenaie, ibid.,
70, 3920 (1946).
the elain of adduct fornation between f3~D-glueoee
pentaaoetate and nethyl, n-butyl and phenyl Grlgnarda
and ahowed the abaence of 0 -glucoae.
Hurd and Holyai (49) extended the reaction to
(49) C. D. Hurd and R. P. Holyai, ibid.r 7 2 ,
1732 (1950).
dlaaocharidea when they reported the ayntheaia of 29 t«tr«-£-»oc tyl-g-D-glucopyra noayl-tri-£-a eetyl-1# 5- anhydre-l-£-phenyl-D-glueitol, and tha eyntheaia of tha eerreapondlng gentiebloae derivative. Moreover a hataraajelia Grignard raagant, 2 -thlenylnagneeluB hromida waa raaotad with tetra-jJ-acetyl-g-D-gluoo- pyranaayl bromide to give tatra-,fl-acetyl-l,5 -onhydra- l-£-(2 -thlenyl)~X>-glucit©l, which waa daaoatylatad to a glaaa.
Raeaatly tha raaotlon of aoylglyeoayl halldaa with
Grignard raaganta haa baan graatly axtandad by Zhdanov and ooworkara (50). The raaetiona hare involved tha
(50) Xu. A. Zhdanov, L. I. Shoharbakava and
T. N . Kgerova, pgUgdy 4hlfl. Bittfc. S. S. S.
403 (1952), Chan, ibatraeta. 2710 (1953), and aubaaquant paper*. uaa of a variety of Grignard raaganta and the augar part haa inoludad derivative* of D-galacto*e, D-nannoaa,
D-glnooae, L-arabinoae, D-xyloae and D-riboae which are liatad in Table 3.
Zallnakl and Mayor (51) have reported the flrat
(51) R. Zalkinaki and R. E. Mayor, J. Or*. Chan.F
23, 810 (1958). 30
•staple if thi "ilaiiijlitloa" of aaotyllnlo flri|n«rdi.
Rotation of tiira-fl*iiit7l-ft-D-|lMOp7r»of7l bronldo
vlth phomylothynylnagnoalnn bronldo, followed by ro-
dmotloa affordod totra-£-aeotyl-l,5-anhydro-l-£-
(2-phonylo thyl )-D-glne It ol •
Aa iatimtii| oxtonalon of tho rotation of Grig-
ntrd roagonta vlth aoylglyeoayl halldoa vaa tho uao of
aalnoaugar dorivativoa (52)* Troataont of 3,A,6-tri-
(52) J. Xoahinnra, I. Mvraaatan and T. Sato,
Ilppom I.g.ktt 2.1.hi. 79. 1503 (1958), Ch.m- lb.tr.nt..
J&, 6562 (1960).
£-aootyl-2-anlno-2-dooxy-a-D-gltteopyranoayl broaldo
hydrobroaldo vlth a varioty of Grignard roagonta affordod
tho eorroapondlng l-.fi-alkyl or l-£-aryl derivatlToa.
Doaeotylatlon of thoao ooaponnda gavo 2-aalno-l,5-
aahydro-2-dooxy-l-£-aubatltatod D-glucitola.
Lantonoa. Aolda and Ratora
Following tho fallnro of tho aeotylatod glyooayl
halldoa to roaot vlth a Grignard roagont (A5), Paal and
Bornatoln (53) roaotod totra-£-aootyl-D-glaeonolaetono
(53) C. Paal and F. Hornatoln, Bor.. 39. 2623 (1906). 31 with pkiaylugBsaiua bromide and obtained a low jlold of tho oxpeeted 1,l-di-£-phenyl-D-glucitol derivative.
Paal and Lahn (51) extended the reaction to the
(54) C. Paal and K. Lahn, JJlU*, J t 2 > 1819 (1907). eater types when they prepared l,l-dl-£-aryl glycerols fron methyl DL-glyoerato and several Grignard roagonta*
The reaction waa then extended to several pentose or hexoae laotone derivatives and the eorrespondlng l,l-dl-£-substituted alditols prepared (55,56).
(55) C. Paal and M. Klnseher, ibid.. 44. 3543
(1911).
(56) C. Paal, 1583 (1916).
The reaetioA of a earboxyllo aeid derivative by
Ohle and Heoht (31) was previously described.
Selectivity in the reaction of an alpha«keto eater was demonstrated by Gakhokldse (57). Treatment of
(57) A. M. G.khokldm., J. O.n. Ch.... (».S.S.E.),
11, 109 (1941)s Ch«». 4b.tr.et.- J5. 5 4 6 4 (1941). methyl 3.1.5-trl-O-mothyl-L-orrthro-pantuloeottate with methylmagneslum iodide resulted In the addition to the katonlo function only, to give a 2-£-nethyl derivative of unknown configuration at that carbon. 32
A recent report by Folkera and coworkera (4 2 ) baa involved tba raaetion of nethyl (nethyl 2 f3 laopropylidene-D-ribofuranoaiduronate) with nathyl* nagnealun iodide to give tba eorraaponding tertiary earbinol at C-5.
Acyclic Aldoaa and Alduloae Derlvatlvee
One of tha aarllaat attanpta to react a Grignard raagant with a carbonyl augar derIra tire waa nada by
Ohla and Danbargla (32), Thua, tha raaetion of 7- deoxy-1,2* 3fA-dl-O-laopropylldene-D-galact0 -6 -hexoaulo-
1,3—pyranoae with nathylnagnaalnn iodide gave tha axpaetad 6,6-di-£-nethyl-l,21 3,4-di-£-ioopropylidene-
D-galacto-pyranoaa. while tha reaction of tha 7,8— dideoxy analog with athylnagnaainn iodide afforded
6,6-di-£-ethyl-l,213,4-dl-£-iaopropylldene-D-galaeto-
pyraooaa.
On the othar hand, tha firat raaetion of a Grig
nard raagant with an aldahydo augar derivative waa n reported by Gatal and Relohateln (38). Tha reaction
(38) X . Gatal and T. Relohateln, Helv. Chin, Acta.
21, 914 (1938).
of 2,3*4,5-dl—O-laopropylidana—aldahydo—P-arablnoae
with nathylnagnaslun iodide gave tha expected 6-deoxy-
L-gulltol and 6-daoxy-D-nannitol derlvatlvee. 33
In 1954 English and Griswold (59) reacted 2,3*4,5-
(59) J. X. English, Jr., and P. H. Griawold, Jr.,
I* A m. 67, 2039 (1945). dl-0-laopropvlldsno-aldehydo-L-arablnoaa with a variety
of Grignard raaganta Including tha nethyl, oyclohexyl,
phenyl and 1-naphthyl analogs and obtained the corres—
ponding eplnerio l-£-subatituted pentltela.
Tha reaction of oyolohazylnagnealun chloride with
2.3*1.5-dA-O-ieopropvlldene-aldehrdo-D-arablnoee gave a oryatalline l-£— cyclohexyl derivative (60), which waa
(60) J. B. English, Jr., and P. H. Griawold, Jr.,
H A A . , 70, 1390 (1948). enantlonorphoua with a previously obtained analog (59).
Bollenbaok and Onderkofler (61) have reacted
(61) G. M. Bollenback and L. A. Underkofler, J.
An. Chan. Soc.. 72, 741 (1950). tetra-O-aeatyl-aldahydo—D-xrloao (62) with netbyl-
(62) M. L. Wolfron, Mildred R. Mewlin and B. E.
■tahly, lild., 53, 4379 (1931). 34 aagneelun iodide and iaalatad and eharaeterised tha reaulting 1-deoxy hexitola.
Tha atereoekealeal eonflguration of tha l-£-phenyl-
D-pentitola (60) vara alaeldatad by Bonaar (63).
(43) V. A. Bonner, ibid.. 2 1 , 3126 (1951).
Recently tha raaetion of an alduloaa derivative
with a Grignard raagant waa revived (42). Thua treat-
nent of nethyl 4-daoxy*2,3~£-iioprop]rlidana-L-lx2ft-
1,4-furano-3-hexuloaIda vlth nathylnagnaainn iodide
gave tha expected tertiary earbinol at C-5.
Anhydra Sngara
Tha aetion of Grignard raaganta on anhydro angara
derivatlvaa waa atudled by Vevth, Rioharda and Wiggina(6 4 ).
(6 4 ) F. H. levth, G. N. Rioharda and L. F.
Wiggina, J. Chan. Soc.f 2 3 3 6 (1950).
In tha flrat of a aarlaa of papara tha behavior of
derivatlvaa of nethyl 2,3-anhydro-o-D-allepyranoalde
toward methylmagaeeiua iodide waa atudled. Tha aola
product waa the 3-daozy-3-iodo-D-glu.coaIda derivative.
Rioharda and Wiggina (6 3 ) than atudled tha aana
(63) G. N. Rioharda and L, F. Wiggina, ibid.f
2442 (1953). 35 naotioB with ethyl and phenylnagneslwn halides. Ia this ease the product waa a 2-deexy-2-halo-D-altreae derivative.
Continuing the atudiea on the atrueture and re activity of anhydre sugars, Stacey and oeworkera (64)
(66) 1. B. Foster, V. 0. Overend, M. Stacey and
G. Vaughan, lfcid., 3308 (1953). investigated the action of dlethylnagnealun on nethyl
2,3-anhydro-4»6-£-bensylldene-a-D-uannoside. The product waa either a 3-deoxy-3-iodo or a 3-deoxy-3-ji- ethyl derivative, depending on the solvent.
The action of nethyl, ethyl and phenylnagnealwn
Iodides waa then extended to the 2,3-anhydro-D-nannoslde derivative (65) by Rioharda (67). The product in this
(67) G. B. Richards, ibli., 4511 (1954). ease waa the 3-deexy-3-lodo-D-altroalde derivative.
In the following year, Richards (68) investigated
(68) G. I. Richards, lbld.f 2013 (1955). the action of diphenylnagneslun on the sane nethyl
2,3-anhydro-4,6-£-bensylldene-«-P<-nannoslde aysten.
The product Isolated here was the 2-deoxy-2-£-phenyl- D-glucose derivative. 36
Finally tha action of magnesium halides alone on anhydro sugar derivatives waa shown to yield 2-deoxy-
2-halo or 3-deoxy-3-halo sugar derivatives, depending on the stereochemistry of the anhydro ring (69).
(69) G. N. Richards, L. F. Wiggins, and W. S.
Wise, ibid. . 496 (1956).
As can be seen fros the foregoing outline, the reactions of anhydro sugar derivatives with Grignard reagents do not show a consistent pattern and more examples are needed before the reaction can be under stood.
Synthesis of Pnsaturated Sugar Derivatives through Grignard Reactions
Synthetic aldltols have been prepared by LeBpleau
(70) from smaller carbon fragments and Grignard reagents.
(70) H. Leepieau, Advances in Carbohydrate Chem..
2, 107 (1946).
The total synthesis of galactitol from monochloro- acetaldehyde and ethynylmagnesium bromide was disclosed in 1934 (71); the resulting l,6-dichloro-2,5-dihydroxy-
(71) K. Leapleau and J. Wiemann, Coapt. rend.f
183 (1934). 37
3 **h«z7 B« waa traatad wltk alkali to give tha teralnal epoxldea, which whan hydroljiad affordod a crystalline l*2*5*6-tetrahydroxy-3-hexyne. Hydrogenation followed by hydraxylatlaa of tha raaulting 3-hexene derivative gave aftar acetylatlon, hexa-£—aoetyl-galaetltol.
Starting froa 2,3—dlohloreproplonaldehyde aad athyaylmagaaalaa braaida aad following tha aaaa toch
at qua, Laapiaau ayathaaisad a eryatalllnc paata-Jl- aoatyl—DL-arabialtol (72).
(72) R. Laapiaau, lhld*» .203, 145 (1936).
A novel aynthaala of 2-deoxy-D—rlboaa, atartlng froa 2,3-£—l*opropylldene-L—glyearaldahyda waa raportad by Hough (73) • Raaetion with allylaagaaalua bronldo
(73) L. Hough, Chta. 4 lad,. (London), 406 (1951). gave a alrupy uaaturatad produet which whan hydroxylatad and ohroaatographad gave a alxture of 3-de©xy-5,6—£— laopropylldene-hexltols• Parlodata oxidation gave tha alxad 2— daoxy-4,5-i)— ieoprnpylidnaa pantoaaa which on acid hydrolyala afforded a airup conalatlng largely of
2—deexy—D—rlboaa. Tha lattar waa tranaforaad to Ita anillde and raganaratad la pure fern.
A eoaprahaaiire aooount on tha raaetion of carbo hydrates with Grignard raaganta waa given by Bonner (74)* 38
(74) V. A. Bonnar, AAt i i m i in CarbohTdrata
251 (1950).
Tabla 3 liats tha raaotiona of earbohjdrataa with Grignard raaganta and tha raaetlon producta.
To avoid duplication, tha work prior to Bonner'a ooapilation (74) haa boon onittad fron tha tabla. Tabla 3 %ha Raactlona of Carbohydrate! with Grlgnard Raaganta
Sugar or darlratlra Grlgnard Raagent Product M.F. Rafarenoaa
Qlycggyl Hilldfli
Trl-£-acutyl-p-L-arabino- CH2-CHCH2MgBr tri-£-acatyl-l-£-allyl- alrup 76 pyranoayl chlorlda 1,5-anhydro-L-arabinitol
Tri-^-acatyl-D-iylo- j-CH^C^H^MgBr tri-£-acatyl-l-£-(ji- 110-111* 76 pyranoayl chlorlda tolyl )-l,5-«nhydro*-D- xylltol
Tri-jJ-acatyl-a-D-ribo- C6H5MgBr tri-jj-acatyl-l, 5-anhydro- 94-95° 77 pyranoayl chlorlda l-£-phanyl-D-ribitol
Tetra-Q-acatyl-a-D-gluco* tatra-j2-acatyl-l,5- pyranoayl chlorlda p-CH^OC^H^MgBr anhydro-l-£-(p-mathoxy- 103-105 50 phanyl )-D-glucitol
2-thienyl MgBr tatra-£-acatyl-l,5- 119-121.5 50 anhydro-l-£-(2-thianylJ- D-glucltol
CH2-CHCH2MgBr tetra-£-acatyl-l-£-allyl- 74.5-75° 50 1,5-anhydro-D-glucitol
C # n HgBr tetra-Jg-acatyl-l, 5- alrup 50 a nhy dr o-l-£-oyclohaxy1- D-glucltol
_ _ Vti iso-C MgBr tatra-£-acatyl-l,5- alrup 50 %© a nhydr o-l-£-i a oa *yl- D-glucltol 40 «*\ t - CM CM « CM CM r» v \ (TV IT\ *rt ift
o (ft * o O O O O o O' 00 o (ft cn cn I 00 tc\ H) «0 o K rH IC\ I CM rH rH CM pH <0 I I I I I o to vO «0 cn CM CM (ft (ft sO 00 o e* CM CM I o i rH p o K I I -H I I I I rH pH 4 I CM I CM O I cm a I rH rH rH O •H I ■H f I H | 9 •H | I H I • P At CM a o n A O H Ar O - t A O | I K I O I -H 4* I I 4» A I P At tO 4* A H p o a rH Wft • O O I OO I Ml rH I Ml I I Ml K I Ml I • o » X pH I O 4 At I NO k I nO K Q vO K o. X K K rH P H A O rH rH *MS pH »JS rH * X | * X O * X M I I P I t« -♦ K K ' ♦ O K H t) H H d A - ♦ c o rH CM *H rH 1 * X d * ■ X * * K • • o> * • • k —' (S'— O KX ( n o * (ft I 4> tn i Jo (ft I I m i Ti v i +» I P I « j d I (ft o I trt 4» I (ft o I (ft I • O f rH S A © i p . 0 * 0 0 * • 0 *—' O »(M S'pH t> | U> ci At ■O (ft I HJ rH | Ml rH I Ml rH I Ml rH I • p H O • rH I • T) «H * 0 | ■H I O f ■H | O f •H | O f *H | r-N • I P I I O 0 rH I rH II rH I H ■ rH T 1 H I rH ■ rH rH (H O l O P 0 | O I ci.5* • I H O • K rH O • K rH • K rH O • K K O I h O I O '-* I a 4 » r t I 4» P P I P P P I P P I P 4» 4> 4> 4» 0 • m> a • TI rH m m • K K-h • • K -H • • K • • K -rl • • O *H o At K rH h S K At t 0 Hi M o 0 o H o O <1 H 0 o M o 0 o x o p a X P X X P (ft • • O 3 m • o 0 • • O • • o o ■ o l d 4-S • O f • a p • * 1 o O H 1 I • rH • J • 1 j O H 1 I O H a •H fl Q « « P rH CM • Ml 00 cm O f *a oo CM O f Ml CM O f Ml «• CM O f — to o a cn At • At X rH X to X At X At At 9 2 x CM X X Eh ♦ to X At At X X X o X Ar m X X o X X x K O' < •I o jr X X X X 99 o 0 (TV X (Tl Cft ♦ O tr\ CM X m X o o X X x CM I I 'O o O o O o c k o
1 1 o O o O 0 o • rH rH 1 Ml X X CM -H 1 1 1 B a • a rH 1 O 1 x i • s a At d -H 0 TJ P 1 X 1 At 1 -H • 0 rH O rH 0 ti 1 rH KrH K o • K K P X P At I H • • • O • X Of O O Ml o O I • a -h 9 rH • rH ■H TJ 9 m 1 K 1 K At | At O Of • Of • Eh CM K At 1 o I O I 1 O.X • o • o nO O O O At 9 At « * fl O At P At P At H r l 9 0 • K • K * B rH K Eh O. Eh P. K\ • o o 43 o H> rH rH 0. O. a. 0. NO P 1 1 0 V 0 0 1 1 -r >4 O h V ON m O' -» P ■ •rH P in p rH rH a • • a 1 rH 1 o | o r", 1 TP rH 1 1 p 1 1 rH p K K rH 1 rH Q P I O X K KrH K 1 V O 0 P o I 1 rH rH ! 0. rH P V rH 1 x I 1 1 43 ol Ol O rH K O K 1 mi u *c\ p. vrs rH MN P rH 1 1 44 • M V X vO K 1 « m •* b - 0 9 1 rH rH 1 rl H 1 o O.P Q rH ti rH 0 P 0 4* m | O m i d o | a o « 't a i 1 1 1 • 1 1 -H - >V4» » K d 1 MJ • ti *■ a K rH rH rH 43 rH 0.|d H K H H M < rH 1 P 1 • p | X K'— K 0, K ^ d 1 O 0 I o s 1 sO i ol'o 1 in O +> 1 rH P 1 rH p 1 « rH • d P 0 1 rH 1 o| 1 P O •> « Oc5| o • Ol O • of d ►.« « KMI P K O 1 p a Ml P TJ O 1 4* O 1 4» o T j ■p i i P I 1 P V p *o o P I I a P p • rH «rl O H O OH) 1 • 'O— » 0 X • I d O | rH O P cm in a * rH CM 1 1 4* 1 1 4* jL * * O I o K • K 1 0 |0 o 0 (0 0 6 | Or-, • o i • O K • 43 0 » h 4* P H 1 u m 1 h • f v rH 1 V P 1 h rH I d p p m 0 • • K HO H • Ml rH • • o s 0(Ml K 0|MJ O oi • xH K 1 Vi O O H h K ■ (4 K o v K d 1 K d 1 K P 1 1 d x a o • a (3 P JO 00 4* 43 00 P X 0 P X O H 43 | th m d p d x 0 1 I 0) • a i • 11 1 • d 43 M d 43 m d cm h • • • a p a CM <£|X P a A P a O P 0 0. p ■ a. 4* •'— P rH m ti mi >4 P P £3 O o u CO h V 00 XX p VV X 00 X 0Q 00 X X • 00 00 •N* CM P XX U >o h X X X CM t*- X o X HD o o a x X 00 o 00 O X X o o X p X P o 00 m rH «r\ x m X a X X O at u X o CM P nO 1 sO l HD 1 X X o rH O O 0.1 o o 1 1 o o p (3 al a o a P U 1 1 Ml a a 1 K a o CM P P ti X a p I X 1 ti a I 1 o a OlP rH 1 O bo a a 9 p d M 1 u KQ V 1 Ml 1 Ml K a p 1 P 1 JO X P O P P V X ->Q a a e 1 V 1 M • K d CM | p O | H rH O P O O (X a • a a K K K rH K P a o p a d J H a • P X P X i a a K a o 0(0 0-0 • o a o oi d M3 X Ml V l a d p o o I a •H P P d P Ml • ■ a P a P p ti o a p mi VIVO 1 K v 1 a p ti KP (HIM I k ) . O) a Si rJ Ml ■ 0. a 1 1 0.x 1 o 1 o 1 1 P < POO vO o o o a d a d N't K V a K v d •>(3 0). v a v a -NO a X 0. a •NO P 0 X P V P V POP d P o V * i h s a K a K - a x o a a 0 rr\ « MX t-* P. E-« 0. CM Ml O p X P Vi o a r3 Acyollc Aldoae and Aldulosg PerlvatlTf o rH rH o o O | 0 TJ rt t r o sd X rH TJ XI TJ (ti h rH T o T Q\ rt rt H o fr K 0 0 t r i 0 t 0 rt 0 0 X O 0 *4 a a K 0 0 ►, 0 H t0 0I h h 1 1 1 1 1 1 1 I I Otrt HOlA »4 A l O rH rH TJ i t t r t r M tH ►» 1 0 O i t 0 0 0 ° * © « 0 a-a i 1 o 1 rH rH t r (4 ti p. (0 A r 0 •rt H rH X rH CM rH O CO OI OI o m X t r d t r M K * 0 I V A t r XH))A 4 •rt O) 0 rH h (ti rH rH H O K rH rt tj0 r TJ XI J T ■rt 0 0 KOi-rt 0I 2 * 2 1 b K J ta i t t r O ►* O ►»ti ti0 I *4 *4 ti OrH o o ia a G,"* | o av4 00 - a I I 0 H H 1 I1 o I h MTJ T M 1 »-3 J T j t 0 0 1 0 K K 0 1 t t 3 I I i t * a X TJ TJ 0 0 0 K o 0 H o CO X TJ G b (4 a ti a o vO NO X) X> X I X I TJ O 33 X O' iH ' O X X H H O rH rH OI TJ -rt co a o O) H «0 « rH x x a x x rt ti Gi A lA rt 3 KQ KQ l>* K ti *4 rHO TJ t r d 2 K I 0 I 0 d ti C0 0 K 0 O 0 O N I 10 I . I I rH rH I (O I ^ TJ 0 • (*\ a Q J T Tj •rt 0 «od * H 0 0 o ►*d •i o 4 0 0 I rt t O I rH M 0 ti o o a o n sO 0 I >0 vO O *f\ rH O o d f• »4 • xf rtI < o 33 X +>•04* t I -t O d • I rH rH I • 0 d a h no C O CM ■ o o h, IM 4,3 I I 1 rt OI »A ••OH I 0 H s o TJ K *4 a O n 3 O 33 VO (ti x I • d CJ (A rHOI rH X X B* »r\ ■*» da oi d rH d «H O -<* M TJ IP U £> 10 VO K OK ■TJ 1 0 0 i • • • I h a « I I I K N I Ot XT X » (ti a o • a a 0 MK u 1 V *4 •O d O ti o n >o KH ' O O rH o l f h q OI 0 X X M> A HO J* OI rH rH O ->t rt ti 0 IX ° O ti TJti Q 2 1 * •I TJrt rt ti tj K m I K • K t I OI • • K 0 o o o tj 0 0 0 h 1 I rt 1 o I a rH rH o x> i 8 IA to Pli O' rt h X PQ *rv XI •| rH OIrH X*OI +j d e» d +j H 0 rH H ->♦ M X >4 0 TJ 0 S o tj o S K K I0 tiTJ 2 •I oi I I G0 I 4 » * • 42 I rt O fc, ti o ti a 1 43 O' O' sO C~ f - c - v© »0 rt> 'O vO o o IA n • o sO CC XT pH o vO o I o o p H rH «0 to «0 1 1 O' O' O' Cl I I I o t" c - c - rH pH O' O' O' 1 1 1 >* 1 K 1 K i 1 1 •rt M •rt K •H XJ •rt 1 t ) 1 •rt 1 rH O R p H O • p H P p H O • pH O R •rt O R K • TJ K • TJ ►* • • ►*TJ TJ K TJ TJ K t j TJ • TJ H « TJ r t « 1 TJ M O wi H o •rt H O -rt 0 1 R 0 1 a 0 CJl r t a ■H R 0 -H R 0 I I ? vO H3? I » I « O -rt o -I- a I pH O pH I s (4 R U 0 TJ I TJ I K n SC ■o | X) | a 0 0 0 « I R I t • I • <-c d • K M ) • » R TJ » R TJ C l TJ r t CM TJ -rH •H R •H R pH pH O rH rH O ►* >* 0 o XJ R R js it m p d m P 0 Si R R t s • R X jO a x x> a. / Table 3 l i M U m m l ) Methyl 2,3-anhydro-4,6-.Q- C2H5MgI ■ethyl 4»6-£-bensyli- 119.5-120° 67 benzylidene-a-D-nanno dene-2,3-dldehydro-2, pyranoside 3-dideoxy-a-D-gluco- pyranoside 0 ■ethyl 4,6-£-bensyli- 154.5-156° 67 dene-2-deoxy-2-iodo-o- D-gluoopyranoside (C6H5)2Mg methyl 4,6-£-benayli- 162.5-163.5° i dene-2-deoxy-2-£-phenyl- a-D— mannopyranoside MgBrj tie thy 1 4,6-jQ-bemyli- 123-124° 69 dene-3-bromo-3-deoxy- o-D-altropyranoside * Reduced product. ^ Product after acetylation. c Structure supported by ultraviolet absorption apeotra. (75) Tu. A. Zhdanov and G. N. Dorofeenko, Doklady Akad. Mauk^ SSSfi. HZ, 433 (1957), 51, 13767 (1957). (76) Xu. A. Zhdanov, G. M. Dorofeenko and L. E. Zhivoglaaova, Doklady Akad. Hauk. SSSR. . 117. 990 (1957); Chem. Abstracts, 8055 (1958). (77) Xu. A. Zhdanov, G. A. Korol'chenko, L. A. Kubasskaya and R. M. Krivoruohko, Doklady Akad. Nauk. SSSR., 129. 1049 (1959); Chem. Abstracts. H, 8*41 (i960). (78) lu. A. Zhdanov and G. A. Korol1chenko and L. A. Kubasskaya, Doklady Akad. Nauk^SSSE.. HI, 1185 (1959); Chem. Abstracts. 8645 (I960). 45 Sygttolll of twilill Deoxy I t x w i Soat Mtoxy-htzoiti hif« long been rtoogiiicd as oonstltueats of many natural compounds (79), and (79) B. C. Xldarflaid, Advances in Carbohydrate 147 (1945). thay aeenr usually aa glyeoaides. For example L- rhaanoaa, a vary eoaaoa constituent of planta (80), (80) X. L. Hlrat and J. K. 1. Jooai, Raaaaroh. 411 (1951). waa obtalnad froa tha flyeoalda Quarcatln (81) la 1854. (81) L. Rifaud, AflA-» 22, 283 (1854). Tarlooa aathoda have baan used for tha aynthaala of tha naturally occurring 6-deoxy-hexoses, and tha majority of tha other theoretically poaaibla laoaara have baan prepared aa wall, Rplaerlaatloh Methoda Lacking tha aaana for Introducing daoxy funotiona In augar aoleeulea, chaalata first attaaptad tha epineris- ation of other known and naturally occurring analogs, differing usually in tha configuration of one carbon 46 atom* However, a limitation in the available 6-deoxy- hexosea, as well aa in the alte of configurational change (this being exclusively at C-2 in moat cases), together with the low yields reported, has made this method somewhat limited in use. Fischer and Herborn (32) synthesized 6-deoxy-L- (82) E. Fischer and H. Herborn, Ber .. 29f 1961 (1896). glucose by epimerizlng L-rhamnonic lactone in hot pyridine. The resulting 6-deoxy-L-gluconolactone was reduced to the sugar with sodium amalgam. The availability of D-fucose from polysaccharides made possible the synthesis of 6-deoxy-D-talose from D-fuconic acid by epimerization with pyridine (83). (83) E. Votocek and C. Krauz, 44, 326 (1911). Votocek and Cerverny (84) then synthesized 6-deoxy- (84) E. Votocek a nd J. Cerverny, 659 (1915) . E-talose from L-fuconic acid. A relatively uncommon 6-deoxy-aIdose is D-rhamnose, which unlike its enantiomorph, does not occur in nature. 6? It was obtained from tba apinarlaatlon of D-gluaene- laatana with pyridine (85)* (8$) I. Totooak and F. Valentin, Chan, llatv. 21. 7 (1927)} gfcti. il, 1696 (1927). Tha pyridine aplnerlaatlon nothod vaa later naed on tha nnaubatitutad radueing augara and haa baan known aa tha Flaeher-Danilov method (86). (86) (a) H. 0. L. Flecher, C. Tauba and S. Saar, Bar.. 60, 679 (1927)j (b) S. Danilov, £. Venus-Daailova and P. Shantarovioh, ibid.. 63, 2269 (1930), Tha aneoaaa of tha apinarisation method dependa in moat oaaaa on whether aona suitable derivative oan be found whioh anablaa good aeparation of tha product from tha atarting material. Suoh a condition vaa realised in tha ayntheala of 6-deoxy-L-tagatoaa from L-fueoae, and purification of tha product by fractional eryatallisation of tha o-nitrophenylhydrasone derivative (87), (87) (a) Jean W. kollaratroa-Barnatt and T. Reieh- ataln, Halv. Chim. lota. 20, 1329 (1937)} (b) I h l A - , 2^, 913 (1938). 48 Reductive Methods Terminal halo derivatives The reduction of terminal halo deoxy auger de rivatives ia one of the oldest and most frequently used methods for introducing a deoxy function in a terminal position, Fischer and Zaeh (8 8 ) observed that the reaction (88) £. Flacher and K. Zach, , 4 5 , 3761 (1912). of D-glucose pentaacetate with hydrogen bromide afforded the unexpected 2 ,3 ,4—tri— acetyl—6— bromo—6-deoxy—a—D— glucopyranosyl bromide. Conversion of the latter to the methyl glycoside and reduction with sine and acetic acid gave the 6-deoxy-D-gluooae derivative which on hydrolysis afforded the well known 6-deoxy-D-glucose in crystalline condition. The synthesis of 6-deoxy-D-galactose was reported, by the same method (8 9 ). (89) K. Freudenberg and K. Raschig, ibid. r 60 1633 (1927). The first 6-deoxy-hexulose was synthesised by Barnett and Reichstein (87a). Reaction of l,2i3,4-di- £-iaopropylidene-6-^J-p-tolylsulfonyl-D-tagatoae with sodium iodide in acetone gave the 6-iodo derivative, 49 thus providing a aonvanlamt ronta for iatroducing tha iodlna atom la a priaarj carbon function. Thia ro- aotion vaa pravlaualy uaad by Lavano and Compton (90) (90) P. k. Lavana aad J. Compton, Biol. Cham.. 1X1. 325 (1935). la tha aynthaaia of 5-daoxy-D-xyloaa. Raduetlon of tha lodo ooapoaad with Ranay alekal (90) aad aubaaquaat hydrolyala affordad 6-daoxy-D-tagatoaa. Tha ayathaaia of 6-daoxy-L-aorboaa followad ahortly aftarwarda (91). It vaa foaad that tha raaetlon of (91) H. Mmllar and T. Ralohataln, HaIt . Chin. A*Ut 11, 263 (1938). 2 t3-j2-iaopropyHdana-lf 6-di-£-p-tolylaulf onyl-a-L- aorbafaraaaaa with aodiua ladlda oould ba tharaally controlled ao aa to glTa a aoao-iodo or a dl-iode darlTatiaa. Tha aaaa bahaTlor vaa obaarvad ia tha aynthaaia of 6-daoxy-D*fruotoaa (92) from 2,3-£-iaopropylidana- (92) V. T. J. Morgan and T. Raichataln, Ibid.. 21, 1023 (1938). l,6-di-£-p~tolylaulfonyl-D-fruetoco. Kaduotlon af tha 50 aoao«lod» o«|poaad with Kaity llekal affordad tha 6-daoxy derivative whloh waa treated with aedlum amalgam to re- ■ova the p-tolylaulfonyl group from C-l and regenerate tha primary aloahalie funetlem. n Mmllar and Jtelehateln (93) duplloatad Lavana and (93) H. M«aiar aad T. Relehatein, Ibid.r 21. 251 (1938). Caaptoa'a (94) aequenee for tha aynthaaia of 6-deoxy- (94) P. A. Lavana and J • Compton, J, .Blfll, Sht»., 111. 