Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Preparation of and nuclear magnetic resonance studies on some specifically fluorinated carbohydrates Manville, John Fieve 1967

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1968_A1 M35.pdf [ 9.05MB ]
Metadata
JSON: 831-1.0062089.json
JSON-LD: 831-1.0062089-ld.json
RDF/XML (Pretty): 831-1.0062089-rdf.xml
RDF/JSON: 831-1.0062089-rdf.json
Turtle: 831-1.0062089-turtle.txt
N-Triples: 831-1.0062089-rdf-ntriples.txt
Original Record: 831-1.0062089-source.json
Full Text
831-1.0062089-fulltext.txt
Citation
831-1.0062089.ris

Full Text

The U n i v e r s i t y of B r i t i s h Columbia FACULTY OF GRADUATE STUDIES PROGRAMME OF THE FINAL ORAL EXAMINATION FOR THE DEGREE OF DOCTOR OF PHILOSOPHY of J.F. MANVILLE B.Se.(Hons.),-The U n i v e r s i t y of B r i t i s h Columbia WEDNESDAY, DECEMBER 20, AT 3:30 P.M. IN ROOM 225, CHEMISTRY BUILDING  COMMITTEE IN CHARGE Chairman: Dr. M. Smith W.R.Cullen L.D. Hayward  I. McT. Cowan D.E. McGreer B.R. James L.D. H a l l  E x t e r n a l Examiner: Derek-Horton . . Department of Chemistry Ohio S t a t e U n i v e r s i t y . 88 West 18th Avenue Columbus, Ohio,43210, U.S.A.  Research S u p e r v i s o r :  L.D. H a l l  \  PREPARATION OF AND NUCLEAR MAGNETIC  RESONANCE  STUDIES ON SPECIFICALLY FLUORINATED CARBOHYDRATES ABSTRACT  The  H and  F n u c l e a r magnetic  resonance  (n.m.r.) s p e c t r a o f a s e r i e s o f h e x o p y r a n o s y l and p e n t o p y r a n o s y l f l u o r i d e s were examined i n some d e t a i l . 19 The F n.m.r. parameters were c o n s i d e r e d a f t e r the •*"H n.m.r. a n a l y s e s ( f i r s t  order) enabled the gross  molecular conformations t o be determined: 19 F  several  n.m.r. s t e r i c dependencies were observed. T h i s study a l s o l e d to the o b s e r v a t i o n t h a t  the in  od-anomers of the p e n t o p y r a n o s y l f l u o r i d e s  the a l t e r n a t e chaiir form (^C^) , which a l l o w s the  f l u o r i n e atom t o adopt an a x i a l Subsequent  orientation.  to these i n i t i a l n.m.r. i n v e s t i -  g a t i o n s , a new r e a c t i o n sequence the  was developed f o r  a d d i t i o n of "XF" t o a l k e n e s .  t i o n sequence to  exist  (AgF and X^) r e s u l t s  cyclohexene  Whereas t h i s r e a c i n trans  ( c o u r t e s y of D. L . J o n e s ) ; i t r e s u l t s  i n both c i s and t r a n s a d d i t i o n s t o c y c l i c  vinyl  e t h e r s , a l t h o u g h the t r a n s adduct(s) always minate:  addition  predo-  a p o s s i b l e r e a c t i o n mechanism i s d i s c u s s e d .  The r e a c t i o n p r o d u c t s to D - g l u c a l t r i a c e t a t e were for  the most p a r t c r y s t a l l i n e .  D-hexopyranosyl for  These  f l u o r i d e s proved t o be e x c e l l e n t models  e x t e n d i n g p r e v i o u s l y observed  dependencies.  2-deoxy-2-halo-  Moreover,  when r e l a t e d t o the 2-deoxy-  D-glycopyranosyl f l u o r i d e s ,  /  electronegative  these compounds r e v e a l e d  t h a t the < o r i e n t a t i o n of remote s u b s t i t u e n t s must p l a y 19 an-important  role  i n determining  - - Finally, ^H-^H  and  ^F-^H  the r e l a t i v e  F chemical  shifts.  s i g n s of a s e r i e s of  c o u p l i n g c o n s t a n t s i n a v a r i e t y of  carbohydrate d e r i v a t i v e s were determined  by n u c l e a r  magnetic double resonance t e c h n i q u e s . With the excep~ 2 19 1 1 1 t i o n of geminal ( J) c o u p l i n g s both F- H and H- H c o u p l i n g s e x h i b i t the same r e l a t i v e s i g n s .  . GRADUATE STUDIES Field  of Study:  Organic  Chemistry  .Topics i n P h y s i c a l Chemistry ,  : ,. ,.-7 :  ,  ;  Seminar i n S p e c i a l T o p i c  Seminar i n Chemistry  J.A.R. Coope . . W.C. L i n L.D. H a l l A. R o s e n t h a l G.G.S. Dutton A.  Rosenthal  Topics i n Inorganic  Organometallic  Chemistry  Topics i n Organic  Organic  Chemistry  Chemistry  W.R..Cullen J..T. Kwon R.C. Thompson N.L.' Paddock ; . -H.C. C l a r k W.R;  Cullen  D.E.-'McGreef L.D.,.Hall. F. McCapra L.D.  Stereochemistry  Carboyhrates  A.  Organic Reaction' Mechanisms  R.E.  Hall  Rosenthal P. R e i d ' Pincock , -I  Related Studies Linear Algebra  W.H.  r  Simons  PUBLICATIONS G.M. Barton and J.F. M a n v i l l e , P r e p a r a t i o n ' a n d S t r u c t of Dimethyl OC-Conidendrin-8-Methyl S u l f o n a t e . >| J . Org. Chem. 30, 659 (1965). . \. D.H. Buss, L . Hough and L.D. H a l l and J.F. Manville'-' A.P.M.R. Study of Carbohydrate 2,3-Ep'oxides and R e l a t e d Compounds. T e t r a h e d r o n , 21, 69 (1965) . L.D.  H a l l and J.F. M a n v i l l e . An'N.M.R. Study of F l u o r i n a t e d Carbohydrates, G l y c o p y r a n o s y l F l u o r Chem. and Ind. (London), 991 (1965). -  L.D.  H a l l and J.F. M a n v i l l e , The Synthesis' of the 3 ; 4 6 - t r i - 0 - a c e t y l and 3,4, 6-tri-0_-benzoyl d e r i v a t i v e s of 2-deoxy-<X-D-arabino-hexopyranosyl f l u o r i d e . Can. J . Chem. 45, 1299 (1967).  L.D.  H a l l and J.F. M a n v i l l e . The R e l a t i v e S i g n s of P r o t o n - P r o t o n C o u p l i n g Constants i n S a t u r a t e d and Unsaturated Carbohydrate D e r i v a t i v e s . Carbohydratt Res. 4, 271 (1967) .  L.D.  H a l l and J.F. M a n v i l l e , The R e l a t i v e S i g n s of F l u o r i n e - P r o t o n S p i n C o u p l i n g Constants of S p e c i f i c a l l y F l u o r i n a t e d C a r b o h y d r a t e s . Chem. and I n d . (London), 468 (1967) .  L . D . H a l l and J.F. M a n v i l l e , The Favored Conformation o f 2 , 3 , 4 - T r i - O - a c e t y l - ^ - D - x y l o p y r a n o s y l F l u o r i d e and Other P e n t o p y r a n o s y l F l u o r i d e s : The Anomeric E f f e c t of a F l u o r i n e S u b s t i t u e n t . Carbohydrate Res. 4, 512 (1967) . L.D.  H a l l and A. T r a c e y and J.F. M a n v i l l e , The S t e r e o s p e c i f i c i t y of Long-Range C o u p l i n g Constants o f S a t u r a t e d Carbohydrate D e r i v a t i v e s . Carbohydrate Res. 4, 514 (1967).  D.L.  Jones and L.D. H a l l and J . F . M a n v i l l e , The A d d i t i o n of the Elements of "XF" t o A l k e n e s . Chem. and Ind. (London), 1787 (1967).  L.D.  H a l l and J.F. M a n v i l l e , S t u d i e s of Carbohydrate D e r i v a t i v e s by N u c l e a r Magnetic Double Resonance P a r t I I , A D e t e r m i n a t i o n of the S i g n s of P r o t o n P r o t o n C o u p l i n g Constants o f S a t u r a t e d and Unsatur a t e d C a r b o h y d r a t e s . Carbohydrate Res., i n p r e s s .  L.D.  H a l l and J.F. M a n v i l l e , S t u d i e s of Carbohydrate D e r i v a t i v e s by N u c l e a r Magnetic Double Resonance P a r t I I I . The Signs of F l u o r i n e - P r o t o n C o u p l i n g Constants. Carbohydrate Res., In p r e s s .  L.D.  H a l l and J.F. M a n v i l l e , The C h e m i s t r y of DeoxySugars, Advances i n Chemistry S e r i e s i n S. H a n e s s i a n XEd.). American Chemical S o c i e t y , i n p r e s s .  THE  PREPARATION OF AND NUCLEAR MAGNETIC RESONANCE STUDIES ON SOME SPECIFICALLY FLUORIMATED CARBOHYDRATES by JOHN FIEYE MANVILLE B.Sc,  U n i v e r s i t y o f E r i t i s h Columbia, 1964  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE  REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY i n t h e department o f CHEMISTRY  We accept t h i s t h e s i s as conforming t o the required  THE  standard  UNIVERSITY OF BRITISH COLUMBIA December, 1967  In  presenting  advanced  Library  agree  this  degree  shall  that  thesis  at the U n i v e r s i t y  make  for extensive  p u r p o s e s may be g r a n t e d  It  financial  gain  is understood  shall  the  B r i t i s h Columbia,  copying  not  The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, C a n a d a  requirements  for  I agree  the  r e f e r e n c e and s t u d y .  of  this  by t h e Head o f my D e p a r t m e n t  thesis  I  o r by h i s  represen-  this  thesis  permission.  an  further  scholarly  be a l l o w e d w i t h o u t my w r i t t e n  Columbia  that  for  that copying or p u b l i c a t i o n of  Depa r t m e n t  Date  of  it freely available for  permission  tatives.  in p a r t i a l f u l f i l m e n t o f  for  (ii)  ABSTRACT  Chairman:  D r . L.D.  Hall  19  1  The  H and  "F n u c l e a r m a g n e t i c  series of hexopyranosyl detail.  to  check  t o be d e t e r m i n e d  t h e anomeric  other techniques. steric  and p e n t o p y r a n o s y l  The *H n.m.r. a n a l y s e s  conformations  The  dependencies  resonance  (first  f l u o r i d e s w e r e e x a m i n e d i n some  order) enabled  the gross  molecular  a n d a t t h e same t i m e p r o v i d e d an o p p o r t u n i t y  assignments  p r e v i o u s l y made t h r o u g h  19  "F n.m.r. p a r a m e t e r s  were  (n.m.r.) s p e c t r a o f a  application  of  were t h e n c o n s i d e r e d and s e v e r a l  observed.  19 The  F.chemical  shifts  are controlled,  i n p a r t , by t h e s p a t i a l  e n t a t i o n o f the f l u o r i n e , but a l s o , by t h e o r i e n t a t i o n or  other substituents.  ori-  o f remote a c e t a t e groups  R u l e s were s u b s e q u e n t l y developed  f o rpredicting the  19 Y chemical hydrate.  shifts  foraxial  fluorines  These r u l e s were used  attached to  to predict  o f a pyranose  carbo-  s h i f t s o f the 19 1 remaining "rare" giycopyranosyl f l u o r i d e s . I t was a l s o n o t e d t h a t t h e "F-'H c o u p l i n g s r e s e m b l e t h e *W-*H c o u p l i n g s i n that. J \ > J , . Moreover ' ' ' trans gauche r  these  J  times  c o u p l i n g s a n d a r e a l s o more s e n s i t i v e This study fluorides  the f l u o r i n e  to their precise steric  environment. the pento-  exist  allows  i n t h e a l t e r n a t e c h a i r form  atom t o a d o p t an a x i a l ,  s e q u e n c e was d e v e l o p e d sequence  l a r g e r t h a n t h e c o r r e s p o n d i n g *H-*H  l e d t o t h e o b s e r v a t i o n t h a t t h e 8-D-anomers of  Subsequent t o these i n i t i a l  reaction  *F chemical  l  '^F-" H c o u p l i n g s a r e s e v e r a l  pyranosyl  the  19  (*C^), w h i c h  orientation. n.m.r. i n v e s t i g a t i o n s ,  f o r t h e a d d i t i o n o f "XF" t o a l k e n e s ,  (AgF and X^) r e s u l t s  a new  reaction  Whereas  this  only i n trans a d d i t i o n t o c y c l o -  (iii)  hexene ( c o u r t e s y o f D.L.  J o n e s ) ; i t r e s u l t s i n both c i s and t r a n s a d d i t i o n s  t o c y c l i c v i n y l e t h e r s , a l t h o u g h the t r a n s a d d u c t ( s ) always predominate: p o s s i b l e r e a c t i o n mechanism i s d i s c u s s e d . CI) was  T h i s r e a c t i o n sequence (X = I , B r ,  f i r s t a p p l i e d s u c c e s s f u l l y to D - g l u c a l t r i a c e t a t e and then  to o t h e r a,B-unsaturated  c y c l i c ethers.  a  The  extended  r e a c t i o n p r o d u c t s to D - g l u c a l  t r i a c e t a t e were f o r the most p a r t c r y s t a l l i n e .  These 2-deoxy-2-halo-D-hexo-  p y r a n o s y l f l u o r i d e s proved t o be e x c e l l e n t :noc!els f o r e x t e n d i n g p r e v i o u s l y o b s e r v e d e l e c t r o n e g a t i v e dependencies. D-glycopyranosyl  Moreover, when r e l a t e d t o t h e 2-deoxy-  f l u o r i d e s , these compounds r e v e a l e d t h a t the o r i e n t a t i o n o f 19  remote s u b s t i t u e n t s must p l a y an i m p o r t a n t r o l e i n - d e t e r m i n i n g  F  chemical  shifts. F i n a l l y , a b r i e f i n t r o d u c t i o n i s g i v e n t o the u t i l i z a t i o n o f both the " s e l e c t i v e i r r a d i a t i o n " and the " s p i n - t i c k l i n g " methods f o r d e t e r m i n i n g the r e l a t i v e s i g n s o f p r o t o n - p r o t o n c o u p l i n g c o n s t a n t s o f derivatives.  For most s a t u r a t e d c a r b o h y d r a t e s the v i c i n a l  carbohydrate ^H-Hl  couplings  have been found t o be p o s i t i v e and the gcminal c o u p l i n g s are n e g a t i v e i n s i g n . For u n s a t u r a t e d d e r i v a t i v e s both v i c i n a l and geminal c o u p l i n g s are p o s i t i v e . The  s i g n s o f the c o u p l i n g s o f an e p i s u l p h i d e d e r i v a t i v e are the same as  o f the s a t u r a t e d c a r b o h y d r a t e s , whereas, the s i g n s f o r an epoxide those o f u n s a t u r a t e d c a r b o h y d r a t e s .  those  resemble  These f i n d i n g s a r c i n a c c o r d w i t h p r e -  v i o u s ' e x p e r i m e n t a l and t h e o r e t i c a l r e s u l t s .  Tt has been demonstrated that  4 the s i g n s o f long-range  ( J) couplings of saturated d e r i v a t i v e s e x h i b i t a  r e g u l a r s t e r e o s p e c i f i c i t y : those between two e q u a t o r i a l l y o r i e n t e d p r o t o n s ( J ) b e i n g p o s i t i v e and those between an a x i a l and an e q u a t o r i a l p r o t o n ('J ) b e i n g n e g a t i v e i n s i g n . These f i n d i n g s are c o n t r a s t e d w i t h t h e e, a p r e v i o u s t h e o r e t i c a l p r e d i c t i o n s and t h e i r p o t e n t i a l as an a d j u n c t . t o e  e  (iv)  stereochemical tives  studies i s discussed.  For u n s a t u r a t e d c a r b o h y d r a t e  deriva-  the long-range couplings are a l l negative i n sign. The " s e l e c t i v e  n e t i c double resonance  irradiation" (n.m.d.r.)  and " s p i n - t i c k l i n g " h o m o n u c l e a r mag-  t e c h n i q u e s have been used t o d e t e r m i n e t h e 10  relative  signs o f the v i c i n a l  giycopyranosyl relative  signs.  fluorides.  F- H c o u p l i n g s o f a s e r i e s o f  I n a l l c a s e s t h e s e two c o u p l i n g s h a v e t h e same  l i e t e r o n u c l e a r d e c o u p l i n g e x p e r i m e n t s on  D-rnannopyranosyl f l u o r i d e vicinal  and g e m i n a l  1  c o u p l i n g between  Fj h a v e t h e same r e l a t i v e  triacetate and signs.  showed t h a t  f o r t h i s derivative the  and t h e g e m i n a l On t h i s b a s i s  a s s i g n e d t o b o t h v i c i n a l , and g e m i n a l  19  1  2-bromo-2-deoxy~ct-  c o u p l i n g between  an a b s o l u t e p o s i t i v e  F- H c o u p l i n g s .  and sign  was  (v)  TABLE OF CONTENTS  INTRODUCTION  ,  1  RESULTS AND DISCUSSION  11  The G i y c o p y r a n o s y l F l u o r i d e s Hexopyranosyl  Fluorides  11 '  Pentopyranosy 1 F l u o r i d e s E l e c t r o p h i l i c Addition Reactions of g l y c a l s  15 37 51  D - G l u c a l T r i a c e t a t e ' (XXXIV)  53  Other a B-U"nsaturated  74  5  C y c l i c Ethers  An N.M.R. Study o f 2-Deoxy-2-llalo-Glycosy 1 F l u o r i d e s  79  The R e l a t i v e S i g n s o f M1-*H and ^ F - * H C o u p l i n g C o n s t a n t s .  85  *H-*H C o u p l i n g C o n s t a n t s .  88  The S i g n s o f V i c i n a l and Geminal C o u p l i n g s  98  The S i g n s o f Long-Range C o u p l i n g s  99  19 1 ' F- 11 C o u p l i n g C o n s t a n t s  103  The S i g n s o f V i c i n a l and Geminal C o u p l i n g s  103  The S i g n s o f Long-Range C o u p l i n g s  116  EXPERIMENTAL  117  S e c t i o n _A:  General Methods  117  S e c t i o n B:  The G i y c o p y r a n o s y l F l u o r i d e s  119  Hexopyranosyl  Fluorides  Pentopyrar.osyl F l u o r i d e s  - . .119 ,..124  (vi) S e c t i o n C: E l e c t r o p h i l i c A d d i t i o n R e a c t i o n s o f D - G l u c a l  S e c t i o n D:  Tri-  a c e t a t e (XXXIV)  126  A d d i t i o n o f the Elements o f " B r F "  126  A d d i t i o n o f the Elements o f " I F "  129  A d d i t i o n o f the Elements o f " C i F "  130  A d d i t i o n o f the Elements o f "BrOBz"  132  A d d i t i o n o f the Elements o f " l O B z "  133  A d d i t i o n o f the Elements o f "ClQBz"  134  S t e r e o s e l e c t i v e Syntheses  o f P r o d u c t s Formed D u r i n g the  A d d i t i o n Reactions of D-Glucal T r i a c e t a t e  (XXXIV)  138  S e c t i o n E: E l e c t r o p h i l i c A d d i t i o n R e a c t i o n s t o Other G l y c a I s  144  Reactions of D-Galactal T r i a c e t a t e  (LVII)  144  R e a c t i o n s o f D - X y l a l D i a c e t a t e (LXIV)  14S  Reactions of D-Arabinal Diacetate (LXXIII)  146  Reactions of V i n y l Acetate  148.  (LXXXI)  Reactions o f 3 4-Dihydro-2H-Pyran (LXXXII)  148  3  R e a c t i o n s o f the O-Acetate o f 3,4-Dihydro-2H-Pyran-2Methanol  149  R e a c t i o n s o f the 0_-p_-Toluene S u l f o n a t e o f 3,4-Dihydro -2I!-Pyran-2-Methanol S e c t i o n F: The  (LXXXIV)  Signs of Carbohydrate  Proton Coupling Constants REFERENCES  P r o t o n - P r o t o n and  150 Fluorine152 154  (vii)  LIST OF TABLES  Table I  F i r s t o r d e r c h e m i c a l s h i f t s o f the f u l l y O - e s t e r i f i e d . Hexopyranosyl  Table I I  22  F i r s t o r d e r c o u p l i n g c o n s t a n t s o f the f u l l y Hexopyranosyl  Table I I I  Fluorides  Induced  O-esterified  Fluorides  23  s h i f t s f o r an a x i a l l y o r i e n t e d f l u o r i n e  substit-  uent f o l l o w i n g i n v e r s i o n o f a "remote" a c e t o x y s u b s t i t u e n t . . 29 T a b l e IV  F i r s t o r d e r c h e m i c a l s h i f t s o f the f u l l y  O-esterified  Pentopyranosyl F l u o r i d e s Table V  39  F i r s t order coupling constants o f the f u l l y O - e s t e r i f i e d Pentopyranosy 1 F l u o r i d e s  40  19 T a b l e VI  The 'V c h e m i c a l s h i f t s o f t h e P e n t o p y r a n o s y l observed and c a l c u l a t e d  Fluorides; 42  19 Table VII  Comparison o f t h e  F chemical  s h i f t s of the Pentopyranosyl  F l u o r i d e s (axial, f l u o r i n e ) with t h e i r r e l a t e d a~Hexopyranosyl T a b l e VIIT  Fluoride  44  Product r a t i o s f o r t h e a d d i t i o n o f t h e elements and o f "XORz" t o D - g l u c a l t r i a c e t a t e  T a b l e TX  configurationally  o f "X! " :  (XXXIV)  63  P r o d u c t s a r i s i n g from "XF" a d d i t i o n r e a c t i o n s t o some a , 8unsaturated c y c l i c ethers  76  Table X  P r o d u c t s a r i s i n g from "XF" a d d i t i o n s t o o t h e r g l y c a l s  77  Table XI  F i r s t o r d e r c h e m i c a l s h i f t s o f t h e "XF" adducts t o D - g l u c a l t r i a c e t a t e (XXXIV)  80  Table X I I  F i r s t o r d e r c o u p l i n g c o n s t a n t s o f t h e "XF" adducts t o D-glucal t r i a c e t a t e  T a b l e XT I I  19  "F n.m.r. parameters fluoride triacetates  (XXXIV)  81  f o r t h e 2-deoxy-2--halo-glycopyrar,osyl 82  (viii)  Table  XIV  S p i n s t a t e a s s i g n m e n t s f o r t h e 11^ and H ,. r e s o n a n c e s of 5 ,6-dideoxy-5,6-epithio-l,2-0-isopropylidene-B-Lidofuranose  Table  XV  Spin  (CVII); relative  sign determination  s t a t e assignments f o r the  , M  and  of B-D-xylopyranose t e t r a a c e t a t e (CXI);  89 resonances  relative  sign determination Table  XVI  The s i g n s o f  92  H- H c o u p l i n g s o f c a r b o h y d r a t e  derivatives...  96  19 Table  XVII  Spin for  s t a t e assignments  f o r the  t h e a- a n d B-anomers o f  benzylidene-D-glucopyranosyl and Table  (XII);  relative  X V I I I The s i g n s o f Giycopyranosyl  F, U  and \\^ r e s o n a n c e s  2,3-di-0-acetyl-4,6-0fluoride,  compounds ( X I )  sign determination  " F - II c o u p l i n g c o n s t a n t s  104 of a series of  Fluorides  110 19  Table  XIX  Spin s t a t e assignments f o r the  'F,  o f 2-bromo-2-deoxy-a-D-mannopyranosyl (XXXV); r e l a t i v e Table  XX  First glucal  Table  XXI  First  XXII  First  resonances  fluoride  triacetate  sign determination  112  o r d e r c h e m i c a l ' s h i f t s o f t h e "XOBz" a d d u c t s triacetate  t o D-  (XXXIV)  order coupling constants  D-glucal Table  and  triacetate  136 o f t h e ''XOBz' a d d u c t s  to  (XXXIV)  o r d e r n.m.r. p a r a m e t e r s o f  iodo-B-D-ribopyranose  1  ...137 l-0-benzoyl-2-deoxy-2-  d i a c e t a t e (LXXX)  147  (ix)  LIST OF  Figure  1  100 MHz  FIGURES  p.m.r.. s p e c t r a o f the a- and  f l u o r i d e t e t r a a c e t a t e s ( I ) and Figure  2  94 MHz  3  220 MHz  4  100 MHz  5  94 MHz  6  94 MHz  (III)  18' B-D-glucopyranosyl  (III)  (XXI) and  20 8-D-xylopyranosyl  (XXII)  f.m.r. s p e c t r a (observed  arabinopyranosyl Figure  8-D-glucopyranosyi  p.m.r. s p e c t r a o f the a- and  fluoride triacetates Figure  17  p.m.r. s p e c t r a o f the a- and  f l u o r i d e t e t r a a c e t a t e s ( I ) and Figure  (III)  f.m.r. s p e c t r a o f the a- and  f l u o r i d e t e t r a a c e t a t e s ( I ) and Figure  B-D-glucopyranosyl  and  fluoride triacetate  38  calculated) of (XXX)  Figure  7  and AgF  100 MHz  8  s p e c t r a o f (A)  54  l-0_-benzoyl~2-bromo-2-deoxy-a( X L V I I I ) and  (B) 2-bromo-2-  fluoride triacetate  100 MHz  l-0_--benzoyl-2-deoxy--2-iodo-a-  s p e c t r a o f (A)  triacetate  iodo-a-D- mannopyranosyl 9  (XXXIV) w i t h  deoxy-a-D-gluccpyranosyl  D-mannopyranose  Figure  100 MHz  (L) and  (XXXVII)  56  (B) 2-deoxy-2-  fluoride triacetate  (XXXIX)  62  s p e c t r a o f (A) 1 ~0-benzoyl--2-chloro-2-deoxy-B-  'D-glucopyranose t r i a c e t a t e  (LVT)  and  (B) 2-chIoro-2-  deoxy-B-D-glucopyranosyl f l u o r i d e t r i a c e t a t e F i g u r e 10  obtained  i n CH CN'/C^ s o l u t i o n . . . ,  D-glucopyranose t r i a c e t a t e  Figure  , . . 46  f.m.r. s p e c t r a o f the r e a c t i o n m i x t u r e  from the r e a c t i o n o f D - g l u c a l t r i a c e t a t e Br  6-D-  P a r t i a l . 100 MHz  (XLV)  spectra of  5,6-epithio-1,2-0-iso-  propylidene-B-L-idofuranose  (CVI.I) ; r e l a t i v e s i g n  determination  70  90  (x) F i g u r e 11  100 MHz s p e c t r a o f S-D-xylopyranose t e t r a a c e t a t e ( C X I ) ; r e l a t i v e sign determination  F i g u r e 12  Partial  93  100 MHz s p e c t r a o f t h e a- and 3-anomers o f 2,3-  di-0-acety1-4,6-O-benzylidene-D-glucopyranosyl  fluoride;  r e l a t i v e sign determination F i g u r e 13  60 MHz s p e c t r a o f 2-bromo-2-deoxy-a-D-mannopyranosyl fluoride triacetate 19  F i g u r e 14  105  (XXXV): H - { F } n.m.d.r 1  1 9  1  'F spectrum and  H spectra of  2-bromo-2-deoxy--a-D-  mannopyranosyl f l u o r i d e t r i a c e t a t e determination F i g u r e 15  60 MHz  107  (XXXV) ; r e l a t i v e s i g n  „  108  s p e c t r a o f 2-bromo-2-deoxy-a-D.-mannopyranosyl  fluoride triacetate  (XXXV); r e l a t i v e s i g n d e t e r m i n a t i o n . . . . 114  (xi)  LIST OF DIAGRAMS AND  FLOW SHEETS  Diagram'  1  The K a r p l u s R e l a t i o n s h i p  Diagram  2  The Favoured C o n f o r m a t i o n s o f the P e n t o p y r a n o s y l  4  Fluoride Triacetates  49  Flow Sheet  i  " B r F " and "RrOBz" a d d i t i o n s t o D - g l u c a l t r i a c e t a t e  Flow Sheet  2  " I F " and "IOBz" a d d i t i o n s t o D - g l u c a l t r i a c e t a t e  Flow Sheet  5  "C1F" and "ClOBz" a d d i t i o n s t o D - g l u c a l t r i a c e t a t e  (XXXIV) 55  (XXXIV).. 61 (XXXIV) 69  (xii)  ACKNOWLEDGMENTS  I wish t o express ray s i n c e r e g r a t i t u d e t o Dr. L.D. M a l l f o r h i s t i r e l e s s e f f o r t s on my b e h a l f , i n t h e d i r e c t i o n o f t h e r e s e a r c h and t h e p r e p a r a t i o n o f t h e t h e s i s . For t h e most generous g i f t s o f samples, which were i n v a l u a b l e d u r i n g t h e e a r l y stages o f t h i s i n v e s t i g a t i o n , am i n d e b t e d  I  t o Dr. C. Pedersen.  My a d m i r a t i o n and many thanks t o Jean M. M a n v i l l e f o r h e r encouragement d u r i n g t h e i n t e r v e n i n g y e a r s and e s pecially  f o r h e r supreme e f f o r t i n t h e t y p i n g o f t h i s manu-  script . F i n a l l y , I wish t o thank t h e N a t i o n a l Research C o u n c i l o f Canada f o r t h e award o f a s t u d e n t s h i p f o r t h e per i o d 1966-1967, t h e M a c M i l l a n ,  R l o e u e l and P o w e l l R i v e r Co.  f o r t h e i r graduate r e s e a r c h s c h o l a r s h i p d u r i n g t h e p e r i o d 1965-1966, t h e B r i t i s h Columbia Sugar R e f i n i n g Company and the U n i v e r s i t y Graduate S c h o l a r s h i p Fund f o r awards d u r i n g the p e r i o d  1964-1965.  INTRODUCTION  Proton magnetic  resonance  (p.m.r.) s p e c t r o s c o p y has, i n r e c e n t  y e a r s , become one o f the most w i d e l y used o f the p h y s i c o c h e m i c a l t e c h n i q u e s . O r g a n i c chemists  i n g e n e r a l , and carbohydrate  chemists  found p.m.r. s p e c t r o s c o p y i n v a l u a b l e as a t o o l  i n p a r t i c u l a r , have  f o r d e t e r m i n i n g the s t r u c t u r e s  o f unknown compounds and f o r s t u d y i n g the conformations tives  in solution.  It i s this  of organic deriva-  l a t t e r f e a t u r e which i s p a r t i c u l a r l y  important  f o r o r g a n i c c h e m i s t s , s i n c e the m a j o r i t y o f o r g a n i c and b i o c h e m i c a l r e a c t i o n s o c c u r i n s o l u t i o n , and p.m.r. i s s t i l l f o r s t u d y i n g organic, molecules The  earliest  s p e c t r o s c o p y , as a t o o l  the o n l y g e n e r a l l y a p p l i c a b l e method  i n the l i q u i d phase.  study which d e l i n e a t e d the unique  f o r s t u d y i n g carbohydrate d e r i v a t i v e s , was that o f  Lemieux, K u l l n i g , B e r n s t e i n and Schneider'''. spectra of a series of f u l l y  the observed  These workers s t u d i e d the p.m.r.  a c e t y l a t e d pyranose  ed the f o l l o w i n g s t e r e o s p e c i f i c (a)  splittings  gauche  a splitting  carbohydrates  and d e s c r i b -  dependencies: o f the ancmeric  are dependent on the r e l a t i v e o r i e n t a t i o n s o f are t r a n s - d i a x i a l ,  p o t e n t i a l o f p.m.r.  proton  resonances  and H^; i f these protons  o f 5-8 Hz i s observed, whereas, i f they are  (a,e o r e,e) , the s p l i t t i n g v a r i e s between 2.5 and 3.2 Hz,  and (b) equatorial  the chemical s h i f t s  are dependent on m o l e c u l a r geometry;  a c e t o x y l protons h a v i n g h i g h e r chemical s h i f t s  those o f a x i a l l y o r i e n t e d  groups  (ca.7.8  ( c a . 8.0 ) T  than  r ) , whereas e q u a t o r i a l r i n g hydrogen  atoms have lower chemical s h i f t s than t h e i r a x i a l c o u n t e r p a r t s . The dihedral  observed v a r i a t i o n  of vicinal  Hi-Hi  c o u p l i n g c o n s t a n t s with  angle was s u b s e q u e n t l y p l a c e d on a s e m i - t h e o r e t i c a l b a s i s by 2  M. K a r p l u s " . H-C-C-H  He proposed  fragment,  the f o r m u l a t i o n , based -on the h y p o t h e t i c a l  -3-  J  2 = J cos i> + K, o  where J i s the c o u p l i n g constant  resulting  hydrogen atoms a t t a c h e d t o a d j a c e n t  carbon  from i n t e r a c t i o n between two atoms and s e p a r a t e d by a d i h e d r a l  * angle  o f <j>.  J  q  and K a r e parameters whose v a l u e s a r e e v a l u a t e d as K = -0.28  and J = 8,5 f o r 0°<A< 90° and J = 9.5 f o r 90° <d>< 180°. o ^ o T  o f t h i s r e l a t i o n s h i p i s shown i n D i a g . l ; the curve  The g e n e r a l ' f  i s not symmetrical  about  the v a l u e < { > = 9 0 ° , and i t p r e d i c t s a s m a l l , n e g a t i v e c o u p l i n g f o r t h i s It was soon r e c o g n i z e d t h a t the J upon the t o t a l  form  value.  parameters were a l s o dependent  e l e c t r o n e g a t i v i t y o f t h e s u b s t i t u e n t s a t t a c h e d t o t h e ll-C-C-H 3 4 5  fragment and s e v e r a l e m p i r i c a l m o d i f i c a t i o n s ' ' t h i s dependence.  The  were suggested  U n f o r t u n a t e l y many workers used the Karplus  s e p a r a t i o n between the C-H bonds when they  along the a x i s o f t h e C-C bond, as i n a Newman p r o j e c t i o n . i n a-D-glucopyranose p e n t a a c e t a t e ,  (shown below),  hydrogens.  