This dissertation ias been microfilmed exactly as received Mic 60-6419

WHITELEY, Thomas Edward. DEOXY SUGARS; "5—DEOXY—D-GLUCOSE".

The Ohio State University, Ph.D., 1960 Chemistry, organic

University Microfilms, Inc., Ann Arbor, Michigan DEOXY SUGARS; "£-EEOXY-D-GLUCOSE"

DISSERTATION

Presented In Partial fulfillm ent of the Requirements

for the Degree Doctor of Philosophy in the

Graduate School of The Ohio State

U n iv e rs ity

by

THOMAS EDWARD WHITELEY, B. A ., M. S c .

THE OHIO STATE UNIVERSITY

I960

Approved by

A d v iser Department of Chemistry ACKNOWLEDGMENT

The author wishes to express his appreciation to Professor

M* L. Wolfram for his guidance and councel in this work,

Drs. W, von Bebenburg, F, Shafizadah and A, Thompson have given

freely of their time and have provided value advice on manipulative

d e t a i l s •

Particular thanks are extended to Dr, L. Kuhn of Aberdeen Proving

Grounds, Md,, through whose efforts the author received a research assistantship with Professor Wolfrom.

Acknowledgment is extended The Ohio State University, the Socony-

Mobil Oil Co, and the Department of Health, Education and Welfare,

Public Health Service, National Institutes of Health for fellowships and assistantships provided by them.

ii TABLE OF CONTENTS

INTRODUCTION ......

STATED!! OF THE PROBLEM ......

HISTORICAL ......

Synthesis of Unsaturated Carbohydrate Derivatives ......

The G lycals and T heir Rearranged Derivatives ......

The Glycoseens ......

Synthesis of 2-Hydroxyglycals .

The S yn th esis o f V in yl Substituted Sugars ......

The R eaction o f Diborane irYith O lefin s ......

The Synthesis of Deo^qjr Sugars ......

Synthesis by Direct Replacement of Hydroxy, Acyloxy or S u lfon yloxy Groups ......

Dooxy Sugars by Opening of Epoxide Rings ......

Deoxysugars From Unsaturated Carbohydrate Derivatives ......

Deoxysugars via Saccharinic Acids ......

The O p tical P rop erties o f the Furanose Sugars ......

DISCUSSION OF RESULTS ......

The .lercaptolysis of Tetra-O-acetyl-a- L-arablhopyranose ......

Acetylation of the Uercaptolysis Product ...... TABLE OF CO'TTETTS (eontd.)

Pa^e

Deoxysugar Synthesis From IT ...... U2

Proof of Structure of Ilercaptolysis Product of Tetra-O-ac etyl-a-L- arabinopyranose ...... h3

An Explanation For the Synthesis of 5*-S-2thyl-5-thio-L-arabinose Diethyl Idthicacetal by hercaptolysis of Tetra-O-acetyl-a-L-arabinopyranose ...... U5

Synthesis of 1,2-0-1sopropylidene- 5 >6-di-O-o-tolylsulfc nyl- a-D-glucose (XI) ...... $h

The Preparation o f l,2-0-lsopropylidene-3 tri-O-D-tolylsu 1fo n y l- a-D-glucose (XI') ...... 55

S y n th e sis o f V inyl Substituted Sugars ...... 56

The Synthesis of 1,2-0- I s opro pyli dene -li-vin yl- a-D-xylo-tetrofuranose(XTII) ...... 56

The S7mthesis of 1,2-0- Is opropylidene-3 -C -n -~ tolylsul fo nyl-L-vir.yl- q-fi-xylo-tetrofuranose (XIV) ...... <8

The Synthesis of 5j6—Dideoxy- 1,2-C-isopropylidene-a-D- . xylo-hexose (XV) ...... 59

The S y n th esis o f 5-Deoxy- 1 , 2 - 0 -iscpropylidene-a- D-xvXo-hexcse (XVI) ...... 59

The Preparation of 5-Deoxy- D-threo-hexose Phenylosazone (XVII) ...... 61

The Preparation of 5-Deoxy-D- threo-hexose Phenylosotriazole (XVITI) ......

iv TABLE CF C0I:TE:!TS (co-itd.)

Pace

The P eriod ate O xidation o f g-Peoxy-D-threo-hexose Phenyloso t r la 2ole (XVIII) ...... 62

The Hydrolyses and Optical Properties of the Synthesized 1 , 2- 0 - 1 sopropylidene-a-D- ighLo-hexoses ...... 62

The O ptical P rop erties o f the Synthesised Tcn-pvranose Sugars ...... 61;

Optical Potatory Dispersion of 1 . 2 - 0- 1 sopropylidene-h-vinyl- a.-D-xvlo-tetrofuransoe (XTII), and 1 . 2 - 0 - 1 sopropylidene-3 - 0- £ - tolylsulfonyl-U-vinyl- a-P-xy lo - 1 c tro furanc s e (XIV) ...... 63

EXPERHIIITAL ...... 7 I*

Synthesis and Proof of Structure of 5-S-Sthyl- 5-thio-L-arabinose Diethyl Dithioacetal ...... 7 I1

Synthesis of 5-S-"'thyl- 5-thio-L-arabino se Diethyl Dithioacetal ...... 7 it

A. Zinc C hloride C a ta ly st ...... 7 I;

h . B oron Tri fluori de C a ta ly st ...... 76

Se fL-:idcro Peroxide Combustion Analysis of P-S-Ethyl-£-thio- L-arabinose Diethyl Dithioacetal (VIII) ...... 76

Preparation of 2,3,ii-Tri-0- ac'. tyl-5-S-ethyl-L-arabinose Diethyl Dithioacetal (II) ...... 79 v ■jabl : op crm a.iTS (contd.)

Paye

Seni^micro Peroxide Combustion Analysis of 2,3 ,h-Tri-0-acetyl- 5-S-ethyl-£-thio-L-arabinose Diethyl Dithioacetal (!l) ...... 79

The Preparation of 2,3,^-Tri- O-acetyl-^-S-ethyl-5-thio-L- arabinose Dimethylcetal (XXXV) ...... n

A+ter:pted Preparation o f 5-Pec:cy-L-arahinose ...... nl

The Deductive Pesulfurization o f 5 -Tthyl-5-thio-L-arabinose Diethyl Pittiioacetal ...... 33

^he C-methyl Determination oj' 1 , 5 -Dideoxy-L-arabinitol (D-lyxitcl) (^V) ...... 8 ?

Attempted Preparation cf l , 5-Pid&oxy-2 , 3 ,U -tr i-G - o-nitrobenzcyl-L- arab in i to1 (D-lyxi to 1 ) ...... f 7

Synthesis and Proof of Structure o f 5 -Decxy-D-xylo-hexo se (" 5 -Deox - EUgHucose'1); Synthesis and Optical Prcoerties of P-Xvlo-hexoses ...... 87

Tlie Preparation o f 1 ,2 -0 - Iscpropylieene-5 , 6- e i - 0 -o - tclylsulfcnyl-a-D-glucose (XI) ...... :7

The Preparation of l,2,-0- lEcprcpylioerte-3,.5,6-tri-O-o- tolylsulfer.yl-a-D-glucose ...... : 5

The S yn th esis o f 1 ,2 - 0 - I scpropyli dene-4i-vinyT-a- D-xylc-- tetrcJuranose (XITI) ...... 89

The S yn th esis o f 1 ,2 - 0 - Isopropylidene- 3 - 0- £ - “ tolylsulfonyl-k-vlnyl-a- D-xylc-tetrofuranc-se (XIV) ...... 90

vi TABLE OF CC:iTE:TS (contd.)

Pa ['e

The Synthesis of 5, 6- D id e o x y -l,2-isoprcpylidene- a-P-xylo-hexose (XV) ...... 90

The Synthesis of 5-Oeoxy- 1 , 2 - 0-isopr opyli dene-a- r-xvTc-hexr se ...... 91

A. Sodiur. Borohycri’e- Alundnuiii Chloride "eduction ...... 91

B. Piborane Ee ucticn ...... 92

SIrupy g-H oxy-P-xylc-hcxose ...... 92

g-i-co::y-D-threo-hexose Phenylos^sone (XVH) ...... 93

5-Be ox -D-threo-hexcse Phenylosotriaz'le ( .nfTT-r j ...... 93

The P riodate Oxidation of the 5-Peoxy-D-thrco-hexose Phenylo.sotrlazole ...... 93

The Acid hydrolysis of the Prepared 1 ,2-0-Is opropyli d.ene Puranose Derivatives ...... 9h

The Optical Potatory Dispersion of 1,2-C- Isop rcpyli cene-U-vinyl-a-D-xylo- tetrofuranose (XIII) and 1,2—O-Isopropylidene- 3 -O-tolylsulfonyl-ij-vi nyl---- D-x y lc - tetrofuranose ...... 96

SUiiiAItY ...... 98

ChFi .1079...... CYCAL EIBLIOGFAPEY ...... 101

AU70BIC TAPBT ...... 112

vii LIST OF FIGURES

Acid hydrolyses of 1,2-0- isopropylidene-D-xylo- “ hexoses in 2.5 N hydrochloric a c id , 0 .2 2 M in**sugar ......

Optical rotatory dispersion curves of 1, 2 - 0 -i sopropylidene - U -vinyl-a -P-xyTo-tetrofuran os e in different solvents ......

Optical rotatory dispersion curve of 1,2-0—iscpropylidene-3-O-p- t o lylsulfonyl-lj -vinyl-«j -P-yylo- tetrofuranose in chloroform

Plot of single terra Drude equation from obtained rotatory dispersion curves

Ultraviolet absorption spectra o f 1 , 2- 0-isopropvlidene-ii-vinyl- a-D-xylo-tetrofuranose in water

viii LIST OF TABLES

Page

T able No.

1. The Synthetic Monodeoxy Aldoses ...... 2£

2. The Synthetic Deoxy-hexuloses ...... 30

3* The Synthetic Dideoxyaldoses ...... 32

li. Free Sugars Which Cannot Form the Pyranose R ing ...... 36

5. Possible Structures of the Mercaptolyses Product From Tetra-O-acetyl-a-L-arabinopyranose ...... 38

6 . Results of Analyses of Unknown Sulfur Containing Carbohydrate ...... UO

7• Product Analysis From Periodate Oxidation of Desulfurlsed Alditol ...... U6

8 * O p tic a l D ata on Some S y n th e size d Non-pyranose Sugars ...... 67

9. Concentrations and Calculated Data for Rotatory Dispersion Curves ...... 97

10. Data From Rotatory Dispersion Curves ...... 97

11. Calculated Data From Drude Equation ...... 97

ix INTRODUCTION

The carbohydrates are a large and very important part of the naturally occurring organic materials* They include such members as

starch, cellulose and sucrose, which play a significant part in world

economy, as well as sugars which occur in only minute amounts but have a

significant role in the life process of the organism in which they are

found ( l ) .

(l) J* C* Sowden in "The Carbohydrates," W. Figman, Editor, Academic Press Inc*, New York, N. Y., 195?, p. 77*

Of the various modifications of sugars which occur naturally, those O in which hydroxyl is replaced with hydrogen are perhaps the most common;

they are known as deoxy sugars* 2-Deoxy-D-erythro-pentose, n2-Deoxy-D-

ribose," is the deoxy sugar which has received the most attention (2)

(2) W. G* Overend and M* Stacey, Advances in Carbohydrate Chem., 8, U5 (1953).

since its discovery by Levene (3) as the sugar component of "thymus

(3) P. A. Levene, L. A* Mike ska and T. Mori, J* Biol* Chem., 85, 785 (1929)* ^ nucleic acid," now known as deoxyribonucleic acid*

The 6-deoxyhexoses are widely occurring, L-rhamnose or 6-deoxy-L- mannose being the most common* The cardiac glycosides contain deoxy

sugars of several kinds (U), and at the present time new deoxy sugars 2

(U) R. Reichstein, Proc. Intern* Congr* Bloc hem., lith Congr., Vienna, 1958, 1, 12k (1 9 5 9 ). are being isolated and identified constantly, especially in antibiotics.

Because of the limited sources and minute quantities in which many deoxy sugars may be obtained from natural products, the synthesis of deoxy sugars is of considerable interest to carbohydrate chemists. These syntheses serve the dual purpose of providing structural confirmation of naturally occurring deoxy sugars and of furnishing new deoxy sugars for configurational and physiological studies*

2-Deoxy-D-arabino-hexose, n2-deoxy-D-glucose,n a synthetic deoxy sugar, has been shown to have some carcinolytic activity. Similarly, synthetic nucleosides have been used and recommended as antim etabolites; deoxynucleoside synthesis is therefore of considerable importance. Such syntheses have involved prior synthesis of the deoxy sugar followed by attachment to a purine or pyrimidine moiety or direct formation of a deoxynucleoside from a nucleoside (5) prepared from normal sugars*

(5 ) C . D . A nderson, L . Goodman and B. R . B aker, J . Am. Chem. S o c ., 81, 3967 (1959).

Thus, the synthesis of deoxy sugars and decxy sugar precursors has great potential in the field of chemotherapy. STATELiBWT OF THE PROBLEM

The objectives of this work have been the followingi

1* The synthesis of deoxy sugar precursors through introduction of a thioethyl moiety on the sugar molecule

2* The synthesis of terminally unsaturated hexoses as deoxy sugar precursors

3* The synthesis of 5-deoxy-P-xy lo-hexose ( deoxy-D-glucoseM )

1*. A study of the optical properties of free sugars in which the pyranose ring cannot form

3 HISTORICAL

Synthesis of Unsaturated Carbohydrate Derivatives

The Olycala and Their Rearranged Derivatives

The first unsaturated sugar derivative was discovered by Fischer and Zach ( 6 ). These workers treated tetra-O-acetyl-a-D-glucopyranosyl

( 6 ) (a) E. Fischer and K. Zach, Sitsber. kgl. preuss. Akad. Wiss., 16, 311 (1913); c. A ., 8 , 73 (19110 5 (b) E. Fischer, Ber., {£, 196 (191U) • bromide "with zinc to give the 1 , 2-unsaturated product, effectively, through the loss of acyloxy bromide. This first compound was named glucal and the name glycal is applied to the unsaturated reaction product of acetohalo sugars in general ( 7 ). The glycals are end ethers and do

(7 ) B. Helferich, Advances in Carbohydrate Chem., 7 ^ 209 (1952). not class as true olefins.

The glycals are the source of two other unsaturated sugar derivatives.

Pseudoglycals are formed when acetylated glycals are heated in water.

The effect is that of loss of the acetyl group on C-3 followed by an ally lie type rearrangement to place the double bond between C-2 and C-3 with a free hydroxyl group appearing on the anomerlc carbon. These compounds, discovered by Fischer ( 6b), are true olefins derived from dihydropyran. The second rearranged glycal is obtained during the deacetylation of pseudoglucal and has been named protoglucal ( 8 ).

I* 5

(8) Id* Bergmann, L. Zervas and J. Engler, Ann., $08, 2$ (1933)*

The assigned structures of the D-glucals are shown below. That of

D-p rotoglucal is especially interesting as the authors assign this structure partly on the observation that the compound gave a positive iodoform test. The conclusion is drawn, that the test indicates the presence of — $— CHt— • This conclusion and the assigned structure are quite likely in error.

I I---- CH CHOH CHO I CH CH CH 1 h oAh CH —■C \J HCOH HCOH hA(loH I _ I I HCO — HCO— HCOH I I AiJHgOH CH20H •OCHg

D -G lucal D-Ps eudo glucal D-Protoglucal

The Glycoseens

The glycoseens are enol ether derivatives in which one of the unsaturated carbon atoms is bonded to the herniacetal oxygen of C -l. The synthesis of these derivatives is invariably the result of an elimination reaction, freudenberg and Brauns (9) observed that l,2i$,6-di-0-

(9) K. Freudenberg and F. Brauns, Ber., $$, 3233 (1922). is opropyliden©- 3-O-g-tolylsulfonyl-a-D-gluco se on treatment with hydrazine yielded not only a 3-hydrazino compound but an unsaturated compound, 3-decocy-l, 2 1$ , 6- d i - 0-isopropylidene-a-D-erythro- 3-hexoseen •

Helferich and Hiramen (10) reacted l,2,3,ii-tetra-0-acetyl-6-deo:y-

(10) B. Helferich and E. Himmen, ibid., 61, 1825 (1928).

6-iodo*

Preudenberg and Raschig (11) found that 6—deaxy-l,2t3,U-di-0-

(11) K. Freuderiberg and K* Raschig, ibid., 62, 373 (1929). isopropylidene- 6-iodo-a-D-galactose eliminates hydrogen iodide on treatment with so dim methoxide to yield the unsaturated derivative

6-deoxy-l,2 *3 ,ii-<±L-0-isopropylidene-a-L-arabino-5-hexoseen.

Helferich and Himmen (12) found that silver fluoride reacted

(12) B. Helferich and E. Himmen, ibid., 62, 2136 (1929). identically with the di <- 0- i sop ropyli dene compound used by Freudenberg and Raschig (U ).