335 (1935). D-guloae, whan thay ayathaalsad 6-deoxy-L-guloae from 5-daaxy-L-xyloaa by tha oyaaohydrla raaetloa aad aab- aaquaat raduetioa of tha aaparatad 6-deoxy-L-gulonolaetone. Tha firat aynthaaia of 6-deoxy-D-altroae waa re- portad by Gut and Prlaa (95) and Involvad tha ouatomary (95) M. Gut and D. A. Prina, Halv. Chlm. 4ctar 2£, 1555 (1946). raduetlon of nathyl 2,3,4-tri-£-a©etyl-6-iod©-D-altro- pyranoalda with Ranay nlekal and aubaaquant hydrolyala. It la noteworthy that In many inataneaa, tha 6*deoxy augara have baan purified by preparing their 51 hydrazones and raganerating tha free augar by reacting tha hydrazone with hanaaldahyda. Terminal unaaturatad (dldahydro) augara and glyooaaana In eartaln caaaa tha hydroganation of unaaturatad derivatives haa bean naad as a aynthatle method for terminal deoxy augara. Apart from tha limited waya of introducing such an unaaturatad function In a terminal position, one would obtain terminal dldeoxy augara froi the corresponding unaaturatad (dldahydro) derivatives. Hence, only the glycoaaena, which are anol athar de rivatives with one unaaturatad carbon atom bonded to the hemlaoatal oxygen of C-l, are of potential uaa aa precursors for 6-deoxy augers. Hera again, tha forma tion of two theoretically possible C-5 epimera should not be overlooked. I----- CH, OH CH, OH t t HCOH HCOH t I HOCH HOCH i 1 HC -- HCOH t I CH C N ■ CH<) c h 2 5,6-didehydro 5,6-glycoseen An example is provided in tha aynthaaia of 6-deoxy- D-galactoae and 6-daoxy-L-altrose from tha reduction of 52 1.21 3.1-dl-Q*l«ftDroBTlld«f-L»ariblBP-h«»QPT«BO»>»5- eenide with a platinum oatalyat (96). (96) X. Freudenberg and X. Raahig, Bar., 62. 373 (1929). Mora recently Jonea and oovorkars (97) have (97) (a) J. X. X. Jonaa and J. L. Thompson, Can. Chan.. 35, 955 (1957)j (b) D. J. Ball, A. X. Flaod and J. X. V. Jonaa, ibid.. 22* 1018 (1959). ajnthaaiaad 5 r6-dldooxv-D-xylo-hexQBQ and 5,6-dideoxy- L-arabino-haxoao from tha corresponding nnaataratad (5,6-didehydro) faranoaaa. Tarnlnal anhydro sugars Tha raduetlon of tarnlnal epoxides haa baan anothar wldaly uaad nathod for tha aynthaaia of 6-deoxy-hexoses. Tha nathod la uaeful becauae of tha relative aaaa of eraating a tarnlnal epoxide in a conveniently aubatltutad angar nolacula. Tha applleatlona have been alnost ex clusively in tha D-glucoae aerlaa. Fraudanbarg and ooworkers (98) prepared 6-deoxy- (98) K. Freudenberg, fi. Rich, C. Knoavanagal and 0. tfestphal, £jt£. , 73, 441 (1940). 53 lr2 -£-i>oprop7 lid«B«*D-glaeoie by the catalytic hydrogenation of the eorreaponding 5,6—anhydro derivative. The earne technique vaa uaed in the aynthaaia of other 6-deoxy-D-glueoae derivetlvea (99-101) and 6-deoxy-L- ( 99) E. lota. 27, 1332 (1944). (100) 4. S. Meyer and T. RelchatelnP Ibid.. 29. 152 (1946). (101) E. J. Relat, R. R. Spencer and fi. R. Baker, Hm Sri. Ch*»., 23, 1753 (1956)• gluooae derivativea (102) aa well aa 6-deoxy-L-idoae (102) F. Blindenbacher qnd T. Relohateln, Helv. Chin. AqU, J i , 1669 (1946). derivativea (100,103). (103) E. J. Reiat, R. R. Spencer and B. R. Baker, 2i, 1757 (1956). Terninal aulfonyloxy and nereapto derivativea Since the extenaion of lithiun a1uninun hydride reduction of primary arylaulfonyloxy groupa to auger derivativea (1 0 4 ), thia method haa gained eonaiderabla 54 (104) H. Schnid and P. Iirrtr, Halv. Chin. Acta. 32, 1371 (1949)• intereat. It la la effect, tha ahortaat way to con- ▼art a hydroxynethyl group to a aathyl group. It haa baaa uaad In tha aynthaaia of 6-deoxy-D-idoae deriva- tlvea (105), 6-deoxy-D-glucoae derivativea (100) and (105) &. Plaehar, H. R . Bolllger and T. Reich- ■tain, 6 (1954). 6-deoxy-L-idoae derivativea (106), and a nunbar of (106) A. 3. Mayer and T. Ealohataln, atIT. ChlM AAiM# _29* 139 (1946). othar eaaaa. Deapite tha ahort-eut, thara ara racant raporta (105) vhara tha reduction of tha tarnlnal iodide la preferred for tha aynthaaia of tarnlnal daoxy haxoaaa. It would ha adequate to aay that In oaaaa where tha producta ara airupy or difficult to cryatalllse, tha ranoval of tha aulfur inpurltlaa nay be tadloua. Moreover, it la evident that thia nathod la applleable only to aubataneaa that ara aolubla In organic aolvanta oannanly uaad in lithlun aluniniun hydride raductioaa. 55 Recently * selective reaotien of a primary jp-tolyl- ittlfoayloxj function aad a modified route to taraiaal deoxy augara vaa raportad (107)* Traataant of 1,3,*- (107) J. Stanafc and L. Tajmr, Chaa. llatr. 52. 551 (1958); Q h t t U J J , 4 H 6 (1959). tri—JB-acetyl-2,6-di-JB—p-tolylaulfonyl-D-glueoae vlth potasalua thloeyanate affordad through a selective ijplaeaiant, tha 6-rhodano derivative which eould ba traaaforaad to a 6-deoxy-D-glucoae derivative by raduetlon vlth Raney nlckal. QjLldltlTt-iltlfaRdl Oxidation of a hlghar augar to tha approprlata 6-deoxy haxoaaa haa aaldoa baan uaad aa a synthetic aathod• An exaapla worthy of mention, la tha syntheala of 6-daoxy-L-gluooaa and lta laolatlon In crystalllna atata by Hudson and eovorkara (108). Tha raduetlon of (108) E. Zlsale, N. K. Rlohtnyar and C. S, Hud son, _im._Cham. Soc.r _73. *71* (1951). D—glueo-D-gttlft-hiptogi diethyl dithloacatal affordad tha daoxy oonpound which waa tranaforned to the 3,5- g-bensylldene derivative. The latter waa oxidised 56 vlth lead tatraaeatata and hydrolysed to give crystal line 6-deoxy-L-glucoae. In other instances, oxidative methods have been used in the carbohydrate field without degradation* Thus, treatnent of oertaln unaaturatad sugar derivatives (glycale) with perbensolo aoid to introduce hydroxyl functions has been used in the synthesis of 6-de oxy-D- allose (109). (109) (a) 4. Vlndaus and G. Schwarts, Machr. Gee. Wisa. Gottinaon Math. Phrsik^ Klaaae. 1 (1926); (b) F. Michael, , 6^, 347 (1930). Inavnlo Methods Quite recently the ensynlc methods have not only provided syntheses for rare deoxy augara but also helped in the understanding of many biological transformations (44). Hough and Jones (110) synthesised 6-deoxy-L-sorbose (110) (a) L. Hough and J. K. H. Jones, Chen. & Ind.. (London). 715 (1952); (b) L. Hough and J. K. H. Jones, f* CfrtM* Sgfi., 4052 (1952). and 6-deoxy-D-fruotose from the condensation of lact- aldehyde and dihydroxyacetone in the presence of an ensyne. 57 Palleroai and Doudoroff (111) found that mannose (111) M. J. Palleroni and N. Doudoroff, J. Biol. £&*»., 21.8, 535 (1956). laonaraao fron Paaudononaa aaaeharonhila transformed D-rhamnoae into 6-deoxy-D—fruetoss# but was ineffective on L-rhamnoae. In L-rbannose isonarasa fron BaeherAchia ooli waa found to transform L-rhannoea into 6-deoxy-L-fructoae aa an initial atap in tha raaotion (112). (112) Dorothy M. Wilson and S. AJ1, J. Bactariol.. 73, U O (1957). Table 4 liata the synthesised 6-deoxy-hexoaes. Table 4 The Synthetic 6-Deoxy-hexoaea Sugar Synonym Occurrence M, P. r o i References Aldoses 6-Deoxy-D-allose D-alloaethylose Digiioxin, Gofruslde 146° -12-1,0°(H20) 109,124 6-Deoxy-L-eltroae L-altroaethyloae sirup -17.3o (H20) 96 6-Deoxy-D-altrose D-altroaethylose alrup +16.2^2°(H20) 95 6-Deoxy-D-galactose D-fucose, glycosides of +110 -75.7° 89, rhodeoae conYolYulacae 140-145° (h 2o ) 96,121 6-Deoxy-L-galactose L-fucose plant gums, sea weeds, blood polysaccharides, -120 — +74 114, sea urchin eggs 145° (H20) 116,120 6-Deoxy-D-glucose D-glucoaethylose glycosides of D-epirhaanose Cinchona and D-lsorhaanose convolYulacea +73-29.7° 88,113 D-chinoroae 139-140* (H20) 115,127 6-Deoxy-L-glucose L-glucoaethylose 143-145° -29.^H 20)a L-laorhaanoae needles 82y 142-144° -30.1°(H20)a 108,116 prlsas CO Table 4 UgflUflWi) 6-Deoxy-D-gulose D-gulomethylose Wallflower 130-131° -38(820)* 94,118 (£] 122,126 £.hfirl 6-Deoxy-L-gulose L-gulomethylose alrup +40.8il.5° (H20,final) 93 6-Deoxy-L-idoee L-idoaethylose 106,125 6-Deoxy-L-nannoae L-rhamnoae Quercetin; 122-126° widespread in (hygro- 80, plants soopic) +9 (^2®) 81,123 6-Deoxy-D-aannose D-rhannose -8.25°(H2 0) 85 6-Deoxy-D-talose D-talomethylose, D-eplfucose, D-epirhodeoae sirup +12 (H20) 83 6-Deoxy-L-taloae L-talonethylose glycosides of L-®plf UC08® Stophanthua aarnentosua sirup -37°(H 0) 84,120 6-Deoxy-D-tagatose D-tagatomethylose sirup -2;2°(H20) 89 6-Deoxy-L-tagatose L-tagatonethylose 68-69° +3-l°(H*0) 87a,81b 6-Deoxy-L-sorbose L-a orbomethylose 88* -27.7°(H20) 91,110 VJl vO Table 4 (continued) 6-Deoxy-D-fructose D - f ruetomethyloae 136-137° +40I3® (EtOH) 92, 110,111 6-Deoxy-L-f ructoae*5 112 * Equilibrium rotation. Paper chromatographic evidence only. (124.) A. Hunger and T. Reichatein, Helv. Chlm. Acta. 35f 1073 (1952). (119) E. Votocek and F, Valentin, Collection Caechoelov. Chan. Goan.r g f 36 (1930). (121) H. H. Schlubach and S. Wagenita, Bar.f 65f 304 (1932). (114) J. A. Widstoe and B. Tollena, B*x., 2J, 132 (1900); Ibid.P 301 (1904). (117) T. Tadokoro and Y. Nakamura, J . Blochea.. (Japan), g t 461 (1923). Table 1 (continued) (120) E. Votocek end V. KttCerenko. Collection Czeohonlov. Chen. Comm.. 2. 17 (1930). (113) E. Fischer and C. Liebermann, Ber. , 26r 2115 (1893). I (115) E. Votocek, Ber. . 11, 819 (1911). \ (127) A. K. Mitra and P. Karrerr Helv. Chin. Acta. 38, 1 (1955). (116) E. Votocek and J. Mikaic. Hull*. Soc. Chin. France, 1 , 13, 3761 (1912). (118) E. Votocek and L. Benea. Chen, liflty. 22. 382. 385 (1928). (122) I. E. Muekat. J. In. Chem. Soc.. 56, 2653 (1931). (126) J. &. Moore. Ch. Tamm and T. Reichatein. Helv. Chin, .tcta, 2 1 , 755 (1951). (125) G. Charalamboua and Elisabeth Percival. J. Chem. Soc.r 2113 (1951). (123) Tollena-Slsner, "iurzea Handbuch der Kohlenhydrate," Berlin , 1935, p. 162. O' H 62 Syithtili of Braaelfd-Chila Sugar* Few branahed-ehaln eirbohydrates have been isolated froi naturally oacurrlng aubatanoaa (4) or synthesised in tha laboratory. Furthermore, tha aala affort haa baaa dlraetad toward tha possible alueidatloa of tha atrueturoa aaeoantarad. It haa baan difficult to a a— tabllah the configuration of an aayaaetrlc tertiary carbon in theaa branohed-chain augara, alnoa there ara no eonpounds of eatabliehad configuration to which thay can ba directly related. The lag in tha aynthetlo development on tha other hand, haa bean primarily due to tha branchad charaotar of theae aolaculaa and tha difficulty of introduolng tha daairad carbon fragnant In a apeoifie position. Tha £-Hydroxymethyl Sugars Tha £-hydroxymethyl tatroaas By far the most abundant branched-ehain sugar la apiosa^ (128) which la present in parsley and Australian (128) C. S. Hudson, Advances In Carbohydrate , 4, 57 (1949). pond weed (189). Apioae vaa first isolated fron tha (129) D. J. Ball, F . A. Iahervood and N. E. Hardwick, J. Chan. Sou.. 3702 (1954). 63 piraltj fliTon* glyeoaide, apiln, by Yongerlohten (130). (130) E. Vongariohtan, Inn., 318. 121 (1901). Hla reaearohee and thoae of Sehmldt (131) aatabllahad (131) 0. Th. Schmidt, Ibid.. 483. 115 (1930). that apioaa ia a branohed-ohain augar containing five oarbona, la tar elaaalfiad aa a 3-£-hydroxynethyl-tetroae. inothar augar vaa laolatad from tha antibiotic oordyaapin (132). It gave aa oaaiona, thua allnlnating (132) H. R. Bentley, K. G. Cunnlnghaa and F. S. Spring, J. Chaa. Soo.. 2301 (1951). tha poaalbllity of a 2-daoxy function, and waa not affaetad by parlodata. Tha augar waa naaad oordycapoaa and waa ahown to ba a 3-deoxy-3—£-hydroxymethyl-tetroae. In 1955, Raphaal and Roxburgh (133) publlahad thalr (133) R. 1. Raphaal and C. M. Roxburgh, 1bid., 3405 (1955). ayntheala of DL—apioaa and DL-cordyoepoae and praparad cryatalllne derivativea of each. Natural apioaa haa tha D-( + ) configuration, and a ayntheala waa recently provided by Gorin and 6 4 Ferlin (134). Treatment of D-fruotohoptonie laotone (134) P* 4. J. Gorin and 4. S. Porlln, Can. J. £fcU‘> 480 (1958). with aodium borohydride gawe after approprlata blocking, 3-g-benay1-2-£-hydroxy methy 1-fl-arablno-baxltol which waa cleaved to 2-0-benayl-3-C-hydroirnthyl-D-glycaro- tatroaa. Debenaylation gave D-( + )-apioae^ or 3-£- hydroxrnethyl-D-glycero-tetroie. It ia noteworthy that a selective oxidation of tha glyool gronplnga oecurrad in tha aaoond atap, tha tertiary hydroxyl group not balng Involved. 1 Tory raoant aynthaaia of L-aploae fron (♦)- tartarlo acid waa raported by Vaygand and Sohmieohen (135). (+)-Tartario acid waa transformed into lta (135) P. Vaygand and R. Schnleohen, Chan. Bar.. 92, 535 (1959). di~£-aeatyl nonoaatar acid chlorida which on traatnant with diaionathana followed by acetic acid gave nethyl tri-0-aoatyl-L-throo-l-pontuloaonete. The latter waa treated with diaaonathana to introduce a potential hydroxynathyl group in the C-4 poaition. The resulting nathyl 4-C-hydroxynethyl-L-throo-pontonate was degraded through tha calcium aalt to L*»aploaes 65 Tha £-hydroxyaethyl pentoses The earliest known sugar iu this aariaa la haaaaeloaa which oooura la haaaaell-tannin (1 3 6 ), (1 3 6 ) K. Flsoher and K. Freudenberg, Bar*, 4 5 , 2709 (1912). It doaa aot ooeur aa a glycoslds but aa tba free aldoaa. Sehaidt (137) aaaigaad tha 2-£-hydroxyaethyl- paatoaa atruetura to haaaaalasa aa It did not giro an (137) 0. Th. Sehaidt, A**., 250 (1929). oaaaona, and poasesssd an hydroxyl group that waa not raadily aatarifiad (138). The optical properties of (138) C. Paal, £i£., 49} 1667 (1916). haaaaeloaa indicated that tha oonfiguratioa of C-2 ia haaaaaloale aoid is tha saaa aa in D-ribonio acid, Tha D-»rlbo ooafiguratlon of the augar waa aatabllahed by tha ayntheala of hananelonle acid and its C-2 epiaer from D-arrthro-psntuloae (139) by the oyanohydrla (139) 0. Th. Sohaldt and K. Heints, Ann.r 515, 77 (1935). raaetloa. Haaaaeloaa thus la 2-£-hydroxynethyl-D-ribooe. 66 V (1 4 0 ) reported the aynthesis of (140) R. J. Woods and A. C. lfeish, Can. J. Chen.. H, 471 (1953). X-fi-hrdroxvnethT1-D-throo-pantoss by tha degradation of 4-£-hydroxynethyl-L-xyluronie acid. The sodium analgan reduction of 2-£-hydroxynethyl-D-xylonolactone afforded another branched-ehain sugar, 2 h y d r o x y - nethyl-D-xyloae. The £-hydroxynethyl hexoaea This elaaa of bfanohed-ohain sugars la quite rare and has not been encountered in nature. Woods and Welsh (141) synthesised 2-jJ-hydroxynethyl- (141) R. J. Woods and A. C. Meish, ibid. f 1 2 , 404 (1954). D-glueose by the sodiun analgan reduction of D—fructo— heptonola otone• The application of the oxo reaction to the glyeals gave branohed-ohain augara (142). Treatnent of tri-£- (142) A. Rosenthal and D. Read, Ibid. . _3_5. 788 (1957). aeetyl-D-galaetose with carbon nonoxide and hydrogen 67 In the preaemoe of an approprlata catalyst gave several compounda of unknown stereochemistry at C-2. A probable produat waa l,5 ~aah7 dro*2 -d«oxx-2 -£-h7 drox7 atth7 l-D* ^LXXA-kexltol, aa oonoludod from periodate and nuclear magnetic reaonanoe etudiee. The £-Fornyl Sugara The £-fornyl pentoaea Streptoae ia the first branohed-ohain augar to have been identified aa a component of the blologioal compound produced by a microorgaoiam, namely the anti biotic atreptomyeln. It la a dloarbonyl augar and ia known only in lta derivatives. Streptoae haa an aaymmetrio tertiary hydroxyl group, and lta atruoture haa been determined by degradation (143). A review on (143) (a) N. G. Brink, F. A. Kuehl, Jr., E. H. Flynm and K. Folkera, J. Am. Cham. Soo.. 68. 2405 (1946) vs (b) ibid.. 70. 2085 (194*)* (c) J. Fried, Doria £. Wals and 0. Winterstelner, ibid.f 68. 2746 (1946). the chemistry of streptoae haa been made by Lemieux and Wolfrom (144). In this article it waa noted (144) R. 0. Lemieux and M. L. Volfrom, Advances in Carbohydrate Chen.. j r 337 (1948). 68 according to previous findings (143) that straptosa aust ba either a 5-deoxy-3*£*forayl-L-ribose or 5- daoxy-3-Ji-formyl-L-lyxose. Since than, tha presence of tha latter configuration haa bean astabliahad by Wolfroa and DeWalt (145), in confirmation of tha work (145) M. L. Wolfroa and C. L. DeWalt, J. Aa. Chaa. Soo.. 70, 3148 (194#). of Folkars and coworkers (1 4 6 ), who baaed their con* (1 4 8 ) P. 1. Kuahl, Jr., Mary M. Bishop, £. H. Plynn and K. Polkara, ibid.. 70, 2613 (194«). figurational asslgnaant on tha application of tha hydraslda rule to polariaatrio data. Other £-forayl sugars Quite recently several higher branched-chaln £*formyl sugars have been reported. Schaffer and Isbell (147) synthesised a branched* (147) R. Schaffer and H. S. Isbell, ibid.. 80 756 (1958). chain trialdehyde sugar derivative. Treatment of 1,2 — Q-leopropylldone-5-aldehydo*D-xylo-l. 4*furano-pento* dlaldose with line gave a 9*aldehvdo-4.-C*f oravl- 69 nonotrlaldose derivative. Tha structure waa later aatabllahad (148) aa being a 9-aldahydo-A-C-formyl-L- (148) R. Schaffer and H. S. Isbell, ibid.. 81. 2178 (1959). lyxo-D-ido-nonotrialdose derivative. Tha aldol condensation of 2,4-£-ethylldene-D- erythroee waa ahovn to give a 1,3 * 5,7-di-£—ethylidene- 3-C-formyl-D-glreero-D-talc-heptltol derivative (149). (149) R. Schaffer, IkU., Jl, 2838 (1959). The £-Alkyl and £-4ryl Sugars Terminal di-£-eubatituted engara The extensive researehea of Paal and coworkers (56 and earlier references) led to an early ayntheala of many 1,l-dl-£-aubstituted hexitola and pentitola. Re actions of augar lactones with Grignard reagents afforded branched-chaln derivatives of L-arabinitol, D-glucitol, galactitol and others. Ohle1s extension (32 and earlier references) of the Grignard reaction to carbonyl sugar derivatives was another significant step in the synthesis of terminal di-£-substituted sugars. 70 Racantly, Folkare and coworkera (42) ayntheaimad mathyl 2,3-.fi-iaopropylidene-5>5-di-£-*athyl-L-lxx*- kazofuranoalda fro* tha corraepending nathyl 6-daoxy- L-It x o -5-hcxuloaIda and nathylnagnaaiu* iedida. Raac- tloa of tha aama raagant with nathyl (nathyl 2,3-fl- laopropylidane-D-ribofuranoelduronata) affordad aathyl 2,3-£-iaopropylidena-5,5-di-£-nethyl-£>-r ibof ura* oeide. An intaraating branchad-ohaim haptoaa haa baan raportad by Ohla and Daplanque (29) aa a byproduct in tha aold hydrolyala of 1,2 :3 , 5-di-iJ-laopropylidene- D-xTlo-hexopyranoaa-5-oen. It vaa tentatively aaaignad tha atructara of 3,7-anhydro-l,2-£-ieopr©pylidene-6«- deoxy-7,7-di-£-nethyl-D-jnlji-l,4-f ura no-5-hop toauloee, with no furthar oonflraation. Tha 3-£-nethyl hazoaca Recently a branohed-chain hazoaa waa laolatad fron tha antlblotle carbonycln and naned nycarcae (150). (150) F. P. Regna, F. A. Hoehatein, ft. L. Wagner, Jr., and ft. B. Woodward, Ibid. r 75, 4625 (1954)* Evidence ooncarning the atruetura waa aecured fron pariodata oxidation atudiaa and the laolatlon of aoetaldehyde and fornic aold. The atruetura 2,6-dldeoxy- 3-£-methyl-hexoae waa aaaignad, but the ateraoehenlatry of nyearoae ia not yat establlahad. 71 4 aimilar branched-chain augar waa laolatad froa tha antibiotic erythromycin (151) and waa aallad (151) P. P. Wiley and 0. Weaver, UJJi*, 2 2* 3422 (1955)• oladlmoae. It waa found that tha hypobromite oxidation of eladinoaa yialda a laotone whloh whan treated with alkali raaulta in a p-ellulnation of a methoxyl group and tha production of an a,f)-unsaturated augar laetome. Froa tha raaulta of tha periodate oxidation of thia aatarial and of eladinoaa ltaelf, Wiley and Weaver (151) have aaaignad the atruoture of a 2 ,6-dideoxy-3-£-methyl- 3 - 2 - thyl-hexoae to eladinoaa. Mo effort haa yet bean aada to aynthaalse thaaa eonpoumde. Table 5 liata tha known branched-chaln naturally occurring and aynthetle aldoaea or their derivatlvea. Tha terninal di~£.-aubetituted augers reported prior to 1950 have been onittad and are compiled in reference (74). Table 5 Tha Branched-Chaln Aldosea Sugar or derivative Synonym Occurrence M.P. Referenoe C-Hydroxymethyl Sugars 130,131 Tatroaes 128,134 3-£- (Hydr oxyaethyl )- D-glvcaro-tetrose D-aplose apiln alrup +6.4 (H20) 3-£-(Hydroxymethyl)- L-glvcero-tetrose L-apiose sirup 135 3-£- (Hydroxymethyl)- DL-glycero-tetroae DL-aplose sirup 133 3-D e oxy-3-£-&ydr oxy- methyl)-DL-glycero- tetroae DL-cordycepoae sirup 133 3-Deoxy-3-£-(hydroxy- ■ethvl-(-)-glveero- tetroae ^ (-) cordycepose Cordycepln 132 Pentoses 2-£-(Hydroxymethyl)- D-rlbose hamamelose haaameli-tannin sirup -13 136,137,139 4-£-(Hydroxy■«thy 1)- 4, 4-di-£-(hydr oxy- D-threo-sentosa methyl)-D-threosa sirup -60 (H20) 140 w Table 5 (continued) 4-£-(Hydr oxyme t hy1- 1 11 - di-£-(hyd r oxy D-threo-pentitol me thy 1 J-D-threltol alrup -10.2°(H20) 140 * 2-£~(Hydroxymethyl )- D-xyloae 106-107° +30-l8°(H20) 140 Hexoses 2 ( Hyd r oxyme t hy1) - D - g lucoae 172.5-173.5° +52-4f(H20) 141 2-£-(Hydroxy«ethyl )- 1,1-d i-£-(hy d r ox y- D - g l u c i t o l nethyl)-D-arabltol airup - 5 . 7 ° ( H 2 0) 141 l,5-Anhydro-l,2- • dideoxy-2-£- (hydroxymethyl)-D- lYxo-hexltol 158-159.5° +37.6°(H,0) 142 C-Formyl Sugara PentOSes 5-Deoxy-3~£**£ ormyl- L - l y x o a e Btreptose streptomycin 14 3 - 1 4 6 Higher £-formyl Sugars 9-Aldo-4-£.“f°rmyl"l» 2: 8,9-di-J2-iaopropylldene- L-x y I o-L-ldo-1,4 j 9,6-d1- ...... 56° Table 5 (continued) l,2t 5,7-Di-2-ethylidene- 3-C-fornvl-D-alvcaro-D- talo-heptltol-3(l),6- pyranoaa 228-229° U 9 ° H 20) 149 Terminal di-C-methyl Su^ara Methyl 2,3-5-laopropylidane- 5,5-dl-C-nethvl-L-lvxo- furanoalde novobiocin** alrup -90°(Me0H) 42 Methyl 2,3-j2-iaopropylidene- 5,S-di-^^^hyl-D-rib o- furanoalde 35-36° -63°(MeOH) 42 3-£-methyl-hexoaea 2,6-Dideoxy-3-£-methyl- carbomycln hexoae mycaroae (magnamycln) 128-129° -31° 150 2 ,6-Dideoxy-3-£-methyl- alrup, 3-j2-methyl-hexoae cladlnoBe erythromycin b.p.120- 32°, 0.05 mm. -23°(H20) 151,152 * Structure not fully eatahllehed. ^ Sugar component in novobiocin la a 5,5-di-£-methyl<-3-^-methyl-1-lyxoae derivative* (152) E. H. Flynn, M. V. Sigal, Jr., P. F. Wiley and K. Garaon, J. An.Chen. Soc.f 3121 (1954). DISC USSIOM OF RESULTS Th* Pypiratlpn of Olwrlc 1,2-^-Iao- propylldono-5-*ldahvdq-D-xvle- 1,4-furano-p*atod1aIdos* It was originally Intended to syhtheslse 1 ,2-g— laonropylldene-5—aldehvdo-D-xvio-1fA-furano-nentodlal- doii and to atudy ita applleatlona to synthesis by condensation with small carbon units. This compound waa aynthaaiied essentially according to the method of Sohaffer and Isbell (12) by the periodate oxidation of 1,2-jB-isopropylldene—D-glucofuranos*, whereby the com pound In question la obtained aa a dimer (13) (Scheme l). Seeding th* crude airupy reaction product with oryatals of the dimer provided by Dr. H. S. Isbell, caused orystallisation. Attempts to engage this crystalline dimer In several reactions In non-aqueoua media were unsuccessful and recovered only starting material for example, the reaction of the dimer with alcoholic hy drogen cyanide did not form the expected oyanohydrln (153). In the dimer th* aldehyde group la not available (153) A. Kuhn and W. Kirschenlohr, Anaew. Cham.r 67, 786 (1955). for reaction under mild conditions, especially In non- aqueous media. Cleavage to the monomer is known to 75 76 I------HC-Ox XH- i > C * HC-Ox CH3 I ch2oh HOCH I I HOCHvO HC------J IO« O ^ O I H I H H O-C-CH, HOC — C— C — C —C — H H I 3 CH. 4 ° dHx H »C H 3 D imer S cheme I occur under auitabla oonditiona (20,21,154), and ia (154) (a) P. E. Papadakla, Qrn. Chan.. 20, 630 (1955)j (b) fi. Schaffer and H. S. Iaball, J. An. Chan. Soo.r 72, 3867 (1957). probably facilitated in appreciably polar nadla. Tha Syntheaia of S-^-Iaopropyl- idcne^-aljjJaaa-P-XTlo-l^-f arano- paatodlaldoaa (III) It aaanad daairabla to have a 1,2-g-ieopropylidene- D-glucofuranoae blocked at C-3 with a auitabla group ao aa to prevent tha product of glycol cleavage fron dinar- ialng. 4 auitabla atarting eonpound waa 3-jQ-bensyl-l,2:5, di-£-iaopropylidene-D-glucofuranoae (155), which could (155) E* Freudenberg, H. v. Hochatattar and H. Sngala, A*£.,JJ8, 666 (1925). be prepared fron tha reaction of 1,2 *5,6-d6-£-ieopropyli- dene-D-glucofuranoae with bansyl chloride in tha preaenoe of alkali. Tha aalaetiva hydrolyaia of tha 3-£-benayl derivative waa affected according to tha nethod of Meyer and Kaichatain (100), and gave 3-j)-benayl-l,2-£- laopropylidana-D-gluoofuranoae (l) aa a alrup. Tha new oryetalline 5,6-bia(p-nltrobenaoyl) derivative (II), of tha latter eonpound waa prepared by tha cuatonary 78 reaotloa with p-nitrobeasoyl chloride in dry pyridine. Tha airupy 3-fi-baaayl-l,2-fi-laopropylidana-D-gluco- furanoaa (I) waa aoatylatad with aeatie anhydrida ia pyridiaa to give tha known oryatallina 5,6-di-H-acetyl- 3-2-ben*yl-l,2-iQ-iiopropylidene-D-gluoof uranoee (100) ia quantitative yield. Daaoatylation with a oatalytie anouat of aodinn aathoxida in nethanol raganaratad ooapound 111 in pura fora aa a oolorlaaa sirup. Treat- aant of this sirup, in dry banaana, with a solution of load tatraaoatata ia banaana, rasultad in tha cleavage of tha aolaoula batwaan C-3 and C-6 to produoa forn- aldahyda and tha daairad 3-fl-b**i*yl-l,2-H-iaopropylidana- 5-aldahvdo-D-xylo-l. 4.