carbon  are viewed  •  F o r example,  t h e d i h e d r a l angle between  i s 60°, w h i l s t < j > = 180° f o r the remaining  gens; whereas, f o r 8-D-glucopyranose p e n t a a c e t a t e , vicinal  relationship  d i h e d r a l angle between two hydrogen atoms on a d j a c e n t  atoms i s t h e a n g u l a r  and  to allow f o r  pairs of v i c i n a l  hydro-  $ = 180° f o r each p a i r o f  -4-  Dihedral  Diag. I.  Angle.  T H EKARPLUS  (°)  RELATIONSHIP  -5-  i n d i s c r i m i n a t e l y and e v e n t u a l l y K a r p l u s h i m s e l f f e l t o b l i g e d t o comment^ on this: "The i n t r o d u c t i o n o f e m p i r i c a l parameters t o a d j u s t the t h e o r e t i c a l f o r m u l a f o r a p a r t i c u l a r s e r i e s o f compounds can be h e l p f u l i n t h i s r e g a r d ... C e r t a i n l y , w i t h our p r e s e n t knowledge, the p e r s o n who attempts t o e s t i m a t e d i h e d r a l a n g l e s t o an a c c u r a c y o f one o r two degrees does so at h i s own p e r i l " . R e c e n t l y , i t has become apparent t h a t v i c i n a l c o u p l i n g c o n s t a n t s are s u b j e c t t o an even w i d e r v a r i e t y o f dependencies  than was  f i r s t apprecia-  7  ted .  Thus, i n a d d i t i o n t o a n g u l a r and e l e c t r o n e g a t i v e dependencies  a so-  8 9 c a l l e d " o r i e n t a t i o n dependence" was p o s t u l a t e d by s e v e r a l workers dependence i s t h a t , f o r a six-membered r i n g system, J  (<S> = 60°)  ' .  This  i s no  9., G  longer equal to J  (<f> = 60°) , however, they are both g r e a t e r than J G  (<ji = 60°).  f Cl  C yO  C l e a r l y , t h i s and o t h e r n o n - s y s t e m a t i c dependencies  of v i c i n a l  c o u p l i n g s g r e a t l y l i m i t the a c c u r a c y and " c o n f i d e n c e l i m i t " i n any study o f c o n f o r m a t i o n s based  on the p.m.r. t e c h n i q u e .  T h i s i s p a r t i c u l a r l y so s i n c e  no g e n e r a l checks can be made on the v a l i d i t y o f those c o n f o r m a t i o n s .  A  f u r t h e r s h o r t c o m i n g o f the p.m.r. method concerns the i n s e n s i t i v i t y o f p.m.r. parameters  toward t h e i r s t e r i c environment;  (For example, the i n h e r e n t  a x i a l : e q u a t o r i a l p r o t o n c h e m i c a l s h i f t d i f f e r e n c e i n c y c l o h e x a n e , as d e t e r mined by low temperature was  o n l y 0.47  p.p.m.).  p.m.r. measurements by s e v e r a l w o r k e r s , ^ ' *  *'^  T h i s low s e n s i t i v i t y can be a s e r i o u s d i s a d v a n t a g e  when i n v e s t i g a t i n g r i n g systems, such as pyranose  c a r b o h y d r a t e s , which  may  be u n d e r g o i n g c o n f o r m a t i o n a l i n v e r s i o n . In p r i n c i p l e , these i n h e r e n t d i s a d v a n t a g e s o f the p.m.r. method c o u l d be e l i m i n a t e d i f a second n u c l e a r magnetic s t e r e o s p e c i f i c dependencies i n the m o l e c u l e under s t u d y .  s p e c i e s , whose n.m.r.  were a l r e a d y known w i t h c e r t a i n t y , was i n c l u d e d The  i n v e s t i g a t i o n o f the n.m.r. parameters  t h i s second n u c l e a r s p e c i e s would, i n e f f e c t , a f f o r d an independent  check  of on  -6-  the geometry o f the compound under i n v e s t i g a t i o n . would thus be e f f e c t i v e l y u t i l i z e d parameters  nucleus  as a " s t e r e o s p e c i f i c probe" and i f i t s  were more s e n s i t i v e t o changes i n s t e r i c environment,  parameters,  then t h e gain i n s e n s i t i v i t y  For  c o u l d be u t i l i z e d  than  p.m.r.  directly.  a v a r i e t y o f r e a s o n s , f l u o r i n e was the most obvious c h o i c e f o r  t h i s second n u c l e u s . n.m.r.  T h i s second  F l u o r i n e i s 100% abundant as the  19 F i s o t o p e and i t s  s i g n a l can be r e a d i l y measured by e s s e n t i a l l y t h e same high  resoiu-  * tion  t e c h n i q u e s as are c o n v e n t i o n a l l y used  the same s e n s i t i v i t y . certain  f o r protons  , with  approximately  More i m p o r t a n t l y , from a c o n f o r m a t i o n a l v i e w p o i n t ,  f l u o r i n e magnetic  resonance  (f.m.r.) parameters  a r e extremely  sen-  sitive  t o t h e p r e c i s e s t e r i c environment o f the f l u o r i n e s u b s t i t u e n t under 13 investigation. F o r example, T i e r s i n v e s t i g a t e d the perfluoro-cyclohexane system, which i s c o n f o r m a t i o n a l l y mobile, and found t h a t the i n h e r e n t a x i a l :  equatorial  19 * F chemical s h i f t d i f f e r e n c e  times m o r e  s e n s i t i v e than t h e c o r r e s p o n d i n g p r o t o n a x i a l : e q u a t o r i a l  shift  difference of cyclohexane^' ^  showed t h a t  (6^ ^ = 18.2 p.p.m.) was c_a. 40  itself.  Similarly,  f o r c y c l o h e x y l f l u o r i d e the chemical s h i f t  8 ,e u  *For a s t a t i c magnetic f i e l d 100.00 MHz and F at 94.071 MHz. 1 9  [f_ ) 2.0.5 =  chemical  Bovey et a l ^ ,  difference  f o r the  p.p.m.  o f 23,500 gauss  *H r e s o n a t e s at  -7-  p r o t o n was was  o n l y 0.46  20.5 p.p.m.  p.p.in, whereas, the f l u o r i n e c h e m i c a l s h i f t  Thus, the f l u o r i n e c h e m i c a l s h i f t d i f f e r e n c e was  c a . 45 times more s e n s i t i v e t o i t s s t e r i c environment o f the p r o t o n a t t a c h e d t o the same carbon atom.  than was  Roberts and  difference again  the s h i f t co-workers^  have used t h i s f e a t u r e t o f a c i l i t a t e the study o f c o n f o r m a t i o n a l l y mobile 1,1-difluoro-cycloalkanes. A l t h o u g h f l u o r i n e was  an obvious c h o i c e as the " s t e r e o s p e c i f i c  p r o b e " , f o r s t u d y i n g carbohydrate, d e r i v a t i v e s , i t s s e l e c t i o n at the s t a r t o f t h i s t h e s i s , c r e a t e d s e v e r a l a t t e n d a n t problems. was  The  f i r s t o f these  the f a c t t h a t o n l y two c l a s s e s o f s p e c i f i c a l l y f l u o r i n a t e d  carbohy-  d r a t e s were known at t h a t t i m e ; these c o n t a i n e d e i t h e r a f l u o r i n e  substit-  uent at the t e r m i n a l carbon atom, the s o - c a l l e d p r i m a r y f l u o r i d e s ' ^  ^  (-CM^R f u n c t i o n a l g r o u p ) , o r a f l u o r i n e s u b s t i t u e n t a t t a c h e d t o the  anomeric  19 c a r b o n , the g l y c o p y r a n o s y l f l u o r i d e s *  ?  0 .  Thus, i t was n e c e s s a r y t o d e v i s e  some method f o r i n t r o d u c i n g f l u o r i n e i n t o s p e c i f i c p o s i t i o n s i n the carbohydrate molecule.  Second, i t was  n e c e s s a r y t o d e v i s e some method f o r de-  t e r m i n i n g the s t r u c t u r e s o f unknown f l u o r i n a t e d ca.rbchydrat.es, s i n c e conv e n t i o n a l t e c h n i q u e s were l i k e l y t o be inadequate i n t h i s p a r t i c u l a r a r e a . F i n a l l y , i t was  n e c e s s a r y t o develop some i n s i g h t i n t o the s t e r e o s p e c i f i c 19 dependencies o f the F n.m.r. parameters themselves. For example, even 19 13 14 though the "F c h e m i c a l s h i f t s o f f l u o r i n a t e d c y c l o h e x a n c s ' were a l r e a d y known t o be e x t r e m e l y s e n s i t i v e t o t h e i r s t e r i c environment, t h i s dependence was unknown.  the n a t u r e o f  A s i m i l a r s i t u a t i o n pertained to v i c i n a l  'F- H c o u p l i n g c o n s t a n t s , f o r which i n t u i t i v e r e a s o n i n g would a n t i c i p a t e l a r g e a n g u l a r and e l e c t r o n e g a t i v e dependencies, but f o r which d a t a were not  available.  definitive  -8-  In view o f t h e s e t h r e e s u b s i d i a r y i n t h i s t h e s i s were aimed i n i t i a l l y  p r o b l e m s , the  at i n v e s t i g a t i n g the  dependencies o f f.m.r. parameters and  to ascertain  studies  presented  stercospecific  the p o t e n t i a l scope o f  10 F n.m.r. as a t o o l f o r e l u c i d a t i n g the sugars.  The  structures  o f unknown f l u o r i n a t e d  g i y c o p y r a n o s y l f l u o r i d e s were, f o r s e v e r a l  the model system f o r t h e s e s t u d i e s .  F i r s t , t h e r e was  r e a s o n s , chosen as  a large v a r i e t y  of  derivatives  e a s i l y a v a i l a b l e t h r o u g h e i t h e r o f two s t e r e o s p e c i f i c r o u t e s 19 been i n i t i a l l y s t u d i e d by Brauns and more r e c e n t l y reviewed  which had  20 by M i c h e e l and known w i t h  Klemer  The  some c e r t a i n t y and  t h e y would c o n t a i n spectra  .  o n l y one  were a n t i c i p a t e d .  were not  I t was  checked by the p.m.r. method. therefore,  Second,  s i m p l e f.m.r.  hoped t h a t t h e r e would be no  f o r which r e a d i l y d e f i n a b l e  f.m.r. -spectra  A l s o , t h e r e was  o f t h e s e compounds were a l r e a d y  ambiguities  i n h e r e n t i n the p r e v i o u s i n v e s t i g a t i o n s  systems " ^ ' ^ ' ^ j  a v a i l a b l e or the  assignments.  c o u l d be  f l u o r i n e atom and  a r i s i n g from t h i s study as was polyfluorinated  configurations  of  geometries  were too complex f o r u n e q u i v o c a l  h i s t o r i c a l precedence i n c h o o s i n g carbo-  h y d r a t e s as model compounds f o r d e t e r m i n i n g n.m.r. s t e r e o s p e c i f i c depend e n c i e s , s i n c e Lemieux et a l * had sugar d e r i v a t i v e s  previously  demonstrated the u s e f u l n e s s  i n d e t e r m i n i n g , f o r example, t h a t a x i a l r i n g hydrogen atoms  r e s o n a t e d to h i g h e r f i e l d than c h e m i c a l l y  similar equatorial  protons.  Subsequent t o these i n i t i a l s t u d i e s , a t t e n t i o n was  directed  towards the development o f a g e n e r a l l y  a p p l i c a b l e method f o r  o f a f l u o r i n e atom i n t o a sugar system, under c o n t r o l l a b l e In view o f the r e c e n t advances which had  been made i n the  introduction  conditions. chemistry  of  23-25 u n s a t u r a t e d sugars developed.  of  , a method based on t h i s f a m i l y o f d e r i v a t i v e s  was  -9-  <? (5 2 7 I t has l o n g been r e c o g n i z e d w i t h halogens  can be r a t i o n a l i z e d  '  t h a t most r e a c t i o n s o f an a l k e n e  as a two s t e p p r o c e s s  involving  initially  a t t a c k by t h e e l e c t r o p h i l i c s p e c i e s , and t h e f o r m a t i o n o f a p o s i t i v e l y charged  transition state.  In normal halogen  a d d i t i o n r e a c t i o n s , t h e second  s t a g e o f t h i s p r o c e s s i n v o l v e s r e a c t i o n o f the t r a n s i t i o n s t a t e w i t h t h e halogen  "anion".  However, i f some o t h e r n u c l e o p h i l e (N) i s p r e s e n t , then i t  can compete w i t h t h e halogen a d d i t i o n product.  anion and r e s u l t  i n t h e f o r m a t i o n o f a mixed  T h i s sequence has been used e x t e n s i v e l y by Lemieux e t a l  28 ?9 f o r t h e a d d i t i o n o f t h e elements o f "XOBz" and "XOMe" t o t h e p l y c a l s . CH 0Ac 2  l ,  AcO  2  Me OH  A g  2  C 0  OMe  OMe  3  As f a r as t h e a d d i t i o n o f t h e elements o f "XF" i s concerned, 31.32  30, Bowers e t a l  had shown t h a t a d d i t i o n o f "XF" t o a l k e n e s c o u l d be e f f e c t e d by u s i n g 33  N-halosuccinimide  and anhydrous l i q u i d HF.  t h i s sequence t o D - g l u c a l t r i a c e t a t e .  Kent and co-workers'  However, t h i s approach was n o t c o n s i d e r e d  CH 0Ac 2  AcO  I. N - b r o m o s u c c i n i m i d e anhydrous liquid H F in  then a p p l i e d  and  Et 0,~78 2  c  -10-  t o be g e n e r a l l y s a t i s f a c t o r y i n view o f the many deep s e a t e d r e a r r a n g e ments which are known"^'^'' t o o c c u r w i t h anhydrous  l i q u i d MF.  Analogous  28 29 t o the approach adopted by Lemicux and co-workers  ' "an  a l t e r n a t i v e method  was developed i n which "XP" was generated from h a l o g e n and AgF. s u c c e s s f u l development  A f t e r the  o f t h i s r e a c t i o n sequence, a thorough r e v i e w o f the  l i t e r a t u r e r e v e a l e d t h a t t h i s approach had been attempted by s e v e r a l workers'36-38 S i n c e the i n i t i a t i o n o f the s t u d i e s d e s c r i b e d i i i t h i s 15 t h e r e has been a surge o f i n t e r e s t b o t h i n f.m.r.  thesis,  39-41 *'  and i n f l u o r i n a t e d  42-44 sugars  ; t h e s e s t u d i e s w i l l be d i s c u s s e d l a t e r .  I t i s noteworthy,  p a r t i c u l a r l y from the s t a n d p o i n t o f c a r b o h y d r a t e work, t h a t  investigations  i n our l a b o r a t o r y have c o n f i r m e d the broad o u t l i n e s d e s c r i b e d i n t h i s  thesis  and have demonstrated the p o t e n t i a l o f f.m.r. as a t o o l f o r the s t r u c t u r a l e l u c i d a t i o n o f unknown f l u o r i d e s .  -11-  RF.SULTS AND DISCUSSION  The G l y c o p y r a n o s y l F l u o r i d e s  The c h o i c e o f h e x o p y r a n o s y l f l u o r i d e s as models f o r s t u d i e s aimed at e l u c i d a t i n g the s t e r e o s p e c i f i c dependencies o f f.m.r. p a r a m e t e r s , was  governed, not o n l y by t h e i r d e s i r a b l e c o n f o r m a t i o n a l and n.m.r. p r o p e r  t i e s , but a l s o by t h e i r ready a v a i l a b i l i t y .  The p r o c e d u r e s a v a i l a b l e f o r  the s y n t h e s i s o f g l y c o p y r a n o s y l f l u o r i d e s have been reviewed by M i c h e e l 19 and Klemer  and have been extended more r e c e n t l y i n a s e r i e s o f papers by 45-51  C. Pedersen and co-workers  .  B r i e f t r e a t m e n t ( c a . 20 m i n . ) , o f a f u l l y  a c y l a t e d pyranose sugar w i t h anhydrous  l i q u i d HF at low temperature  (-78°) a f f o r d s the t h e r m o d y n a m i c a l l y most s t a b l e anomer, which f o r the "common" aldohexoses  has the a - c o n f i g u r a t i o n .  There i s a l s o a v a i l a b l e an  a l t e r a t i v e r e a c t i o n pathway, i n which the f l u o r i n e i s always i n t r o d u c e d t r a n w i t h r e s p e c t t o the e s t e r s u b s t i t u e n t at C^.  I t r e q u i r e s the f u l l y  e s t e r i f i e d g l y c o p y r a n o s y l bromide t o be r e a c t e d w i t h s i l v e r m o n o f l u o r i d e , usually i n acetonitrile solution.  For t h o s e hexoses which have an equa-  t o r i a l e s t e r at C^, t h i s r e a c t i o n sequence B-fluorides.  r e s u l t s i n the f o r m a t i o n o f the  These 8 - f l u o r i d e s are e a s i l y i s o m e r i z e d t o the more s t a b l e 46  a-anomer by b r i e f t r e a t m e n t (at -78 ) w i t h HF  '.  W h i l s t the above g e n e r a l  c o n s i d e r a t i o n s a p p l y t o the pentopyranose s e r i e s , the q u e s t i o n o f r e l a t i v e thermodynamic  s t a b i l i t i e s i s less clear-cut  (vide  infra).  . • *The common aldohexoses (which are g l u c o s e , mannose and g a l a c t o s e are t h o s e sugars most commonly found i n n a t u r e .  -12-  It i s i n t e r e s t i n g that  any e l e c t r o n e g a t i v e  halogen) at C^, shows a marked p r e f e r e n c e though t h i s n e c e s s a r i l y i n v o l v e s  substituent  (such as  f o r an a x i a l o r i e n t a t i o n , even  that s u b s t i t u e n t  a c t i o n s with the a x i a l l y o r i e n t e d s u b s t i t u e n t s  i n non-bonded  at  and at  inter-  .  The r a t i o n a -  lization^  f o r t h i s e f f e c t , which i s termed the"anomeric e f f e c t " ^ ' * ' ' , i s  that there  i s an u n f a v o u r a b l e d i p o l e i n t e r a c t i o n between the oxygen  lone-  p a i r s and the C.-halogen d i p o l e , which i s maximal when the C,-halogen bond is equatorially oriented  (as i n B).  (as i n A) and minimal when i t i s a x i a l l y  The "anomeric e f f e c t " has been formulated  i n several  oriented  alter-  n a t i v e ways, but a l l models p r e d i c t t h a t the a x i a l o r i e n t a t i o n w i l l be the thermodynamically- p r e f e r r e d .  The e f f e c t resembles the b e h a v i o r o f 2-halo-  cyclohexanones, where the a x i a l o r i e n t a t i o n o f the halogen atom i s a l s o favoured^.  Empirical  r u l e s have been f o r m u l a t e d ' ^ ' ^  f o r p r e d i c t i n g which  anomeric f o n f i g u r a t i o n w i l l be thermodynamically f a v o u r e d . extent  the anomeric e f f e c t may compete with s t e r i c  However, t o what  and o t h e r i n t e r a c t i o n s ,  i n d e t e r m i n i n g the favoured anomeric c o n f i g u r a t i o n and r i n g conformation o f poly-O-acetylaldopyranosyl  halides  i s not always c l e a r .  to r e t u r n t o a d i s c u s s i o n o f t h i s p o i n t The pyranosyl  original  I t w i l l be n e c e s s a r y  later.  assignments o f c o n f i g u r a t i o n at C^, f o r the g i y c o -  f l u o r i d e s , were based on o p t i c a l  r o t a t o r y data through a p p l i c a t i o n  -13-  o f Hudson's I s o r o t a t i o n Rules  .  In t h e case o f the p o l y - O - a c e t y l a l d o -  p y r a n o s y l f l u o r i d e s o f those s i m p l e a l d o s e s where both anomeric  forms are  known,there c o u l d be l i t t l e r e a s o n a b l e doubt as t o the c o r r e c t n e s s o f these a s s i g n m e n t s , a l t h o u g h d i r e c t p r o o f by methods such, as X-ray graphic analysis i s lacking. u r a t i o n a l assignment  When o n l y one anomeric  crystallo-  form i s known, c o n f i g -  on the b a s i s o f o p t i c a l r o t a t i o n i s more d i f f i c u l t .  Thus the p r e s e n t s t u d y a f f o r d e d an o p p o r t u n i t y f o r c o n f i r m i n g many o f the p r e v i o u s anomeric  assignments by the c o n v e n t i o n a l p.m.r. method and at  the same time f o r c o n f i r m i n g t h a t the b r i e f HF t r e a t m e n t i n v o l v e d i n many o f the syntheses had not r e s u l t e d i n c o n f i g u r a t i o n a l changes at c e n t r e s o t h e r than C^;  and has a l s o g i v e n some i n d i c a t i o n o f the c o n f o r m a t i o n a l  symmetry o f the pyranose The  ring  (vide  infra).  f l u o r i d e s o b t a i n e d from D-glucopyrancse  can be used t o i l l u s t r a t e t h i s a s p e c t o f the s t u d y . 2.7 Hz c o u p l i n g between H  and H^ i n the spectrum  p e n t a a c e t a t e (I £ I I I ) T  The o b s e r v a t i o n o f a  (See F i g . 1A) o f the  p r o d u c t o b t a i n e d by r e a c t i o n o f the above p e n t a a c e t a t e w i t h HF, c o n f i r m s t h a t these p r o t o n s have a gauche r e l a t i o n s h i p . the a d d i t i o n a l o b s e r v a t i o n o f l a r g e ( c a . S.5  immediately  This, together with  Hz) *H-*H c o u p l i n g s between each  o f the r e m a i n i n g p a i r s o f v i c i n a l p r o t o n s shows u n e q u i v o c a l l y t h a t t h i s compound has the a - D - g l u c o - c o n f i g u r a t i o n ; i t a l s o shows t h a t the compound has a c o n f o r m a t i o n a p p r o x i m a t i n g the ^ C j * symmetry.  A s i m i l a r i n t e r p r e t a t i o n of  the spectrum o f the f l u o r i d e o b t a i n e d from c t - D - g l u c o p y r a n o s y l b r o m i d e  tetra-  *The c o n v e n t i o n adopted i n t h i s t h e s i s , f o r i d e n t i f i c a t i o n o f the two p o s s i b l e c h a i r c o n f o r m a t i o n s , i s based on the s u g g e s t i o n o f L.D. H a l l , any f o u r atoms o f a pyranose r i n g system are used t o d e f i n e a r e f e r e n c e p l a n e and then the r e m a i n i n g atoms are i n d i c a t e d as s u p e r s c r i p t i f they are "above" that, p l a n e o r as a s u b s c r i p t i f they are below. Thus the "normal" c h a i r c o n f o r m a t i o n (CI) i s r e f e r r e d t o as ^Cj i n d i c a t i n g t h a t C4 i s above and Cj_ below the p l a n e d e f i n e d by C , C3, Cg and 0 . On t h i s b a s i s the (IC) c o n f o r m a t i o n i s -Cq 0  2  w  5  -14-  a c e t a t e by AgF exchange, which shows l a r g e c o u p l i n g s between each o f the r i n g p r o t o n s , c o n f i r m s t h a t t h i s d e r i v a t i v e has the B - D - g l u c o - c o n f i g u r a t i o n ( F i g . IB and C ) .  The c o n f o r m a t i o n o f t h i s d e r i v a t i v e w i l l be d i s c u s s e d subsequently;  4 f o r the p r e s e n t we s h a l l tailed  assume t h a t i t i s a l s o has the  symmetry.  A de-  f i r s t - o r d e r a n a l y s i s * was made o f the p.m.r. s p e c t r a o f a l l the d e r i v a -  t i v e s d e s c r i b e d i n t h i s s e c t i o n and i n every i n s t a n c e the parameters s i s t e n t with the p r e v i o u s l y a s s i g n e d s t r u c t u r e s .  These parameters  were con-  are l i s t e d  i n T a b l e s T,II,IV and V. For convenience,  d i s c u s s i o n o f the g l y c o p y r a n o s y l f l u o r i d e s has  been s u b d i v i d e d i n t o two s e c t i o n s , the f i r s t and the second with the pentopyranose  d e a l i n g w i t h the hexopyranose  derivatives.  * A l l o f the s p e c t r a were a n a l y s e d by the s o - c a l l e d f i r s t - o r d e r a n a l y s i s , i n which the chemical s h i f t s and c o u p l i n g c o n s t a n t s were taken d i r e c t l y from the s p e c t r a l s p l i t t i n g s . General accounts o f the methods used f o r the e x p l i c i t a n a l y s i s o f ^ i n t e r a c t i n g vrotofi^^.re described i n Monographs by Pople and co-workers ~ and by Roberts c  HEXOPYRANOSYL FLUORIDES  G e n e r a l l y the s p e c t r a l assignments were q u i t e  straightforward  and f o l l o w e d t h e u s u a l procedure o f matching t h e s p l i t t i n g s o b s e r v e d i n the  individual multiplets.  The s p e c t r a were measured i n t h r e e d i f f e r e n t  s o l v e n t s , ( c h l o r o f o r m - d , a c e t o n e - d ^ , benzene-d^) t o f a c i l i t a t e and where a p p r o p r i a t e , frequency-sweep a l s o employed. of  To i l l u s t r a t e  assignments  s p i n d e c o u p l i n g experiments'were  t h i s g e n e r a l method o f assignment, t h e s n e c t r a  t h e a- ( I ) and 8- ( I I I ) anomers o f D - g l u c o p y r a n o s y l f l u o r i d e  a c e t a t e a r e d e s c r i b e d i n some d e t a i l below. a-anomer ( I ) i n CDCl^ s o l u t i o n  tetra-  The 100 MHz spectrum o f the  ( F i g . 1A) shows, as t h e lowest f i e l d r e s o n -  ance, a d o u b l e t (2.7 Hz) which has an i n t e g r a t e d i n t e n s i t y e q u i v a l e n t t o 0.5 p r o t o n s .  T h i s d o u b l e t can be a s s i g n e d to t h e ]•] resonance i f i t i s  assumed t h a t t h e o t h e r " h a l f " o f t h i s resonance l i e s a t ca.T 4.6; t h e s e p a r a t i o n between t h e two " h a l v e s " c o r r e s p o n d s t o a geminal H^,F^ c o u p l i n g of  52.8 Hz.  The q u a r t e t c e n t r e d at £a. x 5.3 a l s o i n t e g r a t e s f o r 0.5 p r o t o n s  and s i n c e i t e x h i b i t s a s p l i t t i n g  e q u a l t o t h a t observed i n the resonance  a s s i g n e d t o H^, i t can t e n t a t i v e l y be a s s i g n e d t o H^. of  t h e If,, resonance must t h e n , be p a r t i a l l y  triplet  at x 4.86.  The r e m a i n i n g " h a l f "  c o n c e a l e d by t h e r a t h e r broad  I t now remains t o a s s i g n e i t h e r t h i s t r i p l e t , o r t h e one  c e n t r e d a t x 4.52, t o t h e H^ resonance.  Tt i s not p o s s i b l e t o make an  assignment s o l e l y on t h e b a s i s o f s p e c t r a l s p l i t t i n g s s i n c e both o f t h e s e triplets  c o n t a i n the s p l i t t i n g  However, i f t h e t r i p l e t  at T 4.52 would then have been broadened by  c o u p l i n g ^ ; i n f a c t H, and t h e t r i p l e t  Thus, t h e t r i p l e t  0  resonance.  at x 4.86 had been due t o H^, t h e t r a n s i t i o n s  a s s i g n e d t o Hj and the t r i p l e t virtual  o f c a . 9 Hz observed i n t h e  at x 4.52 a r e q u i t e sharp.  at x 4.52 i s a s s i g n e d t o H^ and the t r i p l e t  at x 4.86 .  -16-  to H^.  This l a t t e r t r i p l e t  i s n o t a b l y broadened as a r e s u l t o f v i r t u a l  c o u p l i n g r e s u l t i n g from the !•!,. and t h e two il^ resonances, which a r e thems e l v e s observed as a complex m u l t i p l e t c e n t r e d a t  T  5.6.  The above a s s i g n -  ment o f t h e H, and H. resonances i s a l s o c o n s i s t e n t w i t h t h e cx-anomeric c o n f i g u r a t i o n , i n s o f a r t h a t one would expect an a x i a l f l u o r i n e at  t o p r e f e r e n t i a l l y d e s h i e l d H^ w i t h r e s p e c t t o I-I^.  assignment i s c o r r e c t t h e n , J  = 52.8 Hz and J r ,  1  substituent  I f this  overall  _ = 23.8 Hz, and t h i s i s r, z  c o n f i r m e d by d i r e c t measurement o f t h e f.m.r. spectrum (shown i n P i g . 2A) . In CDCl^ s o l u t i o n at 100 MHz, t h e g-anomcr ( I I I ) g i v e s a p o o r l y r e s o l v e d spectrum ( F i g . I B ) , which does, however, have some f e a t u r e s cons i s t e n t w i t h t h e 3-anomeric c o n f i g u r a t i o n . v a t i o n o f t h e 11^ resonance t o h i g h e r f i e l d of  Most noteworthy i s the o b s e r (ca. x 6.1) than t h e IT  resonance  the a-anomer ( c a . T 5.8); a g a i n , one would expect an a x i a l f l u o r i n e  s t i t u e n t t o have r e s u l t e d i n the p r e f e r e n t i a l d e s h i e l d i n g o f H,..  sub-  The p o o r l y  r e s o l v e d m u l t i p l e t a t c a . T 4.4, i n t e n s i t y 0.5 p r o t o n s , i s a s s i g n a b l e t o p a r t o f t h e anomeric resonance. of  Tt i s q u i t e e v i d e n t t h a t t h e poor r e s o l u t i o n  t h i s resonance i s due t o v i r t u a l c o u p l i n g ^ b e t w e e n o t h e r r i n g p r o t o n s ,  s i n c e the spectrum o f t h e same sample measured i n acetone s o l u t i o n  ( F i g . IC)  now e x h i b i t s one h a l f o f the H^ resonance as a f a i r l y s h a r p l y r e s o l v e d d o u b l e t ( J , - 6.6 Hz) at c a . x 4.3. A t t h e same time t h e H_ and H, resonances J-,2 — I 3 are  now seen t o be c h e m i c a l l y s h i f t e d from one a n o t h e r .  assignment o f t h i s spectrum was s t r a i g h t f o r w a r d .  The r e m a i n i n g  C o n f i r m a t i o n o f these  assignments a g a i n f o l l o w e d from measurement o f t h e f.m.r. s p e c t r a .  For  c h l o r o f o r m s o l u t i o n , t h e f.m.r. spectrum was o b v i o u s l y v i r t u a l l y c o u p l e d (see  F i g . 2B) i n t h e same f a s h i o n as t h e p r o t o n spectrum.  However, i n  acetone s o l u t i o n ( F i g . 2C) a s h a r p q u a r t e t was o b s e r v e d which c o n f i r m e d t h a t the  magnitudes o f J  and J  ., were r e s p e c t i v e l y 52.6 and 12.0 Hz.  -17-  Figure  1.  (A) P a r t i a l 100 MHz  spectrum o f a-D-glucopyranosy1  t e t r a a c e t a t e (I) i n chloroform-d s o l u t i o n . 6-D-glucopyranosyl  fluoride tetraacetate  acetone-d^. s o l u t i o n s .  Partial  100 MHz  fluoride  spectra  of  ( I I I ) i n (B) chloroform-d and  y^F  uw 149.9 p.p.m.  W  137.8 p.p.m.  c  Ml.0 p.p.m. 50 Hz F i p u r e 2. (I)  (A)  "F r e s o n a n c e  in c h ! o r o f o n n - d  tetraacetate  (II!)  solution. in (&)  of a-D-piucopyranosyl F resonance  fluoride  tetraacetate  o f ?-D-s;lucopyranosyl f l u o r i d e  c h l o r o f o r m - d and (C) a c c t n n e - d  solutions.  -19-  M t h o u g h c o n f i d e n t w i t h the above a s s i g n m e n t s , i t was  a pleasure  t o accept, the o p p o r t u n i t y t o c o n f i r m them by measurement o f the s p e c t r a at 220 MHz.  These p.m.r. s p e c t r a , shown i n F i g . 