Mflller (13) also utilized the silver fluoride-pyridine procedure

(13) A. Muller, ibid., 1820 (1931). for preparing the p-me thylgly coside of 2 ,3 ,U-tri-O-benzoyl-6-deoxy-L- arabino-5-hexoseen from methyl 2,3 ,U-tri-0-benzoyl—6-deoxy-6-iodo-p-D- galactoside*

Synthesis of 2-hydroxyglycals

It was discovered by Maurer and Mahn (lU) that if one reacted

(ill) K, Maurer and H, Mahn, Ibid., 60, 1316 (192?)• tetra-0-acetyl-a-D-glucopyranosyl bromide with diethylamine, an elimination of hydrogen bromide was effected to yield 2,3,k,6-tetra-0- acetyl-D-glucal, a compound which differs from the normal glycals in that there is an acyloxy group on C-2 rather than hydrogen. This class of carbohydrate derivatives is known as the 2-hydroxyglycals (15).

(15) Mary Grace B lair, Advances in Carbohydrate Chem,, 9, 97 (195U ).

Later, UFolftom and Husted (16) demonstrated that tetra-O-methyl-D-

(16) 11, L, Wolfrom and D* R. Husted, J , Am, Chem, Soc>, 5 9 , 2559 (1937). glucopyranosyl bromide yielded only the glycosyl amino derivative on treatment with diethylamine but did react with sodium hydroxide in anhydrous dioxane-ether to give the 2,3,U,6-tetra-0-methyl-D-glucal.

Ohio and Deplanque (17) introduced a new procedure for double

(17) H, Ohle and R, Deplanque, Ber,, 66, 12 (1933). bond synthesis in sugars by heating l,2*3,5-di-<>*-i3opropylidene-6-0^

£-tolylsulfcnyl-a-I>-glucose with soda lime • g-Toluenesulfonic acid was eliminated with the production of 6-deoxy-1,2i3,5-di-0-isopropylldene- a-D-3tylo^iexos-5-«ne. Bollinger a^id Prins (18) heated methyl 14, 6- 0 -

(18) H. R. Bollinger and D* A. Prins, Helv* Chim. Acta, 29, 1061 (191*6). benzylidene-3-deoxy-2-O-p-tolylsulfonyl-q-D-arabino-hexoside with soda lime and isolated the respective pseudoglyeal as the elimination product*

This technique was applied by Weygand and Wolz (19) as a convenient

(19) F. Weygand and H. Wolz, Chem* Ber*, 8$, 259 (1952). method for the preparation of 3“8«03ty“l*2t5,6-di^>-isopropylidene-

erythro-3-hexoseen from 1,2 15 ,6-dl-O-isopropylidene-3-0-£- to ly lsu lf onyl-ot-D-glucos e •

The Synthesis of Vinyl Substituted Sugars

The vinyl substituted sugars are a class of sugar compounds in which a vinyl group occurs as a substituent on the terminal carbon. In the

known examples the parent compound is always a hexose and is converted

to a "U^vinyl-tetrose."

The first example of this type of reaction was observed by Ehglish and Levy (20). These investigators found that the treatment of

(20) J. English, Jr., and It. F. Levy, J. Am. Chem. Soc., 78, 281*6 (1 9 5 6 ). “ 5 , 6-an h y d ro - 3- 0- b e n z y l - l , 2-0 -isopropylidene--benzyl-l,2-0—iaopropyHdene-ii-vinyls*-D- xylo-t etroforanoa e »

The other examples in this class of sugars have been prepared by

the reaction of sodium iodide on the vicinally substituted 5,6-di-O-

£-tolylsulfonyl derivatives* Sodium iodide reacts with vicinal

di-O-^-toluenesulfonate esters in such a manner that an olefin is

formed with the double bond between the carbons originally bearing the g-toluenesulfonate groups* This reaction was first recognized by Tipson

and Cretcher (21) and the applications to the alditola have been reviewed

(21) R. S. Tipson and L* H. Cretcher, J. Org* Chem., 8, 9$ (19U 3).

by Tipson (22)*

(22) R* Tipson, Advances in Carbohydrate Chem., £, 108 (1953)*

Bell, Friedman and Williamson (23) reported that 1,2-0-

(2 3 ) D. J. Bell, E. Friedman and S. Williamson, J. Chem. Soc., 252 (1937) *

i8opropylidene-6-0-£-tolylsulfonyl-a-D-glucofuranose on treatment

with sodium iodide in acetone yielded an unsaturated compound containing

no sulfur or iodine* The compound was not further characterised*

Vischer and Reichsteln (2U) attempted the preparation of 6-deoxy-l,2- 10

(21*) E. Vischer and T. Reichstein, Helv. Chira. Acta, 27, 1332 ( 19hh) . “

0-isoproplyidene-6-iodo-5-0-g-tclylaulfonyl-o-D-glucoae from 1,2-0-

isop ropyli dene-5, 6-di-0-j>-tolylsulfonyl-a-D-glucose by th© action of

sodium iodide. They report no product and only a trace of recovered

starting material.

Jones and Thompson (25) treated 1,2-0-isopropylidene-5,6-di-©-j>-

(25) J* K. N. Jones and J. L. Thompson, Can. J. Chem., 35> 955 (1957).

tolylsulfonyl-a-D-glucose and 1,2-0-isopropylidene-3 > 5,6-tri-0-£-

tolylsulfonyl-a-D-glucose with sodium iodide and obtained the sirupy

1,2 -O-is op ropyli dene-k-vinyl-g-D-aylo-tetrofuranose and 1,2-0-

isopropyli den e-3-O-p-tolylsu Ifonyl-b-vinyl-q-D-aylo-tetrofuranoae

respectively.

Ball, flood and Jones (26) prepared crystalline methyl 2,3-di-0-£-

(26) D. J. Ball, A. E. Flood and J. K. N. Jones, ibid., 1018 (1959).

to lylsulfonyl-ii-vinyl-q-L-arablno-tetrofuranoaide from methyl 2,3,5,6-

tetra-0-£-tolylsulfonyl-^-IVgalactofuranoside and sodium iodide. A

sodium amalgam reduction of the di-O-g-tolyldulfonyl compound resulted in

the isolation of crystalline methyl U-vinyl-g-L-arabino-tetrofurenoside• 11

The Reaction of Diborane with Olefins

It Has observed by Brown and Subba Rao (27) that in the presence

(27) H* C. Brown and B. C. Subba Rao, J. Am. Chem* Soc,, 78 . 2582 (1956).

of an aluminum chloride-sodium borohydride solution in bis(2-methoxy-

ethyl)ether ("diglyme") olefins were smoothly transformed into alkyl

boranes • This reaction of diborane or aluminum borohydride was not new.

I). T. Hurd (28) had observed that in the gas phase diborane reacts

(28) D. T. Hurd, ibid,, 70, 2053 (19U6).

with olefins to yield trialkylboranes • The reaction is slow at room

temperature and fast at 100°• These diborane-olefin reactions were also

observed by later workers (29). Similarly aluminum borohydride has been

(29) A. T. Whatley and R. N. Pease, ibid., 76 , 835 (l95U)i F. G. A. Stone and H. J. Emeleus, J. Chem.^Soc., 2755 (1950); F. G. A. Stone and V. A. G. Graham, Chem. and Ind. (London), U 8l (1955)*

observed to form trialkyXboranes in the presence of olefins ( 30) i n th e

(30 ) R. S. Brokaw, E. J. Bo din and R. N. Pease, J. Am. Chem. Soc., |2 , (1950)5 R. S. Brokaw and R. N. Pease, ibid., 72, 3237 (1950).

gas phase and at elevated temperatures• These gas phase reactions are

Interesting but of little synthetic value.

The first practical utilisation of this reaction was due entirely 12 to the choice of the solvent, bis ( 2-me thoxy ethyl) ether, by Broun and

Subba Rao (2?) • Subsequent investigations demonstrated that diborane in ether; rapidly form alkyl boranes with olefins (31); in place of

(31) H. C. Brown and B. C. Subba Rao, J. Org. Chem., 22, 1136 (1 9 5 7 ). diborane its precursor, borobydride-boron halide, may be used. This reaction has been carefully investigated and its applicability and stoichiometry outlined ( 32)*

(32) H. C. Brown and B. C. Subba Rao, J. Am. Chem. Soc., 81, 61i23, 61*28 (1959). ^

The reaction is basically an addition of borane across a double bond to yield a trialkyl borane. The borane may be subjected to

3 R - CH - CI^ + BKj (RC^CH^B oxidation and saponification with alkaline hydro gen peroxide according to the method Johnson and Tan Campen (33), the overall result being the

(33) J* R. Johnson and U. G. Tan Campen, Jr., ibid., 60. 121 (1931). hydration of an olefin in a non-classical (contrary to the Uarkonikoff rule) manner and in the absence of protonic acids (22,26,27). The S yn th esis o f Deoxy Sugars

Synthesis by Direct Replacement of Hydroxy, Acyloxy or Sulfonyloxy groups

Fischer and Zach (3li) > in 1912, discovered that the treatment of

(3U) E. Fischer and K. Zach, Ber., h5_, 3?6l (1912).

D-glucose pentaacetate with liquid hydrogen bromide yielded2 , 3 , l i - t r i - 0- a c e t y l- 6-bromo-6-deoxy-a-T)-glucosyl bromide, which by conversion to the methyl glycoside and reduction with zinc in acetic acid was converted to methyl 2,3,h-tri-0-acetyl-6-deoxy-&-D-glacoside. This compound was

deacetylated and treated with acid completing the synthesis of the

crystalline 6-deo:xy-a-D-glucose, Miso^hamnose.,,

In a similar manner Schlubach and V/agenitz (35) synthesized

(35) H. H. Schlubach and E. Wagenitz, ibid., 65, 30U (1932).

crystalline 6—deoxy-D-galactose, "rhodeose," from penta-O-acetyl-fc-D-

galactopyranose.

In 1927j Freudenberg and Paschig 3 ( 6 ) converted 1,2:3jii-di-O-

(3 6 ) K. Freudenberg and K. Paschig, ibid., 60, 1633 (1927).

isopropylidene-6-0-o-tclylsulfonyl-a-D-galactose to the6 -d eo x y - 6-io d o

compound by treatm ent w ith sodium io d id e in a ceto n e. This iodo

derivative was reduced to the 6-deoxy compound from which the

isopropylidene groups were removed with acid, yielding the free6 -d eoxy-

D-galactose. lU

Muller and Reichstein ( 3 7 ) found that 2,3-0-isopropylidan«-l,6-^-^>-

<37 ) H. Muller and T. Reichstein, Helv. Chin. Acta, 21, 263 (1 9 3 8 ). tolylsulfonyl-a-L-sorbofuranose first reacted with sodium iodide to y i e l d th e 6-d eo x y - 6-iodo derivative and only gave the l, 6-dideoxy-l, 6- diiodo compound under more forceful conditions. Thus both 6—deoxy-L - sorbose and 1 , 6-dideoxy-L-sorbose were synthesized. Fructose derivatives react in an identical manner ( 38 ).

(38) W. T. J. Morgan and T. Reichstein, ibid., 21, 1023 (1938).

The reduction of iodo derivatives obtained by £-tolylsulfonyloxy replacement has sim ilarly been used in the synthesis of 6-deoxy-D - ta g a to s e ( 3 9) , 2, 6-d id eo x y - 3 -O-methyl~D*^ibo-hexose, "D-cymarose" ( 1*0 ),

(39) J. Barnett and T. Reichstein, ibid., 20, 1529 (1937)*

(1*0) D. A. Prins, ibid., 29, 378 (19l*7). and 3 % 6-dideoxy-P-xylo-hexos e ( 1*1 ).

(1*1) 0. 'tfestphal and S. Stirm, Ann., &0, 8 (1 9 5 9 ).

The replacement of a hydroxyl or acyloxy group in a carbohydrate with a thioethyl group is a little understood route to deoxy sugar precursors•

The first reaction of this type was reported by Brigl and l£ coworkers (1*2) who replaced the hydroxyl group on C-2 of 3,U ,£,6-tetra-

(li2) P. Brigl, H. Uuhlschlegel and R. Schinle, Ber., 6h, 2921 (1931).

O-benzoyl-D-glucose diethyl dithioacetal with a thioethyl group to yield

3,U,!>,6-tetra-0^benzoyl-2-S-ethyl-2-thio-D-glucose (mannose?) diethyl dithioacetal. The reaction was carried out in chloroform in the presence of ethane thiol and anhydrous hydrogen chloride.

Wolfrom and Thompson (13) reported that hexa-O-acetyl-D-gluco-

(U3) M. L. Wolfrom and A. Thompson, J. Am. Chem. Soc., $6 180li (193*0 • heptulose on treatment with ethanethiol, zinc chloride and Drier!te (hi;)

(UU) Anhydrous calcium sulfate (’’soluble anhydrite”), a product of W. A. Hammond D rier!te Co., Xenia, Ohio. yielded a product in which two acyloxy groups were replaced by thioethyl groups, one of which was the giy cos idle acyloxy group. The position of the other thioethyl group was not determined* This constitutes the first example of an apparent acyloxy replacement by ethanethiol under acidic conditions in carbohydrates.

More recently, Lemieux (U5), while studying the mercaptolysis of

(U5) R. U. lemieux, Can. J. Chem., 29> 1079 (1951). some sugar acetates, treated penta-0*-acetyl-£-D-glucopyranose with 16 e th a n e th io l under the same co n d itio n s used by Y/olfrom and Thompson (1+3)»

A product was obtained which, after deacetylation, had the physical

constants of the 2-S-ethyl-2-thio-]Vglucose (manncse?) diethyl

dithioacetal of Brigl and associates (1+2). The reaction was also observed with penta-O-acetyl-a-D-glucopyranose after a rather extended

reaction time.

Wolfrom and von Bebenburg (1+6) prepared 3,h,5-tri-0-benzoyl-D-xylose

(1+6) . L. Wolfrora and W. von Bebenburg, J. Am. Gheiu. Soc., 81, 5705 (1759).

diethyl dithioacetal and, following the procedure of Brigl (1+2),

synthesized 3 >l+,5-tri-0-benzoyl-2-S-ethyl-2-thio-D-xylose (lyxose?)

diethyl dithioacetal (1+7) -

(1+7) V/olfrom and W. von Bebenburg, in press.

In the latter case, reductive desulfurization with Raney nickel (1+8)

(1+S) J. Bougault, E. Gattelain and P. Chabrier, Bull. Soc. Chim. (France), [5] 5, 1699 (1938); ibid., [5] 7, 780, 781 (191+0) j R. aozingo, D. E. 7/61 f, S.~A. Harris and K. Folkers, J. Am. Chem. Soc., 65* 1013 ( 191+3 ); V. du Vigneud, D. B. ilelville, K. Folkers, D. F,. Wol?7 R. ;,iozinro, J. C. Keresztesy and S. A. Karris, J. Biol. Chem., U+6, 1+75 (191+2).

of the confound in which the diethyl dithioacetal groups were replaced

by methyl acetal yielded the corresponding 2-deoxy-D-erythro-

pentose (2-deoxy-D-ribose) derivative. Reductive desulfuriza­

tio n o f the d ie th y l d ith io a c e ta l compound (1+9) o f 17

(U9) M* L. Wolfrom and J. V. Karabinos, J. Am* Chew. Soc*, 6 6 , 909 ( 1 9 W -

Wolfrom and von Bebenburg (Ui) conveniently located the thioethyl group

substituted on the carbon chain of the sugar*

Karrer and Boettcher (50) in 1953* reduced 1,2: 3 ,5 -d i-O -

(50) P* Karrer and H* Boettcher, Helv. Chim. Acta, £6, 570 (1953)•

isopropylidene- 6- 0 -£-tolylsulfonyl-

hydride to the corresponding 6-deoxy compound* This introduced a

convenient means of reducing a terminal hydroxyl* Subsequently the

reaction has been applied to the synthesis of 3 * 6-dideoxy-D-xylo- hexose (51), 3 , 6-dideoxy-P-arabino-hexose ( 5 1 ) , 3 , 6-dideoxy-D-lyxo-

(51) C* Fouquey, E. Lederer, 0* Luderitz, J. Polonsky, A. H. Staub, R. Tinelli and 0* Westphal, Compt. rend., 2U6, 2U17 (1958). hexose ( 5 2 ) and 2 , 5 -dideoxy-D-erythro-pentose ( 5 3 )•

(52) C* Fouquey, J. Polonsky, E. Lederer, 0* Westphal, and 0. Luderitz, Nature, 182, 9UU (1958)*

(53) H. Zinner and H* Wigert, Chem. Ber., 92, 2893 (1959).

Wolfrom and Foster (5U) found that the 2-(S-methyl dithiocarbonate)

(5U) M. L. Wolfram and A* 5* Foster, J. Am* Chem* Soc., 7 8 , 1399 (1956). 18 o f m ethyl 3 ,U-O-isopropylidene- 2-thio-£-D-arabinose, produced on thermal rearrangement of the 2-(methyl xanthate) of methyl 3 ,U-0 -isopropylidene- p-H-arabinose, yielded the 2-deoxy-D-erythro-pentose derivative on reductive desulfurization with Haney nickel (U8,U9)• The rearrangement is similar to that of the 3 - 0 -(methyl xanthate) of 1 , 2 i 5 , 6—di-O - isopropylidene-a-D-glucose discovered by Freudenberg and Wolf (5 5 )•

(55) K. Freudenberg and A. Wolf, Ber., 60, 232 (1927).