-furano-pentodlaldoae (111) aa a yallow airup in vary good yiald. This sirup could ba purifiad by distillation in a Hlcknan aolaoular pot still (13^) and was obtainad aa a colorlasa viscous (156) 4 product of tha Fischar Scientific Co., Pittsburgh, Pa. liquid. Tha infrarad absorption spsotrua of this eonpound showed essentially no hydroxyl peak at 2.9 p, but revealed an intense carbonyl peak in tha region of 3.8 p (Fig. 1), accounting for the presence of a free aldehyde group at C-3. The presence of this group was conflraad by the lnnedlate color produced in the Sehlff test. W AV ! LM V 1H M M C M N IWAV! LEN6TH M MtCSONS W AV! LM V 1H M M C M N IWAV! WAVE NUMBERS IN C M ' f * 7 II II II WAVE UN*TM M MKRONS WAV! UM 1M M 80 Evidently, th* blocking of the hydroxyl function •t C-3 in tho atartiag compound (I) had prevented tho dinerlsatlon of the expected aldehyde derivative. The nononerie nature of III waa further aubatantlated by a determination of it* aolecular weight by freesing point depresaion in banaeae. The experimental value found waa 315 and waa the average of three determlna- tiona. The calculated value for 3-.Q-bensyl-l,2-£— laonropTlidene-5-aldehvdo-D-XTlo-l.A-furano-pentodialdoae (III) la 278, calculated for diner 556. Accounting for experimental error* and the fact that such aldehyde compound* tend to hydrate when expoaed to moisture, the experimental value ia in fair agreement with the calculated one for the monomer. Storing the alrup with adequate protection from moisture, over a year, did not change lta physical characteriatica and lta infrared apeotrum remained unohanged except for the appearance of a medium or weak hydroxyl band in the region of 2.9 u, depending on the conditions of storage. The alrupy compound III gave a crystalline aemloarbaaone (IT). The Synthesis of Monomeric 1,2-jj-Iao- propylldcnc-5—aldehrdo-D— 1,4-furano-pcntodlaldoee (T) With 3-0-benmyl-lr 2-0-laop^op:^lidcnc-5-ald*hydo- D-;Judla-l, A-furano-pentodialdoae (III) on hand, an in direct route to 1.2-0-1a opr o py1ldene-5-aldehvd o—D—xv1o- 1,4-furano-pentodialdose (?) was poasible. This was indeed realised whea III waa debensylsted with palladium— on—ohsreosl and hydrogen in ethanol. The prodnet was s eolorleaa sirup whleh showed carbonyl and hydroxyl ab sorption of equal magnitude in the Infrared absorption spectrum (Fig. 2). Th* charsoteristlc substituted phenyl absorptions in the region of 13*15 were absent and this denoted complete debensylatlon. The presenoe of carbonyl absorption in the infrared spectrum was s convincing evidence that the anticipated 5-sldehvdo derivative (V) was obtained. This oompound has never been reported in the aldehyde form before. It should be noted however that the compound ia not very stable at room temperaturet the intensity of the carbonyl peak seems to diminish slightly with time (sbout on* week), and th* sirup acquires s yellowish color. A sample tested after three months of storage at room tempera ture however, still showed some carbonyl absorption in the Infrared spectrum. Seeding a sample of the airup T with crystals of the dimer (13), caused no crystallisa tion even after storing at 0° for 30 days. Th* sirup T gave a crystalline semlaarbasona which had identical constants as those reported by Iwadare (7) for the same derivative. It appears therefore that the selection of synthetic routes to 1.2—0—1sopt opylidene—5—eldehv do—D—xvlo—1fA— 82 furano-pentodialdose (V) and other compounds of similar structure, depends on the conditions of the reaction. The dimerization of the compound In question appears to be acid-catalyzed, and is minimized by using indirect methods not Involving ionic catalysis, as in the de- benzylation of III. The Synthesis of D-jcvlo-Pent odlaldose (VI) The hydrolysis of 1 r2-0-1 sopropylidene-5-aldehvdo- D-xvlo-l.A-furano-pentodialdose (V) on Amberllte IR-120 (H+) (157) gave the free sugar, D-xvlo-pentodlaldose (VI) (157) A product of hohm and Haas Co., Phila delphia , Pa . as a pale yellow sirup. On standing at room temperature for a few days, the color of the sirup darkened consid erably. Treatment of a portion with p-nitrophenylhydrazine afforded the bis(p-nitrophenylhydrazone) as a dark red solid which had constants similar to those reported by Iwadare (7). an attempt to prepare the bls(diethyl dithioacetal) gave a sirup which waa not further in vestigated . The synthesis and reactions of D-xylo-pentodialdose derivatives are shown in Scheme 2. u hsCxc ^d- c h , h x o h ^ ■ ° & ° \ » . ° * H 0 r \ 0 1 0-C-CH. O-C-CH. i » , CH, J CH, Pb (0A c )4 V > x V o . — £ > 0 0 1 O-C-CH. O-C-CH. I * I CH. _ CH, 3 2 m IR-120 (H ) HC=0 I HCOH HOCH V T h c o h Sch em e 2 HCsO 84 The Reaction of 3-£-Benayl-l,2-fl-laopropylldene- S-jJLilmfcjcAa-D-JEylfl-l^-fttrano-pentodialdoae with Methylmagneslum Iodide Tha Synthesis of 3-JB-Ben»yl»6-daoxy-l, 2- fl-iaopropylldeae-L-ldofuranoss (vil) ia compound III haa an unaaakad aldahyda group at C-5, ita uaa aa a synthetic intermediate waa exploited in condenaation reaotlona with other carbon fragments. The reaction of III with methylmagneaium iodide waa found convenient to study because the compound waa soluble in the appropriate organic solvents and waa free of groups that would interfere with the reaction. The Grignard reagent waa prepared In the usual manner froa magnesium turnings and methyl iodide. In all cases the original solvent in the preparation of the reagent was anhydrous ether. When bensene was used as the solvent, the ether was distilled off while dry benzene was simultaneously added to the Grignard reagent. The resulting mixture was not completely homogeneous. When using tetrahydrofuran as solvent, a method described by Lewis and Wright (158) for the preparation of (158) R. N. Lewis and J. R. Wright, J. Am. Chem. Sjifi., 2A, 1253 (1952). ethylmagnesium bromide in a variety of organic solvents, was utilized. After the reagent had been prepared in 85 ether aa usual, the solvent was evaporated to dryness under redueed pressure with the minimum exposure to noisture, sod the residue was taken up in dry tetra- hydrofuran. The latter was previously dried by distilling fron a snail quantity of lithiun aluminium hydride, or by storage over sodium wire, followed by distillation and passage of the dietlllate-through neutral alumina (159). (159) 1 produet of M. hfoelm, JSschwege, Germany. The reaction proper was done by the dropwlse addition of the aldehyde III la the particular solvent, to the Grignard reagent in the same solvent. An almost ten-fold exoess of the Grignard reagent over the alde hyde 111 was used in the case of the reaction in ether. The presence of the reagent in sufficient amount was indicated by a positive Gilman test (160) at the end (160) H. Gilman and F. Schulse, J. Am. Chen. A2, 2002 (1925). of the reaction. It was found that varying the time of the reaction from two hours to six hours, dbd not alter the overall yields. Due to the acid-sensltive nature of the hemlaoetal linkages in the molecule, the oommon decomposition of such Grignard reagents in 86 • qMOUi hydrochloric acid waa avoided, and an aqueoua aaturatad aolutlon of a u o n i u chloride waa aaad in stead, whlob ia known to bo Juat aa effective in daatrojing tho oxooaa roagont (l6l). Tho solubility (161) L. P. Fieaer, "Experiments in Organic Chemistry," D. C. Hoath and Co., Bostofc, Naaa,, 195$, p. 270. of tho product in other presented no problona in ita aeparatlon. Concentration of tho organic oxtraeta afforded a 7 0 % yield of a crystalline ooapound which analysed correctly for tha expected 3-j2“bensyl-6-deoxy- l,2-£-isopropylldene-hexoae. The iaaertion of the ■ethyl group in tha terninal poaition waa further evidenoed by the detection of iodoforn by odor, when the eonpound waa subjected to the conditiona of the Iodoform reaction for watar-insoluble substances (162). (162) R. C. Puaon and C. W. Tullook, J . An. Chen. Soc.r 56, 1638 (1934). The fact that crystalline iodoforn could not be isolated fron the reaction could perhaps be attributed to a aterlc factor. Although the sugar derivative VII is not essen tially hindered at the terninal position, a nodal showa that the successive replacenent of the C-6 nethyl 87 hydrogens by iodine iton, produces the trilodomethyl group vhioh is quite bulky end prone to sterio hind rance by the bensyl group as well as by the hydrogen on C-5* The Infrared spectrum (Fig. 3) of the orystalllne reaction product VII, was essentially similar to that of III (Fig. 1), except for the appearance of an hydroxyl band at 2.9 )i and the disappearance of the oarbonyl band. Although the reaction product could be acetylated with acetlo anhydride in dry pyridine, the product was a sirup. The 5-£-methylsulfonyl derivative however, waa obtained in crystalline condition (VIII). When the Grignard reaction was run in a mixture of beasene and ether, the results were essentially the same as before. The sole crystalline product was VII and this was obtained in a yield of even with a large excess of mathylmagneslum iodide. Finally, when tetrahydrofuran was used aa solvent, no crystalline produot could be isolated, and a yellow sirup consisting largely of the starting material III was recovered. The same result waa obtained (in tetra- hydrofuran) when an inverse addition was performed. WAVt NUMOEOS M CM -1 WAV! NUMMB M CM -1 100 -- y f W * - - - - ! » n«fM • ---— ■ r , i- - J 5 1 - / ■ -- - -- 10 J V \j^J - ■ — ------_ 4 I 4 7 10 M II II M H WAVE LEN6TH K MOONS WAVE IMEIH N MCKMI I * 7 II I I I I WAVE LM6TH W MCftONS WAW lINtIH M M 89 The Assignment of Stereochemical Goafiguratlon to the Grlgnard Rfotloi Product Since the reaction of III with methylmagnealum iodide produces a naw asymmetric center at C-5, thara axlatad tha poaaibilltj of tha formation of two Isomers differing la configuration at C-5* Tha ax- pactad produota vara tharafora 3-iJ-be nay 1-6-de oxy-1,2- £-iaopropylidene-L-idoforanoaa (Til) and 3-J3-bensyl- 6-daoxy-1,2-£-lsopropylldene—D-glucoforanoaa (XX) (Scheme 3). Tha aharp melting point of tha cryatallina reaotion product indicated ita homogeneity, but ainca both expected producta ware hitherto undeacribed in tha literature, tha atereoohenieal configuration of tha product had to bo elucidated by comparison with compounds of known configuration. Tha dabansylatad producta of VII and XI are known. They have bean prepared by tha catalytic hydrogenation or chenioal reduction of tha respective 5,6-anhydro— 1 ,2-£-isopropylidene-hexose derivatives (98,99,101,106). Tha physical constants of these producta, 6«»deoxy—1,2— .Q-isopropylidene-L-idofuranoaa (IX) and 6-deoxy-1, 2-£- isopropylidana—D-gluoofuranosa (XXI), are very similar and do not allow a satisfactory comparison. Tha con stants of tha corresponding known 3,5-di-JJ-acetyl derivatives (98,106) however, are quite different from each other and allow a direct comparison. HCOH HOCH C.H.CHf^^^O C H CH I | « 5 O-C-CH, I 3 CH, MI XX S cheme 3 91 Catalytic debensylation of tha crystalline product VII, 1b athaBolle solution, with hydrogen and palladium- on-chareoal oatalyat required both heat and preaaure. Hydrogenolyala of benayl groups haa been previously effected ualng the aame oatalyat in ethanol and In the preaenee of hydrogen, at room temperature and atmos pheric preaaure (1 6 3 ), and this method haa been applied (163) C. X. Ballou and H. 0. L. Fischer, J. Am. Ch..- SBC.. 2i, 3191 (195*). to the debemiylatlom and simultaneous saturation of the double bond In 3 -£-beniyl-l,2 -£-iaopropylldene- D-xvlo-haxofuranoee-5-oan (1 6 4 ). these oondltiona, (164) J. X. Inglleh, Jr., and M. F. Lory, ibid., 78, 2846 (1956). however, failed to effect any debennylatlon with VII. The milder conditions required by Xngllah and Lory (1 6 4 ) for their compound, nay be due to a more favorable ini tial combination on the catalyst surface due to the presence of the double bond. The debensylatlon product of VII was a crystalline compound, IX, with a melting point and rotation that conformed beat with the constants of 6 -deoxy-1 ,2 -£- isopropylidene-L-ldofuranose. It should be pointed out that the corresponding D-gluco derivative (III) haa a 92 similar malting paint tut a higher negative rotation (98,106). Tha infrarad absorption spectrum of IX (Fig.4) leaked the oheraoterietie substituted phenyl absorptions In tha raglon of 13-15 >*. Compound IX was then aoetjlated using aeetie an hydride in dry pyridine to giro a crystalline diaoetata (X), Tha constants of this compound were in very good agreement with those of 3, 5-di-jJ-aoetyl-6-deoxy-1,2- £-isopropylidena-L-idofuranosa (106). Since a machanloal mixture of 3,5-di-,Q-aoetyl-6-deoxy-1,2-.fi- isopropylldene-L-idofuranose and 3,5-di-3-aeetyl-6- deoxy-1,2-£-iaopropylidene-D-glttoofuranose has physical constants that differ muah from those of either compound, the crystalline product from the Grignard reaction was not a mixture, but a single compound and was 3-£-bensyl- 6-deoxy-l,2-£-isopropylidene-L-ldofuranosa (VII). Scheme 4 shows the synthesis of VII and demonstrates the reactions loading to its configurational assignment. 98 O-C-CH O-C-CH P 4-C CH. CH I HCOAc HCOH f e o — O-'c-CH. O-C—CHa I 1 CH, CH, IX S cheme 4 94 Iwitl|itl*a of the Mother Liquors of tkt Grlgnard Product The sothar liquor* from tha Grignard raaetion uaing athar a a aolirant vara investigated fir at, in an effort to iaolata tha other axpaotad iaener XX. Catalytic debeasylatlon on palladium-on-charcoal in ethanol produced a radueing airup whiah ahoved a oar- bonyl band in tha infrared abaorption apactrum duo to tha praaanoa of aldehyde V. Aeetylation of thia airnp afforded tha crystalline dlaoatata aorraaponding to 3f5-di-£-ac*tyl-6—deoxy-1,2-£-isopropylidene-L- idofuranaaa (X), with phyaical oonatanta matching an authantio sample, Vo trace via found of tha diaoetate aorraaponding to 3, 5-di-£-a c* tyl-6—da oxy-1,2-j^—iso- pro pylidana-D-glue of uranoaa (XXII). Tha presence of tha expected 3-,fi-b*nsyl-6-deoxy-1,2-£-laopropylidana-D- glucofuranoaa (XX) in tha original mother liquora, would have produced a mixed diacetate containing both X and XXII. Thia mixed product haa oonatanta differing from either component, X or XXII. These results then revealed a star*ospeeific ayntheaia of 3-£-beniyl-6- deoxy—l,2-£-isopropylidene—L—idofuranose (Til) and hence of 6-ddoxy-L-idoae derivatives in general, Inveatigatlorn of the mother liquors from the Grig nard reaction in banaene solution gave results as above. Debanxylation of the mother liquors, followed by 95 aoetylatlon of tho product produeod only 3,5-di—fi- acetyl-6-deoxy-l,2-fi-ioopropylidene-L-idofurtnosi (l) in pure forn. While no oryatollino produot oould bo ioolatod from tho produot of tho Grlgnard roaotlon when tetra- hydrofuran waa uaod aa aolvent, a ana 11 anount of 3-fi- bomyl-6-dooxy-l, 2-fi-iaopropylidene-L-idof uranoao (VII) waa proaont in tho airupy product and had fa Ho d to eryatalliso. Thia waa prorod by tho proaoneo of an hydroxyl band in tho infrarod abaorption apootrun of tho airupy product and tho iaolatlon of 3,5-di-fi- acotyl-6-dooxy-l,2-fi-ioopropylidono-L-idofuranoao (I), upon dobonsylation and acotylation of tho airupy product. An Explanation for tho Apparent StorooppoolfIclty in tho Grlgnard Roaotlon It haa boon ahown by Cran and Abd Blhafes (165), (165) D. J. Cran and F. 1. Abd Elhafos, J. An. £kta. 2Jt> 5828 (1952). that in tho roactiona of organonotallie roagenta with certain alieyclic oarbonyl conpounda, in whloh a now aaynnetrle center ia created on a carbon aton adjaoont to an oxiating aaynnetrie cantor in the nolooulo, tho etereocheaioal courao of tho reaction nay bo governed 96 by ateric factor* la accord with tha "Rule of Storlc Control of Asymmetric Induetion" "I"; tha rational# of tha oparatlon of tha rule la different in oaaea where the earbonyl compound carries (roups that can possibly raaot with tha reagent to form a complex, *2*. Tha above two situations ware recently investigated again by Cram and Kopeeky (166) and were represented by (166) D. J. Cram and A. R. Kepeeky, Ibid« P 81. 2748 (1959). an open-ohain modal and a rigid ring modal, correspond* Ing to the above "aterio control", "1", or "group partielpatlon", "2" meehanlama, respectively. Scheme 5 represents the transition atatea of lowest energy of these two medals. The symbols S, H and L stand for small, medium and large groups attaofced to the carbon adjacent to the carbonyl function; Z represents a metal and R 1 is the group to be attached. In an open-ehaln model, the organometalllc reagent coordinates with tha carbonyl oxygen function and tha predominant diasteraolsomer is the one la which the new group R* has approached and attacked from the least hindered side. If, on the other hand, a rigid model is favored due to the presence of a strongly coordinating group such as oxygen or nitrogen on the carbon atom in the S cheme 93 a or p position to tho carbonyl group, then the con figuration of the reacting apeoiea will be fixed, and result In the predominance of one dlastereolsomer or the formation of only one. Many such examples in volving rigid ring models have been reported (167). (167) (a) W. E. Doerlng and T. C. Aschner, ibid.f 21, 838 (194.9); (b) H. S. Moser and E. La Combe, Ibid. f 2Z, 3994, 4 9 9 1 (1950)j (c) B. M. Benjamin, H. J. Schaf fer and Clair J. Collins, ibid. . 22, *>160 (1957). Inan examination of the molecular model of 3-\Q-* benzyl-1,2-£-iaopropyl idene-5-aldshydo-D-xvlo-lfX-furano- pentodlaldose (III), the large size of the benzyl group waa relevant. Considering that the aldehyde group of III haa possible free bond rotation, the open-chain model of type "1" presents reaction pathe little different from the production of the L-ldo Isomer (VII) or the D-gluco isomer (XX). Scheme 6 depicts the transition states of lowest energy in the open-chain model of type "1" for both isomers. The projections are along the C-4*C—5 bonds. Due to the absence of substantially large groups in the vicinity of the reaction center, there doea not appear to exist any apparent hindrance to the attack by the methyl group of the reagent. Thus, either the L-ido or the D-gluco transition states should be about equally favored. 99 H H H C C L- ido H HO C C D~ 9LUCO S cheme 6 1 0 0 The other possible ezplanetlon for the apparent atereoapeolfleity involving a participation in the polar sense, *2*, is quite attractive. One to the tendency of Grlgnard reagents to coordinate with the unshared pair of electrons of oxygen or nitrogen (168), (168) H. L. Cohen and G. F. Wright, J . Ora. Chen.f 18, 632 (1953). one could envisage the formation of a precursor such as (111 a), which has the geometry of a planar five- nenbered ring and is capable of existence from a aterie standpoint. This system is expected to be quite stable (165) and would fix the transition atate in the L-ldo z c c HC-- III a conformation, thus accounting for the stereoapeciflcity found. Such a coordinated cyolio precursor cannot be envisaged for the D-aluco system. 1 0 1 In thia type of reactions, tha character of tha natal aa wall aa tha nature of tha solvent la known to play an important rola (158)* While a ayatamatio atudy of tha influenoe of tha solvent basicity on tha course of a Grlgnard raaotlon la not available, tha general view (158) ia that a solvent more basic than ether would coordinate atrangly with tha natal aton and should retard tha reaction with the carbonyl com pound by retarding tha formation of tha complex, while a feebly baalo solvent should facilitate the reaction. According to this view, the uae of benseae alone aa aolvent in a Grlgnard reaction should increase the yield of product since benaene ia much leas basic than ether. In the case of the reaction of III with methyl- magnesium iodide In benaene however, an appreciable amount of ether was believed to be tenaoloualy held te the Grlgnard reagent (158), which could not be expelled at the boiling point of benaene. The drop in the yield of the product TII is believed to be due to a major extent, to the non-homogeneity of the reaction, due to the low solubility of the etherated Grlgnard reagent in benaene. Using tetrahydrofuran, which is about 50 times aa basic as ether, as the solvent in the reaction of III with methylmagnesium iodide, it was anticipated that any coordination caused by the hemiacetal ring oxygen 102 •a In (111 «) would ba minimized ainot the reagent would tend to coordinate witb the relatively nore abundant solvent aoleoulea. The contribution of a apeclea auch aa (111 a) would therefore be alnlmised with a consequent draatic drop in the yield of product. While thia effeot waa observed, the formation of trace anonnta of the product TII may be attributed to one or both of two reasona. First, deapite the solvation of the Grignard reagent by the aolvent molecules, the carbonyl compound III may have reacted to a small ex tent (169). Secondly, and leas likely, the trace (169) N. Allentoff and G. F. Wright, J. Ora. Chen.. 22, 1 (1957), a mounta may have been formed through a reaction involv ing an open—chain model. In some cases, the increased basicity of a aolvent in auch reactions has altered the nature of the transition atate operating, from a rigid model to an open-chain model (166). The use of tetra— hydrofuran aa a aolvent in Grignard reactions aa well aa in other organometallic reactions haa often led to unexpected results (170). (170) (a) H. Gilman and B. j! Gaj, ibid.f 22, 1165 (1957); (b) D. E. Pearson, Dorotha Cowan and J. D. Beckler, ibid.. 24, 504 (1959); (c) W. B. Bailey and F. Marktacheffel, ibid.r 25, 1797 (I960). 1 0 3 Tho Synthesis of 3-jQ-Bsaayl-6-dooxy-L-ldoao Ctl) and S » M of Itl D M l l l t l T I I The pertinent syntheses art ahovi in Sobaaa 7. Tb« hydrolysis of 3-.fi-bonmyl-6-dooxy-1,2-fi-isopropyl idono-L-idof ursaoso (VII) was perfornod ossontislly according to tho method of Froudonberg and eovorkora (155) for tho hydrolysis of 3-£-bensyl-l,2t5,6-di-£— isopropylidene—D-glucofuranoao• Tho now ooipouad XI was obtainod aa a oolorloaa sirup and was quits puro. It did not roatoro the color of the Sohiff roagont and hence did not contain any of the open-chain (aldehyde) form In solution. The method of hydrolysis used / o (heating at 70 for 5 hr.) would oertalnly indiosto the predominance of tho pyranoso structure, but for convenience the name 3-£-bensyl-6-deoxy-L-ldose la used. Thia ia the first example of a 3-£-bensyl-6-deoxy-hexose• Crystalline derivatives of the airupy XI could be prepared. The phenylosaaone XIII did not crystallise directly from the initial reaction mixture, unlike the phenyleaasonea of many sugar derivativea, but could be crystallised by evaporating the reaction mixture, wash ing the residue with water, and extracting the residue with bensene. The addition of petroleum ether and atorage at 0° caused the phenylosaaone to crystallise in a few hours. The crystalline bensylphenylhydrasons XII could I 3 W 3 H 0 S D K m x ft ft HO HO 1 I HOOH HOOH HO^)H HOOH H0O*H09H*0 HOO*HO*H*0 i H 0. .N . | H N ^ 0 9 I I I I HON“ N = OH H- .OH ft • ft I H O HO | 8..I,H OHN ft 9 3 ft HONNH H OHNNH W h o I EX M ®H0 3... ft 9 ft I HO HO H O HO— 0-0 - 7 * r * 3 T HOOH ft I eh o 901 10ft OAc Ac Oj c«% ch2 o h C«H 6 C H * 0 A c XT Pd-C OAc Ac AcO OAc OAc 221 22 NqBH \ H.COH H.COAc 8 I 8 I HCOH HCOAc I CH.CH OCH CH.CH^OCH 6ft t I SO 2 | HCOH HCOAc HOCH AcOCH I I CH, CH. x m S chem e 7 (contd .) 106 be readily obtained. Reaction of tha airupy XI with 1—benayl-l-phonylhydrasine hydrochloride and sodium aoatata in watar containing aona ethanol, gave a airup after processing, which whan takan up in an ether- patrolaun athar mixture, crystallised aa eolorleaa neadlaa. i problem of theoretical lntereat arose whan tha rotation of 3-j2-bensyl-6~deoxy-L~idose bensylphenyl- hydrasone waa taken in ethanol. The specific rotation waa found to be +44°. It had bean shown by Totocak (171) (171) JE. Totocak, Collection Csachoalov. Cham. Commune.. 