3 were o b t a i n e d by M.S.  u s i n g a 220 MHz crease  s p e c t r o m e t e r i n the V a r i a n Research L a b o r a t o r i e s .  Bhacca  The i n -  i n d i s p e r s i o n as compared w i t h the s p e c t r a measured at 100 MHz  q u i t e r e v e a l i n g and  f u l l y confirms  the former assignments.  is  Noteworthy f o r  the  a-anomer, i s the c l e a r r e s o l u t i o n o f a l l f o u r o f the Hj t r a n s i t i o n s and  all  e i g h t o f the \\^ t r a n s i t i o n s , b e s i d e s  the. Ii;. and the two H^ r e s o n a n c e s . assigned  t o H^. i s s t i l l  r e s u l t o f the H,. and pled  .  simplification  I t i s a p p a r e n t , however, that: the  of  triplet  l e s s w e l l r e s o l v e d than the H^ t r i p l e t , which i s a  the two H^ resonances s t i l l b e i n g  f a i r l y strongly  cou-  In f a c t , the f i r s t - o r d e r assignments made f o r t h e s e resonances  not. s t r i c t l y j u s t i f i a b l e . assignments and  However, t h i s i n no way  i n v a l i d a t e s the  i s not r e q u i r e d f o r the d e t e r m i n a t i o n  symmetry o f the m o l e c u l e as a whole.  In F i g . SB,  f e a t u r e s are more c l e a r l y r e s o l v e d , and the H^  the c o n s i d e r a b l e  o f the  are  other  conformational  some o f the s p e c t r a l  i n p a r t i c u l a r the v i r t u a l c o u p l i n g  resonance has been c o n s i d e r a b l y d i m i n i s h e d .  Note, however, t h a t even  w i t h t h i s i n c r e a s e d d i s p e r s i o n , the spectrum i s l e s s c l e a r l y r e s o l v e d t h a t o f the 100 MHz  spectrum f o r a c e t o n e - d ^ s o l u t i o n .  various r i n g proton  resonances are now  mutually  of  In F i g . 3C,  s h i f t e d so t h a t the  than  the assign-  ment, can be seen more c l e a r l y and t h i s s u b s t a n t i a t e s the assignment made at 100 MHz.  Once a g a i n the assignment o f the  beyond the l i m i t s o f a f i r s t o r d e r a n a l y s i s . H, r  M,  and  proton  resonances i s  As w i l l be d i s c u s s e d  later,  the  resonances are u s u a l l y b e s t r e s o l v e d i n benzene s o l u t i o n s . A l t h o u g h 220 MHz  s p e c t r a were o n l y measured fo.r the above mentioned  g l u c o s y l f l u o r i d e s , a l l . o f the o t h e r h e x o p y r a n o s y l f l u o r i d e s were t o a r i g o r o u s s p e c t r a l assignment at 1.00 MHz  subjected  i n the s o l v e n t s mentioned.  As  -20-  _L  4.5  Figure 3. tetraacetate  -<  1  5.0  —  5.5  (A) P a r t i a l 220 KHz spectrum o f a-D-glucooyranosyl f l u o r i d e (I) i n chloroform-d s o l u t i o n .  C-D-gluconyranosyl f l u o r i d e t e t r a a c e t a t e acetone-d, s o l u t i o n s .  P a r t i a l 220 MHz  spectra of  (III") i n (B) chloroform-d and  (C)  -21-  can he seen from T a b l e s and  I and I I ,  most o f the s p e c t r a were f u l l y  assigned,  i n no i n s t a n c e d i d t h e deduced c o n f i g u r a t i o n s d i s a g r e e w i t h the p r e -  v i o u s l y proposed s t r u c t u r e .  F o r compounds h a v i n g an e q u a t o r i a l l y o r i e n t e d  hydrogen atom a t C^, i t was,  o r c o u r s e , n o t p o s s i b l e t o a s s i g n t h e anomeric  c o n f i g u r a t i o n s o l e l y on the b a s i s o f the ^-'"'2 c o u p l i n g , s i n c e t h i s would be gauche t o both t h e f l u o r i n e and p r o t o n  a t C^.  proton  However, t h e s h i f t  o f the Hg, and i n some i n s t a n c e s t h e H^ resonance c o u l d be r e l a t e d t o an a- r a t h e r than a B - c o n f i g u r a t i o n .  F u r t h e r m o r e , i t was s u b s e q u e n t l y  found  19 t h a t w h i l s t t h e "F s h i f t s o f the a-anomers (I,V) were e s s e n t i a l l y tempe r a t u r e i n v a r i a n t , those o f the 6-anomers ( I I I , V I I I , X V I I I ) were s u b j e c t t o l a r g e (4 t o 8 p.p.m.) s h i f t s f o r a temperature change from 150°K t o 350°K (vide  infra). On the b a s i s o f the above d a t a , i t was f e l t t h a t t h e s t r u c t u r e s  and approximate c o n f o r m a t i o n a l  symmetries o f the d e r i v a t i v e s under i n v e s -  t i g a t i o n were known w i t h some c e r t a i n t y , and at t h i s p o i n t t h e f.m.r. parameters were c o n s i d e r e d . Measurement o f the f.m.r. s p e c t r a gave d i r e c t l y t h e 19 ] 19 F- II c o u p l i n g s and a l s o t h e F c h e m i c a l s h i f t s on which t h e s t e r e o s p e c i f i c 19 dependencies o f F n.m.r. were t o be d e r i v e d . In most i n s t a n c e s t h e r e was 19 3 no d i s c r e p a n c y between the magnitudes o f the "F- H c o u p l i n g s d e r i v e d f o r 1 1 9 the II and t h e F s p e c t r a . One o f the p r i n c i p a l aims o f t h i s i n v e s t i g a t i o n was t o a s c e r t a i n 19  1  •whether o r not t h e s t e r e o s p e c i f i c dependencies o f ' F- H c o u p l i n g s those o f *H-*H c o u p l i n g s .  resembled  The r e s u l t s o u t l i n e d below, t o g e t h e r w i t h sep-  a r a t e r e s u l t s from o u r o w n ^ and o t h e r * '' ^' 19 1  laboratories clearly indicate  t h a t t h e dependencies o f ~F-"H c o u p l i n g s do, i n f a c t c l o s e l y resemble o f *H-*H c o u p l i n g s ; moreover, they a r e c o n s i d e r a b l y l a r g e r and s h o u l d be more s e n s i t i v e t o t h e p r e c i s e s t e r i c environment o f the  fluorine.  those thus  -22TAELE  onnrn  H U C T  I .  CMTMICM.  .vatucs)  < , V . . « J .  SHIFTS  O F THK  FULLY  n-ESTERifiw  nr.iorYBAv.isYL  PLUOStDES.  a  ( I )  c  4.26  5.06  4.52  4.86  5.72  a  4.23  S.02  (.57  4.(15  5.SO  b  4 . 4 !  S.07  4.36  4.74  .  i  M . 4  4.98  4.6S  b  <. 6  .4.80  g  (III)  (XV)  c  3.97  4.sa  3.78  4.19'  3.81  4.36  3.77  4.01  b  4.15  4.56  3.SS  4.07  c  4.26  4.35  —  • a  3.9S  4.37  3.91  4.11  4.74  4.25  3.77  4.16  b  ^1,0  B:  (XVII)  6.35  4.OS  4.37  6.10  4.12  4.32  b  4.58  6.88  3.86  4.21  £  4.52  6.38  4.30  4.39  a  4.37  6.79  —4.32  b  4.96  6.74  4.22  c  4.10  4.79  a  4.04  4.77  b  4.30  c  a  o  (XII)  S  (VII)  a  6.57  5.79  7.00  7.98  7.9S  149 . 9  7.56  7.09  6.00  8.04  14? .5  8.25  8.28  8.30  8.36  1(9 .5  7.89  7.89  7.95  137.8  7.97  7.OS  8.01  141.0  .2S  S.2S  8.30  136.5  5.78 5.85.93  8  149.6  5 .42 5 .26  6.13  4.16  8  5.70 •  —  7.DC  148.6  S.42  5 .55  148.7  5 .40  134.8 P9.7  5 .30  3.97  a  6.08  —  c  S  (XI)  4 . 10  6.01  ^S.9  5.20  a  „  (XVltl)  4.81  9  a  a  (XVI)  4.85  5.88  5.33  5.60  149.9  5.36  149.9  • S.44  5.7S  5.42  149.1  5.33  13S.2  5.45  137.9  S . 4 S  135.2  4.35  6.43  5.83  4.43  —  5.5 •  149.9  5.50  4.30  —  S.5-  148.6  4.78  6.00  4.37  S.6S*  4.37  4.55  6.10  4.40  4.19  4.S9  5.83  4.37  b  S.20  4.55  6.35  4.61  S.92  5.32  C  4.28  5.03  4.40  S.6  a  4.3S  5.12  4.57  5.7  b  4.47  5.04  4.19  e  4.60  4.94  4.75  a  4.45  4.98  4.66  b  4.95  —  .c  4.20  4.82  4.6S  4.43  a  4.17  4.84  4.63  4.47  b  4.18  4.73  4.SO  4 .45  .  5.45  145.8  5.65  5.38  131.8  5.50  —  136.3  S..  151.2  '-A C.&  SA  6.8  S-9  4 . 70  s.ss 5.47 5.66  7.97  7.97  147.S  7.96  8.00  147.5  8.33  8.3S  146.9  7.93  7.94  154.7  7.99  8.0S  138.1  S.32  8.34  134 . 6  5.9:  7.86  7.91  7.97  8.03  151.1  5.91  7.87  7.94  8.01  8.06  ISO.5  5.94  8.27  8.34  8.31  8.35  ISO.l  7.97  8.03  142.4  8.01  8.07  142.9  8.27  8.27  141.9  (V)  c  4.16  4.14  4.IO  (XIII)  a  3.97  4.07  4.13  3.78  5.59  It . O S l  b  4.SS  4.01  3.S9  c  4.21  -4.20  5.6!  a  4.04  -4.20  5.5-'.  b  4.50  •4.01  5.76  The  co-nrcun.I,  iKtMnc  proton  protons  vcre  at  220 VSri  listed  of  At c a .  In c h ' . o T o ' o n " - d  R, - rA- fK  v  1'ovt  the h e n i v ! [ d e n e  r.h.-.e r v c . l  - . P  133.8  8.05  US.2  8.24  8.30  137.9  135.7 138.1  5.44  were  T h r h-.-ntoate  (b) j o h i t l o n .  8.00  5.23  —  5.75  137.7  2-C//3 = &.S7VCH  :.-.ch ^ e j s t i r e d  d t - r  -retorts  vjbstUiie'-.:  7.Sr.  137.6 137.2  The * c t h v !  In ch l o r o f o r a-d  resonated  was o b s e r v e d ethtr  so!o:;on:  {-!!>- o i O O A O I V K rS  at  rrr.toos  3: ca. c.i. 4.5  resonated  136.8  = 8.9-8  3  bcr.lene-d^  7.94 7.97  (c) ,  Irani! t. at  scetorce-d^ c_n. 2 . 5 : .  whilst  the  ca , 6 . S t .  ( a ! and The  iron.stic £<J)  -easrnec*  TAP.LK  ||,  PIRST  c  (XV)  I  (XVII)  a  (XVIII)  8  (XIX)  a  (XX)-  8  (XI)  0  8  IIT.XOPVRANCSYL P U i f i R l H i . S . ( M s )  9.5  9.7  52.8  23.8  9.9  9.3  9.3  53.0  24.1  b  3.1  10.0  9.S  9.4  52.9  23.0  c  t.f,  52.5  12.0  52.6  12.0  23. 6  6.4  b  %7  c  2.8  10.0  10.0  9.7  -  -  -  52.6  I  2.8  9.6  9.6  9.5  4.5  2.6  12.2  S3.2  23. .7  b  2.9  10.0  10.0  9.5  .  53.0  23. .6  52.5  8.0  51.2  12.0  11.9  51.5  10.3  -  $.0  2.7  5.4  •  6.4  i3.S  b  5.7  8.6  C  2.7  I  2.7  b  8.6  8.6  S.O  9.6  9.6  9.6  9.6  9.6  9.6  -  2.6  9.7  9.7  9.7  4.3  c  6.0  7.8  8.5  8.5  5.0  a  6.3  b  6.0  8.0  •O  vS  c  2.8  9.5  9.5  9.5  a  2.6  <>.S  9.S  9.5  -  b  2.7  9.3  9.S  9.S  •  c  4.5  6.0  7.5  7.S  a  6.0  7.8  8.3  8.3 6.5  3.6  52.0  24.3  -  52.5  2S.0  3.7  !2.6  5!.;  24.3  3.6  !2.3  S2.4  10.4  •  -  5.0  3.0  12.2  .  53.4  24.2  53.4  24.1  -  -  53.4  24.3  5.0  5.0  12.0  51.2  7.5  -  -  -  SI.8  11.1  5.2  5.3  -  J.O  9.8  9.7  »  3.0  9.8  9.4  S3.0  24.6  b  3.0  9.9  9.9  SJ.O  24.4  10.2  12.0  •  -  53.1  S.2  6.2  8.0  52.6  •  6.2  7.8  5.8  S3.4  11.6  b  5.8  ^S 2  MO  2.7  11.0  5.8  7.0  11.0  53.0  22.2  10.8  -  2.0  2.8  2.3  1.8  5.5  7.3  10.7  53.0  21.7  :.8  10.0  -  1.8  5.1  7.3  10.8  53.0  21.8  e  6.6  a  7.4  b  7.0  3.4  3.4  vl  -  1.3  4.9  .  53.S  8.0  11.4'  -.52  1-2  '•5  9.5  1.8  10.0  10.0  4.5 .  3.6 .  13.0 .  1.5  10.0  10.0  .  .  .  b  Thf.  R -f v  l.l  9.S  1.S  19  4.9  2.0  a.l %  1.5  covipojnils  j R  listed  M - * M i r t - J at  v  -M  12.6  <S.6  M . S  45.5  -l.i  40.1  M.£  vi9  1.5  »  10.0 M2.5  S2.0  1.5  ial:itlo:is.  21.3  c  1.7  (b)  11.0  c  b  »  11.5  52.3  4.7  c  (XIV)  52.8  b  (VII)  8  FULLY 0 CSTERIFIF.O  10.0  c (XVI)  OF Tlir  2.9  •  a  CONSTANTS  2.7  (1)  t  OP.OCB C O W U N O  220  a b o v ? * > r e n e A s u ft--' MHz l n c M o r o f o r T i - d  for^  in c M c r o f 0 r a - d jolution  a /iowefS  (d) ;  49.0  l . i  48.5  M  6.0  M9.0  6.1  43.5  6.1  48.4  (c) , a c e t o r u - d ^ In a c e t o n e . d ,  (a)  solution  lr.i! b e n : («) .  -24-  F o r those compounds ( I , I T , V I I , I X , X T , X V , X V I I , X I X ) which possess a trans d i a x i a l ]9 ring, a  arrangement o f f l u o r i n e a t  and hydrogen  at  on a pyranose  1  F- H c o u p l i n g o f ca_. 24 Hz i s observed.  t o be e s s e n t i a l l y u n a l t e r e d when t h e  T h i s c o u p l i n g was found  s u b s t i t u e n t was OAc, OBz, OMe, o r  OH and i s a p p r o x i m a t e l y 4 times l a r g e r than those t r a n s d i a x i a l c o u p l i n g s observed f o r  ^ °f  t  n  B-hexopyranosyl 19 1  e  The magnitudes o f v i c i n a l  *H-*H  fluorides.  F- H c o u p l i n g s c o r r e s p o n d i n g t o a  nominal d i h e d r a l a n g l e o f 60° were found t o f a l l  i n two d i s t i n c t  ranges  which a r e : a)  f o r compounds w i t h an a x i a l f l u o r i n e a t proton at  b)  and an e q u a t o r i a l  (compounds V ,VI , X I I I , X I V ) t h e c o u p l i n g i s  Hz. f1.0-1.5 o r compounds w i t h an e q u a t o r i a l f l u o r i n e a t a x i a l proton at C  2  , and  (compounds I I I , I V , V I T I , X , X I I , X V I , X V T I I , X X )  the c o u p l i n g i s 7.5-12.6 Hz. A s i m i l a r c o n f i g u r a t i o n a l dependence has a l s o been observed p r e v i o u s l y f o r *H~*H c o u p l i n g s o f pyranose c a r b o h y d r a t e s * ^ , s t e r o i d a l a c e t a t e s ^ and f o r 9 1 1 o t h e r c a r b o c y c l i c systems' and i s a l s o observed f o r t h e H- H c o u p l i n g s o f the d e r i v a t i v e s under c o n s i d e r a t i o n .  Thus f o r d e r i v a t i v e s  (V,XI11,XIV) i n  which both p r o t o n s a r e e q u a t o r i a l t h e c o u p l i n g i s c a . 1.5 Hz, whereas, f o r derivatives  ( I , V I I , I X , X I , X V , X V I I , X I X ) which have one a x i a l p r o t o n , t h e  c o u p l i n g i s c a . 2.7 Hz. 19 Thus i t i s observed t h a t  1  ~F- H c o u p l i n g s c o r r e s p o n d i n g t o a d i -  h e d r a l angle o f 180° a r e l a r g e r than those which c o r r e s p o n d t o a d i h e d r a l a n g l e o f 60°. T h i s a n g u l a r dependence may be s i m i l a r t o t h a t d e r i v e d by 2 1 1 10 1 Karplus  f o r H- IT c o u p l i n g s .  More i m p o r t a n t l y  F- II c o u p l i n g s a r e  s e v e r a l times g r e a t e r i n magnitude .and a r c thus apt t o be more s e n s i t i v e , ( a b s o l u t e l y ) than t h e c o r r e s p o n d i n g * H- * 11 c o u p l i n g s , t o changes i n d i h e d r a l  -25-  angle.  T h i s aspect i s most l i k e l y t o be advantageous when i n v e s t i g a t i n g  c o n f o r m a t i o n a l l y m o b i l e r i n g systems. A l l o f the d e r i v a t i v e s s t u d i e d e x h i b i t e d a geminal c o u p l i n g approximately  50 Hz,  this coupling.  although  t h e r e are c l e a r l y two  d i s t i n c t ranges f o r  For those m o l e c u l e s w i t h an e q u a t o r i a l s u b s t i t u e n t at  the geminal c o u p l i n g i s ca_. 53.5  Hz, whereas, when the  a x i a l l y o r i e n t e d , t h i s c o u p l i n g has  of  Z^*  substituent i s  a v a l u e o f ca. 49 Hz.  Once again  t h e s e c o u p l i n g s are ca_. 4 t i m e s those found f o r *H-*H geminal  couplings^  i n s i m i l a r environments. 19 The  observation  ted to 4 ( J  two ) and  o f long-range  1  4  F- I! c o u p l i n g s  ( J ) were r e s t r i c -  d i s t i n c t c o n f i g u r a t i o n s , namely the e q u a t o r i a l : e q u a t o r i a l  4 the a x i a l : e q u a t o r i a l ( J  G ,G  4 cr Cjcl  J_  ).  The  p r e f e r r e d arrange-  H j C  ment. i s a g a i n s i m i l a r t o t h a t observed f o r *H-*1! long-range c o u p l i n g s t h a t the  4  J  ( c a . 1 Hz). couplings  e,e  (3-4 Hz)  i s n u m e r i c a l l y g r e a t e r than the ° y  4  J e,a  I t i s i n t e r e s t i n g t o note t h a t no s i g n i f i c a n t  corresponding  or  4  J  in  a,e  long-range  t o the a x i a l : a x i a l c o n f i g u r a t i o n c o u l d be  detected  e i t h e r from the *H s p e c t r a o r from measurement o f the l i n e w i d t h s o f .the f l u o r i n e t r a n s i t i o n s t h e m s e l v e s . 19 g e m i n a l , v i c i n a l and  long-range  A d e t a i l e d d i s c u s s i o n of these 1  F- 1! c o u p l i n g s w i l l be l e f t u n t i l  the  l a s t s e c t i o n o f t h i s t h e s i s where the s i g n s o f t h e s e c o u p l i n g s w i l l a l s o be discussed  (p.85-116) 19 I n s p e c t i o n o f the  the f.m.r. s p e c t r a e n c i e s and having  * F chemical  shifts  ($  values)  obtained  from  (Table I) r e v e a l e d s e v e r a l marked s t e r e o - s p e c i f i c depend-  i t i s convenient to consider  i n i t i a l l y o n l y those d e r i v a t i v e s  equatorially oriented substituents.  s e r i e s ) a f l u o r i n e s u b s t i t u e n t having  For such d e r i v a t i v e s , ( g l u c o -  an e q u a t o r i a l o r i e n t a t i o n (I I I , V I I I ,  -26-  X , X I I , X V I , X V I I I , X X ) has a s h i f t w i t h i n t h e range 4> +131.8* t o <!> +137.8, c  w h i l s t f o r a corresponding  c  a x i a l l y o r i e n t e d f l u o r i n e , t h e s h i f t i s <J> 19  + 147.8  t o 4>  +149.9 p.p.m.  On t h i s b a s i s t h e r e i's an average  F chemical  s h i f t d i f f e r e n c e o f 14.1 p.p.m. between t h e resonances o f an a x i a l  and an  e q u a t o r i a l f l u o r i n e s u b s t i t u e n t and i n every case t h e e q u a t o r i a l f l u o r i n e g i v e s a resonance t o low f i e l d o f i t s a x i a l c o u n t e r p a r t . thus p a r a l l e l s t h a t a l r e a d y r e c o g n i z e d  T h i s dependence 66-68 f o r t h e p.m.r. s h i f t s o f anomeric  60  and  other r i n g protons  " and, i n d e e d , f o r t h e anomeric p r o t o n  the d e r i v a t i v e s under d i s c u s s i o n .  The f.m.r. s h i f t s o f compounds i n t h i s  c l a s s show o n l y a s l i g h t dependence upon t h e n a t u r e s t i t u e n t s attached  o f t h e v a r i o u s Q_-sub-  t o t h e pyranose r i n g , a t l e a s t when these a r e  benzoate o r ' -methyl. which have acetoxy  shifts of  acetate,  Compare f o r example, t h e s h i f t s o f ( I ) and ( I I I )  substituents at  w i t h t h e s h i f t s o f (XIX) and (XX)  which have a b e n z o y l o x y s u b s t i t u e n t and (XVII) and ( X V I I I ) which have a methoxy s u b s t i t u e n t .  When t h e " f r e e " sugars were measured i n aqueous  s o l u t i o n s w i t h e x t e r n a l Freon-11 as r e f e r e n c e , t h e s h i f t o f t h e a-D-glucopyranosyl  fluoride  ( I I ) was e s s e n t i a l l y u n a l t e r e d from t h a t o f t h e f u l l y  a c e t y l a t e d d e r i v a t i v e ( I ) , whereas, t h e s h i f t o f t h e 8 - D - g l u c o p y r a n o s y l fluoride  (IV) r e s o n a t e d  derivative  (III).  to s i g n i f i c a n t l y higher f i e l d  (+8.1 p.p.m.) than  Thus, f o r a l l compounds h a v i n g o n l y e q u a t o r i a l o r i e n t e d 19  s u b s t i t u e n t s , t h e 'F c h e m i c a l  s h i f t provides a convenient  The ranges quoted a r e f o r c h l o r o f o r m  and u n e q u i v o c a l  s o l u t i o n w i t h c a . 20% CFCl.^  as i n t e r n a l r e f e r e n c e ^ and a r e r e f e r r e d t o as (J>  values.  The ^ F  chemical  c s h i f t s a r e somewhat c o n c e n t r a t i o n dependent and v a r y w i t h s o l v e n t t o some e x t e n t , thus they a r e o n l y quoted t o f o u r s i g n i f i c a n t f i g u r e s a l t h o u g h  they  were measured t o at. least, f i v e s i g n i f i c a n t f i g u r e s .  shift  was g r e a t e s t f o r t h e f u l l y  The c o n c e n t r a t i o n  a c y l a t e d g l u c o s e d e r i v a t i v e s ( I ) and ( I T I ) .  The  s h i f t o f t h e a-anomer v a r i e d by o n l y 0.2 p.p.m. over a c o n c e n t r a t i o n range o f 1.0-0.0 m o l a l , whereas, t h a t o f t h e B-anomer v a r i e d by 0.9 p.p.m.  -27-  means f o r i d e n t i f y i n g the o r i e n t a t i o n o f the  fluorine substituent  with  r e s p e c t t o the pyranose r i n g . A s t r i k i n g dependence of configuration  o f remote c e n t r e s i s noted when one  s h i f t of those d e r i v a t i v e s XIV)  F c h e m i c a l s h i f t on changes i n  p o s s e s s i n g an a x i a l s u b s t i t u e n t  i . e . h a v i n g the o-manno c o n f i g u r a t i o n .  The  which a l s o p o s s e s s an a x i a l f l u o r i n e at C^, t o +138.8  which c o i n c i d e s  glucopyranosyl f l u o r i d e s possible  rationales  c o n s i d e r s the  with that  chemical  at C,,  s h i f t of these  (V,XIII  f a l l w i t h i n the range <j>  range p r e v i o u s l y  (III,VIII,X,XII,XVI,XVIII  ft  f o r t h i s observation; e i t h e r that  There are  a l l o f the  p o s s e s s the  s h i f t s are  s e n s i t i v e t o the r e l a t i v e o r i e n t a t i o n o f the  uent a t t a c h e d t o the  adjacent centre.  more a p p r o p r i a t e ; however, at the the  a -I) - c o n f i g u r a t i o n ,  The  +137.6  observed f o r the XX).  or, that  f i e l d o f f.m.r. s p e c t r o s c o p y , a l t h o u g h i t had  Btwo  compounds  f l u o r i n e chemical substit-  l a t t e r e x p l a n a t i o n seemed  time o f t h i s s t u d y i t had  §  derivatives,  i n t h i s group do not extremcly  the  the  no p r e c e d e n t i n  a c o u n t e r p a r t i n the p.m.r.  69 f i e l d ' where i t has u e n t s can  at and  7  1  influence  been shown t h a t the  changes i n the  o r i e n t a t i o n of subst.it-  s h i f t s o f p r o t o n s at remote c e n t r e s .  F u r t h e r f.m.r. s t u d i e s i n t h i s l a b o r a t o r y on sugars f l u o r i n a t e d 1 7 2 63 and at , t o g e t h e r w i t h s p e c i f i c a l l y f l u o r i n a t e d c y c l o h e x a n e s *,  p u b l i s h e d d a t a from f l u o r i n a t e d s t e r o i d s ^ have a l l c o n f i r m e d the  a l i t y of t h i s p a r t i c u l a r s t e r e o s p e c i f i c . s h i f t o u t l i n e d The the  two  galactopyranosyl fluorides  gener-  above.  (VII) ft ( V I I I ) a l s o  exhibit  same g e n e r a l dependence as the D-gluco d e r i v a t i v e s , however, the  inherent  The s h i f t , o f the " f r e e " sugar ( V I ) , measured i n aqueous s o l u t i o n w i t h e x t e r n a l Freon-11 as r e f e r e n c e , was found to be e s s e n t i a l l y u n a l t e r e d . T h i s r e s u l t , p a r a l l e l s t h a t a l r e a d y found f o r the a - g l u c o d e r i v a t i v e (II). If t h i s invariance of chemical s h i f t i s general f o r a l l a x i a l l y o r i e n t e d f l u o r i n e s u b s t i t u e n t s , i t may s e r v e as a c o n v e n i e n t method f o r e s t a b l i s h i n g anomeric configurations.  -28-  a x i a l : e q u a t o r i a l s h i f t d i f f e r e n c e f o r t h e s e d e r i v a t i v e s i s o n l y 8.7 p.p.m. Comparison o f t h e c h e m i c a l s h i f t o f t h e a-anomer ( V I I ) shows t h a t t h i s d e r i v a t i v e resonates t o higher f i e l d vative  than t h e c o r r e s p o n d i n g a - g l u c o  deri-  ( I ) . Thus, i n v e r s i o n o f an a c e t c x y group at. C^ o f a pyranose c a r -  bohydrate  i n d u c e s an u p f i e l d s h i f t on a f l u o r i n e atom a t t h e anomeric c e n t r e . 19 Measurement o f t h e  fluoride tetraacetate  P chemical s h i f t o f a-D-allopyranosyl  (IX) showed t h a t t h e f l u o r i n e o f t h i s d e r i v a t i v e now  r e s o n a t e d t o lower f i e l d  o f ( I ) by 3.9 p.p.m.  When measurement o f t h e p.m.r.  s p e c t r a showed t h i s m o l e c u l e t o have t h e a - c o n f i g u r a t i o n , and t o possess t h e 4 C j symmetry, t h e low f i e l d  s h i f t was a t t r i b u t e d s o l e l y t o a d e s h i e l d i n g  e f f e c t o f an a x i a l a c e t o x y s u b s t i t u e n t on a c i s - a x i a l f l u o r i n e atom.  A  s i m i l a r e f f e c t i s w e l l c h a r a c t e r i z e d i n t h e f i e l d o f p.m.r. s p e c t r o s c o p y ^ ' ^ and has a l s o been observed f o r t h e p.m.r. parameters 19 consideration.  Mien t h e  o f t h e d e r i v a t i v e s under  F c h e m i c a l s h i f t o f t h e 8-anomer (X) was measured,  i t was found t o r e s o n a t e t o h i g h e r f i e l d  than i t s a x i a l c o u n t e r p a r t by 0.6  p.p.m. 19 As a r e s u l t o f these marked s t e r i c dependencies,  F chemical  . s h i f t s do n o t , by t h e m s e l v e s , c o n s t i t u t e u n e q u i v o c a l p r o o f f o r t h e o r i e n t a t i o n of  a f l u o r i n e s u b s t i t u e n t w i t h r e s p e c t t o a six-membered r i n g At t h i s p o i n t , t h e p o s s i b i l i t y t h a t these induced  system.  stereospecific  s h i f t changes on an a x i a l f l u o r i n e were a d d i t i v e , was i n v e s t i g a t e d .  Consider  T a b l e I I I , g i v e n b e l o w , i n which t h e c o n f i g u r a t i o n a l l y i n d u c e d s h i f t changes a r e recorded. To t e s t t h e a d d i t i v i t y o f t h e s e s t e r e o s p e c i f i c dependencies, an attempt its  t o s y n t h e s i z e o c - D - a l t r o p y r a n o s y l f l u o r i d e t e t r a a c e t a t e and measure  "F n.m.r. spectrum was u n d e r t a k e n .  Unfortunately the reaction  resulted  TABLE I I I - Induced S h i f t s f o r an a x i a l l y o r i e n t e d f l u o r i n e s u b s t i t u e n t , f o l l o w i n g i n v e r s i o n o f a "remote" a c e t o x y Compound  O r i e n t a t i o n o f acetate at  substituent  *c  Induced S h i f t p.p.m.  gluco  (I)  2 eq  marino  (V)  ax  eq  eq  + 138 8  -11.1  alio  (IX)  eq  ax  eq  + 146 0  -3.9  eq  eq  ax  + 151 1  + 1.2  C  galacto (VII)  C  3 eq  C  4 eq  + 149 9  0.0  i n a m i x t u r e o f t h e two anomeric f l u o r i d e s , which c o u l d n o t be Nevertheless,  t h e c h e m i c a l s h i f t o f t h e a-anomeric f l u o r i n e (which was 19  identified  separated.  by i t s  1 F- H c o u p l i n g c o n s t a n t s ,  J  p  ,. = 48.3 Hz, .7  = 2 . 7 Hz)  was p r e c i s e l y t h a t p r e d i c t e d on t h e assumption t h a t t h e s e induced  shift  changes a r e t r u l y a d d i t i v e . Calc. s h i f t  <p = S h i f t o f cx-glucose c  AJC^ i n v e r s i o n ) -  A(c^  inversion) = 149.9 - 11.0 - 3.9 -+134.9 Observed s h i f t = Deviation  =  +134.9 0.0 p.p.m.  On t h e b a s i s o f t h e s e e m p i r i c a l r u l e s (Table  I I I ) , for calculating  the c h e m i c a l s h i f t o f an a x i a l l y o r i e n t e d f l u o r i n e atom a t t a c h e d  to the  anomeric carbon o f a pyranose c a r b o h y d r a t e , i t i s p o s s i b l e t o p r e d i c t t h e 19 ' F chemical s h i f t s fluorides.  synthesized  ( <j) v a l u e s ) f o r t h e r e m a i n i n g r a r e hexopyranosy 1  These v a l u e s  a r e c a l c u l a t e d below:  Dr. C. Pedersen has mentioned ( p r i v a t e communication) t h a t he a l s o t h e s e d e r i v a t i v e s , which have f a i l e d t o c r y s t a l l i z e .  -30-  a-D-idopyranosyl f l u o r i d e t e t r a a c e t a t e :  = +149.9-11.1-3.9+1.2 = 136.1  a-D-talopyranosyl  = +149.9-11.1  f l u o r i d e t e t r a a c e t a t e : <*>  a-D-gulopyranosyl f l u o r i d e tetraacetate:^, I t i s not a p p r o p r i a t e  = +149.9  +1.2 = 140.0 -3.9+1.2 = 147.2  t o make s i m i l a r p r e d i c t i o n s f o r e q u a t o r i a l l y o r i e n t e d  f l u o r i n e s u b s t i t u e n t s s i n c e l e s s o f these d e r i v a t i v e s a r e a t p r e s e n t a v a i l a b l e and, f u r t h e r m o r e , t h e r e i s the p o s s i b i l i t y o f  conformational  d i s t o r t i o n f o r t h e s e anomcrs. W h i l s t t h e above d i s c u s s i o n has been p r i m a r i l y concerned w i t h 19 information  associated with the  . F parameters i t i s c o n v e n i e n t t o mention  at t h i s p o i n t , s e v e r a l f u r t h e r a s p e c t s which i n v o l v e some o f t h e *H p a r a meters . The  vicinal  *Ii-*H c o u p l i n g s  o f the a - g l u c o d e r i v a t i v e ( I ) appear  t o support q u i t e s u c c e s s f u l l y the o r i g i n a l , assumption t h a t t h i s d e r i v a t i v e e x i s t s e x c l u s i v e l y i n t h e ^C. symmetry. 1 2 1  Thus J _ „ = 10.0 Hz, J  = 9.6 Hz which i n d i c a t e ' '' t h a t these p r o t o n s a r e i n a t r a n s orientation.  However, t h e v i c i n a l  Hl-Hl  couplings  ( I I I ) a r e i n each case s m a l l e r than t h e i r c o u n t e r p a r t s  ~ J. diaxial  f o r t h e 8-anomer i n t h e a-anomer ( I ) .  I t i s noteworthy t h a t t h e g r e a t e s t d i f f e r e n c e s between a- and B-hexopyranosyl  f l u o r i d e s a r e found i n t h e g l u c o - d e r i v a t i v e s  XIX-XX).  I f i t i s accepted that these smaller couplings  t o time a v e r a g i n g  ( I - I I I , XV-XVI.and  between t h e two c h a i r forms ( C j £ *C  l o c a l o r s t a t i c d i s t o r t i o n s from t h e  a r e due e i t h e r  4  4  ) o r t o some  c h a i r symmetry, i t i s unexpected  t h a t t h e g l u c o - d e r i v a t i v e s would show t h e g r e a t e s t d i f f e r e n c e . theories"  '"  A l l previous  based on non-bended i n t e r a c t i o n s , would l e a d one t o expect  t h e s e d e r i v a t i v e s , more than any o t h e r s , t o e x i s t i n t h e s y m m e t r i c a l ^C^ c h a i r symmetry s i n c e t h i s would have a l l t h e s u b s t i t u e n t groups e q u a t o r i a l .  -31-  It  i s o f f u r t h e r i n t e r e s t t o note t h a t those g l u c o - d e r i v a t i v e s (XVI § XX)  with a benzoyloxy s u b s t i t u e n t (i.e.  at  e x h i b i t the s m a l l e s t  vicinal  couplings,  the maximum d e v i a t i o n from " n o r m a l i t y " . ) The d r i v i n g f o r c e f o r e i t h e r o f these e f f e c t s would be the powerful  "anomeric e f f e c t " o f the ( n o m i n a l l y ) e q u a t o r i a l l y o r i e n t e d s t i t u e n t , which would the a-anomer  f l u o r i n e sub-  tend t o f o r c e i t t o adopt an a x i a l o r i e n t a t i o n .  (I) where the f l u o r i n e s u b s t i t u e n t  i s already  axially  For  oriented  4 i n the  c o n f o r m a t i o n , t h e r e would be no n e c e s s i t y f o r such a d i s t o r t i o n .  F u r t h e r i n d i c a t i o n t h a t the 6-anomer i s s u b j e c t  to a conformational m o b i l i t y , 19  not  f e l t by the a-anomer, f o l l o w e d  f e r e n t temperatures.  the measurement o f t h e  In acetone s o l u t i o n , over the range  F shift  at d i f -  -80° t o +60°, the  19 F shift  o f the a-anomer was e s s e n t i a l l y i n v a r i a n t , w h i l s t t h a t o f the p-  anomer changed erature shift  Over the same temp-  range, the *H s p e c t r a o f the a-anomer showed oiily minor chemical  changes  by c a . 10%. 4 of a  by -8 p.p.m. (+143 t o +135 p.p.m.).  , whilst  f o r the B-anomer, the v i c i n a l  A l t h o u g h . t h i s evidence would  couplings increased  appear to i n d i c a t e the o c c u r r e n c e  1 Cj£  i n v e r s i o n p r o c e s s f o r the B-anomer, i t was not p o s s i b l e t o lower  the temperature s u f f i c i e n t l y t o " f r e e z e " out t h i s i n v e r s i o n .  This  was  unexpected, and bothersome,  s i n c e the energy b a r r i e r f o r the above c h a i r 14 c h a i r i n t e r c o n v e r s i o n was expected t o be of the o r d e r o f 10 Kcal/mole 74 19 I t i s known t h a t some "F s h i f t s are p e r s e temperature depend-  .ent.  However, i t seemed h i g h l y improbable t h a t the s h i f t  o f an equator-  19 ially  'F s u b s t i t u e n t  chemically  should be so markedly  s i m i l a r , but a x i a l l y o r i e n t e d  temperature dependent,  whilst a  f l u o r i n e should be e s s e n t i a l l y  independent o f temperature. The 4,6-0~benzylidcne d e r i v a t i v e s  (XI) and (XII) were examined  n e x t , s i n c e they a r e t r a n s - f u s e d six-membered r i n g systems t h e y s h o u l d , by analogy w i t h t h e t r a n s - c l e c a l i n system  15 75 ' * , be i n c a p a b l e o f undergoing  a  g r o s s , c h a i r - c h a i r c o n f o r m a t i o n a l i n v e r s i o n ; i n p a r t i c u l a r t h e pyranose r i n g 4  s h o u l d be l o c k e d i n t h e low temperature  conformation.  I t was e v i d e n t even b e f o r e t h e  s p e c t r a were r u n , t h a t t h i s a n t i c i p a t i o n was n o t e n t i r e l y  c o r r e c t s i n c e t h e v i c i n a l *H-*H c o u p l i n g s o f the B-anomer ( X I I ) were a g a i n s i g n i f i c a n t l y s m a l l e r than those o f the a-anomer ( X I ) .  The low temperature  run i n d i c a t e d t h a t t h e s e b e n z y l i d e n e d e r i v a t i v e s had n e a r l y t h e same chara c t e r i s t i c s as t h e p a r e n t g l y c o s y l f l u o r i d e s .  However, t h e temperature 19  induced s h i f t o f t h e B-anomer was s m a l l e r ( A  F = 3.5 p.p.m) than b e f o r e  19 F = 8 p. p. m. ) .  ( A  Two The  p o s s i b l e r a t i o n a l e s f o r the source o f t h i s o b s e r v a t i o n  f i r s t i s t h a t t h e observed  remain.  c h e m i c a l s h i f t dependencies r e f l e c t changes  i n t h e rotamer p o p u l a t i o n s o f t h e v a r i o u s e s t e r s u b s t i t u e n t s a t t a c h e d t o t h e ring.  However, i t i s d i f f i c u l t t o see why such changes s h o u l d be r e f l e c t e d  i n t h e s h i f t o f an e q u a t o r i a l , b u t n o t o f an a x i a l , f l u o r i n e s u b s t i t u e n t , i n s o f a r t h a t t h e C2-acetoxy s u b s t i t u e n t i s gauche w i t h r e s p e c t t o t h e f l u o r i n e s u b s t i t u e n t f o r both t h e a- and B- s e r i e s . I f we d i s c o u n t t h e above r a t i o n a l e , t h e f i n a l a l t e r n a t i v e i s t h a t the B-anomers s u f f e r a d i s t o r t i o n about t h e O^C^C,, r e g i o n o f the pyranose r i n g , i n t o a c o n f o r m a t i o n a l symmetry which i s capable o f undergoing  con-  f o r m a t i o n a l i n v e r s i o n p r o c e s s ( e s ) w i t h a v e r y s m a l l a c t i v a t i o n energy b a r r i e r . T h i s would appear t o be c o n s i s t e n t w i t h a l l t h e o b s e r v a t i o n s we have made thus f a r ; however, i t s h o u l d be emphasized t h a t no u n e q u i v o c a l evidence t o support t h i s suggestion i s a v a i l a b l e at t h i s time. evidence  The search f o r such  i s t o be c o n t i n u e d i n t h i s l a b o r a t o r y , (a) by measuring s p e c t r a a t  u l t r a - l o w temperatures  ( c a . -160°) i n the hope o f " f r e e z i n g " out any low-  -33b a r r i e r i n v e r s i o n p r o c e s s e s and (b) by examining other g l y c o s y l for  fluoride derivatives.  the n.m.r. b e h a v i o u r o f  I t i s felt, t h a t unequivocal  the e x i s t e n c e o f a c o n f o r m a t i o n a l i n v e r s i o n process can o n l y be o b t a i n e d  by a c t u a l l y " f r e e z i n g o u t " the process and o b s e r v i n g the s e p a r a t e of  evidence  the p a r t i c i p a t i n g conformers.  resonances  Besides the e x p e r i m e n t a l d i f f i c u l t i e s o f  c o n s t r u c t i n g a s u i t a b l e probe t h e r e are problems c.f f i n d i n g a s o l v e n t i n which the compounds are s u f f i c i e n t l y approximately important  first  order spectra.  s o l u b l e and at the same time g i v e The d i e l e c t r i c o f the s o l v e n t i s a l s o  s i n c e i f i t i s too h i g h the i n h e r e n t d i p o l a r i n t e r a c t i o n s , which  are l i k e l y r e s p o n s i b l e f o r the b e h a v i o u r o f these d e r i v a t i v e s , may w e l l be masked. A d e t a i l e d examination  o f the v i c i n a l  *H-*H c o u p l i n g s a r i s i n g  the C,. and  protons has r e v e a l e d an i n t e r e s t i n g dependence.  rotomer  the C^-C^ bond i s d i f f e r e n t  about  equatorially oriented  s u b s t i t u e n t at  from  The p r e f e r r e d  f o r those compounds h a v i n g an  ( t y p i c a l l y , D-gluco  derivatives)  than f o r those h a v i n g an a x i a l l y o r i e n t e d s u b s t i t u e n t ( D - g a l a c t o d e r i v a t i v e s ) . For compounds having the D-gluco J  r  . = 4 . 5 Hz and J.. ,  - 2.5 Hz.  c o n f i g u r a t i o n , i t i s observed  that  These v a l u e s are c o n s i s t e n t with a p r e -  f e r e n c e f o r t h e rot amer shown i n (A) below, i n which H<- i s gauche with r e s p e c t  H  4  OAc AcO  -34-  to both H  and H, . The d i f f e r e n c e i n magnitude between t h e s e two c o u p l i n g s , 1 2 b o t h o f which have t h e same nominal d i h e d r a l angle (60°) w i t h H i s anticA  b  5  8 9 i p a t e d on t h e b a s i s o f t h e c o n f i g u r a t i o n a l dependence ' Tt has been shown t h a t any p r o t o n which i s a n t i p a r a l l e l negative  s u b s t i t u e n t w i l l give smaller  p r o t o n which i s gauche w i t h r e s p e c t Thus '^2' ' w  l i c n  i  s  of vicinal  t o an e l e c t r o -  (less p o s i t i v e ) couplings  t o t h e same e l e c t r o n e g a t i v e  anti-planar with respect  couplings.  t o 0<. should  than a substituent.  give a smaller  c o u p l i n g than H^ . The c o u p l i n g s c o n f i g u r a t i o n are J,. , 5,6 these values where 11^  observed f o r d e r i v a t i v e s h a v i n g t h e D - g a l a c t o =7  Hz and J _ . -5.5 Hz. 5,6  2  The s u g g e s t i o n  i s that  1  are c o n s i s t e n t with a preference  i s antiparallel  (  f o r t h e rotamer shown i n ( B ) ,  180°) w i t h r e s p e c t  t o \\ , and H^ c  i s gauche.  OAc  I t i s i m p o r t a n t t o note t h a t H^ electronegative  i s not a n t i p a r a l l e l w i t h r e s p e c t  t o any  s u b s t i t u e n t , and hence would be expected t o e x h i b i t a f a i r l y  l a r g e c o u p l i n g w i t h H,.. A simple  ,  r a t i o n a l e f o r t h e above c o n f o r m a t i o n a l  be o f f e r e d as f o l l o w s .  preferences  can  Assume t h a t s t e r i c o r d i p o l a r ( o r both) i n t e r -  a c t i o n s between t h e C^-OAc and C^-OAc groups are o f s u f f i c i e n t magnitude t o e l i m i n a t e any s i g n i f i c a n t  population  o f a rotamer h a v i n g these  substituents  -35o r i e n t e d as i n (C) or (D)  : these i n v o l v e the e q u i v a l e n t  of a 1 , 3 - d i a x i a l  OAc  (C)  (D)  i n t e r a c t i o n on a c y c l o h e x a n e r i n g system. t o e f f e c t i v e l y e l i m i n a t e one it  A l t h o u g h i t i s more d i f f i c u l t - '  r e m a i n i n g conformer f o r each o f the two  i s noteworthy t h a t the r e s u l t s o b t a i n e d  series,  imply t h a t the conformer r e -  p r e s e n t e d i n (E) i s p a r t i c u l a r l y u n f a v o u r e d f o r both c o n f i g u r a t i o n s at  C..  (E) P o s s i b l y t h i s i s due  t o d i p o l a r i n t e r a c t i o n s w i t h the r i n g oxygen s u b s t i t u e n t . 76  A parallel  study  , i n t h i s l a b o r a t o r y , o f the above problem  i n v o l v e d the measurement o f the v i c i n a l M^-P^- c o u p l i n g s 6-deoxy-6-fluoro carbohydrates.  o f a ca_. 30 Hz c o u p l i n g  for  d e r i v a t i v e s h a v i n g the lj-gluco c o n f i g u r a t i o n i m p l i e s a marked p r e f e r e n c e  for  the rotamer e q u i v a l e n t f a s h i o n the ca.  The  observation  of a s e r i e s of  t o (A) i n which H,. and  are a n t i p a r a l l e i .  In  like  15 Hz c o u p l i n g found f o r the D - g a l a c t o s e r i e s i s c o n s i s t e n t  w i t h rotamer ( B ) .  The  i n t e r p r e t a t i o n o u t l i n e d above i s at v a r i a n c e w i t h t h a t 69  previously  p r o f f e r e d by Lemieux and Stevens  rotamer d e p i c t e d i n (F) was p r e f e r r e d .  , who suggested t h a t the  The s t r o n g e s t  argument i n f a v o u r o f  AcO OAc  (F) t h e i r assignment  i s that  C^ and Og, which  i s an apparent d i s a d v a n t a g e o f rotamer  the f u r t h e r i n s i g h t which has been  i t does not have OAc^, gauche w i t h r e s p e c t t o b o t h  as t o the dependencies o f v i c i n a l  *H-*H c o u p l i n g s ^  g a i n e d s i n c e Lemieux and Stevens p u b l i s h e d  appear t o e f f e c t i v e l y e l i m i n a t e t h e i r suggested rotamer. would  (A). N e v e r t h e l e s s ,  t h e i r study, would In p a r t i c u l a r , i t  not seem r e a s o n a b l e t o a s s i g n a c o u p l i n g o f ca_. 4.5 Hz t o an a n t i -  parallel  r e l a t i o n s h i p between two v i c i n a l p r o t o n s .  S i n c e t h e c o m p l e t i o n o f these s t u d i e s on the h e x o p y r a n o s y l f l u o r i d e Jullien  and co-workers have p u b l i s h e d two papers o f r e l e v a n c e ^ ^ ' ' * . 3  workers have been  concerned w i t h the comparison o f the s t e r e o s p e c i f i c  19 encies of  3  These depend-  1 F and  H n.m.r. parameters, and have m a i n l y i n t e r p r e t e d d a t a pub-  l i s h e d p r e v i o u s l y from t h i s and o t h e r l a b o r a t o r i e s . ments p a r a l l e l  those already o u t l i n e d  r e p e a t them h e r e . by t h o s e workers  I n s o f a r t h a t t h e i r com-  i n t h i s t h e s i s , no attempt  i s made t o  I t i s , however, i n t e r e s t i n g t o note t h a t the data o b t a i n e d from s e v e r a l  f l u o r o h y d r i n d e r i v a t i v e s are i n g e n e r a l  w i t h t h e dependencies p r e v i o u s l y o u t l i n e d  i n r e f e r e n c e 82.  accord  -37-  PENTOPYRAMOSYL FLUORTDPS  D u r i n g the i n i t i a l pentopyranosyl  stages o f the p.m.r. i n v e s t i g a t i o n o f the  f l u o r i d e s , i t became e v i d e n t t h a t the [i-anomers c o u l d not  be  4  c o n s i d e r e d t o e x i s t i n the "normal"  c h a i r conformation  ( C ).  In f a c t , a l l  o f the d e r i v a t i v e s i n t h i s s e r i e s w i l l be shown t o have a s i g n i f i c a n t p r e f e r e n c e f o r those c o n f o r m a t i o n a l symmetries i n which the f l u o r i n e uent has an a x i a l o r i e n t a t i o n .  substit-  In o r d e r t o p r e s e n t most c l e a r l y the  evidence  which l e d t o t h i s c o n c l u s i o n , the d a t a o b t a i n e d f o r the l i m i t i n g c a s e s , x y l o p y r a n o s y l f l u o r i d e s , w i l l be d i s c u s s e d i n some d e t a i l ; the d e r i v a t i v e s w i l l then be d i s c u s s e d by  the  remaining  analogy.  At the o u t s e t i t s h o u l d be r e a l i z e d t h a t the D-xylopyranose and D-glucopyranose systems are c l o s e l y r e l a t e d  ; i n f a c t , the s o l e  d i f f e r e n c e i s at C,., where the D-glucose system has an e q u a t o r i a l l y o r i e n t e d h y d r o x y m e t h y l s u b s t i t u e n t i n p l a c e o f Hj.  o f the D-xylose system.  S i n c e the  two systems are i d e n t i c a l i n a l l o t h e r r e g a r d s , they s h o u l d have s i m i l a r n.m.r. parameters. C o n s i d e r the 100 MHz triacetate  p.m.r. spectrum f o r a - D - x y l o p y r a n o s y l  (XXI) shown i n F i g . 4A.  the one a l r e a d y p r e s e n t e d  The  fluoride  resemblance between t h i s spectrum  f o r ct-D-gluconyranosyl  and  fluoride tetraacetate ( I ) ,  i n F i g . 1A (p.\-j ) , i s q u i t e e v i d e n t ; note the s i m i l a r i t y between the W H^ and \\  resonances.  The  t r a n s i t i o n s i n the complex r e g i o n at  x5.0,  which  had not a l r e a d y been a s s i g n e d t o \\^, were a s s i g n e d t o H^ s i n c e they had same s p l i t t i n g c e n t r e d at  T6  (9.7 Hz)  as t h a t found i n H^.  were a s s i g n e d t o the C  being a t t r i b u t e d to H  remaining  resonances  p r o t o n s , the t r i p l e t at h i g h e r  r  since i t displayed a large s p l i t t i n g b a.  (10.8  field.  Hz),  J  c h a r a c t e r i s t i c of a t r a n s - d i a x i a l coupling. s i t i o n s c e n t r e d at  The  the  x 6 . 0 2 , a s s i g n a b l e t o H_  T h i s l e f t the r e m a i n i n g  tran-  ,. which d i s p l a y e d the same geminal  1— ,  !  ,  4.0  F i g u r e 4. (XXI) and  Partial  I  .  100 MHz  I  .  1  .  !  .  5.0  45  1 5.5  .  1  .  1  .  s p e c t r a o f (A) a - D - x y l o p y r a n o s y l f l u o r i d e  (B) B-D-xylopyranosyl  fluoride triacetate  !  6.0  .  I  T  6.5  '  triacetate  (XXII) i n a c e t o n c - d ^  solutions.  -39-  TAHLF. I V .  F I R S T OSPRR-CHfcMIC.M SHIFTS  (,valur».  » values)  OF THE FULLY 0 - F S TI.R IPI H P -  D-PFATOr-iTi.-V.'O.^YL FLIIOIUnr.S.  H  RO'  V~  (XXI) R-OAc  RO.  F  IR  H  2  H  3  H  4  H  S  F  OAc  t  (  "  \  c  <.5J  5.11  4.51  4.55  6.03  6.25  7.90  7.95  7.9S  152.1  a  4.30  5.07  4.SS  4.97  6.02  6.29  7.98  8.02  8.02  151.3  b  4.4s  5.89  4.36  4.96  6.26  6.41  8.31  B.40  8.43  151.3  c  4.05  4.63  3.82  4.SO  5.42  5.92  151.6  (XXVI11)  a  3.94  4.47  3.83  4.39  5.67  5.92  151.0  R-O.lz  h  4.24  4.63  3.64  4.57  6.00  6.21  150.9  e  4.S7  (XXII)  a  4.S4  5.10  R*OAc  b  4.69  -  F  05  l  6.26  5.72  7.88  7.83  7.88  137.0  5.10  6.27  S.76  7.95  7.98  7.9S  136.6  S.73  6.60  6.03  8.39  8.39  8.43  136.1  5.04 4.94  4.85  -  c  4.25  4.70'  4.34  4.70*  5.80  5.40  137.3  (XXIX)  a  4.12  4.52-  4.28  4.52'  5.85  S.36  136.8  R.03:  b  4.42  4.58  4.23  4.87  6.27  5.76  136.7  4.12  4.65  3.79  4.S7  5.95  S.58  (XXIV) R.OAc  (XXV) R.OB:  4.42  4.75  5.8!  6.06  7.84  7.84  7.95  141.4  4.40  4.70  4.80  5.79  6.03  7.92  7.94  8.05  140.4  —  4.95  6.24  6.43  8.27  8.28  8.29  140.4  5.57  5.77  14C.4  4.2-  5.44  S.69  139.9  4.53  6.12  6.26  139.9  6.25  5.89  138.4  .7  4.60  4.13  -  4.3  -  4.14  3.95 4.44  .33  _  (xxx u ;  138.8 137.9  (XXX)  4.51  4.3 .  5.91  5.44  137.8  4.17  4.2 .  5.78  5.54  138.6  4.47  4.1  6.14  5.70  137.7  4.23  4.3  4 .23  4.83  4.3  4.7  4 4.7  5.35  6.14  7.86  7.90  7.93  153.7  5.79  6.72  7.92  7.97  8.07  153.0  6.31  6.51  8.28  8.33  8.35  152.8  ( )  R»OBi  0.  (XXVII). 5»04c  4.54  4.7  5.98  6.27  7.34  7.94  7.97  141.1  4 .40  4.7  S.'J7  6.28  7.87  8.00  8.05  140.7  4.76  4.5  6.09  6.42  8.31  8.40  8.42  140.5  1.22  4.2  5.65  5.96  140.7  4.05  4.1  S.S9  5.35  140.3  4.55  4.0  5.8<3  6.13  140.0  The  co-oounili  and  bjn;ene-d  listed  f i  a^ove were  [h) • o t>:t i n r . s . '  upfield  trc-i  protons  resonated  Freon-Il  t w a s  ca;S -cisurcj  in chlorofo — - d  THc f l u o r i c . ' . - c S e r - . i c . i ! used  as i r . t - - i r . a l  a t c . i . 2t ar.d : i . 2 . 5 : .  shifts  standard.  (c) . a c e t o n e - J  are n'loteJ The ber.toate  (a) t> '  in p.3.^.. ester  in  f.McrD f o n - d  (c 1 ,  a - : c l o n e -<1,  (a)  ar.J  -41-  H- H c o u p l i n g  (1(5.8 Hz)  ns .H  and a much s m a l l e r v i c i n a l c o u p l i n g  (5.7  Hz)  ~> a 19 i n d i c a t i v e o f a gauche r e l a t i o n s h i p w i t h I!,.. Measurement o f the F spectrum s u p p o r t e d t h i s o v e r a l l assignment s i n c e the geminal (53.3 Hz) 19 vicinal  (24.1  between H  Hz)  and  0  1 F- Ii c o u p l i n g s are i n d i c a t i v e o f a t r a n s - d i a x i a l  now  the spectrum ( F i g . 4B)  f l u o r i d e t r i a c e t a t e ( X X I I ) , which was corresponding  B-glucosyl  a-xylopyranosyl  f l u o r i d e (XXI).  worthy i n t h i s r e s p e c t .  (ca.  (Til). 10 Hz)  o f the  8-D-xylopyranosyl  a n t i c i p a t e d t o resemble t h a t o f  The The  H^ and 1L. resonances are p a r t i c u l a r l y n o t e v i c i n a l H^-H,, c o u p l i n g i s o n l y 3.5  Hz which i s  c o u p l i n g o f the g-gluco d e r i v -  F u r t h e r m o r e , n e i t h e r o f the !•!,. resonances e x h i b i t the  large  s p l i t t i n g a n t i c i p a t e d f o r the t r a n s - d i a x i a l c o u p l i n g w i t h H  ..  l i t t l e chance t h a t the exchange r e a c t i o n , used i n  the s y n t h e s i s o f t h i s d e r i v a t i v e from the known a - D - x y l o s y l c o u l d have e f f e c t e d s i m u l t a n e o u s l y  a l r e a d y shown  s i g n i f i c a n t , and  bromide t r i a c e t a t e ,  i n v e r s i o n at both C. and C,, 4 i  s o n a b l e r a t i o n a l e f o r the p.m.r. d a t a was Evidence had  the  Tt i s i m m e d i a t e l y apparent t h a t t h i s expec-  found f o r the c o r r e s p o n d i n g  S i n c e t h e r e seemed t o be  uent t o be  the  f l u o r i d e ( I I I ) and t o a c e r t a i n e x t e n t t h a t o f  t a t i o n i s not f u l f i l l e d .  ative  relation  F^.  Consider  h a l f the v a l u e  and  the o n l y r e a -  based on a c o n f o r m a t i o n a l  inversion.  the "anomeric e f f e c t " o f a f l u o r i n e s u b s t i t i t seemed p o s s i b l e t h a t i t had  d e r i v a t i v e t o adopt a c o n f o r m a t i o n  having  the ^C^  caused t h i s  symmetry; t h i s would a l l o w  the f l u o r i n e s u b s t i t u e n t t o adopt an a x i a l o r i e n t a t i o n but would a l s o r e q u i r e the acetoxy s u b s t i t u e n t s at C^jC^  and  t o be a x i a l l y o r i e n t e d .  i n v e r s i o n would account, f o r the s m a l l magnitudes o f the Hj-H^  This  and H^-H^  couplings  *The C p r o t o n s were a s s i g n e d -on the b a s i s o f the e m p i r i c a l r u l e s advanced by Lemieux and Stevens from c o n s i d e r a t i o n o f s h i e l d i n g parameters o f a c e t o x y s u b s t i t u e n t s on remote carbons. See a l s o r e f . 73. c  -42-  (3.2  and 3.6  Hz)  t o g e t h e r with the r a t h e r s m a l l v i c i n a l  the m u l t i t u d e o f long-range  c o u p l i n g s i n the v a r i o u s  " F-H  resonances.  I f i t i s accepted f o r the present that the g-xylo (XXII 5 XXIX) e x i s t  i n the C 1  o f the o t h e r p e n t o p y r a n o s y l  /}  c o u p l i n g and  0  derivatives  c o n f o r m a t i o n , then i t must be accepted that a l l  fluorides w i l l  adopt  that c h a i r  having the f l u o r i n e s u b s t i t u e n t a x i a l l y o r i e n t e d .  conformation  F u r t h e r , ..more-direct  evidence s u p p o r t i n g t h i s view, which i s c o m p l e t e l y independent arguments based  on the a n g u l a r dependence o f v i c i n a l  .  " F chemical  shifts  (4>  v a l u e s ) o f these  U s i n g the e m p i r i c a l r u l e s d e r i v e d p r e v i o u s l y , chemical s h i f t s  (<i>  v a l u e s ) o f an a x i a l  any  c o u p l i n g s f o l l o w s a con-  19 s i d e r a t i C T ! o f the  of  (see p.29  •  derivatives.  ) for predicting  f l u o r i n e , at the anomeric carbon  the (C^) ,  19 o f a pyranose  carbohydrate and u s i n g the  (XXI) as the r e f e r e n c e (<|>  ' F shift  - 152.1); i t i s p o s s i b l e t o c a l c u l a t e the  v a l u e s f o r a l l the remaining p e n t o p y r a n o s y l exclusively oriented. TABLE VI.  of a-xylopyranosyl f l u o r i d e ^  f l u o r i d e s , assuming t h a t they  exist  i n t h a t conformation h a v i n g the f l u o r i n e s u b s t i t u e n t a x i a l l y These c a l c u l a t e d s h i f t s are presented i n T a b l e VI and are comThe ' F Chemical S h i f t s (<{> v a l u e s ) o f the Pentopyranosyl F l u o r i d e s for:  Compound  Conformation  Orientation C  ct-xylo  (XXI)  a-lyxo  (XXVII)  q-ribo  (XXIV)  a-arabino  (XXXII)  B-xylo  (XXII)  B-lyxo  (  B-ribo  (XXTIT)  B-arabino  (XXX)  )  A  c  A  1  V 1,1  c'  \  2  o f A c e t a t e at C  3  C  Calc.  4  *c  Obs •c  Diff. p.p.m.  eq  eq  eq  -  152 1  -  ax  eq  eq  141. 0  1A1  +0.1  eq  ax  eq  14 8. 2  147 7  -0.5  ax  ax  eq  137. 1  138 4  + 1.3  ax  ax  ax  138. 3  137 0  -1.3  eq  ax  ax  149. 4  ax  eq  ax  142. 2  141 4  -0.8  eq '  eq  ax  1.53. 3  153 7  +0.4  -43-  pared t h e r e w i t h t h e experimental, v a l u e s .  I t can be seen t h a t t h e max-  imum d e v i a t i o n i s e s s e n t i a l l y t h e same f o r b o t h t h e a- and 3-pent.opyranosyl fluorides. U n f o r t u n a t e l y i t i s n o t p o s s i b l e t o p r e d i c t t h e chemical f o r a l l o f those c o n f o r m a t i o n s  shifts  having the f l u o r i n e e q u a t o r i a l l y o r i e n t e d  s i n c e t o o few model compounds a r e a v a i l a b l e .  However, t h e i n h e r e n t a x i a l :  10  equatorial  ~'V s h i f t d i f f e r e n c e (6  ) i s known t o be 12.1 p.p.m. f o r Da, e g l u c o s y l f l u o r i d e t e t r a a c e t a t e s ( IftI I I ) and -0.6 p.p.m. f o r t h e D - a l l o =  derivatives expected  (IXftX) and these v a l u e s can be used t o c a l c u l a t e t h e s h i f t s  f o r t h e B-xylo  (XXII) and B - r i b o ( X X I I I ) d e r i v a t i v e s i f t h e y were  4 t o adopt t h e  conformation.  pyranosyl f l u o r i d e t r i a c e t a t e  F o r example, u s i n g t h e s h i f t o f a-O-xylo(XXI) as r e f e r e n c e , t o g e t h e r w i t h t h e 6^ ^  value f o r the D-glucosyl f l u o r i d e s fluoride triacetate  ( I ) and ( I I I ) t h e B - D - x y l o p y r a n o s y l  (XXII) s h o u l d have a s h i f t o f 140.0 p.p.m.; t h i s i s  +3 p.p.m. from t h e e x p e r i m e n t a l v a l u e , whereas, t h e e r r o r i n t h e v a l u e c a l c u l a t e d f o r t h e ^C^ c o n f o r m a t i o n  i s -1.3 p.p.m.  c a l c u l a t e d value f o r 8-D-ribopyranosyl conformation  In l i k e f a s h i o n , t h e  fluoride triacetate  (XXIII) i n the  i s 148.8 p.p.m., which i s +7.4 p.p.m. from t h e observed  v a l u e ; i n t h i s case t h e e r r o r f o r t h e 19 A further set of  v a l u e i s o n l y -0.8 p.p.m.  F s h i f t comparisons can be f o r m u l a t e d , i n  which each o f t h e pentose d e r i v a t i v e s i s compared w i t h t h e c o n f i g u r a t i o n a l l y r e l a t e d hexose c o u n t e r p a r t .  T h i s i s shown i n T a b l e V I I .  p a r i s o n i t i s c l e a r t h a t an e q u a t o r i a l l y o r i e n t e d acetoxymethyl  I n t h i s comsubstit-  uent a t Cj.  d c s h i e l d s an a x i a l l y o r i e n t e d f l u o r i n e s u b s t i t u e n t a t  2.5 p.p.m.  C l e a r l y , i t would be o f some i n t e r e s t t o o b t a i n t h e r e s t o f t h e  " r a r e " g l y c o p y r a n o s y l f l u o r i d e s i n o r d e r t o complete t h e s e v a r i o u s  by ca_.  comparisons.'  -4419 TABLE V I I .  Comparison o f t h e  F Chemical S h i f t s  (<j> v a l u e s ) o f t h e Pentoses  ( a x i a l f l u o r i n e ) with t h e i r C o n f i g u r a t i o n a l l y Related Pentose  Hexose  *c  *c  a -xylo  (XXI)  a -ribo  + 2.2  a -manno(V) 138.8  141.1 (XXIV)  a -altro(  138.4  134.9  *c (XXII)  p.p.m.  a -ido  (  )  137.0 B--lyxo  (  a -gulo  (  )  B-- r i b o  (XXIII) a - t a l o  (  )  + 1.7  146.0  a -arabino(XXXII)  *c  Diff.  )  +2.3  a - a l i o (IX)  147.7  Hexose  8--xylo  149.9  (XXVII)  Pentose  p.p.m.  a -gluco (I)  152.1 a -lyxo  Diff.  a-Hexoses.  )  141.4 0--arabino(XXX)  +3.5  a -galacto(VII)  153.7  151 .1  + 2.6  I t now remains t o r e t u r n t o t h e d i s c u s s i o n o f t h e o t h e r n.m.r. p a r a meters o f these d e r i v a t i v e s t o see i f these i n d i c a t e any f a i l u r e s o r l i m i t 4 ations i n the previous  arguments, which have been based on s y m m e t r i c a l  and  With t h e e x c e p t i o n  1  C  4  conformations.  o f t h e fi-xylo d e r i v a t i v e s  C^ (XXII,  XXIX) and t h e q - a r a b i n o d e r i v a t i v e s (XXXII, X X X I ) , i t would appear t h a t t h e s y m m e t r i c a l c o n f o r m a t i o n s a r e c o n s i s t e n t w i t h t h e observed parameters. Thus the v i c i n a l c o u p l i n g s J f a l l w i t h i n t h e range 9.5 t o 10.8 Hz, i n agreement ' a, a with values  observed f o r t h e hexose d e r i v a t i v e s .  The v a l u e s  forvicinal J e ,a  couplings  fall  H  3  i n two d i s t i n c t r a n g e s , namely 2.0-3.5 Hz f o r c o u p l i n g s  H , ! I and 11^, and 5.0 - 6.2 Hz f o r those c o u p l i n g s between H 2  t h a t have no a s s o c i a t e d a n t i - p l a n a r e l e c t r o n e g a t i v e ^C^  4 &  between  and H_  e  groups ( d e r i v a t i v e s i n  conformation). The o b s e r v a t i o n  o f such l a r g e v i c i n a l c o u p l i n g s  ( c a . 6 Hz) between  two p r o t o n s t h a t a r e s e p a r a t e d by a d i h e d r a l angle o f 60° i s a t v a r i a n c e that.value  with  a n t i c i p a t e d (ca_. 2.5 Hz) from c o n s i d e r a t i o n o f t h e known c o n f i g 8 9 2 u r a t i o n a l dependencies i n c o n j u n c t i o n w i t h t h e K a r p l u s r e l a t i o n . These large couplings  occurred  i n the q-D-xylosyl  f l u o r i d e s (XXI) and ( X X V I I I ) ,  -45-  which appear t o e x i s t i n the t o t a l l y symmetric conformation by  the remaining c o u p l i n g s .  This v i c i n a l  coupling  as evidenced  i s even l a r g e r than the one  observed i n 2-deoxy-a-arabino-hexopyranosyl f l u o r i d e t r i a c e t a t e (XXXVIII) f o r which H_  , H  i s 5.2 Hz.  It i s therefore  apparent t h a t v i c i n a l  couplings  /C J3. a s s o c i a t e d with a - C ^ - f u n c t i o n , can e x h i b i t much l a r g e r c o u p l i n g s  than was  7 previously anticipated . Measurement o f  19  19 1 F- H  F s p e c t r a showed t h a t the v i c i n a l  couplings  o f these d e r i v a t i v e s were a l s o c o n s i s t e n t with the a n t i c i p a t e d symmetries. For a t r a n s - d i a x i a l r e l a t i o n s h i p between F^ and H^, the c o u p l i n g 26.3  Hz, w h i l s t f o r a gauche r e l a t i o n s h i p between these s u b s t i t u e n t s , a  coupling ported  o f 2 t o 5 Hz i s observed.  