This method was applied by Semy and Poc&k (56) to the synthesis

(56) M. Seray and J* Pocak, Collection Czechoslov. Chem* Conmuns., 21, 1003 (1956)* o f 3 -deoxy-D-ribo-hexose (^-deoxy-D-glucose" ) •

Deoxy sugars by opening of epoxide rings

The most direct synthesis of deoxy sugars via epoxide rings involves direct reduction of the epoxide (eq. l) • Freudenberg and

R C,H—CHR Hg, c a t . RCHgCHR + RCHCHgR ^ 0 or oh OH (1 ) LiAlH^ coworkers ( 5?) hydrogenated 5 >6^anhydro-l> 2-0 -isopropylidene-a-D-glucose,

(57) K. Freudenberg, H. Eich, C. Knoevenagel and W. Westphal, B e r ., J2 .9 Ma (1 9kO). in the presence of a palladium catalyst, to 6-d e o x y - l, 2- 0 -isopropylidene- a-D-glucose. The hydrogenation may also be affected over a nickel catalyst (56)* Chemical reduction idth lithium aluminum hydride opens

(58) E. Vischer and T. Reichstein, Helv. Chim. Acta, 27, 1332 (19UU)j F. Blindenbocher and T• Reichstein, ibid., 31, l669”Tl9U8)• the epoxide ring in the same manner to the substituted 6-deoxy-'D- glucose (59).

(59) E. J. Reist, R. R. Spencer and B. R. Baker, J. Org. Chem., 21 , 1753 (1958).

The opening of epoxide rings fused to the pyranose or six-membered rings in general has been the subject of some theoretical discussion.

Furst and Plattner have suggest a rule for the opening of epoxides so located (60). Briefly stated, the opening of the epoxides w ill proceed

(60) A. Furst and P. A. Plattner, Abs. Papers 12th Intern. Congr. Pure Appl. Chem., U05 (1951)• in such a manner that in the product the two groups are co-axial

(eq. 2). This rule has been reviewed and substantiated in the pyranose 20 sugars (61). There are exceptions to the rule and In general the

(61) (a) W* G. Overend and G* Vaughan, Chem* and Ind., 995 (1 9$$)} (b) F. H. Newth, Quart* Rev., 13, 30 (1959 )} (c) G. Huber and 0. Schier, Helv* Chlm* Acta, U3< 129 (19603* pentoses are less apt to follow It*

An early example of a direct deoxy sugar synthesis by the opening of an Internal epoxide was performed by Prins (62) who hydrogenated

(62) D* A* Prins, Helv* Chlm* Acta, 29* 1 (19U6). methyl 2,3-auihydro-U,6-0-bensyHdene-a-D-mannose with a nickel catalyst to methyl 3~deoxy**x-D-ribo-hexose * The same anhydro sugar opens in the other direction with lithium aluminum hydride to methyl U, 6-O-benzylidene-

2 -de oxy-

( 6 3 ) D. A* Prins, J. Am. Chem. Soc*, 79, 3955 (19^8).

The opening of the epoxide rings is commonly performed with groups which are conveniently reduced to methylene groups • Kent, Stacey and

W iggins ( 6li) treated methyl 2,3-anhydro-p-D-ribopyranoside with hydrogen

( 6U) P. W. Kent, M. Stacey and L. F . Wiggins, J. Chem. Soc., 1232 (19U 9). bromide, a reaction from which the isomeric methyl 3 -bro:no- 3 -deoxy-£-D- xylopyranoside and methyl 2-bromo-2-deoxy-p-I>-arabinopyranoside were isolated* The bromo group was reduced with nickel to the respective deoxypentoses • 21

Jeanloz, Prins and Reichstein (65) treated methyl 2, 3-anhydro-li, 6-

(65) R. Jeanloz, D. A. Prins and T. Reichstein, Helv. Chlm. Acta, 29 , 371 (191 i6 ) .

O-benzylidene-a-D-alloside with thiomethyl sodium which yielded methyl

U , 6-O -benzyli de ne -2 -S-me thy 1-2 -th i o -a~D -all os ide . Reductive d e s u lf u r iz a tio n (U 8 ) of this thio compound resulted in the synthesis of methyl 2-deoxy-a-D-ribo-hexoside.

Treatment of the epoxy compounds with Grignard reagents often yields an iodo compound ( 66 ) which is readily reduced to a deoxy sugar*

( 66 ) F. H. Newth, G. N* Richards and L. F. Wiggins, J. Chem* Soc», 2356 (1950).

This reaction is not clean-cut, quite temperature dependent ( 6 6 ) , can be modified by using organo-zinc compounds ( 6 7 ) and i s som etim es

( 6 7 ) G* N* Richards and L. F. Wiggins, J. Chem. Soc., 2U1*2 (1953)* sensitive to the alkyl substituent of the Grignard reagent ( 6 8 )*

( 6 8 ) G. N* Richards, ib id ., 1*511 (1951*).

It has been demonstrated that 5,6-anhydro-l,2-0-isopropylidene-a-D- glucose reacts with carbon disulfide and potassium hydroxide to yield the trithiocarbonate (69), 1,2-0-isopropylidene-5, 6—di th io - 5 , 6-S- 22

(69) G. P. MoSweeny and L. F. Wiggins, Nature, 168, 87 U (1951) •

thiocarbonyl-a-L-idose (70).

(70) A. M. Creighton and L. N. Owen, J. Chan* Soc., 102U (I960),

Deoxysugars from unsaturated carbohydrate derivatives

Fischer, Bergmann and Schotte (71) brominated D-glucal (6) to

(71) E. Fischer, M. Bergmann and H. Schotte, Ber., 5^, $09 (1920).

2-bromo-2-deoxy-D-glucosyl(mannosyl) bromide and this was converted to

the glucoside(mannoside) with silver oxide in methanol. The bromine in

the 2-position was reduced off with sodium amalgam with the resultant

synthesis of methyl 2-deoxy-D-arablno-hexoside.

Bergmann, Schotte and Lechinsky ( 7 2 ) hydrolysed D-glucal (1) with

(72) M. Bergmann, H. Schotte and W. Lechinsky, ibid., 55* 158 ( 1 9 2 2).

dilute sulfuric acid, which, as an enol ether, hydrolyses rapidly to the

enol, tautomerizes to the aldehyde and recycllzes to the sugar hemiacetal

ring. The end result in this case is the synthesis of 2-deoxy-D-arabino-

hexose ("2-deoxy-D-gluc ose").

The glycal method of 2-deoxysugar synthesis is applicable in cases where the glycal is readily synthesized. In specialized cases such as 2-deoay-D-erythro-petntose ("2-deoxy-D-ribos en ) reactions have been

devised which are more applicable to large scale production.

Diacetylpseudoglucal ( 6) was hydrogenated by Bergmann (73) to the

(7 3 ) M. Bergmann, A nn., U p , 223 (192$)*

dideoxy su g ar U, 6- d i - 0 - a c e ty l -2 , 3 -dideoxy-D-erythro-hexose •

The 6-deoxy-l,2 *3 ,k-dl-0-iBopropylidene-q-L-arabino-5-hexoseen of

Freudenberg and Raschig (11) was hydrogenated by these same investigators to a mixture of isopropylidene sugars which were separated after acid hydrolysis to yield 6-deoxy-D-galactose and 6-deoxy-Ir-altrose.

On hydrolysis of the hexoseens (page 5) with acids, 6-deoxy-5-keto- hexoses have been prepared. In this manner sirupy 6-deoxy-L-arabino- hexose- 5 -u lo s e ( 1 2 ), crystalline 6-deoxy-D-xylo-hexos- 5-u lo s e ( 1 2 ) and

crystalline 6-deoxy-l,2-0-isopropylidene-a-D-3ylo-hexo-l,li-furanoB-5- u lo se ( 1 7 ) were prepared*

Weygand and Wolz ( 7 U) hydrogenated 3“

( 7 U) F. Weygand and H. Wolz, Chem. Ber., 85, 256 (1952).

isopropylidene-a-P-erythro-3-hexoseen (15) stereospecifically to the isopropylidene derivative which upon acid hydrolysis yielded 3-decxy-D- xylo-hexose.

An interesting synthesis of methyl 3 -deoxy-(3-D-ribo-hexoside was

discovered by Lindberg and Theander (75)* Methyl p-B-glucoside was 2U

(75) B. IAndberg and 0. Theander, Acta Chenw Scand., 13, 1226 (1959).

selectively oxidized in the 3-position to the 3-keto derivative which on

hydrogenation over platinum in dilute acid yielded the methyl 5-deoxy*^!-

D-rlbo-hexoside • This is an unusual example of a facile conversion of a

carbonyl function into a methylene group.

Deoxysugars via Saccharinic Acids

When reducing sugars are treated with base there is an internal

oxidation reduction reaction resulting in the synthesis of a deoxyaldonic

acid, called a saccharinic acid (76). When these acids are subjected to

(76) J. C. Sowden, Advances in Carbohydrate Chem., 12, 35 (1957). “

any of the well-known degradative procedure for aldonic acids, a

deoxysugar is produced.

The synthesized deoxysugars are tabulated in Tables 1, 2, and 3 . Table 1

The Synthetic Monodeoxy Aldoses

Sugar Synonyms M.P. [a3pQ (H 20) R eferences

2-Deoxy-fl-D-erythro-pentose 2-deoxy-IV-ribose, 96-98 -9 1 — -58 77 thyminose

2-Decocy-p -L -ery th ro -pentose 2-deoxy-Ir-ribose 92-95 ♦80— +59 78

2-Deoxy-p-D-threo-pentose 2-deoxy-D-xy lo se 92-96 - 22(iimin.) — -2 78b,79

3-Deoxy-D-erythro-pentose 3-deoxy-D-xylose sirup -6 61*,80 \

3-Deoxy-L-erythro-pentose 3-deoxy-L-xylose siru p +9 81

2,3-Di-O-acetyl- siru p *h3 (CHCI3 ) 82 5-

^-Deoxy-D-arabinos e D-arabomethylose 82

5-Deo^y-L-arabinose L-arabomethylose siru p -5 82,83

5-Deoxy-D-xylose D-xylomethylos e siru p ♦13 81*

5-Deoxy-D-lyxos e D-lyxomethylose siru p +32 85,86 rhodestetrose ro \A Table 1 (contd.)

2-Deoxy-D-rlbo-hexose 135-136 +58 65.87

2-Deoxy-q -D-arablno-hexose 2-deoxy-D-glucose 123-125° ♦51*— 7 0 .8 8

2 -Deoxy-3 -O-raethyl- siru p +17 89 D-x y lo -hexose

2-Deoxy-p-D-lyxo-hexose 110 - 112 ° ♦50(iwnin •) -+- +58 90

3-Deoxy-a-D-ribo-hexose 3-deoxy-D-glucose 105.5-107° +102— - +32 56,62,63, 66.75.91

3-Deoxy-p -D-arab ino-hexos e 3-deoxy-P-D-mannose lUl-lU2° +ii6(10min.) —*-+53 68.91.92

3-Deoxy-D-xylo-hexose siru p ♦7 9,19,93

3-Deoxy-D-lyxo-hexose siru p -10 93

6-Deoxy-p-D-allos e U*6° -12°— * --l° 82 ,9^

6-Deoxy-D-altrose siru p 0° 95

6-Deoxy-L-aItrose siru p -17 11

6-De oxy-a-D-gluc os e isorhodeose I 39-IUO0 ♦73—^+30 3^,58,96 ro On Table 1 (contd.)

6-Deoxy-L-glucos e 96b

6-Deoxy-p-D-gulos e 130-131° 4*2 ^ -38 97

6-Deoxy-D-tales e epirhodeose siru p 66,98

6-Deoxy-«x -L -ta lo s e epifucose 116- 118 ° - 22( 10ta in .) - w -2 1 99

6-Deoxy-D-mannose D-rhamnose -6 100

6-Deoxy-D-galactose D-fucose 11*0-11*5° +76 (final) 36, 11*20 35

6-Deoxy-a-L-idose 97*5-100° +2 +26 101

7-De oxy-L-glycero -g-L- rharanoheptose 186-187° -129 — +62 102,103 galac;to--Kep'bose 1

7-Deoxy-L-glycero-L- f?-rhamnoheptose siru p 101* talo-neptose

7-Deoxy-D-g ly c e ro -D- 125- 126° +12 10? manno-hepiose

(77) J . C. Sowden, J . Am. Chem. S o c ., 71, 1397 (191*9), W, G. Overend, id. Stacey and L . F. Wiggens, J . Chem. Soc., 1358 (I9l*9)i I** Hough, Chem. and Ind., 1*06 (1951); J. C. Sowden, J. Am. Chem. Soc., 7 6 , 351*1 (1951*). Table 1 (contd.)

(78 ) (a) J. Wisenheimer and H. Jung, Ber., 60, lb62 (1927)j (b) P. A. Levene and T. Mori, J. Biol. Chem., 8£, 803 (1929).

(79) H. Kiliani and P. Loeffler, Ber., 3 8 , 2667 (1905) •

(80) R. Allerton and Yf. G. Overend, ibid., IJ 48 O (1951) •

(31) S. Mukherjee and A. R. Todd, J. Chem. Soc., 969 (19^7)•

(82) F. Micheel, Ber., 63, 3^7 (1930).

(83) E. Fischer, ibid., 29, 1381 (1896)i 0. Ruff and H. Kohn, ibid., 35, 2360 (1902).

(8U) P. A. Levene and J. Compton, J. Biol. Chem., H I, 325 (1935)*

(85) E. VotoSek, Ber., 50, 35 (1917).

(86) E. VotoSek and F . V alen tin , C o llectio n Czechoslov. Chem. Communs., 2 , 36 (1930); Chem. Ze n tr., I, 25U3 (1930).

(fl?) M. Gut and 0. A. Prins, Helv* Chim. Acta, 30, 1223 (19U7)- *

(88) H. R. B o llin g er and D. A . P rin s , i b i d . , 29, 71 (I9 k 6 )j J . C. Sowden and H. 0 . L. F isc h e r, J . Am. Chem. Soc., 69, 10l*8 (19U7)-

(89) A. C. Machly and T. Reichstein, Helv. Chim. Acta, 30, 1*96 (19U7)*

(90) Ch. Tamm and T. Reichstein, ibid., 35, 61 (1951).

(91) J . W* P r a tt and N. K. Richtrayer, J . Am. Chem. S o c ., 79, 2597 (1957).

(92) H. R. Bollinger and D. A. Prins, Helv. Chim. Acta, 29, 1061 (19U6); G. Rembarz, Chem. Ber., 93, 622 (I9 6 0 ).

05IN> Table 1 (contd,)

(93) H. Huber and T. Reichstein, ibid., 31, 16U5 (19U8 )•

(9U) A. Windaus and 0, Schwarte, Nachr. Ges. Wiss. Gottingen Math. Physik. IQasse, 1 (1926); Chem. Z e n tr., I , 882 (1927); Chem, A b stra c ts, 21, 3618 (1927).

(95) M. Gut and D. A. Prins, Helv. Chim. Acta, 29, 1555 (19U6).

(96) (a) E. Vischer and T. Reichstein, ibid., 27 , I 332 (19UU); (b) E. Fischer and H. Herbom, Ber., 29, 1961 (1896). “

(97) P* A. Levene and J. Compton, J. Biol. Chem., I ll, 335 (1935); H. Kiliani, Ber., 55, 75 2817 (1922); E. Votocek and L. Benes, Chem. listy , 22, 362 , 385 11^28); Chem. Z e n tr., I , 1676 (1929)7

(98) E. Votocek and C. Krauz, Ber., UU, 362 (1911).

(99) E. Votocek and I. Cerveny, ibid., US, 658 (1915)} J* Schmutz, Helv. Chim. Acta, 31, I 719 (19U6).

(100) E. Votocek and R. Valentin, Compt. rend., 183 , 62 (1926); Chem. listy , 21, 7 (1927); Chem. A b s tra c ts, 21, 1969 (1927); E. Votocek, Bull. soc. chim. (France), [U] U3, 19 (1928).

(101) A. S. Meyer and T. Reichstein, Helv. Chim. Acta, 29, 139 (19U6).

(102) E. Fischer and 0 . Piloty, Ber., 23, 3102 (1890).

(103 ) L. Jackson and C. S. Hudson, J . Am. Chem. S o c ., 75* 3000 (1953)*

(10U) E. Fischer and R. S. Morrell, Ber., 27, 382 (189U).

(105) C. Krauz, ibid., U3, U82 (1910).

M VO Table 2

The Synthetic Deoxy-hexuloses

Sugar Synonym M.P. t«]p References

3 ,1*,5,6-Tetra-O-acetyl-l- 1-deoxy-D-fructose 106 deoxy-D-arab in o-hexulo se

3 , 6-Tet ra-O-a.cetyl-1- 1-deoxy-L-fruetos e 106a deoxy-L-arabino-hexulose o 6-Peoxy-L-xylo-hexu lose 6-deoxy-L-sorbose 88 -28 37

6-Deoxy-D-arabino-hexulose 6-deoxy-D-fructose siru p -6 38

6-De oxy-D-lyxo-hexnlo se 6-de oxy-D-tagatos e sirup -2 la

6—De oxy-fl -L-lyxo-hexu los e 6-deoxy-f? -L-taga tos e 68-69° +3 .1* -*■ *3 .0 1*1,107

6-Deoxy-$-keto-L-arabino- siru p 12 hexose

6-Deoxy-$-ketoa-D- 125-126° +l5(10min,) -3k 12,108 xylo-hexose

1, 6-Dideoxy-D-arabino- 38 hexulose

3th,5, 6-Tetra-O-acetyl-l- 1-deoxy-D-psicose 109 deoxy-D-rlbo-hexnlose UJ oft Table 2 (contd.)