3 r 250 (1921). that the benaylphenylhydrasonea of aldoaea having the C-2 hydroxyl located on the right in the Fischer pro jection, have negative optical rotationa and vice versa. Thia rule haa been applied to the configurational assignment of C-2 in the aldoae moiety of novobiocin (^2), where the specific rotation of a 4“£-methyl-5,5- di-£-methyl-pentose bemsylphenylhydraione in methanol waa —4.0°, Hudson (172) haa discussed the above generallaa- (172) C. S. Hudaon, "Relations Between Optical Rotatory Power and Structure in the Sugar Group,” Sflliaillig fiMti, ftX—fcfrfl gl ^tfadir.dp, No. 533, 1926, p. 297. 107 tion (171), and haa commented on lta application* Tha caaa of 3-£-hensyl-6-deoxy-L-idose bensyl- phanylhydrasona (HI) ia an example whara auch a rula cannot ba appliad for configuration aaalgnnant. Un doubtedly, tha banayloxy group on C-3 ia raaponaibla for tha positive rotation* That tha banayl group can influence rotatory power ia ehovn by tha apaoiflc rotationa of VII (with the banayl group) and IX (with tha banayl group removed), which are -63.5* (chloroform) and -7* (chloroform) respectively* A aariaa of new acatylatad derivatives of 6-deoxy- L-idose ware prepared, but ware all airupy aubatancaa. Thua, acatylation of XI by maana of aodium acetate in acetic anhydride at 100° fare a airupy triacetate (XIV). It gave tha correct analyaia and ahowed a apecifie o rotation of -6.5 in chloroforn. lcetylation of XI with acetic anhydride in pyridine gave a similar sirup, with a amall positive apecifie rotation in chloroform. The triacetate XI7 waa debenaylated on palladium-on- o charcoal and hydrogen in ether at 30 and 175 p.a.i. Higher temperatures were avoided in order not to cauae a possible loss of the ester functions. The debenayla- tlon product waa a alrup (XV) and showed a hydroxyl band in the Infrared absorption spectrum. This waa another case where the completion of a reaction waa indicated by a study of the infrared spectrum of the 103 product. Tho speciflo rotation of tho sirupy 1,2,4- tri-£-acetyl-6-deoxy-L-ldoao (IV) waa about +7° in ehlorofora, Thia aubstanca waa then acetylated with acetic anhydride in pyridine to giro 1,2,3,4-tatra-jJ- acetyl-6-deoxy-L-idose (ZVI), also aa a sirup, which had a specific rotation of about +9° in chloroform. 3-£-Bensyl-6-deoxy-L—ldose waa also transformed into 3-£-bensyl-6-deoxy-L-iditol (XVII) which waa a o sirup and had a specific rotation of -15 in methanol. It did not reduce Fehling solution. Aeetylation of XVII with acetic anhydride in pyridine afforded 1,2,4, 5«=te tra -£-a cetyl-3-£-ben»yl-6-de oxy-L-iditol (XVIII). The Attempted Preparation of ^-Deoxy-L— Idose In 194& Meyer and Reichatein (106) reported their synthesis of a new 6-deoxy—L-idose from the acid hydrolysis of 6-deoxy-l,2-£-isopropylidene-L-idofuranose (IX). Storage of the sirupy hydrolysis product over calcium chloride and occasional trituration with acetone, caused crystallization after three months, but no yield was given. The crystals were hygroscopic and muta- rotated in water from an initial low specific rotation of about —2° to about —26° (4 hr.). The same compound waa obtained also from the acid hydrolyaates of 3,5-.Q- cyclohexylidene or 3,5-£-bensylidens derivatives of 109 IX la yields of 33% and 47%, respeetively, by seeding them with oryatala of 6-deoxy-L-idose. Ia tho praaoat work, tha hydrolyaia of 6-deoxy-l,2- £-lsopropylidene-L-idofuraaaaa (IX) waa affaotad aeeordlag to Mayor and Raiehataia (106) by aaaaa of aquaoua aulfurlo aold and alao by a dlffarant aathod (173), on Amberlite IR-120 (H+ ) (157). Investigation (173) F. Shaflaadeh and M. L. Wolfrom, J. Am. 77, 2568 (1955). of tha airupy product on paper chroaatograaa, revealed tha presence in both hydrolysatea, of essentially three distinct spots A, B and C (in Increasing order of nobility and intensity). Other weak spots ware also found in soma eases. Whan authentic samples (obtained from Professor T. Relehstein) of 6-deoxy-L-ldose (106) and 6-deoxy-L-aorbose (91) were likewise chromatographed on paper, both substances ware found to hare the same mobility and were indistinguishable from spot C in that respect. The R values for 6—deoxy-L— sorbose in a number of solvent mixtures are recorded in the literature (IX). Using three of these aolvent mixtures, the R values of spot C were in all eases in good agreement with those reported for 6-deoxy-L-sorbose (Table 6). 1 1 0 The & valuta for 6-deoxy-L-idoae have baan raeordad by Iaharwood (174) by MacLallan, Randall and Snlth(l75) (174) F. 4. Iaharwood and M. 4. Jernyn, Bloehan. 515 (1951). (17$) 4. P. MacLallan, H. M. Randall and D. Snith, Aatle-ghM., Jl, 2020 (1959). on aanplaa provided by Profasaor T. Ralohataln. k third raport (12$) daacrlbed a aynthasla of 6-deoxy- L-idoaa aa a sirup, and Ita Rq waa daternlnad and found to ba tha aana aa that of an authantlo apecinen, again provided by Profaaaor T. Reichatein. By duplication of the above papar ohronatographlc eonditlona (12$, 174» 175), it waa again found that tha R values of Profaaaor Raiohatain,a 6-deoxy-L-idoae, 6-deoxy-L-sorboae and tboaa of apot C in tha praaant investigation, ware tha aana (Tabla 6). Tha three conponanta 4, B and C ware separated by developing the hydrolysate on papar chronatograna, locating the position of tha conponanta in respect to guide spots and eluting the augara fron the located xonea with water. Fron sona C, a colorless sirup waa obtained with a specific rotation of about -27° in water, which agrees well with the value reported by Muller and Raichstein (91) for 6-deoxy-L-sorbose aa Ill veil as that reported by Mayar and Ealohataia (106) for 6-deoxy-L-idoae. Tha alrup alao affordad a crystalline phanyloaasona which had oonatanta similar to thoaa raoordad for tha oaasona of 6-deoxy-L-sorbose (91,110,176), 6-deoxy-L-gulose (93) or 6-deoxy-L-ldose (176) 4. C. iroua and E . L. Kdson, Blochcn. J.. ± 2 , 385 (1956). (106). Tha notarial fron tona B gave a solid too hygros copic for nalting point determination. Fron lona A a aonawhat laaa hygroaoopio auger waa obtained; dao. about 160°. Spraying tha developed and dried ohranatograna con taining aanplaa of A, B and C, alao Ealohatain'a 6-deoxy- L-idoae, Reiehatain's 6-deexy-L-sorbose and a number of eonnon augers, with oolor reagents (Table 7), produced colors which ware in good agreement with thoaa shown by controls with tha oomnon augara (L-arabinose, L-rhannoae and D-fructosa) of astabliahad structure. The table also contains entries on results reported In pertinent litera ture references. Of particular interest was the pink color given by spot A when sprayed with aniline phthalate (177) or aniline oxalate (177,178). These two reagents (177) S. M. Partridge, 16£, UA3 (19A9) 1 1 2 (176) L. Hough, J. K. M. Jones and V. H. Wadaan, J. Choa. Son.. 1702 (1950). ara known to give pink eolora with pantoaaa (177,178) aa wall aa with some aahydro sugars (179). Spraying (179) C. A. Dakkar a ad T. Hashlsuae, Arch. Blochea. Bionhya.. 78, 318 (1958). with raaorelnol in hydroohlorle acid (110,178) or raaorclnol ia trlehloroacatlc acid (180), (tha lattar (180) R. Klevstrand and A. kordal, Acta Cham. Scand.. 1, 1320 (1950). haring tha advantage of not attacking tha papar) gave a rad colar with apota eorraaponding to 6-deoxy-L-idoae (tha color faded after aoaa tine), 6-deoxy-L-aorboae (both aaaplaa provided by Profaaaor T. Raichatain) and with apot C. Thaaa apraylng aganta ara quite apecifie and produce a rad color with katoaaa which era not given by aa aldoaa (110,178). Tha hydroganolyaia of 3-£-bensyl-6-deoxy-L-idose (Zl) afforded a colorlaaa alrup, which whan examined on papar ohroaatograaa aa before showed one dlatinot spot corresponding to spot B fron tha hydrolysate. A faint spot corresponding to spot C waa also present. When a 113 solution of the hydrogenolyaia product vaa heated with phenylhydrasine aoatata, and aaadad with tha phenyloaasone erjitala from a one C, tha oaasone aeparatad on cooling and had an identical Infrarad apectrum and x-ray powder dlffraction pattarn (tha pattern vaa somewhat diffuae), with tha aaad crystals. 1 portion of tha hydrogenolyaia prodact of XI via heated in water with Xmberlite IR-120 (H + ) (157) over a staan bath. Samplea vara withdrawn at intervals of 5 nln.f 30 mln.f 120 mln. and 180 nln. and ware placed on paper chromatograna. Spraying tha developed chromatograms aa before, revealed a aacond apot in addition to the initial apot B. Thia aacond spot, which had appeared even In the 5 min. heated sample, waa chromatographlcally Identioal to apot C and waa of about equal intenalty aa the other apot (B) on tha aaia ohronategran; thia qualitative ralatlonahip did not change over tha 180 nin. period. Schama 8 aumnarlsaa the reaulta obtained from tha acid and reain hydrolyaaa of 6-deoxy-l,2-£-iaopropylidene- L-idofuranoaa (IX), and from the hydrogenolyaia of 3-.Q- benayl-6—deoxy-L-ldoaa (XI). Tha relative paper chromato graphic behavior of the varloua augara dlaeuaaed in thia aection la aketched on a collective ohromatogram. The numbara 1 and 2 on the chromatogram refer to aamplea of 6-deoxy-L-sorboae and 6-deoxy-6-ldoae respectively, both provided by Profaaaor T. Reichatein. The numbers 3, 4, 5 114 CH. h 6 oh OH o O-C-CH c6 h5c h 2 oh IK t XT IR- I20(H ) Pd-C [Sir u p s IR- I20CH) I 1 S p o t s S p o t S p o t s a ,b ,c ,d B B,C /VWVvWV\AAAj S cheme 8 115 and 6 refer to different preparations of 6-deoxy—L—idoaa and these numbers are placed beside the respective source In the scheme* The actual paper chromatographic properties of these sugars are listed in Tables 6 and 7* Table 6 The R Values of the Sugar Components from the Hydrolysis of 6~deoxy-l,2—JQ—Isopropylldene-L— idofuranose (IX) and the Hydregenolysls cf 3— Bensyl-6-deoxy-L—ldoae (XI) RRh RG Rf Sugar S olvent Solvent Solvent S olVent Solvent 1 2 3 1 1 Zone a 0.18 Zone k 0.71 0.62 0.28 0.218 Z one B 1.00 0.95 0.40 0.32 Zone C 1.34 1.32 1.22 0.52 0.44 Z one D 2.6 1.94 1.00 0.77 6-deoxy-L- 1.34, 0.17, s orbose* 1.34* 1.24* 0.45 6-deoxy-L- idose* 0. 5b 0.45 Hydrogenoly- sis product of XI 1.00 0.95 0.40 0.32 Hydr ogenoly- ele product of XI (resin 1.00, 0.95, o 0.31, o o o tree ted) 1.34 1.33 . * 0.45 1 1 6 Rjl^ ■ Rf value with rhaanoae aa reference Rq *» Rf value with tetra-£-nethyl-D-glucoae a a referee * provided by Frofaaaor T. Raiehatein a literature value, rafarenoa 110 b literature value, reference 125 Solvent 1 ■ 1-butanol * ethanol * water (4*1*5 v/v) Solvent 2 s 1-butanoliethanol*water (4;l.lil.9 v/v) Solvent 3 s Ethylacetatexaoetic acidiformlo acid:water (18*3:1*4 ▼/▼)• Table 7 The Color Reactions of the_ Component Sugars (178) (110) (175,181) (177) (177,178) p-Anisidlne Reaorcinol Vanillin Aniline Aniline HC1 HC1 ICIO^ Phthalate oxalate Sugar Recorded found recorded found recorded found recorded found recorded found Zone 1 no oolor pink pink Zone B faint yellow brown brown —•blue Z one C strong red orange red yellow-* yellow — »grey blue orange 6-daoxy-L- red orange*’ ora nge-* idoae* (fades) ~*grey grey blue blue a 6-deoxy-L- strong strong red* red orange-* sorbose* yellow yellow grey blue 6-deoxy-D- atrong* red® fruotoae yellow L-artbl- weak orange pale yellow-* red^ red red* red nose red* yellow0 green b,c L-rhamnose yellows brown orange orange-* brown yellow-* brown blue brown D-fructoae medium medium wine grey* grey-blue-* yellow-* yellow® yellow red blue® green pink 117h _ M 1 1 8 * Provided by Profeaaor T. Reicbsteln a Racordad in referanea 110 b Recorded in raferanea 175 o Raoordad in rafaranca 181 d Racordad in referanea 177 a Racordad in reference 178 (181) M. G. Laabou,, Anal. Chem. r 1449 (1957). 119 Aa littrpr iTidenee baaed oa papor chromatographic ozparlaanta shows that tha acid hydrolysis of 6-deoxy-l,2-fi-iao- propylidene-L-idofaraaoao (II) girea a alxtara of coapounda oonalating of 6-deoxy-L-idose, 6-deoxy-L-sorbose and possibly an anhydro augar (apot A). Whila Reiehstein's 6-deoxy-L-idose haa a aonewhat dlffarant x-ray powder dlffraotioa pattarn than that of 6-dooxy-L-aorboae (alao provided by Profaaaor T. Reiohstein), ita ehroaatographlo prapartlaa art tha aana aa thoaa of 6-daoxy-L-aorboaa, Slnoa Ralehataln'a 6-daoxy-L-ldoaa waa prepared aona 15 years ago (106)t and waa than reported to be quite hygroscopic, there exists the probability that tha crystalline 6-deoxy-L-idoae was transformed into 6- daoxy-L-aorboaa in tha a olid phase, during this period of time. It waa shown by Targha (182) that when l,2-£- (182) L. Targha, Chen. Bor.._87. 1351 (195A). laopropylidane-L-idofuranoaa was hydrolysed with dilute acid, a neutral sirup was obtained which showed a single spot on paper chromatograms. After storing the sirup for 2 days and examining a sample again, there appeared a second apot on the paper which waa identical with an 1 2 0 L-aorbose apot. After staring tha alrup for 75 daya, L-aorboaa crystallised out of tha airup and waa ob- tainad In good yield. It la intaraating to nota that in 1946 Mayor and Raiehatain (100) had praparad L-idoaa aa a alrup by aaaantlally tha aana nothod, but had fallad to raport any tranaforaation to L-aorboaa. Tha inportanca of papar ehronatography aa an analytical tool la thua relevant froi tha diffarant raaulta obtained by Targha (182). Thaaa raaulta vara lnterpratad by Targha (182) aa being due to tha high eonforaational instability of tha idoae configuration, as noted by Reovea (183)* (183) R. S. Reeves, J. An. Chan. Soc.r 72, 1499 (1950). Ha also observed that tha ease of erystalllaatlon of tha L-aorboaa would favor the shifting of tha equilibrium, in tha alrup, to thia form. Tha appearance of a weak apot corresponding to 6-daoxy-L-aorbose (Spot C), when tha neutral hydrogenoly- ala product of XI waa examined on papar chromatograms, suggests tha axiatanca of an instability factor similar to Targha'a findings with L-idoaa (182). Since the conditions of hydrogenolyaia do not involve any acid treatment, the axiatanca of a weak spot corraapondlng to 6-deoxy-L-aorboea may be attributed to the effect of 1 2 1 tftapiratura, and possibly of pressure, in tha hydro- genolyaia reaction. Unlika tha eaaa of L-ldose (182) howavar, tha intensity of tha aaoond apot (C) did not ineraaaa on atoring tha alrupy hydrogenolyaia product for sgme tina (2 weeks), Tha tranaformation of L-ldoae into oryatalllna L-aorboaa (182) involves an equilibrium which la ahiftad toward L-aorboaa and the cryatalllne nature of tha latter conatltutaa a driving force for tha tranaforaation. Such a driving force would not axiat in tha caae of the 6-deoxy-L-idose, a a tha 6— deoxy-L-aorboae did not crystallise. From a eonfornatiemal standpoint, the C—6 hydroxy- mathyl group of L-idoae ia axial in the aoat atabla conformation of ita anoneric forma, while in 6-deoxy-L- idose , C-6 carries the relatively lasa bulky methyl group in the most atabla conformation of ita poaalbla anomeric forma. These conformations are depleted for the respective sugars, in their stable (normal) forms in Schema 9; C 1 refers to the type of conformation (183) and the numbers and the letter U refer to "instability factors." Tha factors governing pyranoalde ring shapea have bean reviewed (183) with two Important conclusions, Pyranoae ring forma assume a chair form in preference to any boat form whenever both are structurally possible. \zz H H HO HO CHfOH H HO HO OH HO HO OH P - L - 1DOSE gc - L - t D O S e "C I” **C l" H , I » 5 HO HO CH CH HO HO OH HO HO OH • - DEOXY>p - L - I DOSE 6-DEOXY-0C - L - id o s e MC I" H,l,5 S cheme 9 123 iij axial group (other than hydrogen) lntredueee an element of inatability Into tha oonfornatlon. Thia altuatiaa la especially lnportant whan an axial hydroxyl group la on C-2, or a hydroxynathyl group on C-5 la araetad on tha aana alda of tha ring vlth another axial group (tha Haaaal and Ottar affect). Theae affeeta ara eonaldarad aa "inatability faotora*. In referring to theae factora,A2 refera to the exhalted lnfluanee of an axial hydroxyl group on C-2, tha C-0 valence of which blaacta tha two C-0 valencee of carbon 1. The Haaaal and Ottar influaaoa la denoted by the aynbol H. Tha property of the apontaneoue 1,6-anhydro forna- tion in ldoae haa bean dlacuaaad on theoratioal grounda (163)♦ Furthernore, tha acid hydrolyale of oertaln D-idoaa derivativea haa bean ahown to give 1,6-aahydro- D-idoae (184). (184) 6. Sorkin and T, Rolchatein, Heir. Chin. AAll, M , 1 (1945). In tha caae of the present investigation 1,6-anhydro formation in the hydrolyale of 6-daoxy-1,2-£-iaopropylIdane- L-idofuranoae (IX) la not poesible, but a 2,5-anhydro farnation could be envisaged. In this connection, a recent report by Dekker and Haahiaume (179) la worthy of mention. They reported that the hydrolyaia of 124 5,6-anhydre-l,2-JJ-ieeprapylideue-D-gluoofuranoae with 0,1 J| a ulf uric told at 100# for five mlautee, giro two ohromatographloally dlatlaet produota: D-glueeae and anothar aubatanea whioh waa aaalgnad tha atructure of 2,5-anhydre-L-ldoae. Thia atruotura waa aubataatiatad by oolar raaetloaa oa papar ehronatograaa, and from tranafornatlan of tha conpoond to known derlvatlvea. Thay raportad thaaa raaulta aa tha flrat Inatanoa of an aeld-eatalysed anhydrldisation af an aldoaa deriva tive. It waa auggaatad In thalr naehanlan that tha aeatal llnkagaa vara hydrolymad prior to tha opanlng of tha anhydro ring and thay propoaad tha aoyelio form af 5,6-amhydre-D-glueoae aa a procureor to tha 2,5- anhydro-L-ideae. Tha lattar compound could ba dlatingu- iahad fron othar anhydro augara, by tha pink color producad with tha anllina exalate apray (177,178). In tha praaant work, apot A gave a pink color with anllina oxalata also, and tha augar component alowly raatorad tha color of tha Schlff reagent. Al though pentoaea are known to give a pink color with tha aame reagent (177,178), tha mild eonditlona of hydroly- ala aaama to preclude tha degradation required for tha formation of a pantoaa. Tha component augar In sona A waa therefore aaalgnad tha tentative etructure of 2,5- anhydro-6-deoxy—haxoae. The formation of thia compound 125 would provide tho first example of s 2,5-anhydre formation in s 6-deoxy-aldose on sold treatment. A possible pathway for tha tranafornatlona observed in tho aeld hydrolyale of 6-dooxy-l,2-£-ieopropylidene- L-ldefursnoae (11) la outllnod in Schono 10. Tho Synthesis of 6-Deoxy-D-glucoae Derivatives In view of tho proforentlal production of 3-.fi-bensyl- 6-deoxy-l,2-£-iaopropylidene-L-idofuranoao (VII), when tho aldehyde III waa reacted with nothylnagnoaiun iodide, it waa dooirad to complete the work by synthesizing the other possible laoner with the D-gluco configuration. The reaction of 3-j2-bensyl-l,2-g-isopropylldene-D- glucofuranose (I) with one mole of p-toluenesulfonyl ohloride in pyridine afforded the corresponding 6-£—p- tolylsulfonyl derivative as a sirup (XIX). Attempts were made to obtain a crystalline acetate derivative, namely, 5-£-acetyl-3-£~bensyl-l,2-£-iaopropylidene-6-5-p-tolyl- sulfonyl-D-glucofuranose, but the product failed to crystallise. Reductive cleavage of the p—tolylsulfonyl group in XIZ with lithium aluminium hydride in ether af forded a sirup containing the deaired 3— bensyl—6—deoxy— 1,2—£j—is opropylidene-D-glucofuranose (XX), contaminated by sulfur impurities. The purification of the crude reaction product by distillation, led to extensive decomposition. The impurities were however, removed by chromatography on column; alumina (159), MagnesoliCelite (5*1) or carbon I2S CH, HC=0 I HCOH HCOH ♦ HO I H,0 HOCH I 0 HCOH I O -d-C H , H O ^ H 1 1 CH. CH. K •-DEOXY-L- I DOSE HCO-H HCOH I t II &> HCjOH -OH CHpH I HOCH <^OH I CH.OH HCOH HOCH I t. I I L -CH HOCH HCOH I I I C H 9 C H s HOCH I CH 9 J 1 h o+ HC=0 It I ,H CH-OH CH OH I 2 I c=o CH.OH I I * HOCH -CH H,OH H,OH I I HCjtOH 2,B-ANHYDRO-«- C H 3 HOCjH deoxy - m e x o se CH. 6- deoxy -L-so rbose S cheme 10 127 adsorbents wore found suitable. For example, develop- ■snt on alumina (159) with other eluted the sugar derivative and some sulfur Impurities* Subsequent development with 95% ethanol eluted a pale yellow solution containing no sulfur. This gave a sirup which had an Identical infrared absorption spectrum to that of VII* Repeated chromatog raph/ gave a less colored sirup, but the final yields were low and the sirup was still pale yellow. At thia stage, however, the sirup could be distilled and obtained in color less form. The identity of compound XX waa established by re ductive removal of the bensyl group to give the known 6-de oxy-1,2-,Q-ia opropylidene— D— glucofuranose (XXI) (98,101) and by acetylatlon of the debensylated product to give the crystalline diacetate (XXII) (98). The present work there fore describes a new method for the synthesis of compounds XXI and XXII. Debenzylation was effected with hydrogen and palladium-on-charcoal in ethanol. The product was obtained as a sirup having a specific rotation that agreed well with the recorded value for the crystalline compound (98,101). Compound XXI had been reported crystalline after distilla tion of an Initial sirup (101). The sirupy XXI was then acetylated with acetic anhydride in pyridine and gave the known crystalline diacetate (XXII). The physical constants of this substance were in good agreement with those recorded for 3,5-di-,Q“Ocetyl-6-deoxy-l,2-Q-isopropylidene-D-gluco- 128 furanose (98,106). The synthesis of 6-deoxy-D-glucose derivatives is outlined In Scheme 11. The Synthesis of 3-j2-Ben«yl-6-dsoxy-l,2-£-.lsopropylldene- D-TTlo-lt4-fnranO"$"hexosuloss (IIIII) The oxidation of 3-.2*-ben*yl-6-deoxy-l,2-£-ieopropyli- dene-L-ldofuranose (VII) was effected with the pyridine- chromium trioxide complex (4.0) . This reagent Is known to oxidize secondary hydroxyl groups to carbonyl groups. Compound VII was a suitable substance for this type of oxidation, since it contained no other group that would be affected. The reagent was prepared by adding powdered chromium trloxlde (1 part) to dry pyridine (11 parts) (CAUTION) with external cooling and stirring under an atmos phere of dry nitrogen gas. When the addition was complete a yellow slurry had been formed. The compound VII, dis solved in dry pyridine, was then added to the slurry and the solution was stirred for 24. hr. with protection from moisture. Infrared absorption analysis proved to be a valuable tool for determining the completion of the reaction. The product of the reaction was a sirup that crystallized partially. A sample of the crystals showed both hydroxyl and carbonyl absorption in the infrared spectrum. Two more oxidations were found necessary to give the pure carbonyl compound XXIII aa large colorless crystals, in an overall yield of 50%. The infrared spectrum of the pure product showed an intense carbonyl peak and essentially no hydroxyl Ift* CHjOH CHgOS^H^CH^ HOCH HOCH k°\ fwv. k°\ •^CH^ U / O C9H5C^SLfO O-C-CH O-C-CH I CH I X K 'c" * L 1AIH4 CH CH _ I 5 HOCH HOCH Pd- C ? C,H,CH O-C-CH 5 O-C-CH I I a CH CH 3 XXI XX CH AcOCH CHEME ? O-C-CH. XXE CH„ 130 peek (Fig. 5). The compound gave a satisfactory analysis and Its moleculsr weight determined by the Rast method was in good agreement with the calculated value. The compound gave a negative Sellwanoff test, but a yellow color was obtained with alcoholic potassium hydroxide. Like in the case of VII and XX, the compound gave the iodoform test (odor), but no crystalline iodoform could be Isolated. Despite the existence of an unmasked carbonyl group in XXIII, the customary crystalline derivatives of car bonyl compounds could not be obtained. The reaction with semicarbaside hydrochloride gave a sirupy product. The reaction with hydroxylamlne hydrochloride in sodium hy- o droxide solution at 90 for 1$ min., or in ethanollc pyridine at reflux temperature, produced a sirup which showed a small carbonyl absorption in the infrared spectrum. These results indicate that the carbonyl group in this com pound is sterically hindered toward these reagents. A shorter route for the preparation of XXIII was the pyridine-chromium trioxide oxidation of 3-.Q— bensyl- 6-deoxy-l,2-J2-iaopropylldene-D-glucofuranose (XX), which is more readily available than the corresponding L-ldo derivative (VII). It was found that two repeated oxidations were necessary in the case of VII. The final oxidation product was a sirup which showed no hydroxyl absorption and revealed an Intense carbonyl peak in the WAVE NUMKXS IN CM-1 WAVE NUMnRS M CM-1 i t r II II WAVE LEN6TH M M CRONS WAVE LENGTH M Ml 132 infrared spectrum. On seeding the elrup with crystals of XXIII, crystallisation occurred. The oversll yield of XXIII In thia ease was lover, but the relative ease of preparing XX in large quantities, was a compensating factor. The synthesis of XXIII is shown in Scheme 12. The Carbonyl Reduction of 3-jj-Bengyl— 6-deoxy~ 1 .2-_Q-laopropylldene-D-xylo- 1,4-furano- 5-hexosulosa with Metal Hydrides A variety of reduction conditions were employed to study their effect on the relative yields of the products Til and XX. After processing the reaction product and storing in the icebox, crystallisation started in a few hours. A minimum period of 20 days was found necessary to effect a quantitative separation of the crystalline product from solution. The crystalline product in all cases was Identical in all respects to VII. The reducing agents used, together with the reaction conditions and yields of the products are listed in Table 8. Investigation of the Mother Liquors from the Reduction Product The mother liquors did not crystallize and were obtained as sirups. The Infrared absorption spectra of these sirups did not reveal any carbonyl absorption thus denoting e complete reduction. When sufficient time was allowed for compound VII to separate out of solution, the remaining mother liquor was relatively 21 3 Vi 3 H O g XX H O — 0-0 TTTXX HOOH HO I H O — 0-0 :o j o -n ch 9o HO— 0-0 SCI Tibia 8 The Reduction of 3-£-Benayl-6-dooxy-lt2-ifl-»laopropylldeno» D-xylo-1.4~fttrano-5-hexosuloee with Metal Hydrides Reducing Agent Solvent Tenp. Tine, Hr., % VII % XI* % Total Sodiun borohydrlde 50$ aqiMeOH 28° 16 59 34.17 93.17 Sodium borohydrlde absolute MeOH 28° 16 55 35.43 90.43 Sodiun borohydrlde absolute MeOH reflux 6 56.1 34.72 90.82 Sodiun borohydrlde^ absolute MeOH 28° 16 58.7 35.60 94.30 Fotassium borohydrlde absolute MeOH 28° 16 60.8 33.30 94.10 Lithlun Aluninlun Hydride ether reflux 5 47.0 43.0 90.00 b Lithium Alunlniun Hydride ether reflux 5 47.34 43.20 90.54 * based on the weight of the sirup XX, dried to constant weight* k inverse addition. 