These v a l u e s  are s i m i l a r t o those r e -  p r e v i o u s l y f o r the hexopyranosyl f l u o r i d e s . Generally  the p e n t o p y r a n o s y l f l u o r i d e s gave c l e a r l y  s p e c t r a , i n at l e a s t one s o l v e n t , and the c o u p l i n g s by  i s 22.2 t o  a first  order  analysis.  spectrum was never f i r s t  extracted  were then e a s i l y  extracted  However, f o r the B-arabino d e r i v a t i v e (XXX) the  order  t h a t some check was r e q u i r e d  resolved  (see F i g . 5) and consequently i t was  to evaluate  from the s p e c t r a l s p l i t t i n g s .  the "guess" c o u p l i n g s These c o u p l i n g s  felt  t h a t were  were t e s t e d by com-  * puting  the t h e o r e t i c a l spectrum based on these "guess" parameters.  This  19 r e s u l t , f o r the It  i s evident  accurate  F spectrum, i s g i v e n below t h e a c t u a l spectrum i n F i g . 5.  t h a t even i n a h i g h l y coupled spectrum  values  f o r the c o u p l i n g s  (J.  . . -*-l) f a i r l y  and chemical s h i f t s can be  obtained.  A f u r t h e r s e t o f i n t e r e s t i n g comparisons concerns the geminal couplings;  F..-H  and H,. -IL .  F o r those d e r i v a t i v e s t h a t possess an a x i a l  * TWO SUM MODE B, program k i n d l y s u p p l i e d by Dr. J . Department, U n i v e r s i t y o f A l b e r t a , Edmonton, A l b e r t a .  MartinjChemistry  153.7  p.p.m.  H ,  B PROTON CHEMICAL. SHIFTS (T) H, H H Hi  4.23 a.83  2  4.66  3  4.62  SPIN-SPIN COUPLING CONSTANTS ( Hz) JFH,  51.0  JFH  2  23.9  JFH  3  OO  ^ F H„ J H, H 2 J  H,H  3  ^ H , H4  OO  2.7 -0.5 O.O  IO. 5 H2H3 J H 2 H 4 -0.2 3.0 J H,H.J  5 0 Hz.  F i g u r e 5.  (A) The  19,  F Spectrum  (B) T h e o r e t i c a l Spectrum,  o f g-D-Arabinopyranosyl F l u o r i d e T r i a c e t a t e  c a l c u l a t e d from the F i r s t - O r d e r parameters  (XXX) i n acetone- d, s o l u t i o n .  (guess) l i s t e d  at the r i g h t  i  -47-  s u b s t i t u e n t at C^, those 53.1  the geminal F^-M^  compounds h a v i n g the t o 53.5  Hz.  c o u p l i n g i s 48.6  c  which p o s s e s s an a x i a l acetoxy  c o u p l i n g ( c a . 13 Hz) XXXIII) having c a . 10.8  Hz.  noted i n the F^-H^  of  couplings  f l u o r i d e s . . However, i t i s i n marked c o n t r a s t w i t h  dependence observed f o r the geminal ^ g ~ ^ t ; XXX),  Hz, w h i l s t  substituent e q u a t o r i a l give couplings  T h i s same dependence was  o f the h e x o p y r a n o s y l  - 49.5  than do those  c o u p l i n g s ; compounds (XXT11 ,XXVT,  3  s u b s t i t u e n t at C^,  display a larger  d e r i v a t i v e s (XXI,XXIV,XXV,XXVII,XXVIIT,  an e q u a t o r i a l l y o r i e n t e d s u b s t i t u e n t , when the c o u p l i n g i s These two  geminal dependences w i l l be d i s c u s s e d l a t e r when  the s i g n s o f these c o u p l i n g s are g i v e n  (see p . H 5 j , f o r the p r e s e n t  i t suffices  t o mention t h a t i n each case the magnitude o f the c o u p l i n g accords w i t h conformation  the  having  the  an a x i a l l y o r i e n t e d f l u o r i n e .  These p e n t o s y l f l u o r i d e d e r i v a t i v e s a l s o e x h i b i t a wide s e l e c t i o n 4 o f long-range c o u p l i n g s a c r o s s f o u r bonds ( .1) which w i l l later  (see p. 9 9 ) .  anticipated  Again t h e i r occurence was  a l s o be  discussed  always i n a c c o r d w i t h  the  conformation. 19  The  two d e r i v a t i v e s whose p r e d i c t e d  F s h i f t s were s i g n i f i c a n t l y  at v a r i a n c e w i t h the o b s e r v e d v a l u e s , namely B - D - x y l o p y r a n o s y l acetate  (XXII) and cs-D-arabinopyranosyl  be d i s c u s s e d .  In a d d i t i o n t o the above d i s c r e p a n c y  o t h e r parameters o f these •in  (<i>  (XXXII) w i l l  trinow  value), several  two d e r i v a t i v e s appear t o be "anomalous"  some r e s p e c t s , resemble the B-gluco  viously.  fluoride triacetate  fluoride  and,  d e r i v a t i v e ( I I I ) discussed  For example, the parameters f o r these d e r i v a t i v e s show the  pregreatest  v a r i a t i o n with solvent. The  vicinal  *H-"'H c o u p l i n g s f o r the B-xylo d e r i v a t i v e s are l a r g e r  than a n t i c i p a t e d f o r the e q u a t o r i a l : e q u a t o r i a l c o u p l i n g s i n the *C  con-  f o r m a t i o n , whereas, t h e c o u p l i n g s f o r the a - a r a b i n o  smaller  4  d e r i v a t i v e s are  -48-  than expected f o r a d e r i v a t i v e h a v i n g a s y m m e t r i c a l The  geminal c o u p l i n g s f o r t h e s e two d e r i v a t i v e s no l o n g e r f i t 4  1  e i t h e r o f t h e ranges expected f o r "pure" data implies  confoi'mation.  or  conformations.  t h a t t h e s e two d e r i v a t i v e s , l i k e t h e S-gluco d e r i v a t i v e  This (III),  are e x c e p t i o n s t o t h e g e n e r a l i t y t h a t s y m m e t r i c a l c o n f o r m a t i o n s a r e f a v o u r e d . I t would appear t h a t  f o r t h e p e n t o p y r a n o s y l f l u o r i d e s , t h e anomeric  of the f l u o r i n e s u b s t i t u e n t  i s s u f f i c i e n t l y predominant  effect  to exert o v e r a l l  c o n t r o l o f t h e c o n f o r m a t i o n a l p r e f e r e n c e , and now t h e d r i v i n g f o r c e f o r c o n f o r m a t i o n a l d i s t o r t i o n i s t h e " c l a s s i c " non-bonded i n t e r a c t i o n between substituents  having 1,3-diaxial  interaction.  In t h i s r e g a r d i t would seem t h a t t h r e e 1 , 3 - d i a x i a l are r e q u i r e d  t o cause a s i g n i f i c a n t d i s t o r t i o n from t h e s y m m e t r i c a l  conformations C 4  whilst  or C . 1  X  4  chair  Thus (XXII,XXIX) and (XXX,XXXI) a r e d i s t o r t e d ,  (XXI,XXIII,XXIV,XXV,XXVI,XXVII,XXVIII,XXX  fewer 1 , 3 - d i a x i a l  and X X X I I T ) , which have  •  i n t e r a c t i o n s appear ( w i t h i n t h e l i m i t s o f t h e s e t e c h n i q u e s ) ,  t o be i n s y m m e t r i c a l c h a i r c o n f o r m a t i o n s , e s s a r y t o c o n s i d e r whether t h e s e d e v i a t i o n s all  interactions  (see D i a g . 2)  Again i t i s nec-  a r e merely t h e r e s u l t o f an o v e r -  i n v e r s i o n p r o c e s s between t h e two c h a i r c o n f o r m a t i o n s , o r , whether they  r e f l e c t d i s t o r t e d - c h a i r , or non-chair  c o n f o r m a t i o n s ; a g a i n t h e d a t a does  not enable a d e f i n i t e c o n c l u s i o n t o be drawn.  Variable  temperature  studies  on t h e B - x y l o d e r i v a t i v e gave s i m i l a r r e s u l t s t o those o b t a i n e d from t h e B-gluco d e r i v a t i v e , b u t now t h e s h i f t o n l y changed by ca_. 2 p.p.m. over t h e same temperature  range.  I t was o f some i n t e r e s t t o compare t h e b e h a v i o u r o f t h e two a c e t a t e derivatives (XXXI),  l i s t e d above w i t h t h e c o r r e s p o n d i n g t r i - O - b e n z o a t e s (XXIX) and  The v i c i n a l H-*H c o u p l i n g s were now much c l o s e r t o those v a l u e s 1 4 a n t i c i p a t e d f o r t h e C. c o n f o r m a t i o n i n t h e 6-D-xylo s e r i e s and t h e C. con1  ' • • OAc  ".' '  /3-xyJouxii)  Diagram 2.  /3-lyxo(  * • • • OAc  )  >S-ribo ( x x m )  The f a v o u r e d c o n f o r m a t i o n s o f t h e p e n t o p y r a n o s y l f l u o r i d e t r i a c e t a t e s .  diaxial interactions  £ - grabino i x x x )  Non-bonded 1:3-  p r e s e n t i n each m o l e c u l e a r e shown as ••«. l i n e s ; t h e F-H i n t e r a c t i o n s  c o n s i d e r e d i n t h i s t r e a t m e n t , t o be s i g n i f i c a n t .  are not  -50-  f o r m a t i o n i n the a - D - a r a b i n o - s e r i e s . a benzoyloxy  s u b s t i t u e n t i s a p p r o x i m a t e l y the same as t h a t o f an acetoxy  stituent, certainly  sub-  i t i s no s m a l l e r , t h i s s u r p r i s i n g o b s e r v a t i o n i m p l i e s  t h a t the anomeric e f f e c t benzoates  S i n c e the c o n f o r m a t i o n a l p r e f e r e n c e o f  o f the f l u o r i n e s u b s t i t u e n t i s g r e a t e r i n the  than i t i s i n the t r i a c e t a t e s .  v a t i o n s are not by themselves ever they do have an obvious  sufficient and  C l e a r l y these two t o warrant  important  isolated  tri-  obser-  f u r t h e r d i s c u s s i o n , how-  i m p l i c a t i o n which m e r i t s  further  investigation. W h i l s t the s t u d i e s d e s c r i b e d i n t h i s s e c t i o n were i n p r o g r e s s , two  o t h e r groups o f workers i n d e p e n d e n t l y r e p o r t e d r e s u l t s which are i n gen73  e r a l a c c o r d w i t h many o f the above o b s e r v a t i o n s . r i b o p y r a n o s e d e r i v a t i v e s and o f the anomeric e f f e c t  concluded  appears  that. "The  Coxon  of  operation, or non-operation  to be the p r i n c i p a l  p a r t i c u l a r c h a i r c o n f o r m a t i o n predominates."  studied a series  f a c t o r d e t e r m i n i n g which  In a somewhat, broader study, '  77c Norton  and T u r n e r  i n v e s t i g a t e d the thermodynamically  o s y l h a l i d e s and a l s o reached a halogen  favoured  pentopyran-  the c o n c l u s i o n that the "anomeric e f f e c t " o f  s u b s t i t u e n t i s o f predominate  importance  i n the c o n t r o l o f pento-  pyranose c o n f o r m a t i o n s . Of p a r t i c u l a r r e l e v a n c e t o the p r e s e n t study was 78 1 report t h a t g - D - x y l o p y r a n o s y l c h l o r i d e t r i a c e t a t e a l s o f a v o u r s the C^ conformation.  T h e i r a n a l y s i s o f the problem  was,  t o an e x t e n t , l e s s  complete  than t h a t d e s c r i b e d i n t h i s t h e s i s and t h e i r c o n c l u s i o n s are no more comp l e t e than those  presented.  a  -51-  F.lectrophilic A d d i t i o n Reactions of Glycals  In view o f t h e many methods now a v a i l a b l e f o r t h e s y n t h e s i s o f 23-25 unsaturated carbohydrate d e r i v a t i v e s  , i t was o f i n t e r e s t t o i n v e s t i g a t e  the u t i l i t y o f such d e r i v a t i v e s as p r e c u r s o r s f o r s p e c i f i c a l l y carbohydrates.  Kent and h i s co-workers  the a d d i t i o n o f t h e elements  fluorinated  3 ^ 79-81 have p r e v i o u s l y r e p o r t e d *'  o f " B r F " and " I F " , generated by l'eaction o f N30 32  h a l o s u c c i n i m i d e w i t h anhydrous l i q u i d MP for  a v a r i e t y o f reasons i t was f e l t  '  , to several glycals.  However,  t h a t t h e s e c o n d i t i o n s were not t o be  g e n e r a l l y a p p l i c a b l e t o u n s a t u r a t e d c a r b o h y d r a t e d e r i v a t i v e s , and a m i l d e r procedure  f o r t h e g e n e r a t i o n o f "XF" was developed.  w i l l be concerned triacetate  The p r e s e n t d i s c u s s i o n  m a i n l y w i t h t h i s a l t e r n a t i v e a d d i t i o n o f "XF" t o D - g l u c a l  (XXXIV), a l t h o u g h r e f e r e n c e w i l l a l s o be made t o r e l a t e d  systems.  As w i l l be seen, i t was p o s s i b l e t o prove t h e s t r u c t u r e s o f t h e s e d e r i v a t i v e s by u s i n g t h e f l u o r i n e magnetic  resonance  technique o u t l i n e d i n the previous  section. The p r e s e n t r e a c t i o n sequence i s b a s i c a l l y an e x t e n s i o n o f t h e 26a concept developed o r i g i n a l l y ' f o r a d d i t i o n o f "BrOMe" t o a l k e n e s , and 28 a p p l i e d s u b s e q u e n t l y t o c a r b o h y d r a t e d e r i v a t i v e s by Lemieux and co-workers  ,  29 In t h e s i m p l e s t c a s e , t h e a l k e n e i s a l l o w e d t o r e a c t w i t h bromine i n methanol s o l u t i o n t o produce both t h e d i b r o m i d e and t h e bromo-methoxy adduct, presumably  v i a t h e i n t e r m e d i a t e bromonium i o n .  t h e s i s r e q u i r e d t h e immediate removal fluoride.  The v a r i a n t proposed  i n this  o f t h e bromide a n i o n by s i l v e r mono-  R e a c t i o n o f t h e conce m i t a n t l y  formed f l u o r i d e a n i o n w i t h the  bromonium i o n i n t e r m e d i a t e , which had been generated i n t h e i n i t i a l the r e a c t i o n , s h o u l d then a f f o r d t h e d e s i r e d "BrF" adduct.  stage o f  As w i l l be shown  b e l o w , t h e above h y p o t h e t i c a l sequence proved t o be s u c c e s s f u l f o r "XF"  -52-  additions  (X = B r , T and CI) t o a , B - u n s a t u r a t e d c y c l i c e t h e r s . U t i l i z a t i o n o f t h e above sequence f o r e f f e c t i n g  "IF"  the a d d i t i o n o f  t o c y c l o h e x e n e has p r e v i o u s l y been the s u b j e c t o f some c o n t r o v e r s y .  Bergman and Shahak"^ used an excess o f cyclohexene as t h e r e a c t i o n  solvent 37  and c h a r a c t e r i z e d the product as 3 - i o d o - c y c l o h e x e n e .  Schmidt and M e i n e r t  used a c e t o n i t r i l e as s o l v e n t and r e p o r t e d t h e i s o l a t i o n o f t r a n s - 2 - i o d o 38 cyclohexyl fluoride.  However, an u n s u c c e s s f u l attempt t o r e p e a t t h i s s t u d y  resulted i n the i s o l a t i o n of N-acetyl-2-iodo-cyclohexylamine.  Recent, work i n  t h i s l a b o r a t o r y , by Mr. David J o n e s , has shown t h a t when a m i x t u r e o f benzene and a c e t o n i t r i l e i s used as s o l v e n t , t h e " I F " adduct can be i s o l a t e d  i n high  y i e l d ; t h e r e a c t i o n w i t h c y c l o h e x e n e f o l l o w s an e x c l u s i v e l y t r a n s mechanism.  ,  -53-  D-GLUCAL TRIACETATE (XXXIV)  When an a c e t o n i t r i l e s o l u t i o n (Flow Sheet  1) was  (XXXIV)  s t i r r e d w i t h s i l v e r m o n o f l u o r i d e , and a s o l u t i o n  bromine (10%, i n benzene) was occurred.  of D-glucai t r i a c e t a t e  of  added d r o p w i s e , an immediate p r e c i p i t a t i o n  Subsequent work up o f the r e a c t i o n m i x t u r e a f f o r d e d a s y r u p , i n  which were o b s e r v e d , t h r e e s e p a r a t e f l u o r i n e resonances  ( F i g . 6) whose  s h i f t s were c h a r a c t e r i s t i c o f p y r a n o s y l f l u o r i d e s ; t h e r e was  no e v i d e n c e f o r  71  72  any p r o d u c t s h a v i n g f l u o r i n e a t t a c h e d t o a secondary carbon  ' '.  The  major  component o f t h i s m i x t u r e r e a d i l y c r y s t a l l i z e d and, as w i l l be shown, below, i t has the s t r u c t u r e 2-bromo-2-deoxy-a-D-mannopyranosyl f l u o r i d e (XXXV).  A second d e r i v a t i v e ,  fluoride triacetate  found t o be  triacetate  2-bromo-2-deoxy-a-D-glucopyranosyl  ( X X X V I I ) , c r y s t a l l i z e d out more s l o w l y .  The t h i r d com-  ponent has not t o d a t e , been o b t a i n e d i n c r y s t a l l i n e form, but i t has been shown t o be 2-bromo-2-deoxy-B-D-glucopyranosyl f l u o r i d e t r i a c e t a t e Evidence l e a d i n g t o the s t r u c t u r a l e l u c i d a t i o n  (XXXVI).  o f t h e s e compounds w i l l now  be  discussed. 10 The "F resonance (<|> +1-19.9) o f compound ( X X X V I I ) , F i g . 6C, showed i n a d d d i t i o n t o the c h a r a c t e r i s t i c geminal "F- H c o u p l i n g (51.7 Hz) a l a r g e 19 1 (25.1 Hz) v i c i n a l f l u o r i n e was  F- II c o u p l i n g , which  immediately i n d i c a t e d  t r a n s - d i a x i a l w i t h the p r o t o n at C^',  that t h i s  t h e r e f o r e , t h i s compound  must have the a - c . o n f i g u r a t i o n . A n a l y s i s o f the p.m.r. spectrum, F i g . 7B, c o n f i r m e d t h a t t h i s compound had the D-£luco c o n f i g u r a t i o n ( l a r g e v i c i n a l c o u p l i n g s o f c a . 9 Hz between H_ ft H_, H„ ft H. and H. ft H ) and c o n f i r m e d ' ° — 2 3 .> 4 4 5 r  123.2 p.p.m.  136.0 p.p.m.  149.9 p.p.m. H — 0  1Q F i g u r e 6. The F Spectrum o f the R e a c t i o n M i x t u r e Obtained (XXXIV) with Br_ and AgF i n CH.CN/C.H. s o l u t i o n .  /  3  6 6  from the R e a c t i o n o f D-Glucal  Triacetate  Br (XLVI)  (XLVII)  (XLVlll)  1.  Br in C H , A g F in C H C N .  2.  N--bromosuccinimide  2  6  6  3  and  anhydrous  liquid HF in E t 0 . 2  3.  Br in C H 2  6  6'  , A g OBz  in C H .  ~*  6  4.  HF.  5.  a, HBr in H O A c ;  6  b, A g F in CH CN.  Flow Sheet I.  3  L-_  4.00 F i g u r e 7. (XLVIII) and solutions.  P a r t i a l 100 MHz  I  . . . . . . .  I .  . . . . . . .  I . .  . . . . .  4.50  I . . . . . . . . .  5.00  I .  .  .  .  .  I . . .  5.50  .  I ....  ,  I  6.00  .  I  I  r  6.50  s p e c t r a o f (A) l-0-benzoyl-2-bromo-2-deoxy-a-D-?luconyranose t r i a c e t a t e  (B) 2-bromo-2-deoxy-a-D-glucopyranosyl  fluoride triacetate  (XXXVII) i n c h l o r o f o r m - d  -57-  the a - c o n f i g u r a t i o n a t The  (J^  2  = 2.5 H z ) .  impure sample o f d e r i v a t i v e (XXXVI), gave a p.m.r. spectrum  consistent with-the  D-gluco c o n f i g u r a t i o n ( J ^ ^  c o n f i g u r a t i o n at C  (J  1  1 2  = 8.0 Hz).  o f t h i s d e r i v a t i v e was t o low f i e l d  9.0 Hz) and w i t h t h e S-  =  The f a c t t h a t t h e  19 F chemical  shift  (<|> =+136.0) o f t h a t o f t h e c o r r e s p o n d i n g c  82 a-anomer (4^.=+149.9) i s a l s o c o n s i s t e n t w i t h t h e i r r e s p e c t i v e anomeric. 19 1 19 c o n f i g u r a t i o n s . The F- H c o u p l i n g s observed i n t h e F spectrum ( F i g . 6R) o f t h i s compound a r e again 50.3  c o n s i s t e n t w i t h t h e above assignment  (geminal,  Hz-; v i c i n a l , 10.0 Hz) . • The f.m.r. spectrum o f compound (XXXV), '(' ig. 6A) e x h i b i t e d a r e s 7  19 onance a t <|> +123,2 which had a v i c i n a l  ] F- H c o u p l i n g o f 2.9 Hz, which  i n d i c a t e d a gauche r e l a t i o n s h i p between these s u b s t i t u e n t s .  Although the  p.m.r. spectrum i n d i c a t e d t h a t t h i s d e r i v a t i v e has t h e D-manno c o n f i g u r a t i o n (J = 3.95 H z ) , t h e v i c i n a l H^-^ c o u p l i n g (1.5 Hz) o f f e r e d no e v i d e n c e c o n c e r n i n g t h e anomeric c o n f i g u r a t i o n . However, t h e o b s e r v a t i o n t h a t t h e 2  3  19 F s h i f t was e s s e n t i a l l y temperature i n v a r i a n t (<j> = 0.16 p.p.m. between +30° and -80°), i n d i c a t e d t h a t t h i s d e r i v a t i v e has t h e a - c o n f i g u r a t i o n . This d e d u c t i o n f o l l o w s comparison w i t h t h e s t u d y o f h e x o p y r a n o s y l f l u o r i d e der i v a t i v e s reported p r e v i o u s l y i n the Hexopyranosyl S e c t i o n . t h a t replacement o f t h e oxygen s u b s t i t u e n t a t C  2  I t i s evident  by a bromine atom does not  19 a l t e r t h i s behaviour s i g n i f i c a n t l y since the assigned  F s h i f t o f (XXXVI), which i s  t h e B - c o n f i g u r a t i o n , changed by 3.2 p.p.m., w h i l s t t h a t o f (XXXVII)  changed by o n l y 0.1 p.p.m.  Thus a s t r a i g h t f o r w a r d a p p l i c a t i o n o f t h e f.m.r.  and p.m.r. methods a f f o r d e d a f a c i l e i d e n t i f i c a t i o n o f t h e t h r e e products.  reaction  S i n c e t h i s was e r a t i n g " B r F " , and  the f i r s t  a p p l i c a t i o n o f t h i s new  method o f gen-  a l s o o f f.m.r. as a method o f s t r u c t u r a l e l u c i d a t i o n , i t  was  d e s i r e a b l e t o c o n f i r m the above assignments by independent s y n t h e s e s .  The  first  of t h e s e s t a r t e d w i t h the s y n t h e s e s o f l-0-benzoyl-2-bromo-2-deoxy-  a-D-mannopyranose (XLVT) and  the c o r r e s p o n d i n g g-P-gluco isomer ( X L V I I ) .  The  29 p r o o f o f s t r u c t u r e o f t h e s e two chemistry  o f the P r e v o s t  spectra.  These two  d e r i v a t i v e s f o l l o w s from the known  r e a c t i o n and  from c o n s i d e r a t i o n o f t h e i r p.m.r.  d e r i v a t i v e s were then r e a c t e d  l i q u i d IIP, under c o n d i t i o n s which are known^'^" dynamically  stable glycopyranosyl  the a-anomer.  Reaction  stereo-  1  s e p a r a t e l y w i t h anhydrous ^  t o a f f o r d the most thermo-  f l u o r i d e which i n the p r e s e n t s e r i e s i s  o f the D-manno-derivative (XLVI) a f f o r d e d  as the  sole  p r o d u c t , a c r y s t a l l i n e m a t e r i a l i d e n t i c a l i n a l l r e s p e c t s w i t h the d e r i v a t i v e p r e v i o u s l y assigned  the q - D - m a n n o - c o n f i g u r a t i o n (XXXV).  r e a c t i o n c o n d i t i o n s , the D - g l u c o - d e r i v a t i v e  Under i d e n t i c a l  (XLVII) gave m a t e r i a l which  the same i n a l l r e s p e c t s w i t h the compound p r e v i o u s l y a s s i g n e d c o n f i g u r a t i o n (XXXVII). detected  by  In one  was  the - D - g l u c o a  such r e a c t i o n a second, minor component  was  f.m.r. s p e c t r o s c o p y which gave an i d e n t i c a l spectrum w i t h t h a t  the m a t e r i a l t e n t a t i v e l y a s s i n g e d t h i s d e r i v a t i v e isomerized  the B - g l u c o c o n f i g u r a t i o n (XXXVI).  r e a d i l y t o the a-anomer ( X X X V I I ) ,  this  Since  provided  46 f u r t h e r evidence  that  (XXXVI) i s the  B-gluco-derivative.  A l t h o u g h the above r e a c t i o n s p r o v i d e d s t r u c t u r e s o f the two a-anomers, i t was factory synthesis  a t t a i n e d as f o l l o w s .  benzoate (XLVII) w i t h HBr 83 glucopyranosyl  d e s i r e a b l e t o o b t a i n a more s a t i s -  f o r the 8 - g l u c o - d e r i v a t i v e  t h i s o b j e c t i v e , was  bromide  r e a s o n a b l e p r o o f f o r the  (XXXVI).  Reaction  P a r t i a l success of  o f the B-D-gluco bromo-  i n g l a c i a l a c e t i c a c i d a f f o r d e d the .  The  corresponding  p.m.r. spectrum o f t h i s crude p r o d u c t showed  t h a t no s t a r t i n g m a t e r i a l remained and  t h a t the bromide had  the q-D-gluco  of  -59-  coifiguration.  T h i s bromide was  then r e a c t e d , w i t h o u t p u r i f i c a t i o n , w i t h  s i l v e r monofluoride i n a c e t o n i t r i l e s o l u t i o n . h i g h y i e l d , as t h e s o l e g l y c o s y l f l u o r i d e cis  p r o d u c t , a-anomer, was  This reaction afforded i n  (f.m.r. showed t h a t none o f the  formed), m a t e r i a l h a v i n g s p e c t r a l  i d e n t i c a l w i t h t h o s e o f the 3 - D - g l u c o s y l f l u o r i d e syrupy m a t e r i a l was  (XXXVI).  properties Initially,  this  c o n t a m i n a t e d w i t h some o f the bromo-benzoate (XLVII)  which was p a r t i a l l y removed by c r y s t a l l i z a t i o n ; however, a l l attempts t o crystallize impurities sequence, glycosyl  (XXXVI) have f a i l e d , even though  i t c o n t a i n s l e s s than 5% o f  (p.m.r.); T.L.C. showed o n l y one s p o t .  A similar  reaction  s t a r t i n g w i t h the D-manno bromo-benzoate (XLVI) gave as the s o l e fluoride  demonstrates  ( f . m . r . ) , the a-mannosyl f l u o r i d e  c o n c l u s i v e l y t h a t the bromine at  exchange r e a c t i o n s .  A g a i n the f l u o r i d e was  (XXXV).  This reaction  p a r t i c i p a t e s d u r i n g these  contaminated w i t h i t s bromo-  benzoate p r e c u r s o r , however, as the crude bromide d i d not c o n t a i n any material  starting  (p.m.r.), the bromo-benzoate (XLVI) must have been formed d u r i n g  the exchange r e a c t i o n i t s e l f  (see l a t e r ) .  o b t a i n e d pure a f t e r f r a c t i o n a l  The mannosyl f l u o r i d e  (XXXV) was  crystallization.  To f u r t h e r c h a r a c t e r i z e the a - I j - m a n n o - d e r i v a t i v e (XXXV) attempts were made t o remove the bromine s u b s t i t u e n t from C.^ by h y d r o g e n o l y s i s , which 84 s h o u l d a f f o r d the known A l t h o u g h a pure specimen olysis  2-deoxy-a-D-arabino-hexopyranosyl  f l u o r i d e (XXXVIII).  c o u l d not be i s o l a t e d from an a t m o s p h e r i c  hydrogen-  ( p a l l a d i u m c a t a l y s t ) , i t was p r e s e n t i n the r e a c t i o n p r o d u c t t o the  e x t e n t o f c a . 40% as e v i d e n c e d by b o t h f.m.r. and p.m.r. s p e c t r o s c o p y . The  f.m.r. spectrum showed, a p a r t from a s m a l l amount o f the s t a r t i n g m a t e r i a l  r e m a i n i n g , and t h e d e s i r e d p r o d u c t ( X X X V I I I ) , no o t h e r g l y c o s y l resonances.  fluoride  I n t e r e s t i n g l y , the p.m.r. spectrum showed t h a t the major  p r o d u c t o f the h y d r o g e n o l y s i s was l j - g l u c a l  triacetate  (XXXIV) .  by-  S i n c e the  -60-  bromo-fluoro  derivative  (XXXV) c o u l d be r e c o v e r e d i n h i g h y i e l d  after  s t i r r i n g w i t h d i - e t h y l a m i n e and p a l l a d i u m - c h a r c o a l a t 100° f o r 2 h r , t h i s by-product  c o u l d n o t have come d i r e c t l y from The  (XXXV).  demonstrated s u c c e s s o f t h e Eh^/AgF reagent  a d d i t i o n o f "BrF" t o D-glucal t r i a c e t a t e  f o r e f f e c t i n g the  (XXXIV), prompted t h e e x t e n s i o n  o f t h i s approach t o t h e a d d i t i o n o f " I F " t o (XXXIV).  Flow sheet 2 o u t l i n e s  the r e a c t i o n s which were s t u d i e d and t h e p r o d u c t s which were i s o l a t e d .  Since  the b a s i c format o f t h i s p a r t o f t h e work p a r a l l e l s t h a t d e s c r i b e d above f o r the a d d i t i o n o f " B r F " , a d e t a i l e d d i s c u s s i o n w i l l i s o u t l i n e d i n the Experimental products  Section.  not. be g i v e n  I t i s s u f f i c i e n t t o s t a t e that the  i s o l a t e d i n c r y s t a l l i n e form were 2-deoxy~2-iodo~ct  fluoride triacetate triacetate  (XLI) ; an impure sample o f syrupy  the a-D-marino-derivative the c o r r e s p o n d i n g  -D-mannopyranosyl  (XXXIX) , 2-deoxy-2-iodo-a-D-glucopyranosyl  pyranosyl fluoride t r i a c e t a t e  ; t h e method  fluoride  2-deoxy-2-iodo-8-D--gluc;o-  (XL) was a l s o i s o l a t e d .  The *H spectrum o f  (XXXIX) i s shown i n F i g . 8B, t o g e t h e r w i t h t h a t o f  1-' b e n z o a t e ( F i g . 8A) f o r  comparison.  At t h i s p o i n t , a comparison w i l l be made o f t h e procedures f o r 30-3? adding t h e elements o f "XF" o u t l i n e d above and t h e Bowers, method" together with a discussion o f points of mechanistic  interest.  33 81 Kent and co-workers  ' " have s t u d i e d t h e Bowers., a d d i t i o n o f  " B r F " and " I F " t o D - g l u c a l t r i a c e t a t e .  T h i s r e a c t i o n has been r e p e a t e d  d u r i n g t h e p r e s e n t s t u d y and w i t h t h e a i d o f f.m.r. s p e c t r o s c o p y , t h e products  (shown i n T a b l e V I I I ) , t o g e t h e r w i t h t h e i r r a t i o s , have been  The major component?, which they r e p o r t e d as t h e B-manno d e r i v a t i v e s to be i d e n t i c a l w i t h t h e q-D-mannopyranosyl f l u o r i d e s  found.  we'iefound  (XXXV f, XXXIX) de33 81 scribed i n this thesis. I t i s evident that the p u b l i s h e d " " ' description o f these d e r i v a t i v e s as p o s s e s s i n g t h e 8-D-manno c o n f i g u r a t i o n , w i l l have t o be  1.  I in C H , A g F in  2.  N-iodosuccinimide and  2  6  CH CN,  6  3  anhydrous  liquid H F in E t 0 . 2  3.  ] in C K , A q O B z 2  4.  6  in  C H .  6  6  HF.  Flow Sheet 2.  6  3.50  F i g u r e 8. (L)  4.00  P a r t i a l 100 MHz  4.50  5.00  5.50  T  6.00  s p e c t r a o f (A) l-0-benzoyl-2-deoxy-2-iodo-a-D-7nannoTy/rano5e  and.