3 fh,5t6,7-Penta-O-acetyl-1- 96b

(106) (a) tf. L. Wolfrom, D. I. Weisblat, W. H. Zophy and S. W. Waisbrot, J. Am. Chem. Soc., Q, 201 (19Ul)j (b) M. L. Wolfrom and R. L. Broun, ibid., 6*5, 1516 (19li3)«

(107) J. Barnett and T. Reichstein, Helv. Chim. Acta, 21, 913 (1938)*

(108) H. Ohle and R. Deplanque, Ber., 66, 12 (1933)*

(109) M. L. Wolfrom, A. Thompson and E. F. Evans, J. Am. Chon, Soc., 67 , 1793 (19^5)• Table 3

The Synthetic Dideoxyaldos es

Sugar Synonym U«P» t»3p References 2, 5-£jdeoxy-D-erythro-pentose 2,6-dideoxy-D-ribose sirup +17 (pyridine) 110

2 , 6-Dide oxy-D-ribo-hexos e dig ito x o se U 0 U ♦50 ao,m

2,6-Dideoxy-L-ribo-hexose siru p 112

2 , 6-Dideoxy-3-0-ciethyl-D- D-oleandrose 62 - 63 ° -12 96 arab ino-hexo s e

2,6-Dideoxy-p-L-arabino-hexose 93-9h° ♦li6(5min.) —*--18 113

2 ,6-Dideoxy-p-D-xylo—hexo se boivinose 100- 103° - 2 +U n ii

2 ,6-Dideoxy-3-0-methyl-JV D -diginose siru p +56 115 lyxo-hexose

2 ,6-Di de oxy-L-lyxo-h exo s e 103 - 106 ° 90(5min.)—*--62 116

3>6-Pideoxy-D—arablno-hexose tyndose 97-99° +2li 117

3 > 6-Dide oxy-D-xylo-hexos e abequose siru p -3 l i l ,117 a

ro Table 3 (contd.)

3 ,6-Dideoxy-D-ribo-hexose p arato se siru p ♦10 117b,118

3 3 6-Dideoxy-L-lyxo-hexose siru p -20 (MeOH) 117b k, 6-Di-0-acetyl-2,3 -dideoxy- 75-76C ♦k2 73,117a D-e ry th ro -heocose

51 6-Di deoxy-O-xylo-hexose 5 ,6-dideoxy-D-glucose 20,69

3 ,k-Dideoxy-erythro-pentose 117

(110) H. Zinner and H. Wigert, Chem. Ber., 92, 2893 (1959).

(111) B. Iselin and T. Reichstein, Helv. Chim. Acta, 2£, 1203 (19UU)$ H. R. Bollinger and P. Ulrich, ibid., 35, 93 (1952).

(112) M. Bergmann and S. Ludewig, Am., k^k, 105 (1923).

(113) B. Iselin and T. Reichstein, Helv. Chim. Acta, £ 7 , llli9 (19UU ) 3 F. Blindenbacher and T. Reichstein, i b i d . , 3 1 , 2062 (191*8 ),

(Ilk) H. Havenstein and T. Reichstein, ibid., 33, kk 6 (1950); 0. Schindler and T. Reichstein, ibid., 35, 730 (1952)j H. P. Bollinger and T. Reichstein, IFid., 3 6 , 302 (1953).

(115) Ch. Tama and T. Reichstein, ibid., £1, I 63O (191*8)•

(116) B. Iselin and T. Reichstein, ibid., 2£, 1200 (l9kk).

u> U) Table 3 (contd.)

(117) (a) Claudine Fouquey, E. Lederer, 0. Luderitz, Judith Polonsky, A. M. Staub, R. Tinelli and 0* Westphal, Compt• rend., 2U 6, 2U17 (1958); (b) Claudine Fouquey, Judith Polonsky and E. Lederer, Bull, soc. chim. (France), 803 (l9 5 £ ).

(118) Claudine Fouquey, Judith Polonsky, E. Lederer, 0. Westphal and 0. Luderitz, Mature, 182, 9Ui (1958).

(119) C. D. Kurd and L. Rosnati, J. Am. Chem. Soc., 77, 2793 (1955)* Optical Proper tie a of the Ruranose Sugars

It has long been recognized (120) that the "normal" ring structure

(120) W. Pigman, "The Carbohydrates," Academic Press, Inc., New York, 1957, p. 29 ff. of sugar8 is the pyranose or six-membered ring* It is no longer uncommon to prepare sugar derivatives in which the furanose ring is present. Free sugars in which the furanose ring is present can exist only if there is no possibility of pyranose ring formation.

Table 1 contains free sugars that cannot form the pyranose modification. This does not guarantee the presence of the furanose form, since the aldehydro or open chain form may well predominate. The molecular rotation has also been calculated. 36

T able U

Free Sugars Which Cannot Form the Pyranose Ring

[a 3d M.W. Ref.

5-Deoxy-Xr-arabinose -5 I3l» -670 82,83

5-Deoxy-D-xylose +13 13h ♦17 U0 8U

6-Deoxy-L-xylo -hexu lose -28 16U -1600 37

6-Deoxy-D-arabino-hexulose -6 16k -980 38

6-Deoxy-D-lyxo-hexulos e -2 I6h -330 39

5-Deoxy-5-thioethyl-D-xylose +15 19U +2920 121

5-Deoxy-5-thi omethyl-D-xylo se ♦22 180 +3960 121

5-O-methyl-D-glucose -7 19U -1350 122

(121) A. L. Raymond, J. Biol* Chem. 107 , 85 (193U).

(122) L* von Vargha, Ber., 69, 2098 (1936)J 0. T* Schmidt, Gertrude Zinke^Allmang and U* Holzach, Chem. Ber*, 90, 1331 (1957). DISCUSSION OF RESULTS

The Mercaptolysis of Tetra-Q-acetyl-q-Ir-arabinopyranose

With the hope of synthesising 2-S-ethyl-2-thio-L-arabinose diethyl

dithioacetal, in a similar manner described for the synthesis of 2-6- ethyl-2-thio-D-glucose diethyl dithioacetal (li5), tetra-0-acetyl-

OAc I chloride and a drying agent, Drierite (Ui). After suitable isolative procedures, a sirupy product, with an unbearable odor, was obtained*

Successive treatment of the material with decolorizing carbon redaced the

color from it's initial dark yellow to a nearly colorless sirup. The treatment had little or no effect on the odor.

A portion of the material was dissolved in methanol and deacetylated by treatment with sodium methoxide until the solution remained strongly basic. The solution was heated briefly and neutralized with an acidic ion exchange resin. The methanol was removed to leave a light yellow sirup which partially crystallized on standing. The crystals were removed by dissolving the accompanying sirup in a hydrocarbon solvent.

The crystals were silky, elongated needles. The persistent bad odor was still with them. Indeed, after several recrystallizations the odor seemed to disappear only to become evident again when the m aterial was

37 38

stored in a sealed container* It is the opinion of the author that the

odor, after recrystallisation, is a characteristic of the material itself

and cannot be removed* The material was shown to contain sulfur, by the

sodium fusion technique* The compound was not reducing*

The m aterial was recrystallized several times and finally sublimed

in a vacuum* The Bublimate (m.p* 65-67°) was submitted for carbon,

hydrogen and sulfur analyses* The possible structures of the crystalline

deacetylated material are shown in Table 5« The results of six separate analyses from three commercial analytical laboratories are in Table 6*

T able 5

Possible Structures of Mercaptolysis Product Ffrom Tetra-Q-acetyl-<+-L-arabinopyranose

S tr u c tu r e %U %S

HC(SEt)2 h 6oh 1 . H06H 1+2.2 7 .8 6 2 5 .0 ho 6h (Sl^OH

B 3(SEt)2 h 6 1 2. Hj L "(oh^3 Ul^^j 8.05 32.1 I -S E t h2c J

C (S E t)2 HC " 3. HC “(QHj2 1+5.3 8.19 37.2 HC 1^6 - ( S E t ) 2 39 Table 5 (contd*)

S tr u c tu r e %C %H %S

h. 1*3.3 7.26 16.51 ■ Q -

(OH). 5 . H ,3Et U5.3 7.61 26.9 S E t

OH 6 . H.SEt 1*6 *6 8.18 3 3 .9 (SEt)* l*o

T ab le 6

Results of Analysis of Unknown Sulfur Containing Carbohydrate

Closest Fit From L ab o rato ry %C £S T able $ (based on S)

1 1*5.9 7 .0 6 3 7 .3 0 3 37*28

1 1*6.2 8 .5 0 37*67 3

2 1*1* .3 8.20 29.3 5

3 1*1* .3 8 .0 3 3lw8 6

3 U2 J 4 7.31* 33.2 6

3 1*3.7 7 .9 9 33.0 2,6

1 Galbraith Laboratories

2 Huffman M icroanalytical Laboratories

3 Schwarzkopf M icroanalytical Laboratory i a

Due to the great variation in these analyses it was decided to attempt the sulfur analysis in these laboratories* The method chosen was that of combustion with sodium peroxide in a semi-micro Parr peroxide bomb (123)* This laboratory had found that this procedure was excellent

(123) A product of Parr Instrument Co., Moline, 111. for the analysis of dithioacetalst it was also known that low results were obtainable from coianercial laboratories employing the micro-Carius method. A blank was first run on a sulfur-containing carbohydrate,

D-arabinose diethyl dithioacetali calculated on S 2h*9$%} found 2h»9%» The analysis of the sulfur-containing product of the mercaptolysis reaction showed a sulfur content of 3 2 .2 and 32 •0$% on two separate runs. From these results a tentative structure corresponding to structure 2 in Table 5 was assigned. It was also believed at this time that the thioethyl group not C-l was on C-2 in agreement with the results of Lemieux

Acetylation of the Mercaptolysis Product

The crystalline mercaptolysis product was acetylated in a pyridine- acetic anhydride solution which upon working-up yielded a colorless sirup which did not crystallize. The sirup was chromatographed on Magnesol-

Celite (12U) and distilled by molecular distillation. The distillate

(12U) Products of Johns-Uansville Company. showed a single strong carbonyl absorption at 5.7 microns and no h 2

absorption for a free hydroxyl group in the infrared. This distillate

was not crystalline• Contnercial analysis gave C, 1 * 9 .H, 7,27%$

S, 27 Semi-micro combustion with sodium peroxide yield sulfur

analyses of 25.05 and 25 .3$. The calculated composition based on a

tri-O -acetyl trithiopentose II, C^H^qS^O^ yielded! C, 5U *2%', H, 7

S , 2$,h%*

C (SB t)2 I ^ HC I (Q lc), HC I HC I -SE t HgC n

Deoxysugar Synthesis From U

The acetyl compound II was converted to the sirupy dimethyl acetal

with mercuric chloride and cadmium carbonate in methanol (125). This

(125) M. L. Wolfrcm, L. J. Tanghe, R. W. George and S. W* Waisbrot, J. Am. Chem. Soc., £0, 132 (1938).

compound was in turn subjected to reductive desulfurization (1*5,1*6) to yield an acetylated deoxy diraethy acetal. The compound was deacetylated

to the sirupy dimethyl acetal which was converted to the free, reducing

sugar by treatment with acid. The free sugar (10 mg.) was reducing but

did not give the expected Dische test (126) for 2-deoxysugars• U3

(126) Z. Dische, Mikrochemie, 8_, U (1930)j R. E. Deriaz, id. Stacey, E . 0 . Teece and L* F . W iggins, J . Cheia* Soc *, 1222 (19U 9).

Treatment of the free sugar with sodium hypoiodite solution (the iodoform test) gave inconclusive results• However treatment of L-rhamnose

(U l) under the same conditions also gave inconclusive results*

CH*

H.OH

m

Proof of Structure of Mercaptolysis Product of Tetra- Q-ac e tyl-

The evidence of the structure of this compound is based on the sulfur analysis of the compound and the following degradative data*

The sulfur analysis of the crystalline product is correct for a pentose chain containing three thioethyl moities* Treatment of the compound with Raney nickel in refluxing ethanol successfully desulfurized the compound yielding a colorless sirup* The sirup gives a positive 0- iodoform test indicating the presence of a group in the molecule*

It should be mentioned in connection with the reductive desulfuriza- tion of this compound that the results are very sensitive to the condition of the Raney nickel. If there is any trace of base remaining in the nickel, the desulfurization of compounds containing the amount of sulfhr (30£) in the above product, is unsatisfactory* The nickel must lib be washed 2-ii days at room temperature with distilled water or extracted in a soxhlet apparatus, with water, for 1-3 days to obtain satisfactory results* Any loss of activity, by loss of adsorbed hydrogen, is regained when the nickel is heated with ethanol during the desulfurization•

During the heating with ethanol, acetaldehyde is evolved and the nickel is as active or more active after the desulfurizatlon than before* The activity is determined by the ease with which it ignites on drying. It is suggested that treatment of Raney nickel with boiling ethanol for

12-36 hours is a convenient means of increasing or restoring catalytic a c t i v i t y .

When the desulfurized sirup is treated with sodium metaperiodate solution and the volatile products passed through &n aqueous solution of

5,5-dimethyl-1,3-cyclohexanedione, "dimedon,” a precipitate was formed, which in its in itial state proved to be a dimorph of the dimedon derivative of acetaldehyde* Proof of this was afforded both by recrystallization to the "normal" dimorph and conversion to the dimedon

"anhydride" identical to that prepared from authentic acetaldehyde dimedon ( 1 2 7 ).

(127) E. C. Homing and M. G. Homing, J. Org. Chem., 11, 95 (19U 6)•

These results not only confirm the results of the iodoform test, but

Indicate the presence of the CH^CHOHCHOH- structure in the molecule because of the fact that periodate ion attacks vicinal hydroxyls preferentially (128). IS

(126) J. M* Bobbitt, Advances in Carbohydrate Chem., II, 1 (19*>6)*

These results also indicate that the desulfurized product is not a tetrahydrofuran or tetrahydropyran derivative which it would be if the trithioethyl compound were a thioglycoside•

Assuming then that the original trithioethyl compound is a diethyl dithioacetal, four structures may be drawn for the desulfurized alditol with a methyl group at the end of the chain in place of the diethyl dithioacetal group and a hydrogen in place of the third thioethyl moiety, on the chain*

CH, CH, CH, OH, 1 3 1 3 1 J HCOH HCOH HCOH 1 1 1 HOCH HOCH CHo HOCH 1 1 1 I HOCH CHo HOCH HOCH 1 1 1 I CHj CHgOH c h 2 < CHjOH

IVV VI VII

Structure VII is eliminated by the iodoform test and because it cannot form acetaldehyde on treatment vdth periodate. The acetaldehyde formation on periodate oxidation also eliminates structure VI*

Structures IV and V satisfy both requirements and the structure must be confirmed by other methods.

Perhaps the most convenient method for distinguishing between structures IV and V is by quantitative periodate oxidation (Equation-3)•

These data were collected and are presented in Table 7* HCOH I HOCH 2 N a lO lt r 2 CH3 CHO ♦ HCOzH I HOCH I CHj

1 7 Bq. 3

P HCOH I HOCH W a I 0 U > CH3 CHO + CHgOHCHgCHO I P CHgOH

T able 7

C alcd .* f o r Found*, E xps, No*

P ro d u c ts 17 7 1 2 3 Acetaldehyde 2 1 2b - -

Formic Acid 1 0 - 0,9 0 .8

3-Hydroxypropanal 0 1 0 .0 0.0 0*0

Formaldehyde 0 0 tr a c e - -

Periodate Consumption 2 1 2b 1 .8 1 .7

Expressed in moles per mole of aldltol oxidized* Alditol not isolated, results based on equimolar periodate uptake and acetaldehyde production* 1*7

Additional confirmation of the structure was provided by chromic acid oxidation of the alditol, a reaction in which the C-methyl groups are converted to acetic acid and the liberated acetic acid determined titrim etrically after distillation. The alditol yielded 1.9 moles of acetic acid per mole of alditol.

On the basis of these data the original trithioethyl compound was assigned the structure of 5-S-ethyl-5-thio-L-arabinose diethyl dithioacetal (VTIl).