134 135 k«M|«uoai and pur*. Th* identity of these *lrup* were th* in all aaa*a and waa aaourad by debensylation and aoetylatlon of th* airupa. Such a proo«dur* afford*d a crystalline oonpound which had id*ntleal physical con- atanta with th* previously obtained and known 3,5-di- £-aoetyl-6*deoxy-l,2-£-lsopropylldene-D-glucofuranose (III). How*v*r, whan a solution in which oryatalllsatlon of Til waa not complete (3 days) waa pr*natur«ly filtered, ainilar d*b*naylation and acetylatlon of th* noth*r liquors, afforded a crystalline dlac*tat* that n*lt*d over a wid* rang*, 75-118#. Th* nixed waiting point of th* diao*tat*s X and XXII, waa In the sen* range. The abov* *xp*rin*nta show that th* crystalline conponent Til can b* quantitatively separated fron a solution containing Til and 3-£~b*nsyl-6-d*oxy-1,2-£- lsopropylidene-D-gluoofuranose (XX), and that th* latt«r can b* obtained as a quite pur* sirup. An Interpretation of the Results of the Metal Hydride Reductions The results (Table 8) indioate that the reduction of XXIII with netal hydrides did not forn one isoner predominantly as was observed in the reaction of III with nethylmagnesium iodide. Since the reaction is of the same general type, the difference in the results could probably be attributed to the replacement of the aldehydlc hydrogen in III by a methyl group in XXIII, 136 thereby Introducing e possible element of sterie hindrance. examination ef the molecular model of XXIII, shows that a precursor such as (XXIII a), oannet be eery stable due to an interference of the methyl group (C-6), 8 (XXIII a) with the result that a planar five-membered coordinated oomplex (163, rigid ring model *2*) cannot contribute effectively toward the stabilisation of the transition state of that particular isomer (L-ldo). It is quite possible therefore, that in this system the reaction of the organometallic reagent with the carbonyl group goes through an open-chaln or carbonyl- coordinated model (165, open-chaln model ”1") which is not restricted by rigid geometry. Scheme 13 deplete the transition state of lowest energy in the open-chaln model of type "I" for the L-ido and D-gluco Isomers. The projections are along the C-4:C-5 bonds. The larger proportion of the L-ido isomer (VII) may perhaps be explained on the basis of a better 197 CH H H CH R' OH C C L-ido CH H HOCH . II C C D- gluco S CHEME 13 138 conformation*1 stability in tho coordinated L-ido model, in which tha methyl group (C-6) la flanked by a large group (C-3) and hydrogen. The predomlnanoe of one isomer over another on the baais of a preferred path of attack of the actual redue- ing species, la believed not to be a predominant factor. The inereese in the alse of the reducing apeclea from BH^ to B(OCH^)Hw as the methanol content of the solution was increased (183) did not alter the yields of the (183) N. G. Gaylord, "Reduction with Complex Metal Hydrides," Intersclenoe, Hew fork, N. T ., (1936). products appreciably. Any sterie effect involving the attack of the reducing apeclea would have clearly altered the yield of the products. In the lithium aluminium hydride reductions, the expected products were formed in almost equal amounts. S*tch trends in reductions with metal hydrides were recently discussed by Beckett and ooworkeri (186). (186) A. H. Beckett, N. J. Harper, A. 0. J. Balon and T. w. E. tfatta, Tetrahedron. 6, 319 (1959). It appears therefore, that the prime factor in these reductions is the initial coordination of the 139 metal atom with the carbonyl oxygen atem, followed by a aon-selective attack of the reducing apecita. The Syntbaala of 3-£-Bensyl-l, 2-£- lsopropylldene-5.5-dl-,£-nethyl- D-xylofuranoaa (HIT) It vac found that 3-£-bensyl-6-deoxy-l,2-£- isopr opylidene-D-xxlXt**!9 X-furano-5-hexosulose (XIIII) reacted snoothly with methylmagneelun Iodide In ether to give a oryatalllne product in 75% yield or tore. The technique uaed was the same aa in the reaction of III with the aaie reagent. The ooapletion of the re action waa deternlned from the infrared abaorptlon apectrun of the crude eryetalline product, which lacked any carbonyl abaorptlon in the 5-6 p. region. Moreover, the phyaloal properties of the purified cryatala differed fron those of XXIII, the cryatala having a higher Melting point, and a less negative apeclflc rotation. The crystalline product gave a good analysis that agreed with the expected atructure of 3-£-bensyl-l,2-£-lso- propyIidene-5^-di-iJ-ne thyl-D-xylof uranoae (XXIV). The inaertlon of the nethyl group at C-5 had produced a tertiary hydroxyl group at that carbon. Thia hydroxyl group waa found difficult to eaterify with acetic anhyd ride in pyridine. Such an attenpt was actually made but reaulted in the darkening of the oolor of the reaction mixture and after adequate processing, an 140 alaost quantitative yield of the crystalline atartlng coapound was recovered. It has been known for a long tlae, that aueh tertiary hydroxyl groupa ara aatarlfiad with aora difficulty than priaary or aaeondary hydroxyl groupa (13®). It may ba possible, hovavar, to achieve aoatylatloa by uaiag aaatyl chloride la pyridine; thia la a aora Tigorona reagent and would raquira aoaa cara during the addition of the reaganta. Tha Synthaaia of l,2-.fl-Icopropylldono- 5 , 5—di-£-nothyl-D—xylofuranoao (XXV ) Thla aubatanca waa obtalnad by the eatalytie dabansylatioa of 3—.Q-bensyl-1,2—g-isopropylldene-5,5— di-£-aethyl-D-xylofuranoaa (XXIV ). The dabensylatlon produot oryatalllaad aa oolorlaaa needles (XXV), and had different phyaioal eonatanta than the corresponding 3~£-ben*yl derivative (XXIV). Tha infrared speetrua of a purified saaple of XXV was siallar to that of XXIV, axeapt that the substituted phenyl absorptions were not present in the foraer, Coapound XXV was a convenient aodel for studying estarlfleatlon reactions since It offers a secondary hydroxyl group at C-3 and a tertiary hydroxyl group at C—5. Acetylation with acetic anhydride In pyridine at 5° for ten alnutea, and subsequent processing gave a quantitative yield of the crystalline starting coapound (XXV). It appears that at this temperature and In a 141 period os short as ton minutes, thoro 1* no selectivity la the esteriflestlon of the seeoadsry hydroxyl group over the tertiery hydroxyl group in XXV. In another ex periment , the reaetsats were mixed end left standing at room temperature for 16 hr. la this esse, the product was a colorless sirup that did not crystallise even on seeding with the starting compound IIV. The infrared absorption spectrum of this sirup showed both hydroxyl and carbonyl absorption. These reaults clearly indicate that oompound XIV was partly acetylated, probably at C-3. Ia contrast to the acetylation experiments with oompound XIV, it was found that bensoylatlon with bensoyl chloride la pyridine esterlfled both hydroxyl groups In XXV smoothly. The product was a sirup, the infrared absorption spectrum of which waa devoid of any hydroxyl bands. The sirupy 3, 5-di-.Q-hensoyl-l, 2-.Q-ieopropylidene- 5,5-dl-£-methyl-D-xylofuranose (XXVII) was suitable for use in the next step without further purification. The Acetolysis of 3,5-Di-£-benaoyl-l,2-£- i a opr opylId o no-5,3-dl-£-mot hy1-D- xylofuraaose 1! XXVI I) The acetolysis of carbohydrate derivatives has been used in many instances. The reaction is of particular value because It performs two operations in one, namely, hydrolysis of a hemlaoetal linkage, followed by 142 acetylatioa of the generated hydroxyl groupa including tha ona on tha anomerle carbon aton. Tha acatolyaia raagant la uaually a nixtura of oonoantratad aulfuria acid, glacial acetic acid and aoetic anhydride. Thua, tha 3,5-di-£-benaoyl derivative (XXVII) was disaelved in a mixture of acetic acid and acetic anhyd ride, and concentrated aulfuric acid waa added dropvlse to tha atirrad mixture at low temperature. After atanding at room tamparatura overnight, the nixtura waa poured into ica-vater and prooaaaad by tha cuatomary extraction and purification procadurea. The product waa oryatalline 1,2-di-£-aoetyl-3,5-di-£-ben«oyl-5,5- di-£-methyl-D-xylofuranoae (XXVIII). Excluding the migration of benaoyl groupa in tho rather atrongly acid medium (101,103), it may be interaatlng to note that thla compound can only aaauma a furanoaa ring form. Seheae 14 llluatratea tha reactions leading to the aynthaaia of these new branchad-chaln augar derlva- tlvea, XIIV-XIVIII. 149 CH- CH- 3 COH CH 3 M 9I. O-C-CH O-C—CH XXIV Pd- C CH. CH. Z s 3 \x>Bz BzCI OBz O-C- O-C —CH. I 3 CH CH. YWU |(Ac )z O XXV H zS 0 4» AcOH C H CH, \COB* OAc S c h e m e 1 4 O Ac XX VIII 1 4 4 The Synthesis of $,S-Pi-S-nethyl-D-xyloaa(XXIX) This now substance waa obtained fro* tha hydrolyais of 1,2- (XXV) using two netheds. Hydrolysis with 0.0$% aqueous P amlforie acid for 2 houra at 70 , affordod XXIX aa a eolorloaa sirup, -10.512 in wator. Thia air up waa strongly reducing to Fabling aolution on warning. It waa aolubla in a aunbar of organio solvents axeapt ether, and an alcoholic aolution of tha conpound did not raatora tha color of tha Sehiff raagant, Tha oen- ditiona of hydrolysis of XXV would favor tha fornation of XXIX in tha pyranose forn. On papar cbronatograna uaing tha solvent nixtura l-butanol:ethanoliwater (4*1*5 ▼ /▼) , tha oonpound had 1,18. Tha airupy 5,5-di-£-nethyl-D-xyloae (XXIX) ia quita atabla at roon tanparatura and can ba kept for a long tina without any visual ohanga in ita phyaical appearance. Thia ia tha firat frea 5,5-di—£-nethyl-pentose to ba synthesised and investigated. Theequilibriun rotation of XXIX waa obtained by hydrolysing a known anount of 1,2-£-iaopropylidene-5,5- di-£-nethyl-D-xylof uranoaa (XXV) with 2 H (i 5) and 4 £ 2.5) hydrochloric acid. The specific rotations of tha aquilibriun dLxtures wera -27.4° and -26.8* respectively and did not change in 24 hours. Due to the similar rotations of 1 ,2-£-iaopropylidene-5,5-di-£-nethyl-D— 145 xylofuranose (XXV) *21°, and 5,5-di-^-^athyl-D- xyloaa (XXIX) £ i j % 5 -27°, tha prograaa of tha hydrolysis could not ba follovad polarimetrlcally. In tha saoond method of hydrolysis, l,2-J2-laopropyli- dene-5,5-di-£-methyl-D-xylofuranose (XXV) was haatad In watar with Amberlite IR-120 (H+) (157), aocording to tha ganaral nothod of Shaflsadah and Wolfrom (173). Con- oantratlon of tha procassad solution gave a oolorlass sirup. A driad sanpla gar# vary good analytical figures. Although tha structure of 5,5-di-£-methyl-D-xyloae (XXIX) was wall established by its node of synthesis and various crystalline derivatives, it was desirable further to substantiate the branohed character of tha molecule. A portion of tha sirup XXIX was transformed into Its methyl glycoside with methanolie hydrogen chloride. Tha glycoside was not isolated, but its aqueous solution was treated with a mixture of 5 £ chromic acid and concentrated sulfuric acid, and the solution was rapidly distilled into ethanolic 2 ,4-dlnltrephenylhydraaine. Aoetone 2,4-di- nltrophenylhydraaone was thus formed and characterised. The same result could be obtained from the free sugar XXIX instead of the glycoside, but the yield of the hydrasone waa much lower. The strong acidity of the medium was evidently the cause of the extensive decomposition of the free sugar. 14.6 8o m Crystalline Dtrlntlrei of 5.5-Di-£-nethyl-D-xyloee The sirupy 5,5-di-£-nethyl-D-xyl©ee (XXIX) waa furthar characterised by ita traneforutlan into a number ef crystalline derivatives (Scheme IS). Tha pheaylesasone XXX aould ba prepared quit# readily bj tha action of the sugar with phenylhydrasine In aqueous aoatio acid} tha oaasona crystallised out of tha rsao- tlon nixtura ia 10-15 ninutea. Four rscrystallisatloaa fron athanol-water gave bright yellow cryatala that wara analytically pure. Tha phanylnnotziasola XXXI waa famed in a aonawhat nodlfiad way. Tha phanyloaaaona XXX waa auapended in water and rafluxed in a aolution containing ouprio sul- fata aa usual. At tha and of tha reaction a fine praalpitata of cuprle oxlda had fornad. Tha aolution waa filtered and deodorised by paaaing it through a column of Daroo G-60 oarbon. Upon concentrating tha affluent aolution, only residual cupric sulfate could ba isolated. Tha column waa tharafora developed with aoatona and tha affluent was concentrated to drynesa. Addition of ether caused crystallisation of the 5. 5-di-£-nethy1-D-xylose phenyloaotrlasole (XXXI) as colorless needles. Usually the oaotrlasolea crystallise out of tha aqueous concentrates and are preferred to tha oeasonea on account of their batter crystallising 147 CH. CH. * H,0 O-C—CH XX2 m NHC.H- I * 5 HC=N n HC H I I C ^ N v I I^N C.H. HOCH HOCH • 6 I Cu I HCOH HCOH m ---- HNNHCH ^COH 2 6 5 / ° \ c h 3 c h b CH, CH, XXX ° * W . HC=N-N-C,H, CH.C.H I 2 6 5 HNNC H OH 2 6 5 H? HOCH I HC Finally, the eryatalline 5,5-di-£,-nethyl-D-xyloae bensylphenylhydraione XIIII waa prepared by reacting an aqueoua athanolio eolation of the sugar XXIX with 1-benayl-l—phenylhydrasine hydrochloride and aodiun aeetate. Tha initial prodnot waa a airup whioh cryatal- lised upon the addition of ether. EXPERIMENTAL All oombustlon analyses were performed by the Galbraith Microanalytlcal Laboratoriea, Knoxville, Tenn. The infrared abaorptlon spectra of solid samples were analysed In potassium bromide pellets while the sirupy substances were analysed aa films using sodium ohlorlde crystals. The apeotra were obtained with the Baird-Atomic infrared recording spectrophotometer (Model B). Magnesol is a synthetic magnesium acid silicate produced by the Weatvaco Division of the Pood Machinery and Chemical Corp., South Charleston, W. Vs. Celite (No. 535) is a siliceous filter aid produced by the Johna-Nanvllle Co., New Tork, N. I. Petroleum ether (b.p. 30-60°) waa used throughout this lnveatlgatlon unless otherwise stated. The Synthesis of D-xvlo—pentodialdose and Derivatives The Preparation of Dimeric 1,2-jj-isopropylldene— urano-pent odi aldose This substance was prepared essentially according to the method of Schaffer and Isbell (12) (Scheme 1). A stirred solution of 10 g. of sodium metaperiodate In £0 ml. of water was treated In the cold with 10 g. of 1,2-jJ- 149 150 isepropylldene-D-glueofuranoa* (187) in •mall portions. (187) D. J. Boll, J. Chen. floe.. 1874 (1935). After stirring for 20 min., tho oxooss porlodsto was decomposed by tho addition of othylone glycol. Tho aolution was coneontratad undor reduced pressure and tho roslduo was dissolved In 10 ml. of wator and waa seeded with crystals of diaerle 1,2-£-lsopropylldene-5- aldohrdo-D-xylo-lrZ.-f ursno-mntodlaldoae (12). Crystal lisation began after about 4 0 hr.j yield 1.5 g*, m.p. 180-183°} recorded for the dimer hemihydrate (12)} o m.p. 180-184 • Due to the slow crystallising nature of the dimer and the low yields, It was found convenient in subsequent Investigations to use the crude sirupy dimer which contained soie formaldehyde. When the dimeric substance (crystalline or sirupy) was reacted with an excess of a 50% absolute ethsnollc solution of hydrogen cyanide, and the mixture was left standing overnight at room temperature, only starting material could be recovered after appropriate processing of the reaction mixture. The results were the same when longer reaction times were allowed. The initial reaction product was a sirup which was reducing to Pehling's solution and failed to give a positive naphthoresor- cinol test for uronic acids. When an aqueous solution 151 •f the sirupy product waa seeded with crystals of the o dimer, crystallisation occurred at 0 end moat of the starting Materiel was recovered. The anticipated in vestigations with this dimeric substance were not attempted due to its relative Inertness toward certain reagents in non-tqueous media. The Preparation of 3-j2-Bensyl-l,2-JJ- iaopropylldene-D-gluoofuranoaa (I) This substance waa prepared essentially according to Meyer and Reichstein (101). An amount corresponding to 127 g. of sirupy 3-£-bensyl-l,2i5,6-di-£-isopropylidene- D-glucofuranose (155) was added to a mixture of glacial aeetio acid (360 ml.) and water (200 ml.) over a period of 10 min. The solution waa kept at 36° for 5 hr. with continuous stirring. It was then neutralised with powder ed potassium oarbonata and taken up in 500 ml. of ether. The ethereal layer waa washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to a yellow sirup (170 g.). This was dissolved in 150 ml. of pyridine (dried by distilling from barium oxide and passing through neutral alumina (a product of M. Woelm, Eschwege, Germany) and 190 ml. of acetic an hydride was added slowly with external cooling. The aolution waa kept at room temperature for 20 hr. after which it was poured into 1 liter of ice-water, extracted with three 250-ml. portions of chloroform and the 152 extracts war# driad over anhydrous sodlun sulfate. Filtration and evaporation of tha solvent gave 127 g. of 5,6-di-Jl-aoetyl-3-fi-bensyl-l,2-£-is opropylidene-D- glueoforanoaa, n.p. 120-121°; Mayar and Reiohstein (101) raport n.p. 119-120° for tha aana conpound. Tba di- aeatata waa daaoatylatad by dissolving in 1 litar of warn abaoluta nathanol and adding a snail anonnt of aodiun nathoxida. Tba aolution, aftar atanding over- nigbt at roon temperature, was nautrallaad with a snail quantity of nothanol-washed imberlite IK-120 (H+) (157) and filtarad. Tha filtrata waa ooncantratad undar raducad praaaura and the residua was takan up in ather. Evaporation of tha lattar solution affordad 3-fi-bensyl-l,2-,2-iaopropylidene-D-glucoforanoaa (l)» a viscous oolorlaaa sirup; yiald 97 g. (100%), 7 j f -47° (a 3.4-, chloroforn); literature records; -46°i0.6° (chloreforn) (101). Tha Synthesis of 3-,fi-Beniyl-l iaopr opylidane-5,6-bia-£-(j>-nitro- bensoyl)-D-gluoofuranose (II ) in anount oorresponding to 3*5 g. of alrupy I waa dissolved in 25 nl. of dry pyrldlna and 4*3 g. of p- nitrobansoyl chloride was added* iftar atanding at roon temperature for 10 hr. the mixture waa poured into ice- water and stirred for 1 hr. The aolution was extracted 153 with two 250-ml. portions of chloroform, tho extracts waahod with an aqnooua saturated aolution of aodium bicarbonate, then with water and dried over anhydrous aodium aulfate. Evaporation of the solvent afforded a pale yellow sirup which orystallised on atanding at room temperature after the addition of a small quantity of ethanol; yield 5 g. Two reorystalliaationa from acetone— petroleum ether gave 3.4 g. of pure erystals; m.p. 116- 117*. -M* U 1.5. acetone), x-ray powder diffraction data (l88)t 11.Ov, 6.68w, 6.15w, 5.68 b (1), (188) Interplanar apaoing, CuKa radiation. Relative intensity eatimated visually; a, strong; m, medium; w, weak; v, very. First three strongest lines are numbered (l, strongest); double numbers indicate approximately equal Intensities. 5.12w, 4.82w, 4.52w, 4.29w, 4.21vw, 3.60n(2), 3.15vw. Anal. Calcd. for C30H28°12M2 1 C > 59.20, H, 4.63, S, 4.64. Found* C, 59.05; H, 4.31; K, 4.83. The Synthesla of 3-£-B«»*7l-l ^-.fi ls opronyl ldono-5-aldohTdo-D—xvlo- 1,4-furane—pentodlaldoae (111) A auapenaion of 210 g. of lead tetraacetate in 1.5 liter of dry benzene waa added gradually to a aolution containing 94 g. of I in 100 ml. of dry benzene. The mixture waa warmed for a few minutes and then filtered. 154 The strong odor of formaldehyde coaid bo immediately detected. Tho filtrate woo ooneontrotod andor roducod prtituro, at o both temperature below 3 0 °, to o polo 7 0 II0 V sirup which woo token ap in 2 0 0 ml. of obooluto othonol ond tho solution filtered. The filtrate woe concentrated, other added, filtered and the final fil trate ooneontrotod under reduced pressure to a sirup; yield 79 g. (92%). Tho infrared spectrum of a sample showed considerable hydroxyl absorption in the 2-3 p region. 4 quantity of the sirup (2 g.) in 2.5 ml. of dry pyridine was aeetylated with oeetlc anhydride (2 , 4 ml.). The color of the solution darkened considerably within 2 hr. of the mixing. After standing at room temperature overnight the dark solution was poured into ime-water and extracted with chloroform. Drying and evaporation of the extracts gave no crystalline compound corresponding to the dlacetate of I, even on seeding and o storing at 0 for a long time. The starting material I had therefore been all oxidised. The pale yellow sirup (79 g.) was then purified by distillation in a Hickman molecular pot still (15*>) at 0.07 mm. The fraction boiling between 80-100° was discarded. 3-Q-Bensyl-l,2- JQ—laoproDylldene-5-aldehvdo-D-xvlo-l.A-furano-pento- dialdose (ill), boiling between 150-155° was oollected as a colorless viscous liquid; yield 55 g., f * J % 5 -86.5* (£ 2.694* ethanol-free chloroform). The infrared 155 spectrum of this oompound (Fig* 1) contained a sharp carbonyl peak and essentially no hydroxyl peak] infrared absorption spectrum data t X 5*8 p (G«0), 9*35, 9.75 p (C-O-C), 13.6, 14.9 p (substituted phenyl). Anal.Calcd■ for C ^ H ^ O ^ i C, 64.77] H, 6.52; mol. wt•, 278. Found: C, 6 4 .8 6 ; H, 6.55; mol. wt. (f.p. in bamene), 315. The sirup was strongly reducing to warm Fehling solution and it produced the characteristic magenta color with the Schlff reagent almost Instantly. The behavior of the sirupy aldehyde upon chromatography on paper using two solvent mixtures; 1-butanol:ethanol: water (4:1:5 v/v) and l-butanol:pyridlaeiwater (3*2:1.5 v/v) was marked by extensive tailing and gave an elongated, fast travelling spot having an Rf value of 0.9 in both solvent mixtures. Spraying agents used were ammonlacal silver nitrate and aqueous ammonium molybdate (189). (189) (a) S. M. Partridge, Bloohen. J.f £2, 238 (1948); (b) H. £1-Khadem and S. Haness Anpj-i Chga., 10, 1965 (1958). 