(B) 2-deoxy-2-iodo-a-D-mannopyranosyl f l u o r i d e t r i a c e t a t e  (XXXIX) i n a c e t o n e - d  A  triacetate solutions.  -63-  TABLE V I I I .  Product R a t i o s f o r t h e A d d i t i o n o f t h e Elements o f "XF" and o f "XOBz" t o D-Glucal T r i a c e t a t e (XXXIV).  V~~^~—-TT"°  Products*  AgF + X  11  F  F x = Br  70%  9%  21%  -  X = I  60%  6%  34%  -  X = Br  55%  9%  30%  7%  X = I  71%  23%  3%  0%  X = Br  31%  26%  42%  X = I  64%  8%  28%  2  I IF + NXS  F  +  AgOBz + X_  2.  -  R a t i o s determined by i n t e g r a t i o n o f the f.m.r./or p.m.r. s p e c t r a . NXS = N - h a l o s u c c i n i m i d e .  -64-  c o r r e c t e d : as a d i r e c t  result  i t i s n e c e s s a r y f o r Kent's p r o o f o f a " c i s "  mechanism t o w i t h s t a n d c l o s e r e x a m i n a t i o n . Bowers  I t i s noteworthy  a d d i t i o n o f "BrF" to D - g l u c a l t r i a c e t a t e  (XXXIV), a product  from the a d d i t i o n o f HF a c r o s s the double bond i s formed, a  -D-arabino-hexopyranosyl  fluoride  (XXXVIII).  t h a t i n the  The  arising  namely, 2-deoxy-  f o r m a t i o n o f t h i s product  35 a was  not a n t i c i p a t e d s i n c e Pedersen' '  with anhydrous  HF a f f o r d s  erythro-hexosyl f l u o r i d e . product r a t i o s , r e s u l t i n g "XF",  has shown t h a t treatment o f (XXXIV)  4,6-di-0_-acetyl-2,3-didehydro-2,3-dideoxy-DHowever, n e g l e c t i n g  the above "by-product", the  from these two d i f f e r e n t methods f o r g e n e r a t i n g  are exttemely c l o s e , which- suggests t h a t they r e s u l t  from a b a s i c a l l y  s i m i l a r medianism. Before d i s c u s s i n g any d e t a i l s o f t h i s mechanism i t i s n e c e s s a r y t o c o n s i d e r the s t e r e o s p e c i f i c i t y o f some o f the r e a c t i o n s encountered d u r i n g the p r o o f o f s t r u c t u r e o f the "BrF" adducts.  The most important o f these  concerns the f l u o r i n e exchange r e a c t i o n s o f the g l y c o s y l bromides i n the c o n v e r s i o n o f (XLVI) t o (XXXV) and  (XLVII) t o (XXXVI).  involved  In both  i n s t a n c e s t h i s r e a c t i o n proceeds t o g i v e e x c l u s i v e l y t r a n s g l y c o s y l  fluorides  which  (or at  i n d i c a t e s t h a t , n e i g h b o u r i n g group p a r t i c i p a t i o n o f a halogen  l e a s t o f Br) s u b s t i t u e n t exchange at C^. to  at C„ i s a powerful i n f l u e n c e c o n t r o l l i n g  It i s p a r t i c u l a r l y significant  fluoride  t h a t the c o n v e r s i o n o f  (XLVII)  (XXXVI) does not l e a d to the f o r m a t i o n o f any o f the "-anomer, which i s  formed,  i n c_a. 9% y i e l d , d u r i n g the "XF"  addition reaction i t s e l f .  This  finding  immediately excludes the p o s s i b i l i t y , which we have thus f a r i g n o r e d , 83  t h a t the "XF" a d d i t i o n merely i n v o l v e s the f o r m a t i o n o f the 1,2-dibromide which  s u b s e q u e n t l y r e a c t s with the s i l v e r  ,  f l u o r i d e t o g i v e the g l y c o s y l  fluoride. The  c o n v e r s i o n o f (XLVI) e x c l u s i v e l y t o (XXXV) demonstrates  conclusively  that  a h a l o g e n atom  course o f the t h i s exchange.  (bromine) at  o f a pyranose c a r b o h y d r a t e c o n t r o l s  exchange r e a c t i o n at C^,  when s i l v e r  T h i s exchange proceeds with  100%  f l u o r i d e i s used t o e f f e c t  retention of  configuration  at C j , p o s s i b l y v i a an S ^ i mechanism, i n which the bromine at Z^ i n the  e j e c t i o n o f the h a l i d e at C^,  which i s s u b s e q u e n t l y d e s t r o y e d by  forming a halonium type  the  incoming n u c l e o p h i l e ,  T h i s observed p a r t i c i p a t i o n o f halogen reactions  79-81  at C 1 has  an  the  (bromine) at C  2  participates  intermediate, F~. i n exchange  33 important s i g n i f i c a n c e as to the proposed mechanisms '  for electrophilic  addition reactions  of g l y c a l s .  Lemieux and  Fraser-  step  formation  28b Reid  proposed f o r such r e a c t i o n s  o f a c y c l i c halonium i o n and t o be  a resonance h y b r i d  t h a t the  o f the  a trans  structures"  (more i m p o r t a n t l y ) c i s p r o d u c t s . c y c l i c halonium i o n resonance with  (A)  (8) and  p r o d u c t s ) not  "XF"  could  clearly  afford  to see  or  why  a d d i t i o n should be  c y c l i c halonium i o n p o s t u l a t e d  i s obviously  f o r t h i s apparent  expected  ( f o r example),  lead to e i t h e r trans  a d i r e c t "XF"  ( C ) , whereas the  to compare the  could  (A)  However, i t i s d i f f i c u l t  i n resonance with e i t h e r  offered  inappropriate  (C)  formed d u r i n g  the halogen exchange r e a c t i o n  be  (C)  statement i s a c c e p t a b l e i n s o f a r t h a t (B) and  i s the  a c t u a l t r a n s i t i o n s t a t e "can  (B)  p r o d u c t , w h i l s t both  a l e s can be  initiating  following canonical  (A) This  t h a t the  (by  (B) or  a in for  lack of formation of c i s - . (C).  dilemma. One  Several i s that  possible rationi t is totally  a d d i t i o n r e a c t i o n v/ith the  exchange r e -  -66-  action.  However, s i n c e p a r t i c u l a r attempts were made d u r i n g  keep the r e a c t i o n c o n d i t i o n f o r these two p o s s i b l e , the  above statement seems to beg  i s that  i n the  has  form  the  sequences the  (C); i t s f o r m a t i o n  from the r i n g oxygen as  as near i d e n t i c a l  issue.  case o f e l e c t r o p h i l i c a d d i t i o n s , the  initially  products,  or t o  necessarily  (A) which by  (C) to be  i o n s A,B,C  then r e a c t  Alternatively, i t  exchange r e a c t i o n s would  lead e x c l u s i v e l y to the t r a n s p r o d u c t .  The  important  i s t h a t i t r e q u i r e s the  i n e q u i l i b r i u m with each o t h e r ,  a reasonable expectation  assistance  (B) which would a l s o l e a d to c i s or trans  analogy with the AgF  t h i s h i g h l y speculative proposal  formed ion  T h i s carbonium i o n c o u l d  d i r e c t l y with F" to g i v e e i t h e r c i s or t r a n s p r o d u c t s . c o u l d change to the carbonium-ion  as  A second r a t i o n a l e  c o u l d r e s u l t from a n c h i m e r i c  i n d i c a t e d below.  t h i s work to  ions  feature  (A),  (B)  r a t h e r than i n resonance.  s i n c e i t must be  recognized  a l l have d i f f e r e n t c o n f o r m a t i o n a l  t h a t the t h r e e  r e q u i r e m e n t s , which  of  and  This i s distinct  should  minimize e f f e c t i v e resonance between them. To  account f o r the  exclusive  formation  of trans products during  exchange r e a c t i o n s , i t would be n e c e s s a r y to p o s t u l a t e halonium i o n such as e q u i l i b r i u m between  (A) with F (A)  and  In view o f the p a u c i t y pursuing  be v e r y  (B) or  AgF  that r e a c t i o n of a  f a s t compared with the  possible  (C).  o f r e a l l y d e f i n i t i v e data i t i s not  t h i s d i s c u s s i o n f u r t h e r at t h i s time.  Instead  worthwhile  i t i s important  to  -67-  draw a t t e n t i o n to the  s i m i l a r i t y between the product r a t i o s f o r these 28b  "XF"  additions  f o r "XOR" "XOR"  and  those p r e v i o u s l y r e p o r t e d  addition.  Obviously,  r e a c t i o n s are s i m i l a r .  t h a t s t u d i e s o f "XF" gaining  by  Lemieux and  the b a s i c c h a r a c t e r i s t i c s o f the  On  this basis  a d d i t i o n r e a c t i o n s may  serve  f a s h i o n the  configurations  Already proved to be selective  one  useful.  o f the p r o d u c t s a r i s i n g  "XF"  presence  o f the  r e a c t i o n s , i t was  , the two  n e c e s s a r y to e f f e c t the Following  p r o d u c t s a r i s i n g from  However, the o b s e r v a t i o n ,  c l o s e l y the  trans by  f.m.r.  o f the q - g l u c o adduct from an " I F " a d d i t i o n to "IOBz" a d d i t i o n .  crude r e a c t i o n mixture by p.m.r. s p e c t r o s c o p y r e v e a l e d  Following  a s i m i l a r r e a c t i o n sequence "BrOBz" a d d i t i o n  (XXXIV) r e s u l t e d i n s i g n i f i c a n t  amounts (ca. 26%)  the  to  of the c i s or a - g l u c o  (XLVIII). It i s t h e r e f o r e , c l e a r l y e s t a b l i s h e d t h a t e l e c t r o p h i l i c  reactions  addition  can r e s u l t i n t r u e c i s a d d i t i o n to the double bond o f  g l y c a l s , although the sult  stereo-  (ca.8%) o f an anomeric resonance c o r r e s p o n d i n g t o the q - g l u c o (LII)  derivative.  adduct  to  unequivocal  l e a d i n g to the  (XXXIV), prompted the r e i n v e s t i g a t i o n o f the o r i g i n a l Inspection  Thus,  been encountered where such a "model" study  a d d i t i o n o f "IOBz" were i s o l a t e d . s p e c t r o s c o p y , o f ca. 9%  additions.  from these r e a c t i o n s .  a d d i t i o n o f "XOBz" t o D - g l u c a l t r i a c e t a t e (XXXIV). 29 Levine  suggest  F chemical s h i f t s  During the course of r e a c t i o n s  syntheses o f the  method o f Lemieux and  "XOR"  hence determine i n a f a c i l e and  s i t u a t i o n has  and  as convenient models f o r  taken o f the wide d i s p e r s i o n o f  monitor the product r a t i o s and  "XF"  i t seems r e a s o n a b l e to  i n s i g h t as t o the nature o f the more general 19  advantage can be  Fraser-Reid  should  be  c i s product  acetylated  i s u s u a l l y a minor component.  This  compared with those found f o r e l e c t r o p h i l i c a d d i t i o n  reactions 6*5 are o b s e r v e d ' ' ' f o r "PI  to cycloalkenes,  i n which e x c l u s i v e t r a n s a d d i t i o n s  re-  -68-  those r e a c t i o n s that the  the  p r o c e e d i n g v i a an  r i n g oxygen o f the  intermediate  c a t i o n , thus a l l o w i n g  t o g l y c a l s should have, as  quite  and  evident  the  of  formation of c i s products.  concept, o f c i s a d d i t i o n o f e l e c t r o p h i l e s  i t s foundation,  [the q-manno d e r i v a t i v e  general  It i s therefore  g l y c a l s must s i g n i f i c a n t l y a l t e r the n a t u r e  It i s r e g r e t t a b l e t h a t the  structure  i o n i c mechanism.  the  i n c o r r e c t assignment o f a  (XXXV)], s i n c e the  result is  o f some importance as f a r as e l e c t r o p h i l i c  obviously  addition  33 reactions  to a,B-unsaturated c y c l i c e t h e r s  E l e c t r o p h i l i c addition reactions  are  concerned.  i n v o l v i n g c h l o r i n e were found to  somewhat more complex than f o r e i t h e r bromine or i o d i n e and separately,  acetonitrile/benzene  s t i r r e d vigorously  w i t h the  s o l u t i o n of D-glucal  w i t h s i l v e r m o n o f l u o r i d e and  s u s p e n s i o n , an  Subsequent work up  described  o f the  r e a c t i o n mixture a f f o r d e d  resonances were d i s c e r n a b l e . to D - g l u c a l  T h i s was  t r i a c e t a t e (XXXIV) has  isomers, the  (f.m.r. d a t a ) .  t r i a c e t a t e (XXXIV)  c h l o r i n e gas  immediate p r e c i p i t a t i o n occurred  f o u r s e p a r a t e " g l y c o s y l fluoride'.''resonances;  diastereo  thus  below.  Mien an was  are  be  the  fourth.being  the  Attempts to e f f e c t "C1F"  (Flow sheet  3).  secondary f l u o r i n e  time t h a t an  r e s u l t e d i n the  bubbled  a syrup, which gave  again no  first  was  "XF"  reaction  f o r m a t i o n of a l l four  B-D-mannopyranosyl f l u o r i d e a d d i t i o n v i a the  Bower's  (XLV)  pro-  30-32 cedure'  ' were t o t a l l y  unsuccessful.  A minor component from the s e v e r a l days at ca. 0°; The  syrupy r e a c t i o n product c r y s t a l l i z e d  i t proved to be  the a-D-mannosyl f l u o r i d e  major component, B - D - g l u c o s y l f l u o r i d e (XLIIT) was  a f t e r seeding with an a u t h e n t i c infra).  sample made by  the AgF  obtained  manno (XLV)  isomers.  These were not  (XLII).  crystalline  exchange method  Remaining in. the mother l i q u o r s were the a-D-gluco  after  (XLIV) and  (vide B-LV  s e p a r a t e d , although the a - D - g l u c o s y l  -69-  CH  OAc 2  A c O \  O  A  (XLIV)  (XLIII)  (XLII)  (XLV)  -0 no fluorides formed  c  + OBz  (LIU)  (LIV)  (LV)  1. C I , AgF in C H /CH C N . ?.'  ^  6  6  OBz  3  2 . N-chlorosuccinimide and anhydrous liquid HF in Et O.3 . C l , AgOBz in C H . 2  6  6  (LVD  4 . HF. 5 . •a.HBrin H O A c ; b, AgF in C H X N . 6 . a , H B r in HOAc-, b . A g O B z in CCI . 4  Flow Sheet 3.  J OBz  J  H  2  H  3  4.00  X  J .  2"l '  f  2  J 6 H  l' n,n HH J  2  4.50  500  *  r V  v;  5.50  6.00  6.50  H  7.00  2  °H F 2  5 J  J  H  2  H  3  ("I  H K 2  hY  f JH|H2  AcO  H  'va' JI X)>< i  V s  M  II  II  6  2  H6  (NH H 6  5  5  l )  J  H  J  J  JH  V u F i g u r e 9. (LVI)  P a r t i a l 100 MHz  5.00  5.50  4  H H. /„V,A C  4.50  H  5  ;  1 6.00  6.50  7.00  s p e c t r a o f (A) l-0_-bcnzoyl-2-chloro~2-deoxy-8-D-glucopyranose t r i a c e t a t e  and (B) 2 - c h l o r o - 2 - d e o x y - S - D - g l u c o p y r a n o s y l f l u o r i d e t r i a c e t a t e  (XLV) i n benzene-d^  solutions.  -71-  fluoride  (XLIV) was  chloro-benzoate The  subsequently  o b t a i n e d v i a the HF r e a c t i o n on the  a  -gluco  (LIII).  p r o o f o f s t r u c t u r e f o r the t h r e e c r y s t a l l i n e f l u o r i d e s f o l l o w e d  the g e n e r a l  format p r e v i o u s l y d e s c r i b e d f o r the "BrF" d e r i v a t i v e s .  the a-D-mannosyl f l u o r i d e  ( X L I I ) was  not i n d e p e n d e n t l y  synthesized  Since and  c h a r a c t e r i z e d , the n.m.r. e v i d e n c e l e a d i n g t o i t s s t r u c t u r a l e l u c i d a t i o n w i l l be p r e s e n t e d The 19  i n some d e t a i l .  19 "F resonance (<j>  +127.8) o f t h i s compound e x h i b i t e d a v i c i n a l  1 F- 11 c o u p l i n g o f 1.9  these s u b s t i t u e n t s . has  Hz, which i n d i c a t e d a gauche r e l a t i o n s h i p between  A l s o the p.m.r. spectrum i n d i c a t e d t h a t t h i s compound  the D-manno c o n f i g u r a t i o n [3 ^ ^ -  3.6  H z ) , however, the anomeric con-  f i g u r a t i o n c o u l d not be determined w i t h a b s o l u t e c e r t a i n t y s i n c e t h e r e would n e c e s s a r i l y be a gauche r e l a t i o n s h i p between e i t h e r the a- o r B-anomers.  The  and both H  and F^ f o r  c l o s e s i m i l a r i t y between the spectrum o f .  t h i s d e r i v a t i v e and t h a t o b t a i n e d p r e v i o u s l y f o r the b r o m o - d e r i v a t i v e  (XXXV)  supported  of  the n - c o n f i g u r a t i o n and  c o n s i d e r a t i o n o f the c h e m i c a l  ( T =6.00, benzene-d^) f u r t h e r supported  shift  the a-anomeric c o n f i g u r a t i o n at  (The s h i f t o f IL. f o r the B-gluco d e r i v a t i v e (XLITI) i s T = 6.S3, The  Hi  n.m.r. spectrum o f the a - g l u c o d e r i v a t i v e (XLTV) was  the same as t h a t found f o r the bromo-analogue 19 1 o f a l a r g e (24 Hz)  vicinal  ( F i g . 7B)  and the  C^.  benzene-d^). essentially observation  'F- H c o u p l i n g l e f t no doubt as t o i t s s t r u c t u r e .  S i n c e a d e r i v a t i v e h a v i n g the B-gluco c o n f i g u r a t i o n (XLI1I) was  obtained  c r y s t a l l i n e , o n l y i n t h i s s e r i e s (X = C I ) , i t s *H n.m.r. spectrum i s shown i n F i g . 9B;  the c o r r e s p o n d i n g  S e v e r a l l o n g range c o u p l i n g s ( X L I I I ) and must a r i s e from  1-' -benzoate (LVI) i s p r e s e n t e d (^J)  f o r comparison.  are c l e a r l y e v i d e n t i n the s p e c t r a o f  c o u p l i n g s i n v o l v i n g the e q u a t o r i a l l y o r i e n t e d  f l u o r i n e s u b s t i t u e n t , s i n c e no l o n g range c o u p l i n g s are e v i d e n t i n the 1-  -72-  benzoate analogue.  A more d e t a i l e d d i s c u s s i o n o f t h e s e  found i n the S e c t i o n on s i g n s o f c o u p l i n g s Only the  4  J couplings  will  be  (p.115).  B-mannosyl f l u o r i d e (XLV)  has  not been a u t h e n t i c a t e d  by  19 means o t h e r than  F n.m.r. s p e c t r o s c o p y .  Several  i n t e r e s t i n g p o i n t s were r e v e a l e d  s y n t h e s e s o f the The  B-gluco-chloro-.fluoride  during  ( X L I I I ) and  the s t e r e o s p e c i f i c  chloro-benzoate  s t e r e o s p e c i f i c r e a c t i o n sequence d e s i g n e d t o produce o n l y the  fluoride  B-glucosyl  ( X L I I I ) , r e s u l t e d i n a m i x t u r e c o n s i s t i n g o f t h r e e components, these  were: s t a r t i n g m a t e r i a l mediate bromide, the fluoride  ( L I I I ) which had  not been c o n v e r t e d i n t o the  B-gluco-benzoate (LVI) and  ( X L I I I ) which was  The  formation  o f the  (p. 64)  was  formed d u r i n g  unreacted s t a r t i n g m a t e r i a l .  The  inter-  B-gluco  Fractional crystal-  components.  B - g l u c o - c h l o r o - b e n z o a t e (LVI)  demonstrates t h a t the " s t a r t i n g " m a t e r i a l (X = Br)  the a n t i c i p a t e d  a g a i n the o n l y f l u o r i d e .  l i z a t i o n , s u c c e s s f u l l y separated a l l three  a AgF  (LVI).  conclusively  formed i n the p r e v i o u s exchanges,  the exchange r e a c t i o n i t s e l f and was  not  p o s s i b i l i t y of c h l o r i n e p a r t i c i p a t i o n i n  exchange r e a c t i o n i s c l e a r l y e s t a b l i s h e d by t h i s r e a c t i o n sequence  s i n c e o n l y t r a n s p r o d u c t s were formed. I t has  p r e v i o u s l y been observed t h a t , i n c o n t r a s t  to e i t h e r  bromine o r i o d i n e , the c h l o r i n e c a t i o n adds t o D - g l u c a l t r i a c e t a t e t o ?8b 85 p r e f e r e n t i a l l y D-gluco a d d u c t s ; c h l o r i n e i t s e l f i s r e p o r t e d " t o > 80%  formation  o f the a - g l u c o s y l  chloride.  '  to  give lead  In a c c o r d w i t h t h i s gen-  e r a l i z a t i o n , the major p r o d u c t s from the attempted a d d i t i o n o f "ClOBz" t o (XXXIV), were the c h l o r o b e n z o a t e ( L I I I ) and, a-glucosyl  c h l o r i d e (LV).  benzoate (LIV)  c o u l d be  c o u l d be i s o l a t e d .  The  somewhat u n e x p e c t e d l y ,  the  A l t h o u g h s m a l l q u a n t i t i e s o f the a-manno c h l o r o -  i s o l a t e d , none o f the t r a n s d i c h l o r i d e (LV) was  B-gluco-isomer  found t o be  (LVI)  extremely s t a b l e  :  -73-  with respect  t o AgOBz, w i t h which i t c o u l d be t r e a t e d under r e f l u x i n C C l ^  s o l u t i o n , and  r e c o v e r e d unchanged.  In f a c t , i t was  necessary to  (LV) t o the c o r r e s p o n d i n g g l u c o s y l bromide, by r e a c t i o n w i t h HBr a c i d , before  successful conversion  In accord  t o the c h l o r o - b e n z o a t e c o u l d be  the  B-D-configuration.  The  experience,  the major p r o d u c t  predominate o v e r c i s a d d i t i o n  i s not observed f o r t h i s r e a c t i o n .  l i k e l y t h a t the f o r m a t i o n  and  B-anomer i s i n f a c t expected f o r the  g l u c o - s e r i c s s i n c e t r a n s a d d i t i o n should anomerization  effected.  a f f o r d s m a i n l y the g l u c o - i s o m e r s ( X L I I I )  (XLIV) ; however, i n c o n t r a s t w i t h p r e v i o u s has  in acetic  w i t h the above r e s u l t from the "ClOBz" a d d i t i o n , r e -  a c t i o n o f (XXXIV) w i t h "C1F"  now  convert  and  I t i s t h e r e f o r e , most  o f the a - g l u c o - d i c h l o r i d e  (cis product),  reflects  the i n s t a b i l i t y o f the t r a n s isomer ( e q u a t o r i a l c h l o r i n e ) , which s u b s e q u e n t l y anomerized, d u r i n g the c h l o r i n a t i o n r e a c t i o n , f o r m i n g the more s t a b l e aanomer ( a x i a l c h l o r i n e ) . The (XXXIV) was obtained  h i g h s t a b i l i t y o f the c h l o r i n e adducts t o D - g l u c a l t r i a c e t a t e  f u r t h e r demonstrated w i t h the f o l l o w i n g r e a c t i o n .  from the c h l o r i n a t i o n o f (XXXIV) was  benzene and  acetonitrile  exchange r e a c t i o n was  (2:1 v/v)  containing s i l v e r monofluoride.  This  observed t o be v e r y s l o w , a f t e r 30 hours at room temp-  ( X L I I ) and  (XLIII).  Moreover, i t was  a-manno-isomer exchanged p r e f e r e n t i a l l y . f o r the m a n n o - d i c h l o r i u c , may a x i a l halogen at  product  d i s s o l v e d i n a s o l u t i o n of  e r a t u r e ca. 5% o f the d i c h l o r i d e s had been c o n v e r t e d i n t o the chloro-fluorides  The  The  trans  observed t h a t  the  f a s t e r r a t e o f exchange, found  r e f l e c t the f a c t t h a t i n t h i s compound the  i s t r a n s - d i a x i a l t o the halogen at  apd  i s therefore  a b l e t o p a r t i c i p a t e more r e a d i l y i n the exchange r e a c t i o n at C. .  _74-  OTHER a,B-UNSATURATED CYCLIC ETHERS  A p p l i c a t i o n of" f.m.r. f o r d e t e r m i n i n g the n a t u r e and r a t i o o f the p r o d u c t s a r i s i n g from "XF" a d d i t i o n r e a c t i o n s t o o t h e r , B-unsaturated a  cyclic  e t h e r s w i l l now be d i s c u s s e d .  S i n c e t h e s e p r o d u c t s were not  i s o l a b l e and were i d e n t i f i e d s o l e l y on the b a s i s o f t h e i r f.m.r. p a r a m e t e r s , these r e s u l t s have not been used d u r i n g the d i s c u s s i o n o f p o s s i b l e mechanisms f o r t h e "XF" a d d i t i o n r e a c t i o n . R e s u l t s a r i s i n g from t h e s e r e a c t i o n s are summarized i n T a b l e s IX ft X.  The  f.m.r. parameters  the E x p e r i m e n t a l s e c t i o n . will  f o r t h e s e r e a c t i o n p r o d u c t s w i l l be found i n  S e v e r a l i n t e r e s t i n g r e s u l t s are r e v e a l e d and these  now be d i s c u s s e d . The "XF" a d d i t i o n r e a c t i o n s t o d i h y d r o p y r a n (LXXXII) r e s u l t e d i n  the f o r m a t i o n o f two p r o d u c t s ; t h e s e are the t r a n s - d i a x i a l ( -gluco) a  isomers.  (a-manno) and c i s  T h e i r i d e n t i f i c a t i o n i s s t r a i g h t f o r w a r d as the c i s isomers 1°.  d i s p l a y e d l a r g e ( c a . 25  Hz) v i c i n a l  1  F- H c o u p l i n g s , i n d i c a t i v e o f a  t r a n s - d i a x i a l arrangement, whereas, the t r a n s isomers showed  small (ca.  1.5 Hz) couplings. The p r o d u c t r a t i o s found f o r the "XF" r e a c t i o n s X,,) are as expected,=80% t r a n s .  (AgF +  The u n u s u a l l y l a r g e p e r c e n t a g e o f c i s form-  a t i o n found f o r the Bowers, r e a c t i o n may  r e f l e c t the f a c t t h a t t h e r e i s now  e q u i l i b r i u m c o n t r o l o v e r the p r o d u c t r a t i o , the c i s p r o d u c t b e i n g the more stable  isomer. The "XF" a d d i t i o n s ( X  pyrans  (LXXXIIT) and  a s m a l l percentage  2  + AgF)  t o those C^ s u b s t i t u t e d d i h y d r o -  (LXXXIV) r e s u l t e d i n f o r m a t i o n o f two t r a n s isomers  ( c a , 5%) o f the c i s isomer (q - g l u c o ) .  and  These r e s u l t s are  q u a l i t a t i v e l y the same as those found p r e v i o u s l y f o r D - g l u c a l t r i a c e t a t e (XXXIV).  The h i g h percentage o f c i s product a r i s i n g from'the "BrF" (Bowers)  -75-  reaction  to  equatorial  ( L X X X I V ) c o u l d be isomer  former c o u l d not  (8-gluco) be  Results  to the  o f "XF"  Section.  their  The  more s t a b l e c i s i s o m e r  ( X ^ + AgF)  Tentative  from comparison w i t h  ( X X X I V ) and  of i s o m e r i z a t i o n of the  trans d i -  (g-gluco)  as  the  detected.  s u m m a r i z e d i n T a b l e X. followed  a result  addition to three  identification  the  results  found  f.m.r. p a r a m e t e r s w h i c h can  product  ratios  acetate  (LVII)  acetoxy  s u b s t i t u e n t at  arising  seem t o r e f l e c t  the  fact  of these  g l y c a l s are  reaction  for D-glucal  be  f r o m "XF"  other  products  triacetate  found i n the  Experimental  addition to D-galactal  that there  i s now  an  axially  [low p e r c e n t a g e o f the q - t a l o isomers  trioriented  (LXI)]  and  .2 these for  results  "XOR"  are  i n agreement w i t h  to the p e n t a l s  of the  ( L X X I T I ) and  the b a s i s of t h e i r v i c i n a l isomers are  very  ication  interesting of the  "F- H  result  diacetate  conformations  (these  spectra). both  Fraser-Reid  The  acetates  the  d e p e n d on  I t was  (LXIV)  two  and  fact  addition on  are  formed  reflect  molecules,  the p r e c i s e  i n the  the  of D-arabinal  i n favourable  ( X=  Br,I  case of  D-arabinal ground  shown i n T a b l e *H  (LXXTII) i s such  one  at  is  )  of a l l four  d i f f e r e n c e i n the  diacetate  there  identif-  formation  i n the  which are  o r i e n t a t i o n s , the  trans-  Nevertheless,  n o t e d t h a t "XF"  results  three  t h a t the  were deduced from d e t a i l e d a n a l y s i s o f t h e i r  conformation are  f r o m "XF"  They were i d e n t i f i e d  the p r e f e r r e d ones.  T h i s r e s u l t may of these  conformations  couplings  products.  whereas, only  (LXXIII).  arising  tentative.  t h a t does not  additions to D-xylal diacetate  state  L e m i e u x and  1  e x p e c t e d t o be  individual  diastereoisomers,  r e a c t i o n products  (LXIV) are 19  one  r e p o r t e d by  addition reactions. Identification  diaxial  those  X, n.m.r. that  pseudo-axial  86 (allylic xylal  effect  diacetate  ) and  the  (LXXIV) has  acetate the  at  acetate  is equatorial. a t C.,  axially  Tn  contrast,  orientated, in  Dthe  is  -76-  TABLF IX.  Products a r i s i n g a,8-unsaturated  from "XF" cyclic  a d d i t i o n r e a c t i o n s t o some  ethers.  % Yield  and C o n f i g u r a t i o n o f Products R  Reactant  o  Reaction F  F  Z>  0  IF (a)  95  BrF(a)  84  BrF(b)  ca.5  (LXXXVIII) (LXXXVI)  16  -  55-60 (LXXXVI)  40-45  (LXXXIX) (LXXXVII) (LXXXVII)  (LXXXII) R-H  (LXXXIII)  IF(a)  78  (XCIII)  17  (XCIV)  ca.5  BrF(a)  57  (XC)  20  (XCI)  IF(a)  76  (XCIX)  18  (C)  5  (CI)  BrF(a)  66  (XCVI)  25  (XCVII)  6  (XCVI11)  BrF(b)  55  (XCVI)  45  (XCVIII)  18  (XCV)  (XCII)  R=C!! OAc 2  ^  __0 \^R (LXXXIV) R=C!l OTs 2  (a) "XF"  generated from AgF  and  X2  (b) "BrF" generated from anhydrous l i q u i d 1!F and  N-bromosuccinimide.  TABLE X.  Products  arising  from*"XF" a d d i t i o n s to, o t h e r  % Yield  and C o n f i g u r a t i o n o f  glycals,  Products 0  Reactant  Reaction 25 (LXI)  41  (LXII)  34  (LXIII)  34  (LVIII)  43  (LTX)  24  (LX)  49  (LXXVIT)  38 (LXXVIII)  13  (LXXIX)  BrF  62  (LXXIV)  20 (LXXV) ,.  •18 (I.XXV.T)  IF  46  (LXIX)  43  (LXX)  8  (LXXI.)*  BrF  55  (LXV)  32  (LXVI)  5  (LXVII)  IF  BrF D-Galactal (LVTI)  IF D-Arabinal (LXXIII)  3  (LXXII)*  8  (LXVIII)*  D-Xylal (LXIV)  "XF" a d d i t i o n r e a c t i o n s u s i n g X, and AgF.  1  *Identification tentative.  -78-  ground  s t a t e conformation.  halogen, the a l l y l i c  effect  a r a b i n a l the r e s u l t i n g ground  As soon as e i t h e r o f these g l y c a l s r e a c t with o f the double bond w i l l be removed: f o r D-  (carbonium  ?) i o n w i l l be i n an e n e r g e t i c a l l y  s t a t e ; however, f o r D - x y l a l , the i o n w i l l  have at l e a s t  uents a x i a l l y o r i e n t e d and w i l l .therefore be e n e r g e t i c a l l y r e s p e c t t o the i n v e r t e d ational  conformer.  