HC(SEt)2

HCOH I HOCH I HOCH I CHgSEt

VIII An Explanation For the Synthesis of 5-£-Ethyl-5-thio-L"arabinoBe Diethyl Dithioacetal by Mercaptolysis of Tetra-Q~acetyl-q-L-arablnopyranoae

There is considerable theoretical interest in a reaction of this type• There are numerous examples of acyloxy replacement by thioalkyl anions (129) both by simple Sjj2 displacement and reactions involving the

(129) E. S. Gould, "Mechanism and Structure in Organic Chemistry," Henry Holt and Co*, New York, N. Y., 1959, p* 259 ff* participation of a neighboring group. Replacement reactions under acidic

conditions, however, are most easily regarded as involving a carbonium ion

or other positively charged species*

The conditions for the formation of 5-S-ethyl-5-thio-L-arabinose

diethyl dithioacetal are definitely of an acidic nature* Tetra-O-ecetyl- a-L-arabinopyranose is reacted with ethanethiol in the presence of zinc

chloride and "D rieriteZ in c chloride is a Lewis Acid of intermediate to low activity in alkylation and acetylation reactions ( 130) and i s

(130) N* 0. Callaway, Cbem. Rev*, 17, 327 (1935)$ 0* C. Denser and R* A* Bilim eier, J* Am* Chem. Soc*, 6k, Coi (I9li2)$ K* Bodendorf and H* Bohme, Am., 516# 1 (1935). “

known to have an effect in reactions involving the loss of a hydroxyl

group, as its use in the Lucas test for distinguishing primary and

secondary alcohols (331)*

(131) H. J. Lucas, J. Am. Chon* Soc*, 52, 802 (1930) It has been convincingly demonstrated by Lemieux (U*>) that the first step in the reaction of pen ta-O-a cetyl-£-D-glucopyranoBe (H ) with ethanethiol in the presence of zinc chloride is the formation of the

1-thio-p-D-glucopyranoside (X). This same author found that the a-D- glucopyranose pentaacetate reacted only slowly under the same reaction conditions* It was suggested that a necessary factor to a successful reaction was the trans relationship of the acyloxy groups on C-l and C-2.

This is conveniently explained in terms of a neighboring group effect in which the acyloxy group on C-2 participates in the loss of the acyloxy moiety on C-l. An added effect is the maintenance of the stereochemistry on C-l (Scheme l) .

CH2OAc )—~Q OAc

OAc IX

CHgOAc

SE t Et SH Ac( OAc X SCHEME I 50

Extending the reaction time, in the presence of a drying agent, enabled Lemieux to Isolate, after de&cetylation, the 2-S-ethy1-2-thio-D- glucose(mannose) diethyl dithioacetal of Brigl and coworkers (h2) in an unstated yield# The yield of the 1-thio-f-D-glucopyranoside was severely cu rtailed #

As the configuration at C-l and C-2 in tetra-O-acetyl-a-L-arabino- pyranose (I) is the same as that in penta-O—acetyl-P-D-glucopyranose (U ), one is justified in assuming that the arabinose acetate w ill yield initially the 1-thio-a-L-arabinopyranoside with ethanethiol and zinc chloride* From this in itial assumption, two general paths may be postulated to account for the thioacetal group on C-l and the thioethyl group on C-£.

Scheme 2 presents a mechanism by which a derivative of Ir^arabinose diethyl dithioacetal would be an intermediate and the thioethyl group on C-f? would appear by replacement of a free hydroxyl group. This route is supported by the work of Brigl et al (h2) and by that of Wolfrom and von Bebenberg (h6,li7) who synthesized 2-S—ethyl-2—thio derivatives of glucose and xylose respectively through a single free hydroxyl on C-2.

An alternative route (Scheme 3) suggests that the thioethyl moiety is introduced on C-5 at the same time that the pyranose ring opens# This general mechanism is supported by the observation that the intermediate,

L-arabinose diethyl dithioacetal, required by scheme 2, has never been isolated as a reaction product, although an effort has been made to isolate it.

The facility with which ortho esters and ortho ester interaediates 51

Ac Ac ZwClt AcQ 0 Ac Et SH Ac Ac Ac

HC(SE t>* Z mCI, A :oac Et SH AeOCH Ac1 Ac AcOCH OAc iHjOH

HCtSEr^ HC(SE t). I HCOAc HCOAc I E t SH I AcOCH AcOCH I I .O-CH AcOCH CH I CHj SE t Z nCI,

S cheme 2 52

Ac OAc Zn CI, EtSH OAc

OAc Ac

PH HCSEt I EtS J.nC\z HCOAo EtSH AcO

Zn CI, Et SH If HC(SEt),

H^OA c I AcOCH I AeOCH I CH,SE t

S cheme 3 form in the carbohydrates (132) undoubtedly is a major factor in the

(132) E. Pacsu, Advances in Carbohydrate Chem., 1, 78 (19U5) • replacement of the hydroxyl group frith ethanethiol under these conditions •

Indeed, with the possible exception of the work of Wolfrom and

Thompson (U3)> all the examples of this type of reaction satisfy the

requirements for orthoester formation. The results of Lemieux (U5)> in which the thioethyl moiety appears on C-2, may be considered as the results of acyl migration under acidic conditions ( 1 3 3 ) tow ards th e

(133) J. M. Sugihara, Advances in Carbohydrate Chem., 8 , $ (195!3)* terminal carbon ultim ately leaving a free hydroxyl on C-2,

An additional piece of evidence concerning the necessity of the

free hydroxyl group, and the orthoester intermediate, was provided by the observation that 2,3,h,5>-tetra-0-acetyl-L-arabinose diethyl dithioacetal when reacted under the identical conditions in which

1,2,3,U-tetra-0-acetyl-a-L—arabinose produced the 5-S-ethyl-5-thio-L- arabinose diethyl dithioacetal, the starting material was recovered unchanged.

The generality of the use of Lewis acid catalysts was also demonstrated by carrying out the reaction of the tetra-O-acetyl-a-L- arabinopyranose in the presence of anhydrous ferric chloride (sublimed) and also with boron trifluoride-etherate• The ferric chloride catalyst yielded a reaction mixture darker than that of zinc chloride and presented no advantages. Boron trifluoride-etherate used once, did increase the yield of the desired product by about £>056 over that obtained by the use of zinc chloride*

Synthesis of 1, 2-Q-l3opropyli dene-5 3 6-di-Q-p-tolylaulfonyl- g-D-glucose (XI)

The selective g-toluenesulfonylation of 1,2-O-isopropylidene-a-D- glucofuranose was performed by Ohle and Dickhauser (13U) with

(13U) H. Ohle and E. Dickhfiuser, Ber., 56, 2593 (1925).

£-toluenesulfonyl chloride in a mixed solvent of pyridine and chloroform with a reported yield of less than 10^. It has been suggested by

Tipson (135) that sulfonylation reactions suffer from considerable side

(135) R* S. Tipson, Advances in Carbohydrate Chem., 8_, 117 (1953). product formation due to the ionic character of the reaction, the

formation of pyridine hydrochloride, and the ease with which sulfonate

esters may be replaced. Tipson recommends the use of solvents such as ether or benzene to suppress side reaction.

Both ether and benzene were tried as cosolvents with pyridine for the g-toluenesulfonylation of 1,2-O-isopropylidene-a-D-glucofuranose•

These experiments were not successful as the in itially formed mono-g- toluenesulfonate ester was not soluble in these solvent mixtures.

Tetrahydrofuran was tried under the same conditions and it was

observed that the reaction took on less color and the pyridine hydro­

chloride precipitated from solution. The yield of 1,2-0-isopropylidene- 55

5,6-di-^-g-tolylsulfonyl-a-D-glucose was increased to 263. There is little doubt that the yield might be further increased by the proper selection of solvents and reaction conditions•

The Preparation of 1a2-Q-IsopropyHde ne-3.5 ,6-t ri-Q -p-t olylsulfonyl- q-D-glucose (XII)

This compound was prepared essentially by the method of Ohle and

Wilcke (136) and as this is a complete £-toluenesulfonylation of a ll the

(136) H. Ohle and H. Wilcke, Ber., 71, 2316 (1938). free hydroxyl groups of 1,2-O-isopropylidene-q-D-glucofuranose, the reaction was carried out in the presence of a large excess of p-toluenesulfonyl chloride which appreciably shortened the reaction time and consequently improved the yield to about 503 based on purified m a te r ia l•

r HC-0

I HOCH TsOCH

HCO HCO

HCOTs HCOTs t CHgOTs CHgOTs

11 in

Ts • £-toIylsulfonyl 56

Synthesis of Vinyl Substituted Sugars

The reaction of sodium iodide with vicinal di-O-g-toluenesulfonates

(20-22) was used to prepare the terminally unsaturated carbohydrates used in this research* The mechanism of this reaction has been investigated by Foster and Overend (137) and is believed to proceed in

(137) A. B. Foster and ff. G. Overend, J. Chem. Soc., 3^52 (1951). two steps. The first (Equation U) involving a simple Sjj2 displacement

R - CH - CH2 OTs + I " w - R - CH - CHgl + "OTs Eq. U OTs OTs

Ts ■ g-toluenesulfonyl by iodide ion of the terminal g-toluenesulfonate group, followed by the abstraction of this terminal iodo group by iodide ion and the loss of the second g-toluenesulfonate in a concerted process (Equation 5)* The

R - CH RCH - CHg ♦ I 2 + *OTs Eq. 5 ^CJTs reaction is slow, even at 100°, only 1*5-60^ complete after 5 hr* ( 137 )*

The Synthesis of 1,2-Q-Isopropylidene-^-vlnyl-q-D-xvlo-tetrofuranose (XIII)

The treatment of 1, 2-O-is op ropy li dene-5*6-di^-g-tolylsulfonyl-^i-

D-glucose with sodium iodide in acetone, at reflux tanperature for 2l*- i*8 hr., resulted in the formation of a dark reddish-brown solution containing suspended sodium g-toluenesulfate• On the basis of the liberated sodium g-toluenesulfonate the reaction was quantitative* The free iodine was removed by reduction with sodium thiosulfate

solution, after removal of the acetone and resolution in chloroform. The

aqueous layer must be exhaustively extracted with chloroform as the

1,2-^isopropylidene-h-vinyl-a-D-xylo-tetrofuranose (XIII) is appreciably

soluble in water.

The first attempt at the synthesis resulted in a light-yellow,

viscous sirup which crystallized spontaneously on distillation. Previous

syntheses of this compound gave only sirups (23 >25). Thereafter the material crystallized on removal of the solvent. The unsaturated

compound is best purified by vacuum sublimation as the impure m aterial

seems to be accompanied by a sirupy impurity with similar solubility

characteristics as the desired compound. A uniform yield of 60-65!? is

obtained of the sublimed product.

I------HC-0 I >(C H 3 )2 HC-0 J 1 HOCH I HCO------I HC II

XIII

The use of higher boiling solvents, as 2-butanone, with their lower reaction times offer no advantages as the elevated temperatures required

for solvent removal result in the loss of some product due to its appreciable vapor pressure. In two runs with 2-butanone as a solvent, at reflux, a satisfactory yield of sodium g-toluenesulfonate was obtained, but the yield of final product was decreased by about 20% •

The Synthesis of l,2-Q-Isopropylldene-3-0-p-tolylsulfonyl-k-vinyl-g-D- x v io -tetro fu ran o se (XIV)

This compound has been previously prepared as a sirup (25) and it has been experienced in this work that the reaction of 1,2-O-isopropylidene- 3,5,6-tri-O-^j-tolylsulfonyl-a-D-glucose (XII) with sodium iodide in acetone is very slow and XIV was obtained crystalline only after extended reaction times, at least h8 hours* The g-toluenesulfonate group on C-3 is not attacked by iodide partly for steric reasons (138) and possibly

(138) Ref. 22, p. 197 also because the five-membered furanose ring is unable to become planar, as would be required in an Sjj2 transition state, due to the fi ve -*nemb e re d ring fused on C-l and C-2 from the O-isopropylidene moiety. The g-toluenesulfonyl group on C-3 also facilitates the work-up of this vinyl compound, compared to the previous vinyl compound XIII, as the compound is not volatile and is not soluble in water. The 1,2-0- i s opropyli dene-3 -O-p-t olylaulf onyl-li.-vinyl-a-IVvlnyl-q-'D-xylo - tetrofuranose (XIV) crystallized as a colorless compound from the light yellow sirup produced in the reaction. I TsOC HOCH HCO CO HC I! CHg XI7

The Synthesis of 5,6-Dideoxy-l,2-Q-t8opropyIidene-a-D- x v lo -h ex o se (XV)

The structure of the synthesized 1 ,2 -fr-i sop ropy lidene-ii-viny 1 -a-D - xylo-tetrofuranose (XIII) was proved by catalytic hydrogenation to the known (20,2f>) crystalline 5,6-dlde oxy -1, 2-O-iaopropy I t dene-a -B-xylo ~ hexose (XV),

The Synthesis of £-Deoxy-l*2-fl-isopropylidene-q-D-3[yly-hexose (XVI) This synthesis was effected essentially by the general procedure of Brown and Subba Rao (27*31*32)* 1,2 -O-Is op ropy li dene -U -vinyl-g-TVxyl o - tetrofuranose (Xin) with sodium borohydride in bis(2-methoxyethyl)ether as solvent was treated with aluminum borohydride dissolved in the same solvent. From this reaction is obtained a trialkylborane. The solvent was removed and the reaction mixture was dissolved in ethanol and oxidized with 30£ hydrogen peroxide in the presence of sodium hydroxide* The result is oxidation of the borane to a borate ester and saponification to the fre e hydroxyl compound*

The in itial reaction* in this case, is complicated by the free hydroxyl on C-3 on the starting material (XIII). The reagent, in this case* reacts with the hydroayl group, liberating hydrogen, and forming a 60

borate ester with consequent destruction of the reagent. For this

reason an excess of reagent is required*

The bis(2-methoxyethyl)ether solvent is removed by distillation

at room temperature and reduced pressure* The complex borane-borate

product is not volatile and is not characterized beyond the removal of

the solvent*

The oxidation is performed as described in the literature (27,31,

32), but the work-up is modified* The base is neutralized with an acidic

ion exchange resin and the solvent is removed under reduced pressure.

The sirupy product is dissolved in a\ery small anount of ether and low

boiling (30-60°) petroleum ether added to incipient cloudiness. The

5-deoxy-1,2 -O -i sopr opy lidene-a-D-glueose (XVI) crystallized spontaneously.

Often a sirupy non-crystallizable impurity accompanies the XVI and is

not removed by recrystallization in organic solvents* This impurity is

readily removed by dissolving XVI in water and treating with deodorizing

carbon; the water is removed under reduced pressure following filtration*

The synthetic sequence frcm XI through the hydrolysis to the free

sugar is presented in Scheme U*

This is the first recorded synthesis of a 5-deoxyhexose. Such a

sugar cannot, in the free state, exist in the pyranose configuration,

which is the normal configuration for the hexoses* The free sugar must be either in the furanose or five-membered ring, a seven-membered ring

or in the aldehyde or open chain configuration. The physiological properties of this sugar may have significance in the cellular metabolism

of hexoses, particularly D-glucose. It is now under test of the

National Institutes of Health* a

CHzOTs CHZ II CH TsOCH,A. N al (CH3)2CO 0 18 hr. \ 1 / 1 I 0 —C(CH3)2 0 — C(CH3)2 xm

(1) NaBH4 -AICI3 (2) H202( OH0

HC=0 I HCOH C H ^ H I HOCH I 0 HCOH H*0 I GHz CH2OH C(CH3)

TVT

Scheme 4 61 a

The structure of the synthesized deoxyhexose -was proved in the fo il owing unequivocal manner.

The Preparation of g-Deoxy-D-threo-hexose Phenylosazone (XVII)

5-Peoxy-l,2-Q-isopropylidene-a-D-xylo-hexose (XVI) was hydrolyzed in 0.1 M hydrochloric acid on a steam bath. The acid was neutralized w ith 0 .1 U sodium hydroxide solution and phenylhydrazine acetate ( 139)

(139) L. F. Fieser, "Rjqperiiaents in Organic Chemistry", D. C. Heath and Co., Boston, Mass., 1955, p»83» solution added. The phenylosazone which was formed on heating, crystallized on cooling. The recrystallized osazone was compared with an authentic sample of 5 -d eoxy-B-threo-hexose phenylosazone prepared from the naturally occurring $-deoxy-D-threo-hexose, "5-deoxy-L-scrbose (lhO)n.

(1U0) A sample of this sugar was sent us by Dr. P. P. Regna, Chas. Pfizer and Co., Inc., Mew York, N. Y.

The physical constants were identical with those recorded by

Regna (1U1).

(U il) P . P . Regna, J . Am. Chem. S o c ., 69, 2i*6 (191*7) •

The Preparation of 5-Deoxy-D-threo-hexose Phenylosotriazole (XVIII)

The phenylosazone, XVII, was oxidized with copper sulfate according to the directions of Hudson and coworkers (11*2) to the osotriazole described by Regna (U*l) . 62

(1I|2) W. T. H a sk in s, R . M. Hamnond and C# S . Hudson, I b i d . , 67, 939 (1 9 W ).

The Periodate Oxidation of 5-Deoxy-D-^|irpo-.hBxosa Phenylo8otriazole (X7III)

The osotriazole, XVIII, Dias treated with one mole of sodium

periodate by the manner of Regna (llil). The insoluble li-formyl-2-

phenyltriazole (XIX) (11*2) was removed and the filtrate "mas treated with

an aqueous solution of 5,5-dimethyl-1,3-cyclohexanedione, "dimedon."