156 The Synthesis of 3-£“Bensyl-l,2-,g- laopropylldene-5-aldahrdo-D-xxJLtt- 1.4-furano-pentedlaldoee fitMlOTbllOM (IV) A aolution of 0,7 g. of III In 7 nl. of ethanol waa nado faintly turbid with water and the turbidity waa restored with a few drops of ethanol. Semloarbaside hydroohlorIda (1 g.) waa then added, followed by aodiun acetate (1 g.). The mixture waa warmed on a boiling water bath for 5 min., then cooled and kept at 0° with oocaaional scratching. Crystals separated after 20 min. These were filtered and washed thoroughly with warm water and dried under reduced pressure In a drying pistol orer boiling waterj yield 0.6 g., m.p. 177-178°, /qJ7*5 -50° (i 1.48, ethanol), x-ray powder diffraction pattern data (188)i U . 0 0 rw, 8.06m, 6.44v, 6.20w, 5.64e(l), 5.27m(2), 4.92m, 4.45n(3), 4 .2 3 m, 3.98m, 3.60m, 3.22w, 2.97w. Anal. Calcd. for C16H21°5N3* C» 57.30; H, 6.31; N, 12.53. Found: C, 57.41; H, 6.35; N, 12.37. The Synthesis of l,2-£-Iaopropylidene-5- aldehydo-D-xylo-1,4-furano- pentodlaldoae (V) One gram of sirupy 3-jJ-benayl-l,2-£-isopropylldene- 5-aldehrdo-D-xylo-l.A-f urano-pentodialdose (III) was dissolved in 25 ml. of absolute ethanol and 0.1 g. of palladium-on-charcoal catalystvma added. The mixture was hydrogenated at 65° under 400 p.a.i. for 4 hr. 157 Filtration of tha oatalyat and evaporation of tha fil trate afforded a colorlesa airup which showed both hydroxyl and oonalderable carbonyl absorbtion in the infrared spectrum (Fig* 2); yield 0.94 g * The characteristic substituted phenyl absorption bands in the region 13- 15 Ji were missing denoting complete hydrogenolysls of the bensyl group. On atanding for about a week at room temperature, the carbonyl peak diminished slightly in magnitude and the airup acquired a pale yellow color. The compound was probably partially dimerlsed. Seeding an aqueous solution with crystals of the dimer (12) and storing in the ice-box, failed to induee crystallisation. To a portion of the fresh sirup (0.19 g«) in 2 ml. of ethanol was added 0.2 g. of semicarbaalde hydro chloride, followed by 0.2 g. of sodium acetste and the solution was made turbid with a few drops of water. Scratching and cooling failed to Induce crystallisation. The solution however, deposited crystals after 2 months; m.p. 208-209° (dec.). Iwadare (7) reports for the same derivative: m.p. 209-209.5° (dec.). in attempt was made to react V with methylmagnesium iodide in a mixture of benzene and ether, but most of the starting aldehyde was recovered as a sirup. Apart from the low solubility of V in suitable solvents for the Grlgnard reaction, the presence of a free hydroxyl group on C-3 formed Insoluble complexes. The reaction waa not further investigated. 158 Tha Synthesis of D-xxJLfc-pentodialdoaa (VI) To on amount of 0.116 g. of sirupy V in 1.5 ml. of water waa addod 1 ml. of Amberllte IR-120 (H+) (157). Tba mixture waa baatad on a ataam bath for 3 hr., than ooolad, whereby tha eolorof tha aolution baeama dark yellow-brown. Evaporation of thia aolution under reduced preeaure afforded a yellow airup (VI); yield 80 mg. Storing AO mg. of the airup In 3 ml. of acetic acid containing 80 mg. of p-nltrophenylhydrasine, formed a dark red aolld overnight; m.p. 185-190° (dec.). Racryatalllsation from ethanol-petroleum ether gave a dark red aolld; m.p. 189-190° (dec.). Iwadare (7) reports for D-zvlo— pontodialdoao bis(p-nltrophenylhydra- sona): m.p. 190-191° (dec.). To a portion of the airup (66 mg.) in 2 ml. of chloroform waa added 0.5 ml. of ethanethlol followed by 0.7 ml. of concentrated hydrochloric acid and the mixture was stirred for 24 hr. Conventional processing of the mixture afforded a sirup that waa not investigated further. 159 The Synthesis of 6-Peoxy-L-idose and PTlT The Synthesis of 3-£-B*asyl-6-d*oxy-l ,2-£- laepropylldene-L-idofuranose (VII). General description of the Grlgnard Apparatus The reaction waa carried out in 3-necked round- bottoned flaaka with ground glaaa Joints, equipped with two efficient condensers on each aide while the central neck carried a separatory funnel. All solvents except benzene were dried by distillation froa lithium aluminium hydride directly Into the reaction vessel through the upper opening of the right hand side condenser, under a alow stream of dry nitrogen. All other openings in the system were protected from molature by Drierit* (190) (190) A product of the W. A. Hammond Co., Xenia, Ohio. guard tubes. Stirring was effected using a magnetic stirrer. Whenever heating waa necessary the reaction vessel was placed In a heating mantle and the whole was rested on the magnetic stirrer. The nitrogen was dried by passage through towers containing concentrated sul furic acid and Drierlte, respectively. The magnesium turnings were of good purity and were made especially for Grlgnard reactions (191). The methyl iodide was 160 (191) A product of Malllnckrodt Chemical Works, St. Louis, Mo. provided froah from bottlaa for each experiment and waa of good purity. A. The Grlgnard Reaotlon Oalng Ether aa Solvent A aolution of 10.5 ml. (0.2 mmolea) of methyl Iodide in 50 ml. of anhydroue ether waa added dropwlae to A.5 g. (0.2 mmolea) of magneelum turnlnga auspended in 100 ml. of dry ether. The reaction aoon atarted and a gentle reflux waa maintained by regulating the rate of addition of the halide. Whan all the magnealum had dissolved, the greylah aolution waa rapidly filtered through cotton wool Into another 3-necked flaak with exelualon of air. A aolution 10 g. (0,03 mmolea) of 3-fl-benay1-1,2-£- iaopropylldono-5-aldahydo-D-xvlo-lfA-furano-pantodlaldose (ill) in 70 ml. of anhydrous ether waa added dropwlae to the refluxlng Grlgnard aolution over a period of 2 hr. The formation of the complex with the Grlgnard reagent waa observed aa aoon aa the drops touched the surface of the solution, but aoon dissolved in the reaotlon mixture. When the addition was complete, the dropping funnel waa rinsed with 50 ml. of ether, the latter waa added to the reaction mixture and refluxlng was continued for an additional 30 min. The cooled, turbid aolution gave a 1 6 1 positive Gilman test (160) and was transferred to a separatory funnel and cautiously added dropwise to 200 ml. of a cold saturated aqueous solution of ammonium chloride under constant and vigorous stirring. The aqueous layer was separated and washed with ether. The combined ether extracts were washed with a small quantity of saturated ammonium chloride solution, then with water and finally dried over anhydrous sodium sulfate. Fil tration and evaporation of the solvent under reduced pressure afforded a sirup which crystallized in a few minutes. The crystals were triturated with a small quantity of cold ether and filtered. The crystals were washed with a cold mixture of ether-petroleum ether; o yield 6.65 g., m.p. 85-86 . The aqueous solutions and washings were concentrated under reduced pressure to a solid mass and the latter was extracted exhaustively with hot chloroform. The extracts were dried and concentrated to a sirup which crystallized on seeding with the above crystals; yield 0.35 g., combined yield 7 g. (70%). hecrysta 11ization from hot petroleum ether containing a few drops of absolute methanol and subsequently from ether-petroleum ether afforded pure needles; yield 6.2 g.# m.p. 93-94°, r < C / \ 5 -63.5°(i 1 .26, chloroform), x-ray powder diffraction data (188): 10.05m, 8.32m, 5.94m, 5.07s(1), 4.92w, 4.74w, 4.52m(2), 4.33w, 4.08m(3), 3.66w, 3.57vw, 3*50vw. Infrared absorption spectrum data 162 (Fig. 2.93 p (OH), 7.27 p (CH3 ), 9.25, 9.50, 9.80 ji (C-O-C), 13.75, 14.50 31 (substituted phenyl). Ansi. Calod. for C1 6 H2 2 O5 : C, 65.28) H, 7.53. Foundi C, 65.14; H, 7.30. This compound was subsequently identified as 3-£- benayl-6-deoxy-l,2-£-isopropylldene-L-idofuranoae (VII ), as will be discussed shortly. It was Insoluble In water, slightly soluble in petroleum ether and was soluble in the eouon organic solvents. It did net reduce Fehling solution. Paper chronetogrephy, using the solvent mix ture 1 -butanol:ethanoltwater (4 :1 * 5 v/v) and spraying with amaoniacal silver nitrate (1 8 9 s), revealed a weak spot having an of 0.73. A sample was subjected to the conditions of the iodoform reaction for insoluble substances (162) as followsi 0 . 5 g. was dissolved in 15 ml. of dioxane and 0.5 ml. of a 1 0 JC sodium hydroxide solution was added dropwlae and the solution was heated at 6 0 ° until a permanent color of iodine persisted. The solution was treated with the necessary amount of base to decolorise the iodine and water was added. Iodoform was strongly detected by odor. 163 B . The Qrlgmrd Reaction Palng Bcnacnc- S.thir i> gglTtnt The Grlgaard reagent waa prepared by adding a aolution of nethyl iodide (10 ml.) in 50 al* of anhydrous ether to a auapenaion of magnesium turnings (3.88 g.) in 50 al. of anhydroaa ether. Vhen all the reaction waa complete, the aolution waa decanted from unreacted aag- neaiua into another 3-necked flask. The ether waa distilled in a dry atreaa of nitrogen while 120 ad. of dry bensene was added in saall portions. When aost of the ether was removed, the teaperature waa raised and a gentle reflux was maintained. 4 aolution of 9 g. of 3-Q-bonayl-l.2-Q-iaopropylidsne-5-aldehydo-D-xvlo-l.4- furano-pentodialdose (III) in 80 al. of dry bensene waa added dropwlae over a period of 1 hr. Refluxing was continued for an additional 2 hr. The aolution was then allowed to cool and was added dropwlse to a cold saturated aqueous solution of aaaonium chloride (250 al.). The bensene layer was separated, washed with water, dried and concentrated under reduced pressure to a sirup which crystallised on standing to give 3.6 g. of the crude o orystalline product VII, a.p. 85-87 . The mother liquor was taken up in ether-petroleua ether and after storing in the icebox afforded a further amount of product; yield 0.4 g., combined yield 4 g. (44%)* The crude product could be purified by recrystalllzatlon as 164 described previously to afford pure material, a.p. o 93-94 • Tha aquaoua solutions from the reaction wore concentrated, extracted with chloroform and the extraeta evaporated to a sirup. This waa oombined with the crystallisetlon mother liquors to give a dark yellow airup which waa reducing to Fehllng aolution and showed a carbonyl peak in the infrared spectrum; yield 4.3 g. C. The Grignard Reaction Daing Tetrahydrofarea aa Solvent Normal addition 4 solution of 9 , 5 ml. of methyl iodide in 10 ml. of anhydrous ether waa added dropwlae to 1 , 5 7 g. of magnesium turnings suspended in 100 ml. of anhydrous ether. When all the metal was consumed, the solution was filtered with exclusion of air and then evaporated to dryness by heating on a water bath at 60° in a rotary stripper for 1 hr. The residue was taken up in 100 ml. of dry tetrahydrofuran and stirred under a nitrogen at mosphere at room temperature. Gilman's color test (160) waa positive at this stags. A solution of 2,05 g. (7.3 mmoles) of 3-0-benavl-1.2-0-isopropylidsne-5-aldehvdo- D-xy1o-1fL ~ t urano-pentodlsldoae (ill) in 20 al. of dry tetrahydrofuran was added to the stirred Grlgnard reagent over a period of 30 mln. Stirring was continued for 3 hr. at 33° after which Gilman's test (160) was still positive, and denoted the presence of residual Grignard 165 reagent. The mixture waa daeompoaad In an aquaoua saturated aolution of aaaonlua ehlorlda at 0°. Ether (150 al.) waa than addad and the organic layer waa aeparatad and waahad with water. Drying and evaporation of the aolvant gave a pale yellow airup whloh waa strongly reducing to Fehling aolution and showed a oarbonyl peak in the infrared spectrum; yield 2. g. Inverse addition The above experiment waa repeated in its entirety but the Grignard reagent in tetrahydrofuran was added to a aolution of the aldehyde III in the same solvent. The results were identical and no erystalllne material could be isolated. The Synthes la of 3-£-Beniyl-6-deoxy- 1 ,2-£-isopropylidene-5-.Q-nethyl- sulfonyl-L-idofuranose (VIIIJ To a cold solution of 3-,fi-bensyl-6-de oxy-1,2-.Q- isopropylldene-L-ldofuranose (VII, 0.3 g*)» in 2 ml. of dry pyridine was added 0.2 ml. of metheneeulfonyl chloride followed by 2 ml. of chloroform. After standing at room temperature for 16 hr., the mixture waa poured into ice- water and stirred for 2 hr. The solid that separated was filtered, washed with petroleum ether and then with an ether-petroleum ether mixture (1:5 v/v), to give colorless needles; yield 0.28 g., m.p. 82-85°. Two recrystallisations 166 fro* ether or chloroform afforded pure material in the form of elongated needlea; m.p. 99-100°, f n j % 5 -60° (i 1*008, ehloroform), x-ray powder diffraction pattern data (188)* 12.02vw, 10.85m, 8.88v, 7.44tv, 5 .4 2 m(2 ), 5.09a(l), 4.69m, 4.57m, 4.23m(3), 3 .8 8 vw, 3.80vv, 3.42vw. The infrared abaorption spectrum ehoved no hydroxyl abaorption. Anal. Calcd. for ci7H24°7S: c» 54.82; U, 6.49; S, 8.60. Found: C, 54.34; H, 6.37; 6.48; S, 8.47. The Stereoohemical Configuration of the Product from the Grignard Reaction - The Preparation of 6 -Deoxy-l,2-,fl- laopropylldene-L-ldofuranoae (ix) Thla substance (IX) had been prepared previously by Meyer and Keichstein (106) by the hydrogenation of the corresponding 5 ,6 -anhydro-3 -J2-benmyl derivative or the corresponding 5 ,6 -anhydro derivative of Baker and co- workers (103). A solution of 0.3 g. of 3-£-bensyl-6- deoxy-l,2-£-isopropylidene-L-idofuranose (VII) in 70 ml. of absolute ethanol was hydrogenated in the Farr apparatus (1 9 2 ) with palladium-on-charcoal catalyst (0.15 g.) (192) Parr Instrument Company, Moline, 111. at room temperature and 28 p.a.i. for 2 4 hr. Filtration and evaporation of the solvent gave unchanged starting material. Hydrogenation was effected at higher 167 temperatures end pressures. To 2.5 g. of VII, dissolved in 50 m1. of othanol, waa addod 0.25 g. of palladium-on- oharcoal catalyst and the mixture waa hydrogenated at 65-68° under 300 p.e.i. for 4 hr. After filtration and evaporation of the solvent under reduoed pressure, a elear alrup (1.75 g.) was obtained which crystallised on standing. A sample melted within the range of melt ing point of the starting material, however its infrared absorption spectrum lacked the characteristic substituted phenyl absorption bands between 13 and 15 u (Fig. 4), thus indicating complete hydrogenolysis of the bensyl group. The crystals were filtered and washed with cold ether to give 6-deoxy-l,2-£-isopropylldene*L-idofuranose (IX); yield 1 g. Seeding the mother liquors afforded further material; yield 0.12 g. (combined yield 1.1 g.), m.p. 88-89°, Z “7° (it 3.4, chloroform); literature records (106); m.p. 90-91° (also m.p. 88-90°, 8 4 -8 8 °), r < o i1 —12.9° (chloroform) and (103) m.p. 90-92°, -7.1° (chlorof orm). Infrared absorption Bpectral d a t a : A ^ £ 2.95 31 (OH), 7.25 31 (CH-j), 9.25, 9.50, 9 . 8 5 3 1 (C-O-C). This compound had an value of 0.78 when chromatographed on paper using the solvent mixture 1-butanol:ethanoltwater (4:1:5 v/v). 1 6 8 The Preparation of 3 t5-Dl-A-«c^tyl- 6— deoxy-1 , 2^-liopr opylldene- L—id ofuranota (X) in mou nt of 0.15 g. of 6-deoxy-l,2-fl-ioopropylidene- L-ldofuranose (IX) was dissolved in 1 ml. of dry pyridine and 1 ml. of aoetic anhydride was added. After standing at room temperature for 16 hr. the mixture was poured into loe-water and extracted with three 150-ml. portione of ehloroform. Evaporation of this aolution afforded a pale yellow sirup which was taken up in toluene (10 ml.) and evaporated to remove the last traces of pyridine. The final sirup crystallised and the crystals were triturated with a mixture of ether-petroleum ether (1:1 v/v), and were filtered; yield 0.18 g. , m.p. (,& 2.12, chloroform); literature (106) records; m.p. 123- (chloroform) Inveatigation of the Mother Liquors from the Grignard Reaction Attempted purification The mother liquors from the Grignard reaction in ether, were taken up in ethanol, treated with decolorising carbon, fllterad and concentrated to a yellowish brown sirup. This alrup was reducing to Fehling solution and its Infrared absorption spectrum showed a carbonyl peak. On paper chromatograaa, using the solvent mixtures 1- butanojiethenoliwater (4:1:5 v/v) and 1-butanol:pyridine» 1 6 9 water (2:1.5*3 v/v), a spot travelled the eame aa the 5-aldehydo derivative (III), end had Kf 0.8. The above airup oould be partially purified by column chromatography a a follovai about 20 mg. waa disaolved im 3 ml. of a mixture of ethyl aoetate and petroleum ether (4*1 v/v) >°d the yellow aolution waa added to a 2.5x20 cm. column of Magneaol-Cellte (5*1). The column waa developed with 20 ml. of the above men tioned advent mixture. After extruaion and atreaking the oolumn with analkaline permanganate aolution, a wide band (2 cm.) wee detected. Klution of thia band with acetone and evaporation of the aolvent gave a pale yellow airup which waa reducing to Fehling aolution and ahowed carbonyl abaorption in the infrared apectrumj yield 15 mg. In another experiment, 0.8 g. of the airup waa diaaolved in 10 ml. of a mixture of ether-petroleum ether (1*2 v/v) and waa added to a 4x20 cm. column of Magnesol- Celite (5*1). The oolumn waa developed with petroleum ether-ether (2:1 v/v) and the progress of a yellow band waa followed with an ultraviolet lamp. Elution Of thia band alao gave a pale yellow airup which waa reducing to Fehling aolution; yield 0.6 g. Another portion of the mother liquor (l g.) was distilled at 115° (oil bath temperature) and 0.1 mm. The distillate waa taken up in ether and evaporated to 170 • colorleaa airup which waa reducing to Fehling aolution] jiold 0.7 g. Tha behavior of all three purification products, namely, fron chronatography and diatlllation, waa identical on paper uaing the solvent nixture 1- butanoltethanoliwater (4:ls5 v/v), showing Rf 0.8 ainilar to the original mother liquors and (III), Bydrogenolyais of mother liquora A. Grignard Reaction Using Ether ae Solvent in amount of 1.7 g. of the airup waa disaolved in 40 ml. of absolute ethanol and hydrogenated in the preaenoe of palladium-on-charcoal (0.5 g.) as deaoribed previously. it the end of the hydrogenation, the aolu tion was filtered and the filtrate waa evaporated under reduced pressure to a colorless airup which waa reducing to Fehling solution; yield 1 g. The Infrared abaorption spectrum showed a small carbonyl peak, but otherwise the apectrum waa similar to that of Ii and the compound showed an identical Rf. A portion of this sirup (0.3 g.) was acetylated with 1.5 nl. of aoetlc anhydride in 1.5 ml. of dry pyridine. After standing at room temperature for 16 hr., the mixture waa poured into ice-water and stirred for 2 hr. Extrac tion with three 100-ml. portions of chloroform, followed by drying and evaporation of the solvent, afforded a airup which crystallised upon trituration with absolute 171 o ethanol; yield 65 ».p. 121-123 • Recrystallisation from methanol-water gave oolorlaaa needles; yiald 30 ag. a.p. 122-123°, not dapraaaad upon adalztura with an authantlc aampla. B, Grignard Reaction Uaing Banaaaa-Ether aa Solvant 4a amount of 1.4 g. of tha airupy aothar liquor in 25 al. of abaoluta athanol waa treated with decolor ising carbon and filtered. To thia filtrate was added 0.14 g* of 10JC palladiua-on-oharooal catalyst and the mixture waa hydrogenated aa described previously. Filtration and evaporation of the solvent afforded a colorleaa airup which showed a small carbonyl absorption band in the infrared absorption spectrum, but otherwise the spectrum was similar to that of IX; yield 0.72 g. 4 portion (0.72 g.) was aoatylated with 2 al. of acetic anhydride In 2 ml. of dry pyridine. 4fter standing at room temperature for 20 hr., the mixture was poured into lce-water and stirred for 2 hr. Extraction with chloro form and evaporation of the solvent afforded colorless o needles; m.p* 122-123 , not depressed upon admixture with an authentic specimen. C. Grignard Reaction Using Tetrahydrofuran aa Solvent 4 portion of the mother liquor (0.5 g.) was debensylated with palladlum-on-charcoal and hydrogen, as described previously, to give a pale yellow sirup 17 2 which was reduolng to Fehling solution and showed s earbonjl paak In tha infrarad absorption speotrumj yield 0.37 g. Tha s i m p (0.37 g.) was acetylated with 3 ml. of acatlo anhydride in 4 *1 * of dry pyridlna. After standing at room tamparatura for 2 0 hr., tha mix- tura was poarad into iee-water and atirrad for 2 hr. Extraction with thrae 100-ml. portions of chloroform and evaporation of tha dried solvent gave a sirup which crystallised after seeding with authentic material and trituration with ather-petroleum ether or ethanol. Tha crystals ware obtained pure after washing with cold ethanol followed by athar-patroleum ether; yield 33 mg., m.p. 123—123.5°* The melting point was not depressed upon admixture with an authentic sample. Tha Synthesis of 3 - Bensyl- 6—deoxy-L-idose (ll) The hydrolysis of 3 -.fi-bensyl-6 -deoxy-l,2-J}-isopr opyli- dene-L-ldofuranose (VII) was oarried out essentially according to the method of Freudenberg and coworkers (195). in amount corresponding to 2 . 9 4 g> of the cry stalline compound VII was dissolved In 12 ml. of methanol and 4.41 ml. of JI sulfuric acid solution was added. The solution was stirred at 70° for 4 hr. after which the methanol was stripped and 3 . of water was added. The solution was heated for an additional hour whereby the rotation of an aliquot was constant. The solution was 17 3 neutralised with barium carbonate, filtered and treated with decolorising carbon. Filtration and evaporation of the solvent afforded a colorless sirup; yield 2.43 g. (95jf). The s i m p was stored over calciun chloride in an evacuated desiccator for 4 8 hr., then dried at 60° in a drying pistolj £ L J ^ -lll0.5° tfi 3#914, ethanol), with no change of rotation on atandlng; infrared ab sorption spectral datat-X**!" 2.9 Ji (OH), 13.5, 14.45 (substituted phenyl). Anal. Calcd. for C ^ H ^ O ^ i C, 61.40; H, 7.13. Found 1 C, 61.00; H, 7.32. On paper chroaatograss using the solvent mixtures 1-butanol:ethanol;water (4:1*5 v/v) and 1-butanol: pyridine:water (3*2:1.5 v/v), a single spot having 0.78 was obtained. The sirup was reducing to Fehling solution but did not restore the color of the Schiff reagent. Acid hydrolysis of the mother liquors from the Grignard reaction, effected in the above manner, gave a reducing airup having identical chromatographic properties as XI. The Synthesis of 3-;S-Bsnsyl-6-deoxy-L-idoas Bensylphenylhydraione (XII) A solution containing 0.85 g. of 3— benayl-6— deoxy—L—ldose (XI) in 25 ml. of ethanol was heated with 0.3 g. of sodium acetate followed by 0.76 g. of 1-benayl 1—phenylhydrazinc hydrochloride. The mixture was 1 7 4 rtfloxtd for 3 hr., troatod with decolorising carbon and filtorad. The filtrate waa evaporated to an oil which waa taken up in chloroform* waahed twice with water and dried over anhydrous aodium aulfate. Evaporation of the solvent gave a airup which waa taken up in ether, and made slightly turbid by the addition of petroleum ether, and stored in the icebox. Crystals deposited after o 2 4 hr.; yield 1.1 g., m.p. 115-116 . An analytical sample, m.p. 120-121°, +44° (a 1, ethanol) was obtained after two reorystallisationa from absolute ethanol. X-ray powder diffraction pattern data (188)t 9.71m, 7.76w, 6.02m, 5.29s(l), 4.92m(2), 4.37m, 3.32n(3), 3.56w, 3.31m, 2.98m, 2.84t«* 2.70vw. Anal. Calcd. for ®26®30®4®2* ^t 71.86} U, 6.96) H, 6.45. Found: C, 71.86} H, 7.05} N, 6.51. The Synthesis of 3-£-Bensyl-6-deoxy-I«-ldose Phenyloaaiono (XIII) An amount corresponding to 0.5 g. of 3-.Q-bensyl- 6-deoxy-L-idoae (XI) was suspended In 10 ml. of water and 0.74 ml. of phenylhydrasine added, followed by 12 drops of acetic acid and 0.2 ml. of a 40$ solution of sodium bisulfite. The mixture was placed in a boiling water bath for 2 hr. When no crystallisation occurred, the solution was taken up in bensene, petroleum ether was added to visual turbidity and the solution was placed 175 in the Icebox. Crystals deposited In a few hours and war# collected and washed wall with water, than with petroleum atbar containing a faw dropa of athanol. Tha oruda crystals, m.p. 93-96°, wara reorystallimed fro* athanol-watar; yiald 0.6 g. of yellow needles, «.P. 95-96®, A . 