i n v e r s i o n exceeds  two  substit-  m e t a s t a b l c with  In the event that the r a t e o f  the r a t e o f a t t a c k by F ~ ,  stable-  conform-  i t i s clearly possible for  the i n t e r m e d i a t e i o n t o form p r o d u c t s from e i t h e r o f i t s two p o s s i b l e  con-  formers, and hence t o form f o u r , r a t h e r than t h r e e adducts. The  a d d i t i o n o f "IOBz" t o D - a r a b i n a l d i a c e t a t e  xylal diacetate resulted respectively. was  (LXXIII) and  D-  i n syrupy mixtures o f t h r e e and f o u r p r o d u c t s ,  Only'one component, from the D - a r a b i n a l a d d i t i o n  obtained c r y s t a l l i n e .  I t proved  to be  benzoyl-2-deoxy-2-iodo-S-D-ribopyranose t i o n o f t h i s molecule i s o f i n t e r e s t ,  reaction  (see E x p e r i m e n t a l s e c t i o n )  diacetate  ( LXXX ).  f o r i t appears  The  1-0-  conforma-'  to have a s i g n i f i c a n t  4 p r e f e r e n c e f o r the symmetric  Cj c o n f o r m a t i o n .  T h i s conformation i s d i f -  64 f e r e n t from that, observed  f o r e i t h e r the t e t r a b e n z o a t e or t e t r a a c e t a t e o f  87 8-D-ribopyra.nose , which may be c o n s i d e r e d time a v e r a g i n g between the two symmetrical c h a i r c o n f o r m a t i o n s , 2 C^ ( 2 : 1 ) . More s t r i k i n g i s the f a c t f  88 t h a t both 2-deoxy and 2-deoxy-2-fluoro-(3-D-ribopyranose t r i b e n z o a t e e x i s t i n the symmetric the "anomeric  c h a i r conformation.  Thus, i t i s again observed  e f f e c t " i s c o n t r o l l e d , i n p a r t , by the n a t u r e  ? ) o f the s u b s t i t u e n t at C  ?  o f a pyranose  carbohydrate.  that  (electronegativity  -79-  AN N.M.R. STUDY OF  The p r o d u c t s glucal triacetate  2-DEOXY-2-HALO-GLYCOSYL FLUORIDES  o b t a i n e d from the " X F " . a d d i t i o n r e a c t i o n s to  (XXXIV) p r o v i d e d an e x c e l l e n t o p p o r t u n i t y f o r extending  19 the  D-  * F n.m.r. dependencies  o f the g l y c o p y r a n o s y l f l u o r i d e s ; these  depend-  e n c i e s are d i s c u s s e d below. The  p.m.r. parameters o f these d e r i v a t i v e s (Tables XI § XII)  f i r m the c o n f i g u r a t i o n s p r e v i o u s l y a s s i g n e d and, more i m p o r t a n t l y , t h a t they a l l have approximately 4 c h a i r symmetry. f o r the  the same c o n f o r m a t i o n a l 1 1  Observation  of large v i c i n a l  indicate  symmetry, namely the  H~ H c o u p l i n g s  B - g l u c o - d e r i v a t i v e s i n d i c a t e t h a t these d e r i v a t i v e s now  i m a t e l y the same c o n f o r m a t i o n a l  con-  (ca. 9  Hz)  have approx-  symmetry as the q - g l u c o - d e r i v a t i v e s .  19 S e v e r a l important ' F s t e r e o s p e c i f i c dependencies were r e v e a l e d i n «. . J. • • ,40,82,84,89,90 «, . . . 19„ l the f.m.r. parameters. As a n t i c i p a t e d , the v i c i n a l F- H c o u p l i n g c o n s t a n t s show the same a n g u l a r dependence as t h a t o f v i c i n a l ^H-^H u  c o u p l i n g c o n s t a n t s ^ ; thus, f o r each p a r t i c u l a r s u b s t i t u e n t at  Jg  a u c  ]  ^  i e  1 F- H c o u p l i n g c o n s t a n t s 8 1 1 e x h i b i t a " c o n f i g u r a t i o n a l dependence" s i m i l a r to t h a t r e p o r t e d f o r H- H  ^t^ans*  Moreover, i t i s observed  c o u p l i n g c o n s t a n t s , thus J  t h a t the gauche  19  ., / J„ . Somewhat more important are the ''a> e» v a r i a t i o n s i n c o u p l i n g s which f o l l o w s e q u e n t i a l change o f the halogen subr  u  H  h  e  s t i t u e n t at Q^-  H  a  The v a l u e s f o r the t r a n s - d i a x i a l  s e r i e s ) , f i t the l i n e a r  H  149.4  (a-gluco  - 10.9Ee  a  91  where e i s the Huggins e l e c t r o n e g a t i v i t y parameter  i n the c o u p l i n g i t s e l f ;  1 F- H c o u p l i n g s  relationship, J„ „ = F > a  s t i t u e n t s attached to  19  and C^,  f o r each o f the sub-  e x c l u d i n g the H a.nd F s u b s t i t u e n t s i n v o l v e d  the standard d e v i a t i o n i s 2.26  *See T a b l e XIII f o r most o f the  1 9  F  Hz.  I f the p o i n t  parameters o f these  (value)  derivatives.  -80-  TABLF. XI.  FIRST ORDER CHEMICAL SHITS  (rvalues, Rvalues) Or THE "XF" ADDUCTS TO r.LIJCAL TRIACETATE.  OAc  "2a  (XLI)  I  AcO (XXXVII)  (XLIV)  (XL)  (XLV)  6,.01  4 .50  4 .93  - 5.8  7..91  7.91  7,.97  139..8  a 4.14  5,.70  4 .56  4 .94  - 5.8  7,.98  8.02  8..04  139..1  b 4.76  6,.68  4 .49  5 .01  8 .26  8.29  8..36  138..9  149 .9  6 .07  4 .49  4 .91  - 5.8  7,.93  7;193  7 .97  5,.69  4 .55  4 .91  - 5.8  7,.98  8,.01  8 .02  144,.3  b 4..78  6 .69  4 .45  4 .99  8..27  8,.29  8 .34  144..2  c 4..33  6.,07  4 .55  4,.91  5.8 -  7,.94  7,.94  7 .98  147.6  4,.17  5.,72  4 .58  4,.89  5.8 -  7,.99  8,.02  8,.02  147.4  b 4,.72  6.,56  4 .49  4,.96  6.06  8,.24  8,.24  8 .30  147. 1  c 4,.52  6,.04  4 .68  4 .98  6.10  7.92  7 .93  7.99  132,,3  a 4, .30  5..95  4 .62  5 .01  7.97  7,.99  8.03  132..8  b 4 . .83  6 .29  4 .75  5 .03  6.51  8.17  8 .18  8.22  132 .5  c 4,.61  6,.14  4,.98  4,.70  6.09  a 4, .55  5,.97  4 .58  4 .96  b4,.89  6,.33  4,.71  4 .99  6.50  c 4,.70  6.15  4,.74  5,.05  6..13  a 4.43  6.00  4,.64  4,.96  b 4 .49  6.36  4,.75  4,.97  CI  3  I  Br  CI  c  AcO  (XLII)  6.17  5.82  c 4,.27  (XXXIX)  (XXXV)  6.13  Br 'a 4, .13  AcO (XXXVI)  c 4.25  Br  6.12  5.79  ;  6.16  5.80  6.11  5.8 5.85  5.7 5.8  7 .94  7.94  7.94  136,.0  7 .98  8.00  8.03  137,.1  8 .19  8.19  8.23  136 .6  5.69  5.85  7,.93  7,.93  7.99  138,.9  5.8  __  7,.97  7,.99  8.0!  139,. 5  6,.53  5.77  5.99  8,.20  8 .21  8.23  13S..9  7.88  7 .89  7 .93  116.9  7.96  7 .98  7 .99  116.7  8.39  8..37  8..39  116.3  —  5.3  5.4  4.5  a 3 .99  5.21  5.42  4.56  5.73  —  b4.,50  5.68  5.42  4.50  6.06  5.84  C4,.17  5.43  4.81  4.53  S.8  7.90  7,.90  7,.94  123.2  a 4 .12  5.29  4.81  4.53  5.8  7.99  E,.00  8,.02  122.9  b 4 .59  5.74  4.83  4.38  8.29  8,.35  8,.35  121 .4  •V4.7  5.8  7.92  7,.92  7,.95  127.8  5.S  7.96  7,.97  7,.99  127.4  5.93  8.21  8 .23  8 .34  127.6  4 .1  C4..28  5.,45  CI 34,.19  5.,32  b4,.56  5..65  5.8  6.08  1-4.5 4.5  —  5.8 •  5.82  4.61  4.34  6.00  5.76  6.01  6.01  C4.24  7.57  8.14  4.68  4.92  5.86  5.66  5.91  7.93  7 .96  7 .99  131.1  (XXXVIII)  34.21  7.56  8.13  4.77  4.98  5.87  5.72  5.95  8.02  8 .02  8 .06  130.5  R = OAc  b4.68  7.77  8.62  4.66  4.8S  6.02  5.70  6.02  8.75  8 .78  8 .82  130.7  c 4.18  7.25  7.93  4.28  (cxvi)  a 4.01  •v7.2  •v.7.8  • 4.22  R = OBz  b 4.52  "•1.5  8.43  •4.14  •  130.1  5.43 S.37  5.57*  5.32  129.9  The compounds l i s t e d above were each measured i n chloroform-d ( c ) , acetone-d benzcne-d  6  (b) s o l u t i o n s .  129.7  5.57*  6  ( 3 ) and  The benzoatc ester protons resonated at ca.2r and at ca. 2.5t.  -81-  TABLE X I I . FIRST ORPF.R COUPLING CONSTANTS OP THF. "XF" ADDUCTS TO CLUCAL TRIACKTATE (XXXIV). (Hz)  COMPOUND  (XLI)  \  J l,2e l , 2 a 2e,2a  X  J\  (XXXVII)  Br  (XL)  CI  I  5.  J & 2  9.4  b  -  -  9.2  10.0  4.1  2.0  _  6)6  J 2  12.6  c  2,.5  10,.7  9.3  9.3  a  2.,5  10,.7  9.2  9.8  b  -  -  -  2..5  10,.9  9.2  9.6  4.4  2.0  12.7  c  1,F  J  2e,F  J  2a.F  50,.5  27.8  51 , .0  28.2  SO .1  27.8  51 .5  25.2  51,.0  25.6  SO .7  25.4  51 2  24.0  2.,7  10,.8  9.3  9.5  a  2,,S  10,.5  9.3  9.3  -  -  51 .5  24.2  b  -  2,.5  10 .5  9.3  9.5  4.5  2.0  12.6  51 .6  24.1  10.7  9..0  9.7 9.0  50.5  9.4  10.8  9,.0  9.6  -  9.3  9..0  -  49.9  11.3  50.4  9.4  10.0 10.3  9.3  9.3  50.3  10.0  9.4  9.4  10.2  9.3  9.5  S .0  2.7  9.6  9.0  9.2  4.S  2.7  9.9  9.2  9.2  9.S  9  9.2  a  g  4  8.4  7.4 7  6  _  4..9  2.6  -  -  12..5  4.6  2.4  12,.5  l  4.3  s  1.5  9  1.3.5  MO  -  .  1.3.7  -  5  9.6  4.4 -  1.7  51.0  10.3  50.5  10.2  51.0  10.6  £1.2  . 10.7  51.1  10.6  51.7 3.9  .  a  CI a 1.8  9.5  -  -  -  9.6 4.1 2.4  1-9.5 .  .  1.9.S 1-9.5 4.4  12.1 SO.9 4.4  -  49.5 1-2  .  49.7 1.9  2.0  12.5 49.6  2.0  12.8  -v2  2.85  13 .9  5.2  10.8  51 .2  5.0  13..6  5.2  11.0  9,.5 9,.6  9,.5  2.9  9,.5 i 5 ..0 1-1.8 M2.2  51,.2  5.3  38.2  2.7  13 .4  5.2  11.0  9,.6  9,.6  51,.0  5.1  38.0  c 1..5  2.5  13 ,S  (cxvi)  a  R = ORz  b  -  The (b)  co-pounds  13..6  listed  solutions.  _  -  above  -  -  were  4,.5  .  51.1 4.3  1 .6 a 1 .5 b 1 .5 C  benzene-d  J  9.5  b  R0^V^2  4.5  9.2  c  0 R  J  9.0  b  (XXXVIII) R = OAc  3.4  11..3 11 .3  c  (XLII)  J  1)..1  CI a  I  J  2,.5 2,.4  c  (XXXIX)  ''2e,3 2a,3  2,.4  b  (XLV)  J  c a  I  F (XLIV)  J  4,.8  2.2  _  _  -  -  each measured  12.5  .3  -  -  -  13.4  in chloroform-d  (c),  38.0  51..1  5.3  38.3  1-51,.1  5.3  38.0  50.,8  4.8  38.0  acetone-d-  o  (a)  and  -82-  TABLH X I I I .  F Chemical S h i f t s  and v i c i n a l  3  2-Deoxy-2-Halo-Glycopyranosyl  F  ( a - g l u c o -)  38.0  125.2  15.3/10.7  139.8  27.8  132.3  9.3  3.0°  144.9  25.2  136.0  10.0  127.8  1.9  C  147.6  24.0  138.9  10.6  138.8  1.5  C  149.9  23.8  137.8  12.0  131.1  X = I  5.3  C  131.1  116.9  4.3  C  X = Br  123.1  X = CI  X = OAc  a  U n l e s s o t h e r w i s e s t a t e d s p e c t r a were measured i n CDCl^  b  c o n t a i n i n g ca.20% CFC1- (<j) v a l u e s i n p.p.m.) J  c  F i r s t - o r d e r parameters ( H z ) .  In d C  G  (CD.,),CO s o l u t i o n c o n t a i n i n g ca.20% CFC1 ,.  See r e f e r e n c e 84. e  (8-gluco•JF,H2a  JF,H2e  I!  F JF,H2a  *c  *c X =  Fluoride Triacetates.  \  (a-manno- ) D  for  V  V-  Compound  'F- II C o u p l i n g C o n s t a n t s  See r e f e r e n c e 82 and t h e Hexopyranosyl  Section.  solutions  -83-  f o r X = H i s e x c l u d e d the r e l a t i o n s h i p i s J„ h  now  the s t a n d a r d  „ = 78.5 a' 2a  -  4.7Zc,  H  d e v i a t i o n i s reduced t o 0.6,,  In l i k e  Hz.  f a s h i o n the gauche c o u p l i n g s  f o r the a-manno-series f i t  the r e l a t i o n s h i p JV F  with  a standard  comes 23.5  Hz,  ,. = 38.7 a» 2e  d e v i a t i o n o f 0.2. 8  i f one  - 3.2Ee,  H  Hz.  The  value  f o r the i n t e r c e p t  be-  90  f o l l o w s the s u g g e s t i o n  o f Abraham et a l  and  considers  only those e l e c t r o n e g a t i v e s u b s t i t u e n t s t h a t are a n t i p l a n a r to e i t h e r o f  the  coupling nuclei . The  remaining s e t o f c o u p l i n g s  do not have the X  substituent  90 a n t i p l a n a r to e i t h e r o f the c o u p l i n g n u c l e i these c o u p l i n g s equated  do not  e x h i b i t the  (B-gluco  same t r e n d as found above.  as expected • It can  be  to  the standard  deviation i s  0.75  Hz,  where e i s the Huggins e l e c t r o n e g a t i v i t y  parameter f o r each o f the s u b s t i t u e n t s a t t a c h e d H and  series);  V substituents  i n v o l v e d i n the c o u p l i n g  to  itself.  and  C^,  excluding  Tf the p o i n t  the  (value)  f o r X = H i s removed the r e l a t i o n s h i p i s J„ *c> 2a  = -25.7  +  5.21c,  n  the standard  d e v i a t i o n i s reduced t o 0.1^  experimental  justification  Abraham. C a v a l i i  and  Hz.  These f i n d i n g s p r o v i d e  f o r the e m p i r i c a l dependencies suggested  Pachler  90  by  some  -84-  I t i s observed  that the  F s h i f t s f o r each o f t h e t h r e e s e t s o f  compounds i n c r e a s e r e g u l a r l y through  t h e s e r i e s X = I , B r , C I , which i s i n 92  a c c o r d w i t h t h e "Q-parameter" dependence o f Hruska e t a l  .  I t s h o u l d be  p o i n t e d out t h a t t h i s i s an e m p i r i c a l c o r r e l a t i o n and i s so s t a t e d i n t h e i r paper: "As t h e r e appears t o be no adequate t h e o r e t i c a l model at p r e s e n t , i t may be w o r t h w h i l e t o have an e m p i r i c a l c o r r e l a t i o n o f t h e o r t h o s h i f t s w i t h some p r o p e r t i e s o f t h e s u b s t i t u e n t . " However, comparison o f t h e above s h i f t s w i t h those o f t h e 2 - d e o x y - d e r i v a t i v e s , (X - II) shows t h a t , when a h a l o g e n  s u b s t i t u e n t i s p l a c e d i n a gauche, r e 19  l a t i o n s h i p with respect t o the f l u o r i n e  ( a - and g - g l u c o - s e r i e s ) t h e "F  resonance (<j> v a l u e ) i s s h i f t e d t o h i g h f i e l d , whereas, a halogen  substit-  uent i n an a n t i - p l a n a r o r i e n t a t i o n r e s u l t s i n a s h i f t t o low f i e l d . it  i s evident that a p r e v i o u s l y unrecognized  dependent, i s a l s o i m p o r t a n t .  Thus,  f a c t o r , which must be a n g u l a r  I t i s i n t e r e s t i n g t o note t h a t t h e r e i s a  s y s t e m a t i c d i f f e r e n c e between t h e induced s h i f t s o f t h e a- and B - g l u c o - s c r i e s the r a t i o b e i n g 1.24' - 0.03 : 1, which may w e l l r e f l e c t an induced o f t h e pyranose r i n g from t h e " c y c l o h e x a n e - c h a i r " symmetry.  distortion  The R e l a t i v e Signs o f *I!-*H and ^ F - ^ H C o u p l i n g Constants  In the p a s t , the m a j o r i t y o f r e l a t i v e s i g n d e t e r m i n a t i o n s by the 93 94 n u c l e a r magnetic  double resonance  (n.m.d.r.) t e c h n i q u e  '  took l i t t l e , o r  no, cognizance o f t h e r e l a t i v e s t e r e o c h e m i s t r y o f the n u c l e i involved; this p a r t i c u l a r f a c e t o f the problem has been g e n e r a l l y o v e r l o o k e d i n s p i t e o f t h e f a c t t h a t s e v e r a l important t h e o r i e s o f Hl-*H c o u p l i n g c o n s t a n t s p r e d i c t 2,6,95,96  changes o f s i g n f o r some p a r t i c u l a r s t e r e o r e l a t i o n s h i p s .  Since a  l a r g e number o f carbohydrates were a v a i l a b l e which p r e s e n t e d a v a r i e t y o f d i f f e r e n t r e l a t i v e o r i e n t a t i o n s , o f p r o t o n and f l u o r i n e s u b s t i t u e n t s , i t seemed a p p r o p r i a t e t o study the s i g n s o f the c o u p l i n g c o n s t a n t s o f a s e l e c t i o n o f these d e r i v a t i v e s .  Besides o f f e r i n g some check  on the a c c u r a c y o f some o f the  t h e o r i e s p r e s e n t l y a v a i l a b l e f o r p r e d i c t i n g the a b s o l u t e magnitudes o f ^H-^K c o u p l i n g c o n s t a n t s , these s i g n d e t e r m i n a t i o n s s h o u l d be o f some i n t e r e s t t o those attempting computer a n a l y s e s o f complex p.m.r. s p e c t r a o f carbohydrate atives.  deriv-  In the event t h a t any o f the c o u p l i n g s s h o u l d evidence a s t e r e o s p e c i f i c  dependence o f s i g n , then t h i s would o f f e r a f u r t h e r approach mining conformations by the n.m.r. method.  towards d e t e r -  As w i l l be seen, the long-range  c o u p l i n g s o f s a t u r a t e d carbohydrate d e r i v a t i v e s do indeed e x h i b i t such a s i g n dependence. At the same time i t was o f i n t e r e s t t o determine . o f the  19 1 82 97 98 "F-. H c o u p l i n g s because r e c e n t r e s u l t s from t h i s '" ' and o t h e r  laboratories  40 89 99 ' "' have i n d i c a t e d t h a t v i c i n a l  e x h i b i t a fundamentally two  19 1 1 1 F- H and H- 11 c o u p l i n g s  s i m i l a r a n g u l a r dependence; t h i s i m p l i e s t h a t these  s e t s o f c o u p l i n g s are l i k e l y  anism  r e l a t i v e signs  t r a n s m i t t e d by a b a s i c a l l y  and i f t h i s i s so then the s i g n s o f the two.sets  be s i m i l a r .  As w i l l be seen below, the v i c i n a l  s i m i l a r mech-  o f c o u p l i n g s should  ^ F - * ! i and *H-*H c o u p l i n g s  -86-  10 examined are a l l a b s o l u t e l y p o s i t i v e i n s i g n , whereas geminal p o s i t i v e and  Hi-Hi  geminal  couplings  are n e g a t i v e  '  }  F- i l are  ^F-Hl  long-range  c o u p l i n g s e x h i b i t the same s i g n dependence as found f o r Before  1  Hi-Hi  couplings.  d i s c u s s i n g the r e s u l t s , i t i s r e l e v a n t t o i n d i c a t e b r i e f l y  what i s i m p l i e d by a " p o s i t i v e " o r a " n e g a t i v e " c o u p l i n g c o n s t a n t . s i m p l e s t model f o r r a t i o n a l i z i n g the o b s e r v a t i o n  t h a t s p i n c o u p l i n g con-  s t a n t s can d i f f e r i n s i g n i s based on the McConnell e x t e n s i o n ^ ^ Dirac-Van Vleck m o d e l ^ H s e t s o f assumptions. t o be o p p o s i t e  T h i s approach i s based on two q u i t e  via  of  the  reasonable  F i r s t , t h a t the s p i n of a bonding e l e c t r o n w i l l  t o t h a t o f i t s a s s o c i a t e d n u c l e u s .and that any two  i n .bonding o r b i t a l w i l l have paired s p i n s  Hi-Hi  The  tend  electrons  (Pauli. P r i n c i p l e ) ; second, t h a t  s p i n c o u p l i n g s , i n s a t u r a t e d systems, are t r a n s f e r r e d p r e d o m i n a n t l y  the s - s h e l l e l e c t r o n s o f the n u c l e i  contact  interaction).  between two n u c l e i  The  having  i n v o l v e d (the s o - c a l l e d Fermi  model then s t a t e s t h a t 3ny  spin-spin coupling  a n t i p a r a l l e i s p i n s w i l l be d e f i n e d as p o s i t i v e ,  w h i l s t i f the n u c l e a r s p i n s are p a r a l l e l , then the c o u p l i n g c o n s t a n t negative.  It. i s easy t o see on t h i s b a s i s how 3  will  be  i t i s p o s s i b l e f o r the  c o u p l i n g s between the p r o t o n s o f an Sp - h y b r i d i z e d system t o a l t e r n a t e i n s i g n depending upon the number o f bonds s e p a r a t i n g the p r o t o n s . symbolisms " $ " and s p i n and  " I " and  " $  " 4- " f o r the senses o f an e l e c t r o n s p i n , c o n s i d e r  the  e l e c t r o n s p i n s f o r the d i r e c t l y bonded  1 C-  H system.  T h i s i s shown below i n (A) where i s can be seen t h a t 13  C  $  +  ' +  t Hi  (positive)  two n u c l e a r s p i n s are o r i e n t e d a n t i p a r a l l e l and t h u s , by J  the  " t o i n d i c a t e the two p o s s i b l e senses o f a n u c l e a r  most s t a b l e arrangement o f n u c l e a r and 13  Using  ("^C-H')  i s t a k e n t o be p o s i t i v e .  Extending  the (A)  definition,^'^  t h i s formalism  t o geminal  and  -87-  vicinal  H- II c o u p l i n g s as shown i n (B) and  (C) r e s p e c t i v e l y , l e a d s t o the  t  H$ r  T  II $ 4- +  C  C  C  T  +  i  T + $H  (negative)  (B)  f ?H  (positive)  (C)  e x p e c t a t i o n t h a t geminal c o u p l i n g s should be n e g a t i v e i n s i g n , w h i l s t v i c i n a l c o u p l i n g s s h o u l d be p o s i t i v e .  A f u r t h e r extension to i n c l u d e  "long-range"  c o u p l i n g s a c r o s s f o u r bonds l e a d s t o the p r e d i c t i o n t h a t such c o u p l i n g s s h o u l d be n e g a t i v e i n s i g n .  As w i l l be seen below t h i s a l t e r n a t i n g v e c t o r  model s u c c e s s f u l l y p r e d i c t s the r e l a t i v e s i g n s o f geminal and v i c i n a l  ^Il-Hl  c o u p l i n g s f o r the s a t u r a t e d systems encountered i n c a r b o h y d r a t e d e r i v a t i v e s but i s u n s u c c e s s f u l f o r the long-range  couplings.  I t i s a l s o not  f o r those c o u p l i n g s which are t r a n s m i t t e d v i a H - e l e c t r o n s  suitable  (vide i n f r a ) .  N e v e r t h e l e s s , i t p r o v i d e s a c o n c e p t u a l l y s i m p l e model f o r the f o l l o w i n g discussions.  -88-  H- 11 COUPLING CONSTANTS  A l l o f t h e s i g n d e t e r m i n a t i o n s by n.m.d.r. u t i l i z e e i t h e r t h e ,, . . . .,102,103 "selective irradiation" t  ^ ,, . ,,103,104 or the " s p i n t i c k l i n g "  , . methods. A  t y p i c a l a p p l i c a t i o n o f each o f these approaches i s o u t l i n e d below.  Both  approaches a r e o n l y a p p l i c a b l e t o systems h a v i n g a t l e a s t t h r e e m u t u a l l y c o u p l e d s p i n s , such as an AMX-  o r an ABX system.  In e f f e c t , t h e s p i n  s t a t e s o f one n u c l e a r s p e c i e s a r e used t o p r e d i c t t h e course o f a double resonance e x p e r i m e n t ' i n v o l v i n g t h e o t h e r two n u c l e i . 'Hie f i r s t approach, ultaneous  " s e l e c t i v e i r r a d i a t i o n " , i n v o l v e s t h e sim-  i r r a d i a t i o n o f the t r a n s i t i o n s a s s o c i a t e d with a p a r t i c u l a r  s p e c t r a l s p l i t t i n g and r e s u l t s i n t h e c o l l a p s e o f a s s o c i a t e d t r a n s i t i o n s i n ano t h e r resonance,  thus s i m p l i f y i n g t h e spectrum.  T h i s method w i l l be d i s -  cussed w i t h r e f e r e n c e t o t h e d e t e r m i n a t i o n o f the r e l a t i v e s i g n s o f J • , 5,6 and .1,, ^» o f 5 , 6 - d i d e o x y - 5 / 5 - e p i t h i o - l ,2-0_-isopropylidcne-3-L- - i d o f u r a n o s e (CVII).  The complete spectrum o f t h i s compound has been p r e v i o u s l y p u b l i s h e d  elsewhere^*'  and F i g . 10A shows o n l y t h e C^ methylene p r o t o n  The equal s p a c i n g s s m a l l geminal  1,2; 3,4; 5,6 and 7,8 c o r r e s p o n d  resonances.  to the c h a r a c t e r i s t i c a l l y  c o u p l i n g c o n s t a n t o f e.pithio d e r i v a t i v e s and thus t h e  splittings  1,3 and 2,4 correspond  correspond  to  to  ^, w h i l s t t h e s p l i t t i n g s 5,7 and 6,3  ^ i .  I f we f o l l o w t h e u s u a l c o n v e n t i o n and r e p r e s e n t t h e two p o s s i b l e s p i n s t a t e s o f each p r o t o n as " a " and "B", then we can make t h e s p i n - s t a t e assignment f o r t h e t r a n s i t i o n s o f t h e H i n T a b l e XIV.  T h i s Tab 1e has been drawn on the assumption  c o u n= l i n e^— s J 5_ 5,, J5_^ 5 ' and ft 3  r  }  and H ^ i r e s o n a n c e s ,  f  ft  :•.—  which i s shown  t h a t each o f the  ,• have the same r e l a t i v e s i g n . I t e f f e c t i v e l y  l a b e l s each o f t h e t r a n s i t i o n s 1 t o S i n terms o f tine s p i n - s t a t e s o f i t s  -89-  neighbouring protons.  TABLE XIV  S p i n s t a t e assignment f o r the H  and H^'  resonances o f 5 , 6 - d i -  d e o x y - 5 , 6 - e p i t h i o - l , 2 - 0 - i s o p r o p y l i d e n e - 8 - L - i d o f u r a n o s e ( C V I I ) , based on the assumption t h a t a l l o f the c o u p l i n g s J,. ^, J,. ^' and relative  ^' have the same  signs.  1!  Transition  No.  Spin States of H  1  a  2  a  V  6 3  4  5  6  8  8  a a  Neighbouring Protons  1L' 6  C o n s i d e r now  a  8  a  ,  7  8  a  8  B  B  a  6  8  the experiment r e p r e s e n t e d i n F i g . 10B i n which  t r a n s i t i o n s 1 and 2 a r c s e l e c t i v e l y i r r a d i a t e d w i t h a r a d i o f r e q u e n c y f i e l d t  *  (H„) s l i g h t l y g r e a t e r i n magnitude than J , to T a b l e XIv,  ' t h a t i s = 2 Hz.  According  t h e s e two t r a n s i t i o n s c o r r e s p o n d t o !-!<. i n the " a " s p i n - s t a t e  and t h e r e f o r e the two t r a n s i t i o n s o f the I!^> resonance which a l s o c o r r e s p o n d *The s t r e n g t h o f the d e c o u p l i n g f i e l d (j-Lp i s r e a d i l y determined by the method o f B l o c h and S i e g c r t ^ ^ . C o n s i d e r a double resonance experiment i n which any r e s o n a n c e , A say, i s i r r a d i a t e d w h i l s t some o t h e r resonance, X say, i s o b s e r v e d ; w i t h = 0, l e t the s e p a r a t i o n between A and X be " A V Q " Hz. • When H^ i s t u r n e d on, the X resonance w i l l be d i s p l a c e d away from the p o i n t o f i r r a d i a t i o n and the new frequency s e p a r a t i o n between A and X w i l l then be "A\>r)" Hz. Both AVQ and Av^ can be measured d i r e c t l y from the "normal' and " d e c o u p l e d " s p e c t r a r e s p e c t i v e l y and then the s t r e n g t h o f the d e c o u p l i n g f i e l d f i n Hz) i s g i v e n by (Avfj - A V Q ) ^ . (See a l s o r e f . 107.) * H  2  = YH/27T  -90-  X  H —  'H  H  6  'H lH  5  6  'H »H  H l  6  6  I  P l  - „ t  r c  ,0.  (A, .00 m  spectra, of the  S ^ t t ~ * t - « * * « - I , transitions  and  (C, Selective  1  n a n c e s . f 5,6-dideoxv-5.6-.R. th,.- ,-  (CV„, i n c o r o o - d h l  6  5 6 78  3 4  12  5  f  r a  of  (B) and CO indicate the precise point of i r r a d i a t i o n .  ...««»•  (»  *«• W  ™  *  "  P a t t  ""  -91-  to  H = " a " should c o l l a p s e , t h a t i s t r a n s i t i o n s 5 £ 6.  seen g two  i n F i g . 10B 1  t h a t t h i s i s so and thus the r e l a t i v e s i g n s o f J  vicinal  couplings d i f f e r e d  , and Had  i n s i g n then the above experiment  F i g . IOC  the f i r s t t o be developed,  limitations. determine  the above experimental  Fortunately, this  signs' of two  method o f s i g n d e t e r m i n a t i o n  i t was  only p o s s i b l e to  l i m i t a t i o n does not apply to the s o - c a l l e d " s p i n - p e r t u r -  r e f e r e n c e f o r a double  The b a s i c approach f o r t h i s  resonance  experiment,  alter-  s e t o f n u c l e a r s p i n s t a t e s as however, f o r s p i n - t i c k l i n g —>  (]^2  a c o m p a r a t i v e l y weak r a d i o f r e q u e n c y f i e l d  the observed  was  i t does have s e v e r a l e x p e r i m e n t a l  n a t i v e method again i n v o l v e s the use o f one  energy  "B".  o f the t h r e e p o s s i b l e c o u p l i n g c o n s t a n t s .  b a t i o n " or " s p i n - t i c k l i n g " experiment.  -experiments,  =  For example, i n the above experiment-,  the r e l a t i v e  in  a s e l e c t i v e c o l l a p s e of  to \l  t r a n s i t i o n s 7 § 8 each of which correspond  historically  "B",  shows the c o n f i r m a t o r y experiment  which i r r a d i a t i o n o f t r a n s i t i o n s 3 5 4 causes  Although  the  would have  i n the c o l l a p s e o f the I l ^ i t r a n s i t i o n s c o r r e s p o n d i n g to  namely t r a n s i t i o n s 7 & S.  two  clearly  are the same, as had o r i g i n a l l y been assumed i n T a b l e X l v .  resulted  of  I t can he  <<  l i n e ) i s a p p l i e d to a s i n g l e t r a n s i t i o n .  IJ2  =  w  * '' c  t  This perturbs  1  the  l e v e l s a s s o c i a t e d w i t h t h a t p a r t i c u l a r t r a n s i t i o n which i n t u r n  r e s u l t s i n the " d o u b l e t t i n g " o f any o t h e r t r a n s i t i o n s  i n the spectrum  have an energy  perturbed  level  i n common with e i t h e r o f the two  which  energy  * levels. The  d e t e r m i n a t i o n o f the r e l a t i v e s i g n s o f  B-D-xylopyranosc  r  ., g  <_  a  and J . r  g  ^  of  t e t r a a c e t a t e (CXI) p r o v i d e s a c l e a r example o f t h i s  approach.  *See r e f e r e n c e 104 f o r a d i s c u s s i o n o f t h i s p o i n t . B r i e f l y , the decoupling f i e l d makes p o s s i b l e t r a n s i t i o n s c o r r e s p o n d i n g t o F - 0 which are n o r m a l l y ~ f o r b i d d e n . Thus t r a n s i t i o n s are observed c o r r e s p o n d i n g to both F, = ± 1 and 0. z  -92-  The spectrum o f t h i s t e t r a a c e t a t e  (CXI) i s shown i n F i g . 11A,  w h i l s t t h e c o r r e s p o n d i n g s p i n - s t a t e assignment f o r t h e H^, 11^ and resonances i s shown i n T a b l e  XV .  In o r d e r t o s i m p l i f y t h e r e g i o n a t  TABLE XV. S p i n - s t a t e assignment f o r t h e spectrum o f g-D-xylopyranose a c e t a t e (CXI) based on the assumption t h a t have t h e same r e l a t i v e  T r a n s i t i o n No.  Spin States of  H  3  Neighbouring  H  4  Protons  H  5e  H  5a  ca.  ^  9  10  11  13  12  14  15  16  a  a  B  a  B  a  B  B  a  6  a  a  8  B  a  B  a  a  a  ft  a  B  B  B  (H  =0.6  r  g  &  1  2  3  4  5  6  7  8  a  B  a  B  a  B  a  B  a  a  B  B  ct  a p p l i e d to  a  the  B  B  H^ x'esonance  q u a r t e t t o c o l l a p s e t o a d o u b l e t , thus a l l o w i n g t h e  t r a n s i t i o n s t o be seen more c l e a r l y . field  and J . ^ a l l  sign.  5T , a s t r o n g d e c o u p l i n g f i e l d was f i r s t  which caused t h e  tetra-  F o l l o w i n g t h i s , a r a t h e r weak d e c o u p l i n g  Hz) was a p p l i e d t o t h e h i g h e s t f i e l d  resonance ( F i g . 