The precipitated dimedon adduct of 3-hydroxypropanal (XX) was collected

and identified by comparison with an authentic sample of the derivative*

The sequence which proved the structure of the sugar is presented

in scheme 5* This degradation procedure proves the configuration at C-5

and C-6 and as no other carbons are involved in the synthesis the total

absolute configuration of the sugar is known.

The Hydrolyses and Optical Properties of the Synthesized 1.2 -Q-Iso pr opyli dene -ct-D-xvlo-hexo s e s

5-Deoxy-1, 2-0-i sopropyli dene-q-D-xylo-hexos e (XVT) was hydrolyzed

to the free sugar in hot O.l N hydrochloric acid, the acid removed with

a basic ion exchange resin and the water removed. The resulting sirup

was azeotropically dried with absolute ethanol to a hygroscopic glass

which turned brown on standing.

A rotation, [d]^ ♦ 2li, was obtained on the glass, a value which might be doubted because of the difficulty in purifying a non-crystalline,

non-volatile substance and because of the difficulty in weighing a

hygroscopic m aterial. 63

NH0 I HC = 0 N, I HC H HCOH I I 0 NHNHg HOCH C N, I HOAc I N 0 HCOH HOCH I I CH2 HCOH I I CH2OH CH2 I CH2OH xsn

C u ®

- N H tf \ HC \ | N - 0 | N - 0 Ci / 0 / / N IO4 IN CHO HOCH Tmc I + HCOH CHO I CH9 I c h 2o h c h 2oh XX

S cheme 5 6ii

The acid hydrolysis of XVI at room temperature in 2.5 N hydrochloric acid was followed polarimetrically and the rotation of the free sugar calculated front the final value. An [a]jj of *2h° was again found*

The validity of a rotation thus obtained was demonstrated by the hydrolysis of 1,2-0-isopropylideneHi-D-glucofuranose under identical conditions to a final value of [ a +53° • This is the same equilibrium value obtained with glucose in aqueous solution.

The rotation values obtained by following the acid hydrolysis polarim etrically (Figure l) for 1,2-O-isopropylidene-a-D-glucofuranose,

5-deoxy-lj2-0-isopropylidene-q-D-xylo-hexose (XVI), 5,6-dideoxy-l,2-0- isopropylidene-q-D-xylo-hexose (XV) and 1,2-0-isopropylidene-li-vinyl- a-D-xylo-tetrofuranose (XUI) are presented in Table 8.

The Optical Properties of the Synthesized Non-pyranose Sugars

The calculated rotations of g-deoxy-5-xylo-hexose, 5|6-dideoxy-D- xylo-hexose and It-vinyl-D-xylo-tetrose, as iw ll as their molecular rotations, are presented in table 8* One sugar from table li is included for comparison.

The data suggest that a configurational sim ilarity exists between

5 j 6-dideoxy-D-xylo-hexose. it-vinyl-D-xylo-tetrose and 5-deaxy-D-xylose .

The difference between the molecular rotation of these sugars and that of

5-deoxy-D-aylo-hexose is probably due to the contribution of the septanose or seven-mestoered ring configuration (XXX) along with the furanose configuration (XXII) or the aldehyde form (XXIII) or both* The difference is probably not caused by more aldehyde fona (XXIH) or Figure 1 Acid Hydrolyses of 1,2-0-1 sopropylidene-D-xylo-hexoses in 2.5 N hydrochloric acid* 0.22 M in sugar.

65 66

/ A 1*2 -O—I sopropyli dene-a -D-glu co furano s e O 5-D eo x y -l , 2 -Q—i sopro py ll dene - a -P-xylo-hexo 3 e £ □ 5 16-Dideoxy-l, 2-O -i s opropyli dene-a-D-xylo-hexose ^ X 1,2-C-I sopropyli dene-L-vi nyl-a-B-xylo- 4- tetro furanose

t — 1— 1------1— r~ "1 1 1 1 1 10 SO to 40 90 90 90 100 IIO ItO TIME (MINUTES) 67 Table 8

Optical Data on Some Synthesized Non-pyranoae Sugars

Sugar [afoCHgO) CMfcCHgO)

5-deoxy-D-xylo-hexose ♦21* 3900

5,6-dideoxy-D-xylo-hexose +8 1200

J*-vinyl-D-xylo-tetrose +11 1600

5-deoxy-D-xylose* ♦13 17 U0

Included from table 1*

furanose sugar than In the other sugars as there is no reason why these forma should be more stable in 5-deoxy-TVxylo-hexose than in the others.

These data also suggest that the unsaturated sugar, 1*-vinyl-D-xylo- tetrose, does not undergo appreciable allylie rearrangement during the time of hydrolysis (21* hr*). Such an ally lie rearrangement would cause the loss of asymmetry on C-3 and -would be expected to have considerable effect on the optical properties.

1------1------CH0H CHOH CHO 1 1 1 HC0H HCOH HCOH 1 1 i H0CH HOCH HOCH 1 1 1 HCOR HCO------HCOH 1 1 1 CHp 1 T 2 f 2 CH2 O- 1 CHgOH CHgOH

XXI x x n XXIII 68

Optical Rotatory Dispersion of 1,2-Q-Is opropylidene-lt-vlnyl-tt-IHcyla.- tetrofuranose (Xin) and !,2-{)rIsopropylidene-3-{HBrtolyl8ulfonyl-4i- ▼inyl-g-D-xvlO"tetrofUranose (XIV)

Additional physical data were collected on those compounds, which, due to their possessing a chromophore (vinyl group) on an asymmetric carbon, could be expected to have interesting rotatory dispersion curves.

This was found to be true as both of the ii-vinyl compounds exhibited a

Cotton effect (lij3)»

(lii3) C. Djerassi, "Optical Rotatory Dispersion," McGraw-Hill Book Company, Inc., flew York, N. Y., p. 13 (I960).

The curve of 1,2-O-isopropylidene-li.-vinyl-

(Figure 2) was recorded in three solvents* chloroform, methanol and water. There was a definite shift to shorter wave lengths as the solvent polarity increased (lltli), and as the molarity was the same in all cases,

(UUJU) ref. 125a, p. 29 note the rotation increase with solvent polarity was very marked.

The curve of 1,2-O-isopropylidene-3-0-p--tolylsulfonyl-U-vinyl- a-D-xylo-tetrofuranos e in chloroform (Figure 3 ) was of the same general

shape and amplitude as that of the previous vinyl compound in the same

solvent. There was however a shift to a longer wave length (250 mp-*-283 mp)

in the 3“0-£-tolylsulfonyl derivative.

The distinct shape of the curves suggests that such data might be used in structural determination in compounds of this series, as it has been quite extensively used in other compounds (lh5)« Figure 2

Optical rotatory dispersion curves of 1, 2-O-i sopropy lidene- li-vinyl-^i-D-xylo-tetrofuranose in different solvents*

F igure 3

Optical rotatory dispersion curve of 1,2-O-isopropylidene 3-Q-^-tolylsulfonyl-It-vinyl-q-D-xylo-tetrofuranose in chloroform.

69 70

MeOH CHCIi

so o 400 800 800 TOO UfX

888 too 800 400 800 800 700 71

(11*5) re f* 125a, pages 1*1-275.

It is interesting to note that the rotation at the D line (569 mp)

does not exhibit the solvent effects in the same order as previously men­

tioned* For XIII the for the various solvents are -61.6°, -1*8*2°, and -67*3° in eater, methanol, and chloroform respectively. For XIV the

is -51*5° for chloroform.

It eas observed that the dispersion curves of XIII in chloroform and eater and that of XIV in chloroform obeyed the simple Drude equation a • where a is the observed rotation at A,, k is a constant, X, , is

the wave length at which the rotation is observed and is the wave

length at the maximum of the absorbing band* Figure 1* illustrates the

linear relationship of i plotted against \*, the test for the simple a Drude equation. The XIII in methanol seems to obey a complex Drude

equation and is not show* •

It is possible to calculate the X0 from these data* Values of 207,

211* and 226 mp have been calculated for X III in water, in chloroform and

XIV in chloroform respectively. The observed value for X^for X III in water is 202 mp (Figure 5)* F ig u re U

Plot of single term Drude equation from obtained rotatory dispersion curves •

F ig u re 5

U ltraviolet absorption spectra of 1,2-0-isopropylidene- U-vinyl-g-D-xylo-tetrofuranose in water.

72 73 4'

I SIT IN Ht0 C X V IN CHCI, 9 XU IN CHCI,

T TTT T T T T ~ T T" 14 f 7 50 55 34 X * X 1 0 '

£02

€

£10 310 EXPERIMENTAL

Synthesis and Proof of Structure of 5-S.-Ethyl.-5-thio-L- arabinose Diethyl Dithioacetal

Synthesis of 5-&-Ethyl-g-thio-L-arablnose Diethyl Dithioacetal

A* Zinc chloride catalyst

To a solution of 85 g. of tetra-O-acetyl-a-L-arabinopyranose in

$00 ml. of ethanethiol was added 50 g. of freshly fused and pulverized zinc chloride and 85 g« of D rierite (Wi) (10-20 mesh)* A magnetic stirring bar was placed in the flask and the flask sealed after the in itial exothermic mixing of the ethanethiol and zinc chloride. The mixture was stirred for two days at room temperature. At the end of this time the suspension was poured, with stirring, into approximately

1 lite r of saturated aqueous sodium bicarbonate solution. When the evolution of carbon dioxide ceased, 500 ml. of chloroform was carefully stirred into the heavy, pasty zinc carbonate precipitate. The mixture was filtered with reduced pressure and the zinc carbonate washed by suspending in chloroform and refiltering. The chloroform layer was removed, dried over sodium sulfate and evaporated on a steam bath, in an efficient hood, to a clear, colorless mobile sirup (112 g.).

An amount of 100 g. of the sirup was dissolved in methanol, dried over magnesium sulfate, filtered and deacetylated by the addition of 3 g. of sodium methoxide. The solution was raised to the boiling point and an additional 2 g. of sodium methoxide added. After one hour the solution was neutralized with IR-120 (11*6) and the methanol removed under reduced 75

(21x6) A product of Rohm and Haas Co., Philadelphia, Pa. p r e s s u r e . The sirupy residue was dissolved in Skellysolve C (UU7) and

(11x7) A product of Skelly Oil Co., Kansas City, Mo. petroleum-ether (b.p. 30-60°) added to incipient cloudiness.

C rystallization was spontaneous and additional petroleum-ether was added to complete the crystallization. The crystals were rmoved by filtration under reduced pressure and washed with petroleum-ether

(yield 20 g.). The crystals were successfully "deodorized" by recrystallization from Skellysolve B (1U7) and treatment with decolorizing carbon. A sample was sublimed at 50 microns pressure and 70° bath temperaturej m.p. 65-67°, -16.1 (C 3.li, pyridine), x-ray powder diffraction data ( 3JU8)t U*lU s (3), 10.57 s (1), 7.6U vw, 6.97 vw, 5*39 vw,

U.85 m, 1x63 li.l$ s (2), 3*75 w, 3.21 (w), 2.32 (w ).

(1U8) Interplanar spacing, CuKg radiation. Relative intensity, estimated visually) s, strong) m, medium) w, weak) v, very. First three strongest lines are numbered (1, strongest)) double numbers indicate approximately equal intensities.

Considerable difficulty was experienced by comnercial laboratories in analyzing this compound. There were variations in the carbon-hydro gens as well as the sulfur analysis. These results are given in Table 6. The results shown are those obtained in these laboratories by semi-micro peroxide combustion. 76

Anal. Calcd. for S, 32.1

Founds S, 32.2, 32.05 (semi-micro combustion).

The illtrate from the crystals was evaporated under reduced pressure, to a clear sirup with considerable odor. The sirup could not be induced to crystallize nor could the odor be removed with decolorizing carbon.

B. Boron Trifluoride Catalyst

To a suspension of 20 g. of tetra-<>-acetyl-a-L-arabinopyranose and

20 g. of D rierite (Uli) in 100 ml. of ethanethiol was added 25 g* of freshly distilled boron trifluoride-etherate, in small portions. When the in itial exothermic reaction had subsided, the flask was sealed and the reaction mixture stirred, with a magnetic stirring bar, for four days. At the end of this time the flask was opened and the mixture was slowly poured into a saturated sodium bicarbonate solution. Chloroform,

100 m l., was added to the aqueous mixture and the mixture heated on a steam bath until the chloroform boiled away. An additional 200 ml. of chloroform was added to the cooled solution and the zinc carbonate was removed by filtration under reduced pressure* The chloroform layer was removed, dried over sodium sulfate and evaporated on a steam bath to a clear sirup. The sirup was deacetylated and the product was isolated as in the previous experiment. A total yield of 7*3 g* was received. The product was in every way identical to that in the proceeding experiment*

Semi-micro Peroxide Combustion Analysis of 5-S-Ethyl-5-thio-L- arabinose Diethyl Dithioacetal (71II)

The sulfur content of VIII was determined by combustion with sodium peroxide in a sesdnmicro Parr Bomb (123). The procedure was that of 77

Lincoln, Carney and Wagner (11*9) as presented in the manual accompanying

(lii9) R. M. Lincoln, A. S. Carney and W. C. Wagner, Ind. Bng. Chem., Anal. Ed., 1^, 3^8 (19Ul).

the apparatus (l£0).

(l£0) "Peroxide Bomb, Apparatus and Methods," Parr Instrument Company, Moline, 111., Manual No. 121, p. 3U.

In the bottom of the semi-micro bomb container (D, Figure 6) was

placed 200 mg. of finely ground (to pass a 100 mesh sieve) potassium perchlorate* On this was placed £8.9 mg. of V III. Powdered sucrose

(to pass 100 mesh sieve) (aporox* l£0 ug.) to give a total of about

200 mg. of combustible m aterial. Sodium peroxide was added with a

special dipper of U g. capacity. The bomb was assembled and shaken to

mix the ingredients thoroughly. The bomb was suspended by the ring on

the container cover (A, Figure 6) of the bomb and water placed in the

depressed area between the screw cap (B, Figure 6) and the container

cover. The bomb was ignited for 30 min. by heating the bottom of the

container with the tip of a compressed air-gas flame. The water in the

top prevents the neoprene gasket (C, Figure 6) from over-heating. The bomb was cooled in running water and the container and-the container cover were placed in a 1*00 ml. beaker with just enough water to cover them.

The beaker was covered with a v/atch glass to prevent any of the contents

from spattering out.

When the sodium peroxide dissolved the container and cover were 78

F ig u re 6

A B C

D

removed and rinsed with distilled water; this rinse water was added to the water in which the peroxide had been dissolved. The solution was neutralized with conc. hydrochloric acid and about 0.5 ml. excess added.

The solution was filtered and the filte r paper carefully washed with distilled water. Saturated bromine water (3 ml.) was added to the filtrate to oxidize any sulfite present to sulfate and the solution was heated on a steam bath until the bromine had a ll evaporated. The solution was exactly neutralized, to methyl orange, with sodium hydroxide and

0.5 ml. of 1 N hydrochloric acid added. The solution was heated and

3-5 ml. of 10^ aqueous barium chloride solution added and this solution was heated overnight on a steam bath. The solution was cooled and filtered through a previously weighed porcelain crucible with a porous bottom for filtering. The barium sulfate was washed well with distilled water and dried at 110° to constant weight. The percent sulfur is represented by the equation ■* IBgi * IT .7^1*, where 13 •731* mg. sam ple represents the percent sulfur in BaSO^. The barium sulfate in this experiment was 137*6 mg. representing 32»0$% sulfur in VIII.

A second analysis with h5*6 mg. of VIII yield 106.7 mg. of barium sulfate indicating 32.2$ sulfur in VUE. 79

P re p a ra tio n o f 2 ,3 »U-Tri-Q-ac etyl-5-&-ethyl-L-arabinose Diethyl Dithioacetal (II)

To 100 ml. of pyridine was added 16 g. of VIII and the solution was cooled to U° in an ice bath. To the cooled solution wasadded 25 ml. of acetic anhydride and the flask was allowed to come to room temperature.

The acetylation mixture was maintained at this temperature for 2 days and then poured into an ice-water mixture which was stirred overnight to hydrolyze the excess acetic anhydride. The solution was extracted with chloroform and the chloroform layer washed several times with water.

The chloroform was dried over sodium sulfate, filtered and the solvent removed under reduced pressure to yield 21.7 g» a clear sirup.

A portion of the sirup was choiruatographed on Magnesol-Celite (12U)

(in a 5*1 proportion) with a benzene-tert-butyl alcohol (500*1) developer.

On a column IUi mm. x 230 mm., the acetate appeared as a band from 112 mm. to 173 mm., measuring from the top of the column when 7$0 ml. of the developer had passed through the column. This band was removed by sectioning and the material eluted with acetone. The acetone was filtered and removed under reduced pressure to yield a colorless sirup which would not crystallize.

This sirup was further purified by molecular distillation at 65-70° temperature and 2-5 microns pressure. It still did not crystallize.