7 £ 5 ♦35.712 (j, 0.28, pyridina 2i athanol 3 ▼/▼). Anal. Calod. for C25H28°3W4* C* 69.18; H, 6.52; », 12.95. found t C, 68.60; H, 6 .4 6 ; N, 12.4 6 . Tha Synthaaia of Trl-.fl-<>«*,fc7l-3-,g-bensyl- 6-daexy-L-ldoas (XIV) A. Sodln* Acatata Mathod An amount of 6 ml. of aoatio anhydrida waa haatad to 100° and 0.44 g* of sodium aoatata waa gradually addad with atirrlng. To this solution waa added 0.8 g. of 3-,fi-bensyl-6-deoxy-L-idose (XI) oxer a period of 10 min. Tha mixture waa heated at 90-100° for 2 hr., then waa cooled and poured into 100 ml. of ioa-water and atlrrad. Tha aolution waa extracted aaTaral times with a total of 200 ml. of chloroform. The extracts ware dried over anhydrous sodium sulfate and wara evaporated to a sirup. This was stored overnight In an evacuated desiccator over phosphorus pentoxldo; yiald 0.475 g., / d J * 3 -6.84° U A.747, chloroform); infrared absorption spectral datai no 5.7 )x (acetate C-0), 176 7*2 (CH3), 8.00, 8.10 y. (acetate (C-O-C), 13.5, 14.4 (substituted phenyl). 4nal. Calcd. for C^g^^Ogt C, 59.96; H, 6.33. Foundi C, 60.26; H, 6.23. B. Acetic Anhydrids-Pyrldine Method An amount of 0.5 g. of 3-£~t>*n*yl~*6-8eoxy~L-idose (XI) was dissolved In 2 ml. of dry pyridine and 1.5 ml. of aoetlo anhydride was added. The mixture was left standing at room temperature for 24 hr. and was then poured into loe-vater and stirred for 3 hr. The solution was extracted with four 200-ml. portions of chloroform, dried and evaporated to a yellow sirup. This was taken up in 10 al. of toluene and eonoentrated again. Treating the solution with decolorising carbon, filtration and evaporation of the solvent, afforded a oolorless sirup; yield 0.35 g. (4150, +2.58° (£ 3.486, chloroform); infrared absorption spectral data ldentioal with those of the product obtained from the sodium acetate method of acetylation. 1 7 7 Tha Synthesis of 1,2,4-Trl-£-aeetyl- 6-daexy-L-ldoas (IT) To sn aaount of 0.81 g« of tri-£-acetyl-3-£- bensyl-6-deoxy-L-ldose (XI) la 40 ml. of anhydrous ether, vss added 80 mg. of palladlum-on-eharcoal catalyst sad the Mixture was hydrogenated at 37-38° and 125 p.s.i. for 3*5 hr. Filtration and evaporation of the solvent afforded a colorleaa sirup; yield 0.54 g* (87%). Thia sirup was distilled at 120° and 25 m m .; 5.148, chloroform); infrared abaorp tion spectral data* X 2.8-2.9 jx (OH), 5.7 ji (acetate C»0), 8.10 )i (acetate C-O-C), 13-15 (weak substituted phenyl). Anal. Calcd. for C12Hlg0g : C, 49.65; H, 6.20. Found: C, 51.1 6 j H, 6.47. The Synthesis of 1,2,3,4-Te tra-J}-acetyl- 6-deoxy-L-ldose (XVI) The sirupy 1,2,4-trl-£-acetyl-6-deoxy-L-ldoae (XV, 0.25 g.) was dissolved in 2 nl. of dry pyridine and 0.4 nl* of acetic anhydride was added. The Mixture was left standing at roon temperature for 20 hr. after which it waa heated for a few Minutes at 40-50°. It was then poured Into ice-water and stirred for 1 hr. Extraction with three 100-al. portions of chloroform, drying and evaporation of the solvent afforded a sirup; 0.3 g. This was dissolved in ethanol, treated with X76 decolorising carbon and filtered. The colorleaa fil trate waa ooncentrated under reduced preaaure to a clear sirup; yield 0.2 g., +8,68° (.g 4*26, ethanol); Infrared abaorption spectral d a t a i ^ ^ x * no (OH), 5.7 jx (acetate 0=0), 8.10 >i (acetate C-O-C), 13-15 jx (very weak substituted phenyl). Trituration of the airup with ether and storing at 0° for a f ew months did not oauae oryatallization. The Synthesis of 3-JB-Bensyl- 6-deoxy-L-ldltol (iVIl) The method of reduction used was essentially that described by Davidson and Meyer (193). in amount of (193) E. A. Davidson and K. Meyer, J. Am. Chen. S$£., 76, 5686 (1954). 0.3 g. of 3-\Q-bensyl-6-deoxy-L-idose (XI) was disaolved In 16 ml. of a 60% aqueous methanol aolution. This solution was added dropwise to a cold solution of a borate buffer (18 ml., 0.1 M, pH 6), containing 0.14 g. o of sodium borohydride. The solution was stirred at 0 for 2 hr., then at room temperature for 1.5 hr. The solution was neutralised with acetic acid and the pH was adjusted to 5 and the solution added to a mlxed-bed resin column (23x1.5 cm.) containing Amberlite MB 1 (157), previously washed with 50% aqueous methanol. 179 The affluent and washings ware oomblned end concentrated o under reduced presaure below 45 to a airup. Traces of water were elluinated by repeated addition of methanol and evaporation. k colorleaa airup waa obtained that did not reduce Fehling solution; yield 0.12 g, , /i_7£5 -15° (i 2.4, ethanol). The Synthesis of Tetr*-fi-icetyl-3-.fi- boniyl-L-lditol (XVIII) To an amount of 60 mg. of 3-£~bensyl-6-deoxy-L- iditol (XVII) in 2 ml. of dry pyridine waa added 0.5 ml. of acetic anhydride. The aolution waa left standing at room temperature for 20 hr., after which it was poured into ice-water and atirred. Extraction of the aolution with three 100-ml. portions of chloroform, drying and evaporation of the solvent gave a colorleaa airup; — 2 yield 78.4 mg., -5*7ll# 1*56, ethanol). The sirup waa soluble in all common organic solvents. The Attempted Preparation of 6-Peoxy-L-ldoae A. Resin Hydrolysis of 6-Deoxy-l,2-,fl- laopropylldene-L-ldofuranose (IX) This substance waa hydrolysed essentially according to the method of Shaflsadeh and Wolfrom (173). An amount of 0.65 g. of IX waa dissolved in 17.5 ml. of water and 5 ml. of Amberlite IR-120 (H+) (157) was added. The mixture was heated over a steam bath for 3 hr. with 180 occasional addition of water to keep the volume constant* The solution was filtered, the resin was washed well with wara water and tha solution was concentrated under reduced pressure to a yellowish sirup which was reducing to Feh ling solution} yield 0.4 g. After drying over caloiua chloride, the sirup weighed 0.37 g. (71%). Preliminary investigation of this sirup on paper chromatograms using the solvent mixture 1-butanol: ethanol:water (4:lt5 v/v) and spraying with ammonlacal silver nitrate (l89a) or ammonium molybdate aolution (189b), revealed four spots, the third spot from the top being the most intense with medium velocity while the fourth spot waa diffuse and of high mobility* Column Chromatography An amount of 0.25 g. of the sirup in 15 ml. of a mixture of petroleum ether (b.p. 65-115°) and 1-butanol saturated with water (111 v/v), was added to a column (2.5x20cm.) packed with cellulose powder (194). The (194) Genuine Whatman, standard Grade, W. and K. Balaton, Ltd., England. effluent was collected in 5-ml. fractions. From cuts numbers 8,9,10 and 11 was obtained a light yellow sirup; yield 0.1 g. (eluate 1). Successive developing with mixtures of petroleum ether (b.p. 65-115°), 1-butanol 1 81 saturated with watar and 95% aqueous athanol having tha following proportional (liltl v/v), (ltli2 v/v) and (1:1*3 v/v) respectively, alutad no aagar notarial. Elution with 95% aquaoua athanol gava a yellow sirup; yiald 30 ng. (aluata 2). Subaaquant developing with ineraaaad pareantagaa of watar in athanol gava no sugars. Paper chromatographic investigations showed that aluata 1 consisted of the originally fast moving component, while aluate 2 contained the three relative ly slower moving sugars. Further attempts to achieve separation of these sugara on columns were not success ful. Paper Chromatography A total of 50 mg. of the slrupy hydrolysate in 0.25 ml. of watar waa spread evenly along a line S cm. long and 0.5 cm. wide on a 12x42 cm. Whatman No. 1 paper. Two guide spots from the same sugar solution were placed at both ends of this line. Four such papers, carrying 0.2 g. (total) of the sugar, were developed in the des cending manner In the solvent mixture 1-butanol:ethanol: water (4*li5 v/v) for 42 hr, at room temperature. At the end of this time, the papers were dried and the guide spots were cut into long strips and sprayed to locate thf positions of the sugars. Three sones, A, B and C, were located on the paper at the following 1 6 2 distances from the starting line respectively* 17.5 cm., 25*5 oa. and 33 cm. The faster moving component D was left to drip down the paper into a dish and was collected. The relative intensity of the spots were C (most intense) B A (least intense). The sonea were elated with water and the solutions were lyophilised. From sone A was obtained a hygroscopic solid, that gave a positive Mollsch test for sugars; yield A.9 mg., dec. 160°. This substance did not give a crystalline osasone. Zone B gave a very hygroscopic solid; yield 12.6 mg. Zone C afforded a sirup; yield 70 mg., .Za_7^ -23.712° (^ 0.675, water); recorded (91,110) 6-deoxy-L-sorbose: -27.7*0.5° (water) and - 7 ^ -25*2° (water), reapactively; also recorded (106) for 6-deoxy-L-ldose: l U l 1 -26° (water). A portion of the above sirup (15 ng.), in 1 ml. of water, was heated with phenyl- hydrasine acetate reagent (3 mmolea) in a boiling water bath for 20 mln. whereby on scratching the aides of the container, crystallisation commenced. The crystals were filtered and gave 11.8 mg. of yellow needles, m.p. 178—180° (dec.). Recrystallisation from ethanol—water afforded needles, m.p. 182-18A° (dee.); recorded (91, 110,176) for 6-deoxy-L-sorbose phenylosasone* m.p. 183- 18A° (dec.) (91,110) and m.p. 168-172° (176), also recorded for 6-deoxy-L-guloae phenylosasone (93) and 6-deoxy-L-ldose phenylosasone (106), m.p. 183-18^° 1 8 3 (dec.)} x-ray powder diffraction data (188)t 10*05v, 7.68vv, 4.98m(3), 4.07e(l), 4.10n(2), 3.80vv, 3.56t w , 3.47v, 3.19v, 3.05w, 2.85v. Ia oaa axpariaant tha aolution froa aona B (con taining about 2 ag. of a augar substance), dapoaitad o 1.7 ag. of a crystalline solid, a.p. 60-61 , aftar several aontha. Tha aixad aalting point with authantle 6-daoxy-L-sorbose (91), a.p. 88°, waa 80-83°. Thia substance waa not readily soluble in cold water in contrast to 6-deoxy-L-eorboae, but waa soluble in acetone and did not give a Molisoh test. Due to the snail quan tity, it could not be further investigated) x-ray powder diffraction data (188)i l6.07a(2), 10.37w, 8.48s(l), 5.73vw, 5.01a, 4.79a, 4.57vv, 4.18n(3), 3.66v, 3.37a, 3.20w, 2.92w, 2.76v. For coaparatiTa reasons, tha x-ray powder diffraction data (188) for authentic 6-deoxy-L-sorboae (91) and Reichstein'a 6-deoxy-L-idoae (106) wera taken. 6-Deoxy- L-aorbosa: 9.40w, 7.13a(3), 5.96(l), 5.21w, 4.69n(2), 4.33a, 4.00w, 3.80vw, 3.57a, 3.35vv, 3.20w, 3.09vw, 2.97w, 2.86w. 6-Deoxy-L-idoae*: 7.02a(3), 5.67s(l), 5.15a(2), * Due to the hygroscopic nature of this substance, a sample could not be ground so aa to give hoaoganeous lines in the x-ray pattern. The lines were therefore "grainy". 184 4.74*, 4.46*, 4.17*, 3.90vw, 3.69w , 3.29 w , 3.00vw, 2.90w, 2•52w, 2.34w. B. A d d Hydrolysis of 6—D a oxy- 1 , 2 i«o~ propylidene-L-idofariao»» (II) This substance (IX) waa hydrolysed essentially according to tha nothod of Mayer and Ralohataln (106), except that the concentration of the acid uaed waa 0.5% (1.4 *1.) lnatead of 1% (0.7 *1.) aa In the original procedure (106). An a*ount of 0.13 g. of cryatalllne IX (recrystallised three tinea fro* ether•petroleum ether) waa dissolved in 1.4 *1. of 0.5% sulfuric acid aolution and warmed at 70° for 2 hr. The solution waa neutralised with powdered bariu* carbonate and was fil tered through decolorising carbon. Evaporation of the o solution below 50 afforded a colorless airup. A aample waa lmnediately chromatographed on paper ualng the solvent mixture 1-butanoltethanol:water (4*1:5 v/v). Three spots corresponding to sonea A, B and C appeared on spraying the paper. In addition a fourth weak spot (sone a, Rf 0.18), travelling even slower than spot A, appeared. The faster moving component D, detected in the resin hydrolysate of IX was absent. C. Hydrogenolyais of 3-fl~Bensyl-6- deoxy-L-ldoaa (XI) To an amount of 0.1 g. of 3-£-bensyl-6-deoxy-L- idose (XI) in 25 *1. of absolute ethanol, was added 185 10 Mg. of palladium-on-charcoal catalyst and tha mixture waa hydrogenated at 65° and 500 p.a.i. for A»5 hr. Fil tration and coneantratlon of tha aolution under reduced pressure and at low temperature gave a colorless airup; yield 80 mg., -1«9° (a 2.616, water). A sample of this airup showed a single distinct spot on paper chromatograms, travelling the aame aa the component in sons 8 (spot B) from the hydrolysate of 6-deoxy-l,2- £~isopropylidene-L-idofuranose (IX), and in certain eases, an additional faint apot having tha same mobility as the oomponent in sona C (spot C) also appeared. A portion of the alrupy hydrogenolyals product (20 mg.) waa heated with 2 ml. of a solution containing 2 mmoles of phenylhydraslne acetate for 30 mln. On seeding the cooled solution with the osasone crystals obtained from the component in sone G, a yellow osasone separated; yield A.A mg., m.p. 160-166° (dec.); recorded (91,110, 176) for 6-deoxy-L-sorbose phenylosasone: m.p. 183-18A (dec.) (91,110) and m.p. 168-172° (176), also recorded for 6-deoxy-L-gulose phenylosasone (93) and 6-deoxy-L- idose phanylosasone (106), m.p. 183-18A° (dec.). The x—ray powder diffraction pattern of the osasone waa quite diffuse but otherwise identical to an authentic pattern (seed crystals). Furthermore the infrared ab sorption spectrum of the osasone was identical to that of an authentic sample. 186 Behavior of the hydrogenolysle product In acid aolution An anount of about 10-15 mg* of the colorleaa slrupy hydrogenolysis product (giving essentially one apot on paper chronatograns corresponding to spot B) waa heatad over a steam bath In the presence of Amber— lite IE-12 0 (H+) (157) In water. Samples were withdrawn at Intervals of 5 nin., 30 aln.t 2 hr.( and 3 hr. and placed on paper chronatograns and developed aa before. On spraying the dried papers, a second spot had appeared on the papera and corresponded to spot C from the pre vious ezperlnents. This second apot had appeared even In the 5 nln. heated sample and waa nearly of equal intenalty aa the initial apot (B) on the sane chromato gram. The apot corresponding to the 3 hr. heated sample was also of equal intensity as the Initial spot B. A scheme of the experiments attempted with IX and XI, together with a sketch of the chromatographic results are presented on page llA(Scheme 8). The chromatographic properties of the components obtained from the hydrolysis of IX and from the hydrogenolysis of XI, are H a t e d in Tables 6 and 7. Ifi7 The Synthesis of 6-Deoxy-D-glucoae ParlntiTea The Preparation of 3*-£-Bensyl-l,2-£-i»opropylidene- 6-£-p-1 olyla ulfonyl-D-gluoofnra no aa (XIX) — To an amount of 40 g. of 3-£-ben*yl-l,2-£-iso- propylidona-D-glueofuranose (I) in 120 ml. of dry pyridine waa added a cold aolution of 30.7 g. (1.3 mole) of p-tolueneaulfonyl ohloride in 1 4 0 ml. of chloroform and the mixture waa left standing at room temperature for 20 hr. Water (10 ml.) woe then added and the mixture waa kept at room temperature for an additional 2 hr. The solution waa concentrated under reduced pressure to a sirup and the latter was extracted with ether. The ethereal extracts were washed with a aolution of sodium carbonate, then with water and were finally dried. Filtration and evapora tion of the solvent afforded a clear yellowish airup which contained sulfur impurities as indicated by a sodium fusion test; yield 30 g. Thia airup was used in the subsequent step* Acetylstion of 0.24 g. of the sirup with acetic anhydride in pyridine failed to afford the anticipated 5— £— acetyl-3-,2-benzyl—1,2- £—isopropylidene-6-£—tolylaulfonyl-D-glucofuranose in crystalline form and was not further investigated. 183 The Synthesis of 3-.fi-Bern ay 1-6-deoxy-l, 2-fi- iaopropylldsne-D-glucofuranoae (ll) A solution of 3-fl-bensyl-l,2-fi-isopropylidene- 6-fi-p-tolylaulfonyl-D-glucofuranoie (XIX, 13.7 g.) In 120 Ml. of anhydrous other was added dropwlse to a auspenelon of llthiuM aluminium hydride (2.5 g.) in 100 nl. of anhydroua ether. The mixture was stirred and refluxed gently with Drierite (190) protection for 2 4 hr., then the exeeaa hydride was decomposed by the careful addition of water and the mixture was extracted with ether. The ethereal extracts were dried and evacuated to a dark yellow airup containing sulfur Impurities as waa ahown by a aodium fusion teat. When a portion of the airup waa subjected to the conditions of the Iodoform reaction (162), iodoform was strongly detected by odor. Attempted distillation of thla crude airup led to extensive decomposition. The airup (6 g.) was dissolved in ether and added to a column (6x30 cm.) containing neutral alumina pow der (159), and the column waa developed with ether. A yellow band soon appeared and waa eluted out. It was found to contain a sugar substance (Moliach teat) and a sulfur impurity. Subsequent elution with 95% ethanol gave a pale yellow airup containing no sulfur and having an Infrared absorption spectrum identical to that of 3-£-bensyl-6-deoxy-l,2-fi-iaopropylldene-L-ldofuranose 1 8 9 (VII); yield 4 g, The crude sirup could also bs chroaato- grapbsd on MsgnesoliCellte (5*1) and eluted with a 6*4 (v/v) mixture of ethanol and petroleum ether, or on a earbon oolumn (Darco 5iCe3Llte l) and eluted with acetone. In all cases repeated chromatography was necessary to arrive at a purer product. The final sirup was still pale yellow but could be distilled without excessive decomposition. Distillation of a portion at 150° and 0,1 mm. gave an essentially colorless sirup which waa soluble in ether but insoluble in petroleum ether, j T % J ^ -67.5° (ji 3.704, chloroform). Anal. Calcd. for ^x6H22°5t C» 65.28; H, 7,53* Found* C, 65*38} H, 7.64* Attempts to obtain a crystalline 5-fi-methylaulfonyl derivative as in the case of 711, or a 5-£-aeetyl de- rivatlve, were not successful. The Preparation of 6-Deoxy-l,2-£-isopropylldene- D-glucofuranose (XII) This substance XXI had been prepared previously by Freudenberg and coworkers (98) from the hydrogenation of of the corresponding 5,6-anhydro derivative, and by Baker and ooworkers (101) from the hydride reduction of the same derivative. An amount of 0.42 g. of 3-£~ benayl-6-deoxy-l,2-£-isopropylidene-D-glucof uranose (XX) was dissolved in 25 ml. of absolute ethanol and the solution waa filtered through a b ed of decolorising 190 carbon. Tha oolorlaaa solution waa than hydrogenated at 65-70° and 500 p.a.i. in tha praaanoa of palladium- on-ohareoal catalyst for 3.5 hr. Filtration and atapo- ration of tha solvent yielded a semi-crystalline product. Thia waa taken up in benzene, filtered and the solution made turbid with petroleum ether. Tha aolntion failed to crystallize and waa evaporated to a colorless airup yield 0 . 2 4 f., “19 1.5, chloroform); litera ture (101) records; —26.3° (chlorofora). Tha Preparation of 3,5-Dl-^-acetyl-6-deoxy-1,2-.fi- iaopropylidaaa-D-gluoofuranose (XIII) Tha above obtained airupy Material (XXI , 0.2 g.) waa aoatylatad with 2 ml. of aoatic anhydride in 2 nl. of dry pyridine. The Mixture waa left standing at roon temperature for 16 hr. after which it was poured in ice- watar and atirrad for 2 hr. Extraction with chloroforn, drying and evaporation of tha extracts gave a crystalline substance; yield 0 .24 g., m.p. 86-87°. Recrystallization froM athar-petrolauM ether afforded pure material, m.p. 87-88°, rci2^ ♦20° (£ 2.34, chloroform); recorded (106) for 3, 5-di-fi-acetyl-6-deoxy-l,2-fi-isopropylidene-D- glueofuranoaat m.p. 88-89°, / The Synthesis of 3-\fi-Bensyl-6-deoxy-l,2-jQ-isopr opyli- dsne-D-xylQ-l,4.-furano-5—hsxosulose (XIIIl) and its Reduction with Metal Hydrides Pyridine-Chromium Trloxlde Oxidation of 3-J&-Bensyl-6-»de oxy-1, 2-jQ-la opr opylldsne - L—Idofuranoaa (VII) Dry pyridine (75 ml.) was placed in a 3-necked round- bottomed flask and the whole Immersed in an Ice-bath. When the temperature had dropped to 10°, 7.43 g. of powdered chromium trloxide waa added In email portions (CAUTION) while the solution was stirred under a slow stream of dry nitrogen. When the solution became too viscous, aa the yellow complex was being formed, the tern— perature was allowed to rise to 20°. At the end of the addition (20 min.) a thick yellow slurry formed. A solution of 3-J2-benayl-6-deoxy—l,2-.Q-iBopropylidene—L- idofuranose (VII, 10 g.) in 100 ml. of dry pyridine was then added dropwise to the complex with stirring. After the addition was complete, the mixture (now possessing a dark brown color) was stirred under an atmosphere of dry nitrogen for 24 hr. Moat of the pyridine was evapo rated under reduced pressure and the resulting brown residue was suspended in 25 ml. of water and extracted with three 150-ml. portions of ether* The dried (sodium sulfate) ethereal extracts (essentially colorless) were evaporated to a yellow sirup which partially crystallized 192 on standing. The Infrared absorption spectrum of a dried sample of the filtered and washed (petroleum ether) crystals, m.p, 75-85°, showed hydroxyl and carbonyl peaks of equal magnitude. The crystalline product and the remaining sirup were combined and the preceding oxi dation was repeated to give a similar airup, which crystallised partially. The crystals were removed by filtration and washed with petroleum ether; yield 7.22 g. (72.2$), m.p. 4.9-51°, A small portion was sublimed at 95° and 0.9 mm. to give colorless crystals, m.p. 51-52°. The infrared spectrum of this compound showed both hydroxyl and carbonyl absorption peaks, the former being in much smaller magnitude as compared to the latter. Finally, a third oxidation was performed on the total product of the preceding oxidation to give colorless needles; yield 5.08 g. (overall 50$). Three recrystal- lizatlons from ether-petroleum ether afforded pure material; m.p. 55-56°, -89° (i 1.533, chloroform); infrared absorption spectral data: (Fig. 5)i P- (C=0), 9.22, 9.51, 9.8 ji (C-O-C), 13.8, 14.6 j i (substituted phenyl); x-ray powder diffraction data (188): 10.25m, 8.5m, 5.90m, 5.24s(l), 4.84m(3), 4.64m(2), 4.39w, 4.04w, 3.78vw, 3.45vw. Aflil. Cal cd. for 0, 65.73; H, 6.86; mol, wt., 294. Found: C, 65.50; H, 6.53; mol. wt. (Rast) 292. 