Semi-micro Peroxide Combustion Analysis of 2,3,U-Tri-fl-acetyl-5-S.-ethyl- 5-thio-L-arabinose Diethyl Dithioacetal (n )

As the acetyl compound was not crystalline the technique for sodium peroxide combustion was modified. The sample was placed in a previously weighed gelatin capsule (size 0). The total weight was recorded. The capsules weigh about 80 mg. In a representative run a 59.U mg. sample of the triacetyl compound was placed in the capsule. The potassium perchlorate initiator (200 mg.) was placed in the bottom of the container and enough powder sucrose (60 mg.) to give a to tal of 200 mg. combustible material was placed on top of it. The capsule was then placed on top of this and the U g. portion of sodium peroxide poured over the top.

The container was sealed and ignited, as in the previous experiment, but without any mixing of the contents. The remainder of the analysis was carried out as before. There was obtained 113 .6 mg. barium sulfate. A blank run on the gelatin capsule alone yielded h*2 mg. o f barium sulfate which was introdiced as a correction factor. The total barium sulfate from the sample then was 109 mg. representing 25 *3^ sulfur in the sample. A similar run on 3^.5 mg. of sample yielded 62.9 mg. of barium sulfate indicating 25.05$ sulfur content. The calculated sulfur content is 25 •h%»

The Preparation of 2,3 ,h-Tri-Q-acetyl-5-^.-ethyl-5-thio L-arabinose Dimethyl Acetal (XXIV)

To a solution of 10 g. of 2,3,i;-tri-O-acetyl-5-S-ethyl-5-thio-L- arabinose diethyl dithioacetal in 100 ml. of absolute methanol was added

50 g. of cadmium carbonate. The suspension was stirred and a solution of 50 g. of mercuric chloride in 75 ml. of methanol was added. The mixture was stirred while refluxing for ij hr. The mixture was filtered with suction into a flask containing a small amount of fresh carbonate. The solvent was removed under reduced pressure and the residue e i dissolved in chloroform. The chloroform solution was filtered and residual mercuric chloride removed by -washing the chloroform layer -with

20% aqueous sodium iodide solution. The chloroform layer was washed with water, dried over sodium sulfate and the solvent removed under reduced pressure to yield a colorless sirup which did not crystallize. The sirup was distilled at 1$0- 160° bath temperature and 0 .1 mm. pressure} yield i* g. of sirupy XXIV.

Attempted Preparation of 5-Deoxy-L-arabinose

The dimethyl acetal XXIV, from the proceeding experiment was dissolved in ethanol and subjected to reductive desulfurization with 60-70 g . o f

Raney nickel. The mixture was heated with stirring for 12 hr. and the nickel removed by filtratio n . The solvent was removed under reduced pressure to yield a colorless sirup. Infrared examination of this sirup showed the presence of free hydroxyl indicating that partial deacetylation had taken place during the reductive desulfurization.

The m aterial was reacetylated with pyridine-acetic anhydride as described for the acetylation of VIII. The substance remained sirupy.

This compound (XXV) was deacetylated in hot methanol in the presence of sodium methoxide for 1 hr. The solution was neutralized with IR-120 (IL 16) and the solvent removed under reduced pressure to yield sirupy 5-d eo x y -

L-^arabinose d im eth y l a c e ta l (XXVI) • The d im ethyl a c e ta l XXVI, was h e a te d for 1 hr. on a steam bath in 0.1 N hydrochloric acid. The solution was cooled and treated with IR-U5 ( 1U6 ) to remove the acid. The aqueous solution was treated with carbon, filtered and the water removed under 82 reduced pressure. There remained about 10 mg. of a colorless sirup.

The sirup was reducing, gave a negative Blsche test for 2~deoxy sugars and on treatment with sodium hypoiodite the odor of iodoform could be

detected but no precipitate was evident. Since this substance was apparently not a 2-deoxy sugar, it was not further investigated.

The reaction sequence from 5-S-ethyl-?-thio-L-arabinose diethyl dithioacetal is shown in Scheme 6.

HC(SEt)o HCOH HCQAc 2 HO9H C^H^N AcOCH HOCH Aco 6h Ac20 H2CSEt I^C SE t VIII n

MeOH HgCl2 1 CdCO*

HC(OMe), H C (01fe)9 h )q A ACCAc £ AcOgH Mi Aco6h AcOgH Ac0<5h CHj Ac20 EtOH H gC SEt

XXV XXIV

NaOMe MeOH

HC(0Me)9 HgOH c HOgH HOgH CHj

XXVI

Scheme 6 The Reductive Desulfurization of 5-S-Ethyl-S-thlo-

L-arabinose Diethyl Dithioacetal

To a solution of 1.0 g. of 5-S-ethyl-5-thio-L-arabinose diethyl

dithioacetal in 75 ml. of absolute alcohol was added 15-20 g. of neutral

Raney nickel. The solution was heated under reflux, with stirring, for

IjB hr. At the end of this time the nickel was extracted with ethanol

in a soxhlet extraction apparatus. A very finely divided, light yellow

suspension was evident in the filtrate, possibly nickel subsulfide.

The ethanol was removed under reduced pressure to a clear sirup with the former suspended m aterial present with carbon and then with a mixture of IR -120 ( l h 6 ) acidic ion exchange and IR-1i5 (ll* 6 ) b a s ic

exchange resin. The water was removed under reduced pressure to a

colorless sirup which was dried under high vacuum conditions} yield

160 mg., [aj2^ +5.5 (c 1 , H20 ).

The sirup gave a negative test for sulfur using the sodium fusion

te c h n iq u e .

To a s o lu tio n o f O.O 78 mg. (0.65 mnole) of the preceeding sirup in

2 5 .0 ml. of water was added 25-0 ml. of 0.1060 M (2.650 mmoles) sodium meta periodate solution. After 10 minutes, a 5»0-ml. aliquot was removed and added to a solution of 25.0 ml. of 0.009i*3 M (0.236 mmole)

of sodium arsenite solution containing 1.0 ml. of 20% aqueous sodium iodide and 1.0 ml, of saturated aqueous sodium bicarbonate solution.

After 15 min., the excess sodium arsenite was back titrated with

0.01212 M iodine solution. A total of 6.75 ml. (0.082 nmole) of iodine

solution was required as determined by the starch-iodine complex end point. Subtraction shows that 0.15U mmoles of arsenite was consumed by the

excess periodate in the aliquot. The aliquot contained 10$ of the total

periodate or 0*265 nmole. Simple subtraction again shows that there was

0.111 nmole of periodate consumed in the aliquot, by the desulfurized

alditol, or 1.11 mmole in the total solution. This is 1.71 moles of

periodate consumed per mole of alditol. Similar results were obtained

in other runs (page 1*6 ).

A portion of the sirup was sim ilarly oxidized with sodium periodate

under such conditions that any volatile aldehyde produced was swept out

of the solution with a slow stream of nitrogen. The gas was swept

through a solution of 0.1*$ (saturated) 5,5-dimeth'l-l,3-cyclohexanedione,

" dimedon, n in water. Actually the gas was swept through two such solutions in series to insure that any volatile aldehyde would have time to react with the reagent.

After the reaction had proceeded 10 min., a small aliquot was removed and periodate consumption was calculated.

When the reaction had proceeded 12 hr., no further precipitate was observed to form in the dimedon solution. The precipitate of dimedon adduct was removed by filtratio n , washed with water and dried, m.p. 11*0-

11*2°, x-ray powder diffraction data (11*8): 13.60 m, 8 . 59m, 7 .6 3 s ( 2 ) ,

6.92w, 6.13 s(3), 5.85 s(l), 1*.91 m, l*.62m, 1*.22 m, 3*^7 w, 3-50 w,

3.1*1 vw, 3-05 vw, 2.93 vw.

The melting point indicated that the dimedon adduct was that of acetaldehyde (m.p. ll*l-ll*2°)j however, a comparison of x-ray powder diffraction patterns showed marked differences. An authenic sample of acetaldehyde dimedon had the following x-ray powder diffraction data

(ll*8)t 9.12 m(2,2), 6.92 m(2,2), 5.3li m(3), 5.13 s(l), i *.70 vw, 1*.06 vw,

3.65 vw, 3.1*6 vw, 3*35 vw, 3.00 vw.

When the acetaldehyde dimedon obtained experimentally was recrystallized from methanol-water and was seeded with authentic acetaldehyde dimedon a crystalline material was received which was identical in every way to authentic acetaldehyde dimedon.

Additional evidence of the identity was provided by conversion to the dimedon "anhydride'* ( 127 ) by recrystallization from methanol-water to which 2 drops of conc. hydrochloric acid was added. The material was identical to that prepared from authentic acetaldehyde dimedon

(m.p. 175-176°) and had the following x-ray powder diffraction data

(11*8)* 1 1.95 rn(2), 5.97 VW, 5*73 M(3), 5.21 s(l), 5-3^ m, 3.97 vw,

3.25 w, 2.88 w.

The C-methyl Determination of l,5-Dideoxy-L-arabinitol(I>-lyxitol) (IV)

The C-methyl determination of IV was performed by the Kuhn-Roth technique (151) in the manner outlined by Pregl and Grant (1 5 2 ).

(151) R. Kuhn and H. R oth, B e r ., 66, 1271* (1 9 3 3 ).

(152) F. Pregl, "Quantitative Organic Microanalysis," 5th Ed., Edited by J. Grant, The Blakiston Co., Philadelphia, Pa., 195l> p. 206.

In a 50 ml. flask fitted with a reflux condenser was placed 60*8 mg.

(0.506 ranole) of IV. To this was added 10 ml. of 1.68 U chromium trioxide solution and 2 ml. of conc. sulfuric acid. The solution was refluxed 2 hr. and cooled. The condenser was washed with a small 86 amount of water which was added to the oxidizing solution* The excess

Cr+^ was destroyed by the careful, dropwise addition of a solution of

hydrazine hydrate in water (1*1). The hydrazine solution was added

until the oxidizing mixture Just showed a green tin t. The solution was

then neutralized with dilute base and reacidified by the addition of

1 ml. of 85£ phosphoric add. The solution was distilled and the

distillate was collected in 10-25 ml. fractions. Water was occasionally

added to the distilling flask to maintain its volume. The fractions

were then titrated to the phenolphthalein end point with 0.0250 N

sodium hydroxide. The results are shown below.

fraction 141. base Total nmoles base

1 5 .7 5 0.11+1* 2 17.05 0 .670 3 7-1*0 0.855 ii 3 .0 0 0.930 5 0 .3 0 0.938 6 0 .0 0 0.938

These data represent 1.86 C-methyl groups per mole of IV. A

determination on L-rhamnitol XXVII indicated a C-methyl value of

0 .9 7 .

9h 2oh HOCH HOCH HCOH 1 HCOH 1

XXVII

A drop or two of 10£ barium chloride should be added to the distillate fractions after titration to insure that none of the sulfate ion, hence phosphoric acid, had splashed over*

Attempted Preparation of l,5-W .deoxy-2,3,lj-tri-0-|>-nitrobenzoyl-L- arabini tol (D -lyxitol)

To a solution of 0.5 g. of 1,5-dideoxy-L-arabinitol in 5 ml. of p;/ridine v»as added a solution of 3»S> of £-nitrobenzoyl chloride 50 (??

excess) in 10 ml. of chlorofom. After two days at room temperature,

2 ml. of water was added to the solution. After 10 min. more the

solution was poured into 100 ml. of water. The mixture was allowed to

stand overnight, with stirring. The mixture was then extracted with

chloroform and the chloroform washed several times with water. The

chlorofonn solution was dried over sodium sulfate and the solvent

removed under reduced pressure. The tris(£-nitrobenzoate) was not

crystalline.

S y n th e sis and Proof of Structure of 5-Deoxy-D-xyio-hexose (w5-Decxy-P-glucosew) ; S y n th e sis and Optical Properties of D-xylc-Hexases

The Preparation of 1,2-0-1s op r op v li dene -5 ,6-di-0-p-toly 1 sulfonyl-q-D- glucose (XI)

To a cooled solution of $0 g. of 1,2-O-isopropylidene-a-D-

glucofuranose in 200 ml. pyridine was added, dropwise with stirring,

a solution of 100 g. p-toluenesulfonyl chloride [commercial material

was recrystallized from Skellysolve C( 11*7)) in iiOO ml. of

tetrahydrofuran. When the addition was completed, the solution was removed from the cooling bath and allowed to warm to room temperature.

The solution was set aside for 3 to U days at room temperature during which time pyridine hydrochloride crystallised out. At the end of this time 750 ml. of chloroform was added and the solution extracted 6-times with lfJOOnml. portions of cold water. The chloroform layer was then dried over sodium sulfate and evaporated under reduced pressure. Water was added to the sirupy residue and re-evaporated to remove most of the residual pyridine. The product crystallized during the last operation.

The crude material was recrystallized by dissolving directly in hot abs. ethanol and coolingj yield 30 g., m.p. 157-9° [lit. 160°, ( 13It) 3*

The Preparation of 1,2-0-isopropylidene-3,5>,6-tri-O - tolylsulfonyl-q-D-glucose (XII)

To a cooled solution of 27.5 g* (0.125 mole) of 1,2-0-isopropylidene- a-D-glucofuranose in 200 ml. of pyridine was added a solution of 11j3 g> of £-toluenesulfonyl chloride (100^ excess) in 300 ml. of pyridine. The addition v/as at such a rate that the temperature did not rise above

10-15°. When the addition was complete the solution was allowed to warm to room temperature, at which temp rature it stood for 2 days. At the end of this time 300 ml. of chloroform and 20 ml. of water were added to the solution. After an additional 1/2 hr. the entire solution was poured into 2 liters of water and an additional 300 m l. o f chloroform added. The chloroform layer was removed and washed 10-15 times with cold water. The organic layer was then dried over sodium sulfate, filtered and the chloroform removed under reduced pressure.

The sirup was taken up in ethanol and seeded with 1,2-0-isopropylidene- 89

3,5*6-tiu-0-g-tolylsulfonyl-a-D-glucose. After one day the crystalline material was removed by filtratio n , washed with ethanol and dried; yield 39.2 g. (1*8%), m.p. 126-129°. This material is pure enough to use for the reaction with sodium iodide. A fraction was recrystallized from absolute ethanol, m.p. 131- 1 3 2 .5°; reported 128-129° ( 136) .

The Synthesis of 1,2-0-Isopropylidene-U-vinyl-q-D-x^lo-tetrofuranose (XIII)

1,2-0-1 sopropylidene-5, 6-di-O-p-tolylsulfonyl-a-D-gluccse (XI)

(20 g ., 0 . 01* mole) was dissolved in 200 ml. of acetone and 5k g . (300% excess) of anhydrous sodium iodide added. The solution was heated under reflux, with stirring, for 18 hr., during which time the color became dark reddish-brown. The solution was filtered warm and the sodium p-toluenesulfonate was washed with acetone; yield 15.6 g. (100%). The acetone was removed under reduced pressure and the resulting solid mass dissolved in chloroform and water. A portion of 30% sodium thiosulfate solution was added to reduce the free iodine. The chloroform layer was separated and the aqueous solution extracted four times with fresh chloroform (the unsaturated compound is quite soluble in water). The combined chloroform extracts were dried over sodium sulfate and the chloroform was removed under reduced pressure. The resulting yellow sirup crystallized on distilling at 60-80° and 0.05-0.10 mm. pressure. The material was further purified by sublimation (0.05-0.10 mm. Hg.,

30-hO0), yield 5.10 g. ( 68 %), m.p. 59-60°, [a]2^ -58.8° (C 2.8, H 20 ), x-ray powder diffraction data (U* 8 )* 8.93 s (3 ) , 6.68 m, 5-29 m,

5*06 s (1), li .67 s ( 2 ) , li.38 m, U.OU w, 3 .7 5 vw, 3 .6 6 m, 3 . 3I* w, 3.15 w,

2.81* w, 2 .7 6 w, 2.55 m, 2.1*2 vw, 2.3k w. - A nal. Calcd. fo r C0H . 0 * C, £8 .0 ; h , 7 .5 7 . y H i li Found: C, 5 8 .1 ; H, 7 -5 2 .

The Synthesis of 1,2-0- 1sopropylidene-3-0-p-tolylsuIfony1- U-vinyl-q-T)-xylo-tetrofUranose

A solution of 63 g. (0.092 mole) of l,2-0-isopropylidene-3,£,6- t r i -

0-£-tolylsulfonyl-a-D-glucose in£00 ml. of acetone was refluxed, under stirring, with U£ g. of sodium iodide (300^ excess) for2k h r. The scdium p-toluenesulfonate was removed by filtration (3 7 . 7 g . , 10£^) and the acetone removed under reduced pressure. The residue was dissolved in chloroform, washed with water, aqueous thiosulfate solution, and dried over sodium sulfate. The chloroform was removed under reduced pressure to a light yellow sirup which crystallized on standing. The 1,2-0- isopropylidene-3 - 0 -jo-tolylsulfonyl-ii -vinyl-a-D-xylo-tetrofuranose was recrystallized from Skellysclve B; yield 21.2 g. (67-5^), m.p. 6£ -66.£ ° , 21 5 p* -£ l* 5 (C 7 .6 CKCL^), x-ray powder diffraction data (lii8 )t

3.£l s(l,l), 6.£2 s ( 2) , £.U6 m(3), h.9U m, ii.37 s(l,l), 3-97 m, 3.80 m,

3.63 w, 2.92 w, 2 .3£ vw.

A nal. Calcd. fo r C ^ H ^ O ^ gi S, 9.1*.

Found: S, 9.2.

The Synthesis of £,6-Didcoxy-l,2-lsopropylidene-a-D-xylo-hexose (XV)

A solution of 2 g. of 1,2-0-is opropyli dene-h-vinyl-a-D-xylo- tetrofuranose in 100 ml. of absolute ethanol was hydrogenated at room temperature and 3 atmospheres hydrogen for 3 hr. in the presence of

0.2 g. of 10% palladium on carbon catalyst. The solution was filtered and T/he solvent removed under reduced pressure. The resulting sirup 9 1 crystallized on standing. The crystalline 5, 6-dideoxy-1,2-0- isopropylidene-q-D-xylo-hexose was recrystallized twice from cyclohexane; yield 0.1*6 g., m.p. 7l*-75°, ta]2^ -2l* (C 3* ^ 0 ), reported m.p. 79-79*6°

(20).

The Synthesis of 5-Deoxy-l,2-0-isopropylidene-a-P-xylo-hexose

A. Sodium borohydride - Aluminum ch lo rid e red u ction

To a solution of sodium borohydride (1.62g., 0.0328 mole) and aluminum chloride (1.1*1 g., 0.010) in 1*5 nil. bis(2-methoxyethyl) ether was added, dropwise with stirring under nitrogen, IX (3 g., 0.0161 mole) in 10 ml. of the same solvent. Hhen the addition was completed the mixture was stirred 2 hr. at room temperature and then heated an a d d itio n a l h r. on a steam b ath . The ex cess reagent was destroyed by the dropwise addition of methanol. The solvents were removed under reduced pressure and the sirupy residue dissolved in 10 ml. of abs. ethanol and 2 g. of pulverized sodium hydroxide was added. The mixture was stirred and 1.2-1.5 ml. of 30% hydrogen perioxide added. After stirring

1 hr., the mixture was filtered free of inorganic salts, neutralized with IH-120 (ll*6) and evaporated to a sirup, under reduced pressure, the sirup partially crystallized on standing. The material was recrysiallized from ether-pet. ether (b.p. 30-60°) and sublimed

(0.01 mm. Kg, 90° bath temp.), yield 0.97 g*i m.p. 9l*.6°, -9.3°

(C l i 3 , HgO ), -? .6° (C 0.7, CHCL3 ), x-ray powder diffraction data (ll*8)j 9.35 vw, 8.21* m (2), 5.66 m (3)* 1*.6? s (1), 1*.12 vw,

3-91 w, 3.66 w, 3*53 3*28 vw, 3*03 vw, 2.81* w, 2.69 vw. Anal. Calcd. for C, 53-0; H, 7.90

Found: C, 53*0 3 H, 8 .0 k .

B. Diborane reduction

To a solution of sodium borohydride (3*56 g., 0,09k mole), 1,2-0- isopropylidene-k-vinyl-q-D-xylo-tetrofuranose (5.0 g., 0.027 mole) in

75 ml. tetrahydrofuan (153) was added, dropwise with stirring, a

(153) This reagent is conveniently dried and the peroxides removed by passing through a column of chromatographic grade alumina, immediately before use. solution of 1.8 g.(0.0127 mole) of freshly distilled boron trifuluoride- etherate in 10 ml. of tetrahydrofuran. The addition of the boron trifluoride solution was carried out over a period of 1 hr. During the reaction a slow stream of dry nitrogen was passed through the container which was cooled externally with tap water.

The reaction mixture was stirred an additional hour following the addition of the boron trifluoride and the excess diborane was destroyed by the dropwise addition of methanol. The solvent was removed under reduced pressure and the product oxidized and isolated as in the preceeding experiment $ yield 3-93 g*

Sirupy 5-Peoxy-D-xvlo-hexose

To a solution of 0.5 g. of XVI in 10 ml. H20 was added 2.0 g.

Amberlite rR-120 (15k). This mixture was heated on a steam bath for

(15k) F. Shafizadeh and M. L. Wolfrom, J. Am. Chem. Soc., 77j 2568 (1955). 93

3 hr., filtered and evaporated under reduced pressure to a colorless sirup. The sirup was dried by several additions of absolute ethanol with subsequent evaporation under reduced pressure to give a colorless, hygroscopic g la ss; [a] D 21*.3° (C 2 .6 , HgO). The g la ss becomes sirupy on standing exposed to the atmosphere and becomes light amber in color.

5-heoxy-D-threo-hexose Phenylosazone (XVII)

The 5-deoxy isopropylidene compound XVI (100 mg., 0.1*9 nmole) was dissolved in 2.0 ml. 0.1 N hydrochloric acid and heated on a steam bath

for 1.5 hr. Ihe solution was cooled and 2.0 m l. 0 .1 Td sodium hydroxide added. To the neutral solution, 1.6 ml. of a solution of phenylhydrazine a c eta te (1 mmole/ml.) vas added and this solution was heated an additional

30 min. The osazone which crystallized on standing, was filtered off, washed well vdth water and recrystallized on standing, was filtered off, washed well with water and re crystallized from 1 . 1* m l. o f 60% aqueous

ethanol; yield 1*5 mg., m.p. 153-5° (lit. 153°), x-ray powder diffraction

data (liiS)* 10.53 m, 9.1*2 w, 6.92 vw, 5*55 m (3)* U .80 m ( 2 ) , 1*.56 s ( 1 ),

i*.-27 n», 3*87 vw, 3.38 vw, 3.33 m, 3.23 vw, 3 .09 w.

I-Deoxv-D-three-hexose Phenylosotriazole (XVIII)

This compound was prepared by th e d ir e c tio n s o f Regna (11*1), m.p.

11*1.5-11*2° (reported 11*9°), x-ray powder d iffr a c tio n data* 12.35 w,

7.50 m, 6.1*6 s ( 2 ) , I*.89 v s ( 1 ,1 ) , U.51 s , U .33 m, l*.0l* m, 3-85 m,

3*59 w, 3 . 1*2 vw (1,1), 3*23 s (3 ) , 2.95 vw, 2.88 w, 2.68 vw, 2.1*6 m,

2.1*3 v .

The Periodate Oxidation of the 5-Deoxy-D-threo-hexose Phenylosotriazole

The periodate oxidation of this compound was carried out in the 9h manner of Hudson and coworkers (1H2). The Ii-fon.iyl-2-phenyltriazole was removed by filtration and dried, m.p. 68-69°. The identity of this compound was confirmed by comparison w ith a sample prepared from

D-arabino-hexose phenylosotriazole (125), x-ray powder diffraction data ( l 2j.fi) t 8 .U0 m, 6.22 s (3 ) , 5 .0 2 s ( 2 , 2 ) , U.20 w, 3.82 w, 3 .7 6 w, 3 .iJj s (1), 3.23 s ( 1 , 1 ), 2.92 w, 2.80 w, 2.55 w, 2 .3 6 w.

To the filtrate was added an aqueous dime do11 solution. V/ithin

2h hr. a precipitate formed. The precipitate of 3-hydroxypropanal dimedcn was removed by filtration and dried, m.o. 208 - 210°, reported 206° ( l l i l ) .

The material was identical to that prepared from 3-hydroxypropanal (155)#

(155) J. U. Mef, Ann., 335, 219 (190U) . x-ray powder diffraction data: 11.71 vs ( 1 ) , 9 .3 9 vw, 5.58 vw, 5*°2 m,

$ .k h s ( 2 ) , 5.07 w, h . 68 w, U.28 m (3 ) , 3*90 w, 3 .3 2 w.

The Acid Hydrolysis of the Prepared 1,2-C-Isoprcpylidene Furanose Derivatives

A sample o f the compound (3OO-I1OO mg.) was accurately weighed and dissolved in 10 ml. of water in a 10 ml. volumetric flask. The rotation was taken on the solution and the specific rotation calculated.

U.O ml. of the above solution was pipetted into a 5 ml. volumetric flask. To this solution was added concentrated hydrochloric acid to

5.0 ml. volume. The time of addition was taken as zero time. The resulting solution is about 2 .5 N . A portion of the solution was rapidly transferred to a 2 dm. pclarimeter tube and readings begun to follow the course of hydrolysis.

Prom the addition of the acid to the commencement of readings the ela p sed time was 2 -2 .^ m inu tes. The r e s u lt s are g r a p h ic a lly shown in

Figure 1. Tbe rotations obtained on the free sugars are given in

Table 8 . The Optical Rotatory Dispersion of 1. 2-Q-Isopropylidene-k-'vinyl-q-D-ocylo- tetrofuranose (XUl) and l,2-0-Isopropylldene-3-0-tolylsulfonyl-h-vinyl- g-D-grlo-tetroftiranose (XIV)

The optical rotatory dispersions of XIII and XIV were taken on an

Automatic Recording Spectropolarimeter, Series 1, Model 260/655/850/

8lO-6ln (156). The recordings were made on samples in a 1 cm. quartz

(156) A product of Rudolph Instruments Engineering Co., Little Palls, N.J.

cell on a continuous scan from 700 wp. to 200 mp or to the cut-off point of the solvent (chloroform, 2UB mp; methanol, 210 mp water, 185 mp.

The s lit width was 1 mtn. throughout the recording with a symmetrical angle of 2°. The setting was such that 5 cm. of amplitude was the

equivalent of 1° rotation. The reproducability was such that the base lines or zero points at the beginning and end of the runs (a time spread

of 2 hr.) were only 0.02° rotation different, measured at 589 mp (the

*»D" l i n e ) .

The concentrations, solvents and calculated data from the

dispersion curves are presented in Table 9. The optical rotatory

dispersion curves are presented in Figures 2 and 3.

The data necessary for calculating a simple Drude equation are in

Table 10. The calculated and k values are presented in Table 11.

Plots of the simple Drude equations and the ultraviolet spectra of

XIII in water are in Figures 1* and 5 respectively. T able 9

Concentrations and Calculated Data for Rotatory Dispersion Curves

21 *5 Cmp. S o lv en t Cone. M Cone. g./lO O m l. (a ] J

XHI HgO 0.235 U.37 -61.8 XHI MeOH 0.223 lwl5 -U8.2 X m CHOI, 0.221* 1*.16 -67.3 XIV CHC35 0.222 7.57 -51.5

T able 10

Data flron Rotatory Dispersion Curves

x m teOH) 2 J, (HgO) x m xm (CHCl-*) XT7 (CHClu) xlO -a - i/g •<* - 1/ a -a -l/« a 1/ a 285 l*’.8If 6.tU (FJi*8 227 5.15 5.58 0.179 250 6.25 3.76 0.266 3.50 0.278 3 .7 0.270 283 8.01 2.00 0 .5 0 2.3 0.1*35 3 .5 2 0.281* 300 9.00 1.72 0.582 1.63 0.613 1 .8 6 0.538 2.80 0.358 350 12.25 1.02 0.98 0.92 1.09 1.10 0.910 1.58 0.633 l*oo 16.00 0 .6 9 1.1*5 0.62 1.61 O.72 1 .3 6 1.02 0.980 1*50 20.25 0 .5 1 1.96 0.1*2 2.38 0.52 1.92 0.72 1.39 500 25.00 0.1*0 2.50 0 .3 2 3*12 0 .1*0 2 .5 0 0 .5 6 1.79 550 30.25 0.32 3.12 0.21* 1*.17 O.32 3.12 0 . 1*1* 2.27 600 36.00 0.26 3.85 0.20 5.00 0 .2 6 3.81* 0 .3 6 2.78

T able 11

Calculated Data From Drude Equation

Cnp» Solvent 0 (c a lc d .) 0 (observed) k

XIII 1^0 207 mi 202 mu 8.35 x m MeOH - _ x m c ic i3 211* mu - 8.23 XIV C K lj 226 mu - 11.1 SUUiAHr

1. The mercaptolysis of tetra-O-acetyl-a-L-arabinopyranose has been affected and a crystalline product obtained upon deacetylation.

2. General catalysis of the mercaptolysis reaction by Lewis acids has been demonstrated#

3. 1, E>-Bideoxy-L-arabinitol(B-lyxitol) has been prepared by the reductive desulfurization of 5-S-ethyl-t-thio-L-arabinose diethyl dithioacetal.

ii. The structural identity of l,5-dideoxy-L-arabinitol(D-lyxitol) has been demonstrated by periodate studies and C-methyl determination.

5. The structure of the deacetylated mercaptolysis product proven in an unequivocal manner to be 5-S-ethyl-t-thio-L-arabinose diethyl dithioacetal.

6. A new dimorph of acetaldehyde ’'dimedon" is described*

7. 1, 5-Hideoxy-L-arabinitol(D-lyxitol) has been p-nitrobenzoylated but did not £ive a crystalline product.

8. Sirupy tri-O-acetyl-5-S-ethyl-5-thio-L-arabinose diethyl dithioacetal has been synthesized.

9. The difficulty in obtaining suitable analyses, especially sulfur, for compounds of this structure has been demonstrated.

10. A satisfactory method of sulfur analysis, for these compounds, is outlined, utilizing semi-micro peroxide combustion.

11. A modified and improved synthesis of 1,2-0-isopropylidene-

5,6-0-j>-tolysulfonyl-a-D-glucose is introduced.

1 2 . C it/'s talline 1 ,2-0-isopropyli dene-k-vinyl-g-D-xylo-tetro furano se has been synthesised and its structure demonstrated by conversion to the known 5 » 6-dideoxy-1 , 2-Q-isoprop vllden e -g -D-xylo-hexose.

13. Crystalline 1, 2-O-isopropyli dene-3-0-£-tolylsulfonyl-ii-vinyl- a-D-xylo-tetrofuranose has been synthesized.

1U. The first 5—deoxysugar, 5-deoxrr- l ,2-0-i sopropylidene-D^xylo- hexose ("^-deoxy-D-glucose") has been synthesized by hydroboration of

1,2-O-isopropylidene-U-vinyl-a-D-xylo-te trofuranose and oxidation of the resulting borane.

15. Sirupy 5-deoxy -D-xylo-hexose has been prepared and is optical rotation demonstrated by two different methods.

16. The acid hydrolyses of 5j6-dideoxy-1,2-0-isopropylidene-a-D- xylo-tetro furano se, 1, 2-O-isopropylidene-h-vinyl-q-D-xylo-tetrofuranose and 5-deoxy-1, 2-Q-isopropylidene-g-D-xylo-hexose have been followed polarimetrically and the rotations of the free sugars calculated from the end-points •

17• The molecular rotations of the synthesized D-xylo-hexoses have been calculated conformational sim ilarities are suggested between g)6-dideoxy-D-xylo-hexose, U-vinyl-D-xylo-tetrose and the previously prepared 5-deoxy-D-xylose.

18. The contribution of a seven-membered, septanose, ring is suggested for 5-deoxy-D-xvlo-hexose in aqueous solution.

19. The optical rotatory dispersion of 1,2-G-isopropylidene-ii- vinyl-q-D-xylo-tetrofuranose and 1,2-0-isopropylidene-3-0-£-tolylsulfonyl- 100 k-vinyl-g-D-xylo-tetrofuranose have been observed to exhibit a Cotton e f f e c t .

20. A marked effect of solvent polarity on the optical rotatory dispersion of 1,2-0-isopropylldene-li-vinyi-a-D-xylo-tetrofuranose has been observed.

21. The value for the constant of the simule Drude equation has been calculated at several wave-lengths for 1,2-0-isopropyli dene-lj-vinyl a-D -glucofuranose in w ater. This compound does obey the sim ple Drude eq u ation . CHRONOLOGICAL BIBLIOGRAPHY

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1960 165 1*7 16 : L. Vfolfrom and 7r. von Bebenburg, in p ress * AUTOBIOGRAPHY

I , Thomas Edward W hiteley, the son of Vernon Albwrt Whiteley and

Marlon Elisabeth Prefer W hiteley, was born In Dttnawuir, California, on October ll*, 1932. After attending eleven grade schools and two high schools I graduated from Vest Seattle High School In Seattle, Washington, in 195>0« On the completion of two years of a Junior eollege curriculum at Eastern Montana College of Education in B illings, Montana, I enrolled in the University of Colorado, Boulder, Coloreds,in 1952. On June 20, 1953 I married a former c las mate from Montana, Ellen LaVerne W olff. Upon receiving my Bachelor of Arts degree from Colorado in August of 1951* I moved to South Carolina. I received a Master of Science degree, under the guidance of Professor D. P. DeTar, from the University of

South Carolina In Columbia, South Carolina, in 1956. Proa there I joined the staff of the research laborato rice of Eastman Kodak Company,

Rochester, New Ycrk. After seven months w th Eastman Kodak I entered the army and had the good fortune to be assigned to Aberdeen Proving

Grounds, lid.,and to be able to work with Dr. L. Kuhn. Khlle I was in th e army my ir-n, Brian James White ley, was born on April 21*, 1957* I

spent six months in the army and entered The Ohio State University

immediately on being released on September 15, 1957* It m s during my

stay at The Ohio State University that my second child, Brenda Elizabeth Whiteley, was bom on March 9, 1959. I received a research assistants hip,

from Professor M. J *olfrom, on a project sponsored by the Department of

Health, Education and *?elfkre, Public Health Service, Rational Institutes

of Health. Or, July 1, 1959,1 received a Department of Chemistry fello w sh ip sponsored by th e Socony-M obil 01.1 Company. I l l