193 This compound failed to give the Sellwanoff toot for ketoses, but gave o yellow oolor with alcoholic potassium hydroxide. When a sample was subjected to the conditions of the Iodoform reaction (162), the odor of Iodoform was strongly detected. Reaction with semlcarbaside hydro chloride failed to give a crystalline aemioarbazone. The reaction with hydroxylamine hydrochloride in sodium hydroxide solution at 90° for 15 min., or in ethanolic pyridine at reflux temperature for 2 hr., produced a sirup which showed a small carbonyl peak in the infrared absorption spectrum, denoting an incomplete reaction. Pyridine-Chromlum Trloxlde Oxidation of 3-£-Bensyl-6-deoxy~l,2-£-lsopropylldene- P-gl ucofuranose (XX) The pyridlne-chromium trioxide complex was prepared aa described previously, from 2.24 g. of chromium tri oxide and 25 ml. of dry pyridine. A solution containing 3*0 g. of 3-fi-benzyl-6-deoxy-l,2-£-isopropylidene-D- glucofuranose (XX, previously purified by chromatography on alumina) in 25 ml. of dry pyridine was then added dropwlse to the yellow Blurry with stirring. When the addition was complete, the mixture was stirred for 24 hr. and processed as described previously. The product was a sirup which showed a strong carbonyl band in the in frared spectrum, together with a small hydroxyl band; yield 2.5 g. The above oxidation was repeated and the 194- product waa processed to give a pale yellow sirup; yield 2.4 g. The airup crystallised upon seeding with 3-.Q-bensyl- 6-deoxy-l,2-£-is opropylidene-D-ju^a-l,4-furano-5- hexosulose (XIIII) to give colorless needles; yield 1,2 g., m.p. 54-55°, not depressed upon admixture with authentic material (XXIII). The Reduction of 3-£-Bensyl-6-deoxy-l,2-Q- isopr opylldene-D-jeiXtt-1,4-furano-5- hexosulose with Metal Hydrides A. Sodium borohydrlde In 50% aqueous methanol (v/v) To a solution of 0.5 g. of 3-.Q-benxyl-6-deoxy-1,2-,2- isopropyl ldene-D-jxlfi-1»4-furano-5-kexosulose (XXIII) in 20 ml. of 50% aqueous methanol (v/v), was added 65 mg. of sodium borohydrlde In small amounts. The immediate evolution of gas was noticed. The solution was left standing at room temperature for 16 hr. after which water (10 ml.) was added and the solution was extracted with two 10-ml. portions of chloroform. Drying and evapora tion of the solvent afforded a colorless sirup which was taken up in 2 ml. of ether and 4 ml, of petroleum ether was added. On storing the solution in the icebox for 20 days, crystals (colorless needles) formed and were collected; yield 0.296 g. (59%), m.p. 90-91°; mixed with authentic 3—.Q-benzyl-6—deoxy—1,2—£ — is opr opylldene — L-ldofuranose (VII); m.p. 91-92°. The infrared spectrum 1 9 5 of the product was Identical with that of VII. It showed no carbonyl peak but showed en hydroxyl peak. The mother liquors from the reaction were concentrated to a sirup (0.17 g.) which failed to crystallize and had no carbonyl peak in the Infrared spectrum but showed an hydroxyl peak. The infrared spectrum was identical with that of VII or XI. B. Sodium borohydrlde in absolute methanol (at 28°) The foregoing experiment was repeated at 23° using absolute methanol aa solvent. The processing conditions were the same; yield 0.275 g. (55%), m.p. 92-93°, unde pressed upon admixture with authentic VII. The mother liquora afforded a colorless sirup which failed to crystallise; yield 0.177 g. (35.43%). C. Sodium borohydrlde In absolute methanol (reflux) The above experiment using absolute methanol as solvent was repeated, but the mixture was refluxed for 6 hr., then was cooled and processed aa before; yield 0.281 g. (56.1%), m.p. 92-93°, undepressed upon admixture with authentic VII. The mother liquors gave a colorless sirup which failed to crystallize; yield 0.173 g. (34.7%). 1 9 6 D. Sodium borohydrlde in absolute methanol (lnTerflt addition) Experiment B waa repeated except that the sugar solution (10 ml.) was added dropwlse to the borohydrlde solution (10 ml.) and proceeded In the uaual manner. The product crystallized as usual; yield 0.294 g. (58.7$), m.p. 91-92°; mixed with authentic VII, m.p. 92-93°. The mother liquors gave a colorless sirup; yield 0.178 g. (35.6$). £. Potassium borohydrlde In absolute methanol (at 28^) To a solution of 0.5 g. of 3-.Q-benzyl-6-deoxy-1,2- Q-ls opropylldene-P-XYlo-1f4-furano-5-hexosulo3e (XXIII) in 20 ml. of absolute methanol was added 94.8 mg. of potassium borohydrlde in small portions. The solution was left at room temperature for 16 hr. and was processed as before. The product crystallized; yield 0.304 g. (60.8$), m.p. 92—93 , undepressed upon admixture with authentic material (VII). The mother liquors were concentrated to a colorless sirup; yield 0.167 g. (33.3%). F. Lithium aluminium hydride in ether (at k solution containing 0.5 g. of XXIII in 10 ml. of anhydrous ether was added dropwlse to a refluxing ethereal solution of lithium aluminium hydride (93.5 mg.) in 25 ml. of ether. The mixture was stirred and refluxed for 5 hr. after which it was decomposed with water. The ether layer 1 9 7 waa separated, washed with water, dried and evaporated to a airup. This waa dissolved in 2 ml. of ether and 4 ml. of petroleum ether waa added and the solution was stored in the icebox as before. The crystals were collected; yield 0.235 g. (4-7%), m.p. 78-82°; mixed with authentic VII, m.p. 85-90°. The two compounds had Identical infrared spectra. The mother liquors gave a colorless sirup; yield 0.215 g. (43%). G. Lithium aluminium hydride in ether (at 35°. inverse addition) The above experiment was repeated except that the lithium aluminium hydride in ether was added to the sugar solution in ether. Processing as before gave a crystalline substance; yield 0.237 g. (47.34%), m.p. 85-87°; mixed with VII, m.p. 87-89°. The mother liquors afforded a colorless sirup; yield 0.216 g. (43.2%). Investigation of the Mother Liquors from the Metal Hydride Reductions of 3-0-Benzyl—6- deoxy—1,2-^-iaopropylldene-D-^y^a—1 f 4- furano-5-hexoeuloae (XXIII) Provided the solutions were given sufficient time for crystallization, practically all of the crystalline VII could be separated by filtration, leaving behind a sirup which was relatively homogeneous and pure. 198 Hydrogenolysia and acetylatlon In a typical experiment, a solution containing 87 mg. of the mother liquor in 20 ml. of absolute ethanol was hydrogenated with palladium-on-charcoal catalyst at 65° and 500 p.s.l. for A hr. Filtration of the catalyst and evaporation of the solvent afforded a colorless sirup which lacked the characteristic substituted phenyl absorptions in the infrared spectrum; yield 57 mg. Acetylatlon of an amount corresponding to 50 mg. with •cetic anhydride in pyridine at room temperature gave after conventional processing, a sirup which crystallised on standing to give crude crystals; yield 22 mg., m.p. 80-85°. Recrystallisation from methanol-water afforded colorless fine needles, m.p. 86-87°, undepressed upon admixture with authentic crystals (XXII). In another experiment in which crystallization of VII was not complete, the formed crystals were prematurely filtered and the mother liquor was subjected to catalytic debenzylation and acetylatlon of the product thereof. A crystalline substance was obtained having m.p. 75—110°. The mixed melting point of 3,5—dl— acety1—6—deoxy—1,2 — £-isopropylidene-L-idofuranose (X) and 3,5~dl-£-acetyl- 6-deoxy-l,2—.Q-isopropylidene-D-glucofuranose (XXII) was 72—118°; recorded mixed melting point (106) for (X) and (XXII) Is also 72-118°. 199 The Synthesis of 5»5-Dl-£-methyl-D-xylose and b o m of its D>rly>tl?t» Tha Synthesis of 3?«£-Bsniyl-l,2-£- laopropylidens-5,5-dl-C-methyl- D-xylofuranose (lliv) 4 solution of 1 g. (34 mmoles) of 3-j2-bensyl-6- deoxv-1.2-0-1 aopropylidene-D-xvIo-1 r Z.-f urano-5-htioauloae (XXXII) In 10 ml. of anhydrous ethar was added dropwlse and with stirring over a period of 30 mln., to 30 ml. of an ethereal solution of methylmagnesium iodide (5 molar exoeas), made from 0.375 g. magnesium turnings and 5 ml. of methyl iodide. The mixture was gently refluxed for 1.$ hr., at the end of which time Gilman's color test (160) was positive. The solution was then cautiously added dropwlse into a cold saturated aqueous solution of ammonium chloride (50 ml.) with vigorous stirring. The organic layer was separated and was washed with water. The aqueous solutions were washed with ether and the com bined ethereal extracts were dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure, afforded a colorless sirup which crystal lised spontaneously upon the addition of ether (2 ml.), to give colorless needles* yield 0.5 g., m.p. 76-80°. 4 second crop from the mother liquors yielded a further 0.23 g. of product. The combined aqueous layers were evaporated to dryness under reduced pressure and the residue was extracted with chloroform. Evaporation of 200 the solvent and seeding gave 20 mg. of crystals. The total yield of crystalline product was 0.75, (7550 . Tha product waa recrystallized three times from petroleum ether to give pure material; yield 0.6 g., m.p. 91—92°, /i.7*5 -4911° U 1 .192, chloroform); infrared absorption spectral data:\*®J 2.9 Ji (OH), 13.75, 14.5 jx (sub stituted phenyl), no carbonyl absorption; x-ray powder diffraction data (188): 10.62s(l), 7.46m, 6.20m, 5.34m, 5.12m, 4.65m(3), 4.42m(2), 4.02w, 3.73w, 3.60w, 3.41vw, 3.24vw. Anal. Calcd. for 66.21j H, 7.84* Found: C, 66.43; H» 7.88. An attempt was made to acetylate this compound. To 50 mg. of XXIV in 1 ml. of dry pyridine was added 0.1 ml. of acetic anhydride. The mixture was left standing at room temperature for 16 hr. during which period the color of the solution had become dark yellow. The solution waa poured into ice-watar and extracted with chloroform. Drying and evaporation of the extracts afforded a sirup which crystallized on standing to give the starting material almost quantitatively; m.p. 90-91°, undepressed. The Synthesis of 1, 2-.Q-I8 opr opylldene— 5,5-di-£-methyl-D-xylofuranose (XXV) A solution of 0.4 g. of 3-<2-benzyl-l,2-iQ-isopropyli- dene-5,5-di-£-methyl-D-xylofuranose (XXIV) in 30 ml. of absolute ethanol was hydrogenated in the presence of 201 palladlum-on-charcoal catalyst (50 mg.) at 75° and 500 p.a.i. for 4 hr. The solution waa then filtered and the filtrate waa evaporated to yield a crystal line product. Trituration with petroleum ether and filtration gave colorless needles; yield 0.16 g., m.p. 113-115°. A second crop of 60 mg. was obtained from the mother liquors. Three reorystallizations from ether-petroleum ether afforded pure material; yield 0.154- g.f m.p. 115-116°, -21+1° (ft 1.75, water); infrared absorption spectral data: 2.9 u max (OH), no substituted phenyl absorptions in the region 13-15 Ji; x-ray powder diffraction data (188): 11.30m, 9.60m, 7.74m, 7.08m, 6.18m, 5.59m, 5.29s(l), 4.95m(2), 4-.30m(3), 3.52vw, 3.16v w . Anal. Calcd. for C ^ H ^ O ^ C, 55.03; H, 8.31. Found: C, 55.06; H, 8.32. The Attempted Synthesis of 3,5-Di-£-acetyl- 1 ,2-jQ-lsopropylldene-5, 5-dl-£-methyl- D-xylofuranose (XXVI) To an amount of 50 mg. of XXV in 1 m l . of dry pyridine was added 0.06 ml. of acetic anhydride at 5°. The mixture was left standing at 5° for 10 min. with occasional shaking. The solution was then poured in lce-water and extracted with chloroform. Drying and evaporation of the solvent gave a quantitative yield of starting material (XXV), m.p. 114-115°. 2 02 In a second experiment! the above procedure was repeated except that the acetylated mixture was left standing at room temperature for 16 hr. Similar pro cessing afforded a sirup. The infrared absorption spectrum of this sirup showed both hydroxyl and carbonyl peaks denoting a partial acetylatlon! possibly at C-3. This airup was not further investigated. The synthesis of 3,5-Di-.Q-benzoyl—1,2-£- Isopr opylidene-5,5-di-fi-methyl- D—xylofuranose (XXVII ) An amount of 0.1 g. of 1,2-fi-isopropylidene-5,5- di-£,-aethyl-D-xylofuranose (XXV) in 2 ml. of dry pyridine was cooled to 5°. Benzoyl chloride (0.1 ml.) was then added dropwlse with stirring, over a period of 1 ain., followed by 1 ml. of chloroform to give a homogeneous solution. After stirring for 1 hr. at 5°, the solution was left standing at room temperature for 24 hr. It was then poured into ice-water, extracted with chloro form and the extracts were washed successively with aqueous sodium bicarbonate solution and water and dried with anhydrous magnesium sulfate. Filtration and evaporation gave a dark sirup which contained benzoic anhydride as indicated in the infrared spectrum; yield 0.2 infrared absorption spectrum data:A£*^m 5.55 g., DB Jl *U (anhydride C«0), 5.80 p (benzoate C*0), 7.75, 9.0 jx (benzoate G-O-C), no hydroxyl absorption. This material was suitable for the next step. 203 The Synthesis of 1,2-Di-£—acetyl- 3, 5-di-,fl-bens oyl- 5 , 5-di-£-methyl- D-xylof uranose (iXVIII) To a solution of 0.2 g. (0.-47 nmoles) of crude XXVII in 2.15 ml* of acetic acid and 0.26 nl• of acetic anhydride, was added 0.16 ml. of 96% sulfuric acid dropwlse with stirring, the temperature being maintained at about 10-15°. After standing at room temperature overnight, the mixture was poured into 50 ml. of ice- water and stirred for 30 nin. The solution was extracted with three 20-ml. portions of chloroform and the extracts were washed with excess sodium bicarbonate solution and water. Drying over anhydrous magnesium sulfate and evaporation of the solvent af forded a crystalline substance; yield 50 mg., m.p. 122—125°. The mother liquors afforded a further 35 mg* of crystals; combined yield 85 mg. Three recryetal- llzatlons from ethanol-petroleum ether afforded pure crystals, m.p. 127-128°. Anal. Calcd. for C25ii26°8: C* 66.65; ^ 5.82. Found: C, 66.33; H, 6.08. The Synthesis of 5,5-Dl-£-methyl-D-xylose (XXIX) A . Acid Hydrolysis of 1,2-j^-Isopropylidene- 5, 5-dl-£.-me thyl-D-xylof uranose (XXV ) An amount of 56.6 mg. of XXV was heated with 1.5 ml. of 0.05% sulfuric acid for 2 hr. at 70°. The solution 204 was than neutralized with powdered barlua carbonate, filtered and the filtrate was evaporated under reduced pressure to a airup; yield 45 mg.# Z~ (jj 0.86, water) . Thla airup waa strongly reducing to Fehllng solu tion on warming. It was soluble in water, alcohol and acetone but was insoluble in ether. On paper chromato grams, using the solvent mixture 1-butanol:ethanol: water (4*1:5 v/v), the compound had Rri* 1.18. It did not restore the color of the Schlff reagent. The colorless airup (XXIX) was found to be quite stable at room temperature. B. Kesin Hydrolysis of 1,2—£-Isopropylldene- 5,5-dl-fi.-methyl-D-xylofuranose (XXV) To an amount of 66 mg. of XXV in 1.75 m l . of water was added 0.5 nl. of Amberlite IR-120 (H+) (157). The mixture was placed on a steam bath for 3 hr. with occasional addition of water to keep the volume con stant. The mixture was then filtered and the resin was washed well with warm water. The combined filtrate and washings were evaporated to a colorless sirup which was dried under reduced pressure for 2 hr.; yield 50 mg. Anal. Calcd. for C?Hl605: C, 46.65; H, 8.95. Found: C, 4 6 .6 8 ; H, 8.70. The equilibrium rotation of 5,5-di—£-methyl-D- xylose (XXIX) was obtained by hydrolyzing a known amount 205 of 1,2-£—isopropylidene-5,5-di-£-methyl-D-xylofuranose (XXV) as follows* 0.306 g. was hydrolysed with 2 Jt hydrochloric acid at room temperature; -27.*° Cfi 5, assuming complete hydrolysis; no change in 24 hr.). Hydrolysis of the same amount with 4 hydrochlorio acid _ _2 c q at room temperature gave L ix J^ -26.8 (i 2.5, assuming complete hydrolysis; no change in 24 hr.). The hydroly sis in both cases cound not be followed polarimetrically with time due to the similarity in the rotations of the starting material (XXV), ,/cLT^ -21*1°, and the product of hydrolysis (XXIX), /oI7£5 -27°. A portion of the sirup (XXIX, 0.2 g.) was dissolved in methanolic hydrogen chloride and left standing at room temperature for 24 hr. The solution was then neutralised with Duolite 4-4 (195). The resulting (195) 4 product of the Chemical Process Company, San Francisco, Calif. solution was concentrated to a small volume. To this was added 10 ml. of a solution of 7.5 ml. of 5 ii chromic acid and 2.5 ml. of concentrated sulfuric acid. The solution was distilled rapidly into ethanollc 2,4-dinitrophenylhydrszine. Acetone 2,4-dinitrophenyl- hydrazone was filtered and recrystallized from acetone; yield 50 mg., m.p. 125-126°, identical with an authentic sa mple. 206 The result could be obtained by oxidising XXIX directly, but the yield of the hydrasone waa muoh lower* The Synthesis of 5 , 5-Di-£-methyl-D-xyloae Phenylosasone (ZZZ) The acid hydrolysate from l,2-£-isopropylidene- 5,5-dl-£-methy1-D-xylofuranose (XXV, 6 ml.), containing about 0.15 g. of 5,5-di-£-methyl-D-xylose (XXIX), was neutralised with 2 Jj sodium hydroxide and the solution was allowed to evaporate slowly to a volume of 3 ml. The solution was pipetted out from the crystallized sodium chloride, 3 ml. of phenylhydrazlne reagent (3 mmoles) was added and the mixture was heated in a boiling water bath. The crystalline osasone was formed in 15 min. and was filtered and washed well with water, dilute acetic acid and finally with a 1:1 (v/v) mixture of ethanol and petroleum ether; yield 64 mg., m.p. 185- 187° (dec.). Four recrystallizations from ethanol-water afforded an analytically pure sample, m.p. 188-190° (dec.). Calcd. for ci9H24°3N4t ^» 6 4 .08; H, 6.78; ■, 15.74. Found: C, 64.27; H, 6.82; N, 15.61. The Synthesis of 5,5-Dl-£-nethyl-D-xylose Phenylosotriasole (XXXI). An amount of 60 mg. of the phenyloaazone (XXX) was suspended in 10 ml. of water containing 0.12 g. of cuprlo sulfate pentahydrate and the mixture was refluxed for 1 hr. ill of the material was then in solution and 207 a fine precipitate of copper oxide had formed. The solution vas refluxed for an additional 0.9 hr., then was added to a column (1x10 cn.) of Darco G-60 carbon. The eluate vas evaporated to dryness to give only residual cuprlc sulfate. The column was then developed with acetone and the eluate was concentrated to dryness. Addition of ether caused crystallization. A few drops of petroleum ether were then added. Recrystallization from hot water gave colorless needles; yield 10 mg., m.p. 97- 98°. The Synthesis of 5,5-Di-£-methyl-D-xylose Bensylphenylhydrasone (XXXII) The acid hydrolyzate of l,2-£-isopropylidene—5,5- di-fi-methyl-D-xylofuranose (XXV, A ml.) containing about 0.1 g. of 5,5-di-£-methyl-D-xylose (XXIX), was neutralised with 2 Jg sodium hydroxide and the solution was allowed to evaporate to dryness slowly. The residue was treated with absolute ethanol (5 ml.) and the solution was filtered. The filtrate waa evaporated to a sirup and a solution of 0.3A g. of sodium acetate in 3 ml. of water was added, followed by 0.16 g. of 1-benzyl-l-phenylhydrazine hydrochloride. Sufficient ethanol was added to give a homogeneous solution and the solution was refluxed for 2 hr. Decolorizatlon with Daroo G-60 carbon, filtration and evaporation 208 afforded a airup. The lattar was taken up in chloroform (20 Hi.) and washed with water. The chloroform solu tion was then dried and evaporated to a airup which crystallised upon the addition of ether (2 ml.). Recrystallisation from ether-petroleum ether gave pale yellow crystals; yield 50 mg., m.p. 77-78°, -20° (£ 0.92, ethanol). SUMMARY 1. The resistance of the dimeric 1 ,2-£-i*opropyl- idene-5-eldehTdo-D-3CYlo-lr A-furano-pentodlaldose to react with anhydrous hydrogen cyanide in absolute ethanol has been demonstrated. 2. A new acyolie dialdoae derivative, 3-£-benzyl- 1.2-0-laopropylidene-5-aldehydo-D-xylo-l«A-furano- pentodlaldose and its crystalline semicarbazone have been synthesised. 3. The monomeric 1t2-0-lBODropylldene-5-aldehydo- D-xylo-1.A-furano-pentodialdose has been synthesized and characterised by infrared spectral analysis and crystalline derivatives. 4. The free D-xylo-oentodialdose has been Isolated as a airup and its instability was demonstrated. 5. The reaction of 3-fi-bensyl-l,2-£-isopropylidene- urano-pentodialdose with methyl- magnesium iodide in three solvent systems has been studied, and a mechanism has been proposed to interpret the results. 6. The sole crystalline product from the Grignard reaction has been identified as the new 3-£-bensyl-6- deoxy-1,2-£-isopropylldene-L-idofuranose and its 5-£-methylaulfonyl derivative was synthesized. The 209 210 configurational assignment of the crystalline Grignard product was established by its transformation to the known 3,5-di-£-acetyl-6-deoxy-l,2-£-iaopropylidene-L- ldof uranose . 7. The mother liquors of the Grignard reactions were investigated and the absence of 3-£-benzyl-6-deoxy- 1,2-vQ-isopropylidene-D-glucofuranose was demonstrated. 8. The synthesis of the first 3-.Q-benayl-6-de oxy- hexose, 3-i2-ben»yl-6-deoxy-L-idose was described. Its crystalline phenylosazone and benzylphenylhydrazone derivatives have also been synthesized. 9* The following new derivatives of 3-,2-benzyl- 6—deoxy-L-idose have been synthesized: trl—£-acetyl- 3-J2-benzyl-6-deoxy-L-idose , 3-i2“be*izyl-6-deoxy-L-iditol, tetra-.Q-acetyl-3-.Q-benzy1-6-deoxy-L-iditol. 10. The following new derivatives of 6-deoxy-L— idose have been synthesized: 1,2 ,4- tri-.Q-acetyl-6-deoxy— L-idose, 1,2, 3, 4-t etra-.Q-acetyl-6-de oxy-L-idose . 11. An attempt has been made to prepare 6-deoxy-L- idose from the acid hydrolysis of 6-deoxy-1,2-0— isopropylidene-L-idofuranose. The instability of 6-deoxy-L-idose in acid medium and its transformation to 6—deoxy-L—sorbose has been demonstrated by paper chromatography experiments. The hydrogenolysis of 211 3-£-bensyl-6-deoxy-L-idose has been shown to give mainly 6-deoxy-L-idose as a sirup. 12. Tha new 3- 13. The synthesis of a new crystalline aldulose derivative, 3-fi-benayl-6-deoxy-1,2-£-isopropylidene- D-x t I q -1,A-furino-5-heioauloae using the pyrldine- chromium trioxide reagent, has been described. 14* The reduction of 3-jQ-bensyl-6-deoxy-1,2-£- isopropylldene-P-xYlo-l.A-furano-5-he*osuloae with sodium borohydrlde, potassium borohydrlde and lithium aluminium hydride using a variety of conditions was studied and the identity of the reaction products in these reductions has been established. A mechanism has been presented to Interpret the results of the hydride reductions. 15. The reaction of 3-j2-bensyl-6-deoxy-l, 2-Q- iaopropylldene-D-xylo-1rA-furano-5-hexosulose with methylmagneslum iodide has been described. The crystal line product has been shown to be 3-£-bensyl-l,2-J2- isopropylidene-5,5-di-£-methy1-D-xylofuranose• This reaction has opened the way to a new group of branched— chain sugars. 212 16. The inertness of the C-5 tertiary hydroxyl group of thle branched-chein derivative toward! acetyl- ation with aeetio anhydride in pyridine has been demonstrated. 17. The aynthesia of crystalline 1 ,2-.Q-ieopropyl- idene-5,5-di-£-»ethyl-D-xylofuranose has been described. Aoetylation experiments using acetio anhydride in pyridine with this compound have been attempted and a selectivity was observed. 18. The sirupy 3,5-di-£-bena.oyl-l,2-,Q-isopropyl- idene-5,5-di-£-methyl-D-xylofuranose haa been synthesised by reaction of the parent oompound with bensoyl chloride in pyridine. The acetolyeis of 3,5-di-£-ben»oyl-l,2- j2-ieopropylldene-5,5-di-£-methyl-D-xylofuranose and the syntheaia of crystalline l,2-.2-acetyl-3,5-di-.Q-benaoyl- 5.5-di-£-methyl-D-xylofuranose has been described. 19. The first free 5,5-di-£-methyl-pentosei 5,5- di-£-methyl-D-xyloae has been synthesized and Its equilibrium rotation has been determined. 20. 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My aacondary aehool adnoation bagan at tha Collega dn Lycaa Francais in Alaxandria and waa oomplatad at tha Collaga Fatriar- eal In Cairo, whan I received my Baccalauraata in Soiancaa in 1952. In tha aama yaar I won a aanlor high aohool national oontaat In Engliah langnaga or ganised by tha Egyptian Ministry of Education, and was awarded a four-year collega scholarship. In the fall of 1952 I entered the Faculty of Science at the Uni versity of Alaxandria where I majored in Geology and Chemistry. I graduated with a Bachelor of Science, Special Chemistry, Honors degree im 1956. During my collaga years I was very active in sports and had gained national recognition in tha sports of basketball and rowing. Following my graduation in 1956, I was employed by tha Starch Products Co., in Alaxandris,as a research chemist. I kept in close touch with the Chemistry De partment of the University of Alexandria, where I was engaged in a part-time research problem In tha field of polysaocharides under the supervision of Dr. H. El-Khade 227 Having received from Frofaasor M. L. Volfrom a raaaarch aasiatantship sponaorad by tha Department of Health, Education,and Welfare, Publio Health Service, national Instltutea of Health, I came to The Ohio State University in the fall of 1957 to obtain a Ph. D. degree. On December 28, 1957, I waa married to the former Dimltra C, Demetrlou, a former college olaeamate from the University of Alexandria, who waa working for a M, Sc* degree with Profeaaor M. L . Volfrom. On Auguat 1, 1959, I waa privileged to receive a C. F. Kettering Raaaarch Foundation fellowship for a period of one year, after which I returned to my initial position of research aselatant•