118). T h i s caused j u s t two o f the II  t r a n s i t i o n of the H transitions  5 a  (2,4 i n  T a b l e XV ) t o be s p l i t  i n t o d o u b l e t s , w h i l s t the o t h e r two t r a n s i t i o n s (1,3)  remained u n p e r t u r b e d .  A subsequent experiment ( F i g . l l C ) demonstrated  i r r a d i a t i o n o f the lowest f i e l d  transition of H  r  that  r e s u l t e d i n the s e l e c t i v e  5a p e r t u r b a t i o n o f t r a n s i t i o n s 1 and 3. The r a t i o n a l e o f t h e s e o b s e r v a t i o n s i s as f o l l o w s .  L e t us assume  Figure 11.  (A) P a r t i a l -.1-00• MHz  spectrum of BrD-xyJopyrano.se.. tct-racetate (CXI) i n acetone-d  s o l u t i o n ; ' (3) and (C), f r e q u e n c y - s w e c p ' t r i p l c relio nance experiments i n which H^ i s i r r a d i a t e ^ w i t h a strong f i e l d  (Ji = IS Hz) w h i l s t a s i n g l e t r a n s i t i o n of the H  w i t h a weak f i e l d  0  (H  = -0.6 Hz) .  _ i _  _ V  .  5 a  resonance i s i r r a d i a t e  1  6  -94-  t h a t the r e l a t i v e s i e n s o f J . and J . a r e i d e n t i c a l and c o n s i d e r t h e 4,5e 4,5a r  case in which t h e h i g h e s t sition  f i e l d II  (8) c o r r e s p o n d s t o  a l s o have  r  transition i s irradiated.  = "8" and thus o n l y those H  = "6" should be p e r t u r b e d ,  This  tran-  transitions  which  t h a t i s , t r a n s i t i o n s 2 and 4.  Since  the experiment. ( F i g . U B ) f o l l o w s j u s t t h i s sequence, i t f o l l o w s t h a t ^ and J . do i n f a c t have t h e same r e l a t i v e s i g n s . A g a i n t h i s r e s u l t was 4,5a  g  r  q u i t e s i m p l y confirmed was i r r a d i a t e d  by a f u r t h e r experiment i n which an  ( F i g . 11C). A f u r t h e r r e l e v a n t o b s e r v a t i o n  e x p e r i m e n t s concerns t h e r e l a t i v e r e s o l u t i o n from t h e p e r t u r b e d  transitions.  case one o f t h e d o u b l e t s Fig.  U B , the doublet  - "a" line f o r t h e s e two  o f the two d o u b l e t s  arising  I t can be seen q u i t e c l e a r l y t h a t i n each  i s more c o m p l e t e l y  r e s o l v e d than t h e o t h e r :  in  a r i s i n g from t h e o r i g i n a l t r a n s i t i o n 4 i s r e s o l v e d  to the b a s e - l i n e , w h i l s t  the other doublet  a r i s i n g from t r a n s i t i o n 2 i s o n l y 104  p a r t i a l l y resolved. doublet  This observation  can a l s o be r a t i o n a l i z e d :  the  w i l l be s h a r p l y r e s o l v e d whenever t h e " n o n - c o n n e c t i v e " s p i n s t a t e s o f  the two t r a n s i t i o n s  i n v o l v e d i n t h e experiment a r e t h e same (both ' V o r  b o t h " 8 " ) , and w i l l be l e s s s h a r p l y r e s o l v e d when t h e " n o n - c o n n e c t i v e " s p i n s t a t e s are d i f f e r e n t .  T h i s can be seen i n t h e s p i n - s t a t e diagram f o r t h e  experiment i n which t r a n s i t i o n 8 i s i r r a d i a t e d ; t h i s t r a n s i t i o n has t h e "connective"  s p i n - s t a t e \\ = "8", and as i t has a l r e a d y been seen, t h i s  means t h a t t r a n s i t i o n s  2 and 4 a r e t h e ones which w i l l be p e r t u r b e d ,  they a l s o have II = "8".  Now t r a n s i t i o n 8 c o r r e s p o n d s t o Hg  t r a n s i t i o n 4 corresponds t o H  since  = "B" and  = "8"; thus these two " n o n - c o n n e c t i v e " s p i n  s t a t e s a r e t h e same, b o t h "8"; and t h e r e f o r e t r a n s i t i o n 4 s h o u l d become s p l i t into a sharply resolved doublet.  The " n o n - c o n n e c t i v e " s p i n s t a t e s f o r t r a n -  s i t i o n s 8 and 2 a r e , however, d i f f e r e n t , and a c c o r d i n g l y t r a n s i t i o n 2 i s perturbed  to a poorly  resolved•doublet.  S i n c e , i n b o t h o f t h e s p i n - t i c k l i n g experiments d e p i c t e d i n F i g . 11 only a single  t r a n s i t i o n i s i r r a d i a t e d , s i g n i n f o r m a t i o n can a l s o be e x t r a c t e d  -95-  from the p e r t u r b a t i o n s caused i n the H^ resonance as w e l l as from the H  C e  resonance.  In t h i s p a r t i c u l a r c a s e , these p e r t u r b a t i o n s a r e , however,  l e s s o b v i o u s because the H^ resonance i s c o m p l i c a t e d  by c o u p l i n g w i t h H  a s - w e l l as w i t h Il_ and 1L ; f u r t h e r m o r e , some o f the H. t r a n s i t i o n s 5e 5a ' 4 obscured by the \\^ resonance, even when  i s strongly irradiated.  are Never-  t h e l e s s , the p e r t u r b a t i o n s produced by i r r a d i a t i n g s i n g l e t r a n s i t i o n s i n Hj.  and which are d e p i c t e d s c h e m a t i c a l l y below the s p e c t r a i n F i g . n ,  c l o s e l y r e l a t e d t o the s p i n - s t a t e assignments i n T a b l e .the r e l a t i v e s i g n s o f  g  a  and  ^ are o p p o s i t e .  XV  and  are  show t h a t  T h i s r e s u l t i s most  c l e a r l y v i s i b l e i f a t t e n t i o n i s d i r e c t e d towards.the outermost t r a n s i t i o n s o f the H^ r e s o n a n c e , namely t r a n s i t i o n s 9 and (an Mg  e  = "a" t r a n s i t i o n ) perturbs  16.  l i n e 9 (which  I r r a d i a t i o n of l i n e 8 i s an H  s i t i o n ) , t h i s g i v e s the s i g n r e l a t i o n s h i p mentioned above.  = "8" t r a n Thus, f o r t h i s  8-D-xylo d e r i v a t i v e ( C X I ) , the r e l a t i v e s i g n s o f the c o u p l i n g c o n s t a n t s  are  found t o be * J . _ , ± J , _ , and + J 4,5e 4,5a 5e,5a. r  The  P  c h o i c e as t o which o f the above methods s h o u l d be used f o r a  p a r t i c u l a r sign determination  i s governed by the r e l a t i v e magnitudes o f  the v a r i o u s c o u p l i n g s under c o n s i d e r a t i o n . c l e a r l y separated  I f a p a i r of t r a n s i t i o n s  are  from the remainder o f the m u l t i p l e t , as w e l l as a l l o t h e r  r e l a t e d t r a n s i t i o n s , and the c o u p l i n g t o be i r r a d i a t e d i s f a i r l y ( l e s s than 5 H z ) , then the s e l e c t i v e - i r r a d i a t i o n t e c h n i q u e However, eacli d e c o u p l i n g  small  i s suitable.  experiment can l e a d t o the d e t e r m i n a t i o n  o f only-  two r e l a t i v e s i g n s and t h e r e f o r e , the s p i n - t i c k l i n g method i s p r e f e r r e d as i t can g e n e r a l l y l e a d t o a l l t h r e e s i g n s , even though the end r e s u l t i s a spectrum which i s more c o m p l i c a t e d Any  experimental  than the  determination  original.  o f s i g n by n.m.d.r. y i e l d s  the r e l a t i v e s i g n s o f the c o u p l i n g s under c o n s i d e r a t i o n .  These may,  only however,  -96-  TABLE XVI. The Signs o f Proton-Proton S p i n - C o u p l i n g Constants o f Carbohydrate Derivatives . 3  Signs and Magnitudes  Compound  o f Relevant  Coupling Constants.  (Hz)  3-0-Acetyl-B,6-dideoxy-l,2J  5,6  +  1 0  J  4,5  +  4  "  3  ;  J  J  5,6  +  4  '  2  ;  J  J  4,6«-  O-isopropylidene-ct-D-xylo-  -°  ;  J  5,6-  +  1 7  '  1  ;  4  ;  hex-5-enofuranose. (CIII)  b  1,6-Anhydro-B-D-idopyranose triacetate.  4,6  +  -  1  J  5,6  +  '  4  3  (CV)° 5,6-Anhydro-l,2-0-isopropylidenea-D-glucofuranose. (CIV) ' b  d  1,6-Anhydro-B-D-mannopyranose  +  -  2  8  ;  J  6,6'  +  4  l,2  +  2  -  8 5  3  •• J  l,3  +  1  "  6  '  J  2,3  +  5  -  S  > 3,4  J  5,6  +  6  -  5 5 :  J  4,5  +  4  '  8  triacetate. (CVT)  °-  5,6'  b  \ S  +  J  1  +  K  -  5  5  6  J  J  ;  4,5  +  -°  '  1  6  5 ,6-Dideoxy-5 ,6-epitliio-1,2-_0_isopropylidene-B-L-idofuranose. be (CVII)' ' =  J  5,6'  +  5  -  3  5  J  6,6'-  1 ; 4 5  5,6-Dideoxy-1,2-0-isopropylidenea-p-xylo-hex-5-enofuranose . (CII) ' b  f  J  J  6,6'  J  l,2  +  6  '  J  5.6  +  4  -  8 5 ;  J  3,4  +  3  -  2  +  2  -  ;  5  :  5,6 J  ' 5,6' J  4,6  ' ' ]  6  ;  J  +  4,6'-  '  1 7  l  -  A  D-Glucal t r i a c e t a t e . (XXXIV) Methyl  g  4  ;  J  2,3  +  3  "  +  2  3  '  2  5  l,3"  J  1  V  3  B-D-glucopyranoside  tetracetate. (CVIII) B-D-Ribopyranose  J  5.6'  -  4  ;  J  6,6'-  tetracetate. (CIX)  g  1 2  g  ;  J  2,3  +  2  ;  J  2,4  +  °-  8  -  3  3  -97-  TABLE XVI  (continued)  2-Deoxy-8-D-arabino-hexopyranose tetracetate. (CX)  J. + 2.4 l,2e J  2e,3  +  J  l,3  " °'  S  > 2a,3  '°  5  ; . ! , - + 9.8 1,2a J  l-0-Benzoyl-2-chloro-2-deoxy-aD-glucopyranose  triacetate. J  (LIII)  b  1-0-Benzoyl-2-deoxy-2-iodo-aD-mannopyranose  2,3  J  triacetate.  (D  -  6  ' l,2 J  +  3  -  6  .  7  l,3 ' °- ' l,5 I " ' l,2 ' 65  3  J  g  + 1 0  0  J  12.4  -°  I ' '  ' 1,S  4  + 1 1  ; J_ , 2e,2a  2  j  +  4  -  J  0  65  J  5  +1  6  3  2-Bromo-2-deoxy-a-D-glucopyranosyl fluoride  triacetate.  J  (XXXVIi)  l,3  " °"  4  2,4  " °-  3  ;  J  l,2  +  2  '  > 2,3  5  J  + 1 0  -  7  b  2-Bromo-2-deoxy-a-D-mannopyranosyl fluoride  triacetate.  J  (XXXV)  J  triacetate. J  (XLI)  b  2-Deoxy-2-iodo-a-D-mannopyranosyl fluoride  +  3  '  9 S :  J  3,4  +  9  -  5 0  h  (XXXIX)  l , 3 - °" > l , 5 l ° ' l l , 2 2  2,3  Jj  triacetate.  B-D-xylopyranose  J  b  2-Deoxy-2-iodo-a-D-glucopyranosyl fluoride  • 2,3  \  3  +  U  2  J  :  +2  4  A  - 0.5  2  J  + 1.5  ; J ; J  ?  4  2  ;  - 0.45;  J  • 4.3  ;  3  }  ^  |0.2J •  9.5  E  tetracetate. J  (CXI)  g  4,5e  +  4  '°  • 4,Sa J  +  8  '  5  ;  J  5e,5a  -  1 1  "  8  (a) A l l r e l a t i v e s i g n s i n t h i s t a b l e were determined by the s p i n t i c k l i n g method. (b) In c h l o r o f o r m - d s o l u t i o n . (c) In benzene-d^ s o l u t i o n , (d) T h i s compound was measured i n both c h l o r o f o r m and acetone s o l u t i o n s : the magnitudes o f the c o u p l i n g s were s o l v e n t dependent. (e) S e l e c t i v e i r r a d i a t i o n was a l s o used t o determine the r e l a t i v e s i g n s o f .T_ , and J ,,. ( f ) The v a l u e , 5,6. b,o of J , i s an average v a l u e . (g) In acetone-d, s o l u t i o n . c  f  r  -98-  108  be p l a c e d on an a b s o l u t e b a s i s as f o l l o w s .  Hl-Hl  that v i c i n a l couplings.  E a r l y e x p e r i m e n t s showed  1  '  09 A  c o u p l i n g s have t h e same r e l a t i v e s i g n s as * 3 C-Hl  I f the assumption i s made t h a t t h e *"'C-H-! c o u p l i n g i s a b s o l u t e l y  p o s i t i v e , then i t f o l l o w s * ^ absolutely positive.  Hi-*!!  that v i c i n a l  8  Confirmation  couplings  are a l s o  o f t h i s assignment was c l a i m e d  by Buck-  ingham and McLauchlan*** on the b a s i s o f an n.m.r. study o f p _ - n i t r o t o l u e n e i n the p r e s e n c e o f a p o w e r f u l  e l e c t r o s t a t i c f i e l d ; the v i c i n a l  proton  c o u p l i n g was found t o be a b s o l u t e l y p o s i t i v e .  Although the conclusions o f 112 t h i s p a r t i c u l a r experiment have been q u e s t i o n e d , a r e c e n t study o f c y c l o 113 propane and c y c l o b u t a n e v i c i n a l couplings  i n nematic s o l u t i o n s , has i n d e p e n d e n t l y  t o be a b s o l u t e l y p o s i t i v e .  I n the p r e s e n t  ments have been based on t h e assumption t h a t a l l v i c i n a l couplings  are absolutely p o s i t i v e .  The r e s u l t s o b t a i n e d  shown  study,  assign-  proton-proton f o r *H-*H c o u p l i n g s  are summarized i n T a b l e X V I . * The  S i g n s o f V i c i n a l and Geminal The  Couplings  early theoretical studies  2  '  '  of vicinal  and geminal  c o u p l i n g s p r e d i c t e d t h a t b o t h s e t s o f c o u p l i n g s s h o u l d have t h e same s i g n s . Subsequent s i g n d e t e r m i n a t i o n s  e s t a b l i s h e d * ^ ' t h a t v i c i n a l c o uipplliinnggss a£r e 8  a b s o l u t e l y p o s i t i v e , w h i l s t geminal c o u p l i n g s  can have e i t h e r s i g n  117,118  depending upon the p r e c i s e h y b r i d i z a t i o n o f the p a r t i c u l a r c a r b o n ; they a r e 3 u s u a l l y negative The  f o r Sp - h y b r i d i z e d systems.  r e s u l t s obtained  the above e x p e c t a t i o n .  f o r d e r i v a t i v e s (CVIII,CX) a r e i n a c c o r d -  with  In c o n t r a s t t o t h i s f i n d i n g , d e r i v a t i v e s ( C I I ) and ( C U T  * F o r a r e c e n t review c o n s t a n t s , see r e f . 114.  o f the t h e o r y o f n u c l e a r s p i n - s p i n c o u p l i n g  -99-  have both v i c i n a l  and  geminal c o u p l i n g s  i n the s i g n s o f geminal c o u p l i n g s o f the epoxide  (CIV)  and  s i g n o f the e p i s u l p h i d e  positive.  (CVII).  (CVII) c o u p l i n g (CIV)  interesting variation  f o l l o w s from a comparison o f the  episulphide  system, t h a t o f the epoxide  An  It i s evident  i s t y p i c a l o f an Sp  is typical  o f an Sp  2  couplings  that w h i l s t 3  the  -hybridized  -hybridized  system.  121 Previous  comparative s t u d i e s o f " e p i - " d e r i v a t i v e s have r e p o r t e d  i n v e r s i o n , and  on t h i s b a s i s i t seems h i g h l y p r o b a b l e t h a t the geminal  o f the 5,6-epimine d e r i v a t i v e r e l a t e d to in  this  (CIV)  and  sign  coupling  (CVII) should be p o s i t i v e  sign. Whilst  vicinal  the  couplings  above s i g n d e t e r m i n a t i o n s  corresponding  remains the q u e s t i o n  o f the  90°  According  d i h e d r a l angle.  f u r t h e r e s t a b l i s h the  to d i h e d r a l angles  s i g n s o f the v i c i n a l  to the Karplus  o f 60°  and  coupling  180°,  signs there  corresponding 2 6  calculation '  and  of  to a  c e r t a i n mod-  i f i c a t i o n s * ^ a small n e g a t i v e c o u p l i n g i s p r e d i c t e d . In c o n t r a s t o t h e r c a l 119 120 5 culations "' and m o d i f i c a t i o n s a l l p r e d i c t a small p o s i t i v e c o u p l i n g . It would be o f some i n t e r e s t , t h e r e f o r e , to determine the s i g n o f a v i c i n a l p l i n g corresponding  to t h i s  cou-  geometry.  Although t h i s s i g n i n v e r s i o n should  not  i n v a l i d a t e the  stereo-  122 s p e c i f i c dependencies o u t l i n e d by  Buss et a l  , f o r the v i c i n a l  o f e p i - d e r i v a t i v e s , these dependencies should at The  be  t r e a t e d with  couplings  some c a u t i o n  present. Signs  o f Long-Range C o u p l i n g  According  Constants*  to the McConnell e x t e n s i o n  2 3  o f the Dirac-Van V l e c k  Vector  4 model, a i l long  range c o u p l i n g s  across  f o u r bonds i n s a t u r a t e d  systems  ( J)  should be n e g a t i v e i n s i g n . A more recent t h e o r e t i c a l study by B a r f i e l d has i n d i c a t e d t h a t i f the s o l e mechanism f o r long-range c o u p l i n g i s v i a the bonding 2  electrons  .—_.  ( the " i n d i r e c t  —  _—.  " mechanism ) , 'then <.—•  4.  J)  ,e  —-—e , i  and  -100-  4  J  c o u p l i n g s should both be p o s i t i v e  3,6  •  should be n e g a t i v e  in sign:  in sign, whilst •  has  a l s o been made  through  space  a, a  couplings  and  - 0.2  Hz.  three  The  suggestion  4 that  J  e  c o u p l i n g s are i n f a c t t r a n s m i t t e d  g  (the " d i r e c t " mechanism) as a r e s u l t o f o v e r l a p o f the  lobes o f the two record  125 '  J  the r e s p e c t i v e magnitudes o f these  c o u p l i n g s were p r e d i c t e d to be +1.16, + 0.65 124  4  C-H  bonds.  Although  f o r some time, a d e f i n i t i v e  "tail"  these c o n f l i c t i n g views have been on  study o f t h i s p o i n t has been delayed  the d i f f i c u l t y o f f i n d i n g d e r i v a t i v e s which would g i v e s p e c t r a showing  by the  a p p r o p r i a t e c o u p l i n g s i n a form s u i t a b l e f o r r e l a t i v e s i g n d e t e r m i n a t i o n s . F o r t u n a t e l y pyranose carbohydrate and  d e r i v a t i v e s are s u i t a b l e  for this  purpose  a study o f d e r i v a t i v e s (XXXV,XXXVII,XXXIX,XLI,L,LI 11,CV,CVI,CIX) has,  with no e x c e p t i o n s , shown t h a t + 1.6  Hz), w h i l s t  4  j*  e  ^ c o u p l i n g s are p o s i t i v e  (+ 0.8  to  c o u p l i n g s are n e g a t i v e i n s i g n (-0.2 to -0.7 Hz). —~ 4 Thus the s i g n and magnitude o f the J c o u p l i n g s are i n extremely c l o s e e, c 4  J  e, a  agreement with  B a r f i e l d ' s c a l c u l a t i o n s and  imply t h a t such  couplings  occur  v i a the " i n d i r e c t " r a t h e r than the " d i r e c t " mechanism, which had p r e v i o u s l y , and  e r r o n e o u s l y , been s u p p o s e d * . 24  c o u p l i n g s o f pyranose sugars * s i g n s are o p p o s i t e .  W h i l s t the magnitudes o f the  are i n accord with  4  J  the p r e d i c t e d v a l u e ,  T h i s s i g n i n v e r s i o n should p r o v i d e an extremely  their  val-  uable e x t e n s i o n o f the s e l e c t i o n o f s t e r e o s p e c i f i c dependencies which are available  f o r c o n f i g u r a t i o n a l and  conformational  assignments.  In p a r t i c u l a r ,  4 f o r s t u d i e s o f d e r i v a t i v e s which show J c o u p l i n g s 4 4 whose magnitudes are inbetween those n o r m a l l y found f o r J and J e,e •.Professor M. B a r f i e I d i s c u r r e n t l y r e i n v e s t i g a t i n g h i s t h ee,a oretical ".Proresscr *\. u r l en a n a l y s i s o f long-range *H- H c o u p l i n g s * ^ . it  should  f i n d some use  1  -101-  couplings.  S i n c e these  s t u d i e s were completed, P a c h l e r and Underwood  127 have r e p o r t e d exhibit  4 t h a t the  J couplings  o f eight pterocarpan  derivatives  a s i g n i n v e r s i o n s i m i l a r t o t h a t observed f o r pyranosc d e r i v a t i v e s .  It i s noteworthy t h a t the magnitudes o f the long-range c o u p l i n g s i n the p r e s e n t  study  are c o n s i d e r a b l y  s m a l l e r than those  observed  found f o r s t r a i n e d  128 ring for  systems 4 J  a, a  .  I t i s a l s o o f some i n t e r e s t  coupling.  that there  is little  The s o l e p o s s i b l e example found i n t h i s study  evidence i s an  apparent c o u p l i n g o f +0.75 Hz between the H^ and 1!^ resonances o f methyl8-0-glucuronate t e t r a a c e t a t e (CXII). beyond the f i r s t  order  Although t h i s spectrum was c l e a r l y  l i m i t s o f Husher and C o r c y ^ , the f a c t t h a t the  c o u p l i n g changed from +0.75 Hz i n c h l o r o f o r m  t o 0.60 Hz i n acetone s o l u t i o n ,  suggests t h a t i t would be unwise t o base any d i s c u s s i o n on t h i s one example.  ] 29 Long-range c o u p l i n g s  occur  so w i d e l y  i n furanose d e r i v a t i v e s  t h a t i t i s seldom p o s s i b l e t o r e s o l v e and observe them d i r e c t l y . t a i l e d n.m.d.r. study,  In a de-  1^, 2 -0_-isopropylidene-3^-0_-acetyl-4 -cyano-tetra1^0 hydrofuran-1 ,2 ,3„-triol, P a c h l e r and V.'esscls " showed that the s i g n s o f j a ' a' 8 4 all  the  J c o u p l i n g s were The  a  negative.  long-range c o u p l i n g s  o f the u n s a t u r a t e d  C I I , O i l ) were a l l found t o be n e g a t i v e t h a t the epoxide  i n sign.  d e r i v a t i v e s (XXXIV,  I t i s i n t e r e s t i n g t o note  (CIV) e x h i b i t s a long-range c o u p l i n g o f s i m i l a r magnitude  to t h a t shown by the 5,6-ene ( C I I ) , whereas no such c o u p l i n g s observed f o r the e p i s u l p h i d e  (CVII).  s i m i l a r i t y between the c o u p l i n g s  T h i s supports  o f (CIV) and ( C I I ) .  can be  the p r e v i o u s l y observed The mechanism o f protonG  proton  coupling i n unsaturated  systems  r**  G *7  , has been d i s c u s s e d p r e v i o u s l y ; '>"'  -102-  W h i l s t t h i s study r e p r e s e n t s the f i r s t  systematic i n v e s t i g a t i o n  o f the s i g n s o f carbohydrate c o u p l i n g c o n s t a n t s , t h e r e have been p r e v i o u s ] 3 ] -13 3 isolated  studies  , i n p a r t i c u l a r Coxon, Jennings and McLauchlan  have r e c e n t l y d e t e r m i n e d * , 3 4  D-glycero-pent-2-enopyranosyl  the s i g n s o f c o u p l i n g s o f derivatives.  3,4-dichloro-4-deoxy-  -103-  *"F-*H COUPLING CONSTANTS  102 103 Since a d e t a i l e d and  d i s c u s s i o n of the " s e l e c t i v e - i r r a d i a t i o n ' '  the " s p i n - t i c k l i n g " * ^ ' * ^ 3  4  '  methods f o r d e t e r m i n i n g t h e r e l a t i v e s i g n s o f  c o u p l i n g c o n s t a n t s was g i v e n above, i t i s s u f f i c i e n t t o make o n l y b r i e f mention o f t h e g e n e r a l approach.  I n c o n t r a s t t o t h e d e t e r m i n a t i o n o f *H-*H  s i g n s , where " s p i n - t i c k l i n g " was found t o be t h e p r e f e r r e d method, s e l e c t i v e ly i r r a d i a t i o n i s often suitable  f o r the determination o f the 19 1  T h i s i s because t h e l a r g e (ca_. 50 Hz) geminal separates the f l u o r i n e - s p i n of t h e l l j t r a n s i t i o n s  1 F- 1! s i g n s .  F- H c o u p l i n g  effectively  s t a t e s " a " from t h e f l u o r i n e - s p i n  so t h a t one s e t can be r e a d i l y  states."g"  irradiated  without  p e r t u r b i n g t h e o t h e r . T h i s i s i l l u s t r a t e d below. The S i g n s o f V i c i n a l and Geminal C o u p l i n g s The s p e c t r a i n F i g . by  12 show t y p i c a l examples o f s i g n d e t e r m i n a t i o n s  t h e frequency-sweep s e l e c t i v e  i r r a d i a t i o n technique, whilst  T a b l e XVlJshows  the  c o r r e s p o n d i n g s p i n - s t a t e assignments f o r t h e 11^ and H^ resonances o f  the  compounds i n v o l v e d .  F i g . 12 shows t h e p a r t i a l p.m.r. spectrum o f 2,3-  di-0-acetyl-4,6-0-benzylidenc-ct -D-glucopyranosyl f l u o r i d e  ( X I ) , R^ = H, 19  R  = p) w h i l s t  itions  Fig.  12B shows t h e e f f e c t  (5,6) o f t h e \\ resonance.  i n the c o l l a p s e o f t r a n s i t i o n s spin-states. are  o f i r r a d i a t i n g the  F =ct t r a n s -  I t i s c l e a r l y evident that t h i s 19  9,10 and 11,1.2 which a l s o have  F =cc  Hence i t f o l l o w s t h a t t h e r e l a t i v e s i g n s o f ..T ^ and Jp ^  t h e same.  p  Fig.  12C,D show r e s p e c t i v e l y  t h e "normal" and  "irradiated"  s p e c t r a o f 2 , 3 - d i - 0 - a c e t y l - 4 ,6-0_-benzylidenc-6-D-glucopyranosyl (XU,  R  = F, R 1  results  = H) .  Again, the r e l a t i v e signs o f J  2  same, s i n c e i r r a d i a t i o n o f t h e l o w - f i e l d  and J r ,  transitions  fluoride  1  are t h e ' j-  (5 f 6) o f t h e 11^ t  -= 104 -  T a b l e XVII  19  S p i n s t a t e assignments  f o r the  F,  and  resonances  o f :- ( A ) , 2,3-  d i - O j - a c e t y l - 4 ,6-0_-benzylidene-a-D-glucopyranosyl  fluoride  (XI) and  di-0-acetyl-4,6-0_-benzylidene-8-D-glucopyranosyl  fluoride  (XII).  are assumed t o be  A l l signs  positive.  Set A Transition  (B) , 2,3-  1 9  No.  F  1 2 1 9  3  4  F  Spin States of  H  1  a  a  B  6  a  3  a  8  l  H  5  6  7  8  9  10  a  a  3  3  a  a  11  a. a  3  2  12  13  14  15  16  a  a  B  B  B  B  8  a  B  a  3  a  3  B  B  8  a  Neighbouring  a  a  a  a  B  B  12  14  15  Nucleii  Set B Transition  1 9  No.  '12 1 9  F  H  "l 3  4  F  5  6  7  8  9  10  11  a  a  8  3  a  a  a  Spin States of  Neighbouring  "l  " 2 H  Nucleii  H  resonance  a  a  8  8  a  8  a  8  3  a  B  a  2  13 3  a  3  16 8 3  ce  3  a  a  3  3  a  8  a  a  8  a  3  a  8  3  3  e f f e c t s d e c o u p l i n g o f the l o w - f i e l d t r a n s i t i o n s  (9 § 10 and 11 ft  12) o f the I-L, resonance. A l l o f the homonuclear d e c o u p l i n g experiments  performed  on  do-  B  lib  1  5.00  4.50  4.00  I  1  4.50  4.00  5.50  T  BIO  5  4 M 450  4.00 Pi cure  12.  P a r t i a l 100 MH?. F)  H.R, transitions i n acetone-d  5  (X!)  4  00  spectra of:-  i n acctone-d  00  W  solution.  (O  T  ft**  4.50  5.00  2 , J - d i - 0 - a c e t y l - 4 ,6-0-benzy 1 i d e n e - D - f : l u c o p y r a n o s y 1 f l u o r i d e  solution,  Q  (A) t h e " n o m n l " s p e c t r u m  and  (B) w i t h i r r a d i a t i o n o f  2 , 3 - d i -0-accty!-<1 ,6-0-benzy 1 i d c n e - P - D - < ; l u c o [ i y r a n o s y I f l u o r i d e < (  00  the " n o r n a i " spectrum  and  ( R j = F ,R ;  (D) w i t h i r r a d i a t i o n o f t r a n s i t i o n s  2  = H) 5f,6.  (Kll)  5.50  -106-  r i v a t i v e s T , I I I ,X,XI,XII,XXI,XXITI,XXV,XXXV,XXXVIII,XLV  and CXTII and  summarized i n T a b l e XVM, i n d i c a t e d t h a t t h e r e l a t i v e s i g n s o f J J„  9  [ ;  ^ and  are the same, and i t was o f i n t e r e s t t o p l a c e t h e s e o b s e r v a t i o n s on  an a b s o l u t e b a s i s .  S i n c e i t i s a l r e a d y known t h a t v i c i n a l  11- II c o u p l i n g s  a r c a b s o l u t e l y p o s i t i v e i n s i g n t h i s o b j e c t i v e c o u l d be a c h i e v e d by d e t e r m i n i n g t h e r e l a t i v e s i g n s o f .1^  and  ^.  T h i s would i n v o l v e  selective  10 i r r a d i a t i o n o f part o f the  F spectrum w h i l s t o b s e r v i n g t h e 11 ^ resonance:  2-bromo-2-deoxy-a-D-mannopyranosyl  fluoride triacetate  (XXXV) had s p e c t r a l  p r o p e r t i e s a t 60 MHz which were s u i t e d t o such an experiment ( F i g . 13A). I n i t i a l l y t h e "F resonance f r e q u e n c y o f (XXXV) was l o c a t e d by 19 sweeping t h e  1  *F d e c o u p l e r output, u n t i l complete d e c o u p l i n g o f t h e  spectrum was o b s e r v e d .  H  I t can be seen from F i g s . 13B,13C t h a t the power  output (H^) o f t h e SD-60 d e c o u p l e r was not s u f f i c i e n t t o decouple s i m u l t *  a n e o u s l y b o t h t h e H^ and 19 i n F i g . 13C, where t h e  resonances from t h e f l u o r i n e spectrum.  Thus  "F f r e q u e n c y had beeii chosen f o r o p t i m a l d e c o u p l i n g  o f t h e H^ r e s o n a n c e , t h e H^ resonance i s o n l y p a r t i a l l y d e c o u p l e d , w i t h each o f t h e two " p a r t s " o f t h e resonance d i s p l a c e d towards t h e c o m p l e t e l y decoupled p o s i t i o n , which i s shown i n F i g . 13B. Having l o c a t e d i n t h i s f a s h i o n , t h e approximate f r e q u e n c y o f t h e 19 *F r e s o n a n c e , two s e l e c t i v e - i r r a d i a t i o n experiments were then performed, and 19 the r e s u l t s o f t h e s e  a r e shown i n F i g . 14.  The  F f r e q u e n c y was s e l e c t e d  (see E x p e r i m e n t a l ) so t h a t t r a n s i t i o n s 3 ft 4 c o u l d be i r r a d i a t e d ( F i g . 14B) * I t s h o u l d be remembered t h a t t h e s e experiments were performed under f i e l d - s w e e p c o n d i t i o n s so t h a t t h e F d e c o u p l i n g f r e q u e n c y i s swept, w h i l s t the 1-H spectrum i s scanned. To e f f e c t d e c o u p l i n g o f b o t h Hj and 11 ^, f o r t h e same s e t t i n g o f the SD-60 d e c o u p l e r , would r e q u i r e a power output a t l e a s t as g r e a t as t h e sum o f t h e bandwidth o f t h e -F resonance (53 Hz) p l u s t h e chemical, s h i f t s e p a r a t i o n between H^ and i - ^ (76 Hz) , p l u s the bandwidth o f the H2 r e s o n a n c e , t h a t i s 13S Hz,  4.0 F i g u r e 13.  P a r t l a I 60 MHz  fluoride triacetate and  4.5  5.0  6.0  r  spectrum o f 2-bromo-2-deoxy-a-D-mannopyranosyl  (XXXV) i n c h l o r o f o r m  (C) w i t h i r r a d i a t i o n at the f l u o r i n e  c o u p l i n g o f the H, and H r e s o n a n c e s ?  5.5  solution;  (A) normal s p e c t r u m , (f  f r e q u e n c y t o e f f e c t o p t i m a l de-  respectively.  + 123.2 pprn  B  i 4.0  0  4.0  F i g u r e 14. triacetate  (A)  1 9  T6.0  F resonance c f 2-bromo-2-deoxy- -D-nannopyranosyl a  (XXXV) i n c h l o r o f o r m s o l u t i o n ;  effect of i r r a d i a t i n g  1 9  (B)  l  fluoride  H spectrum of (XXXV) shoving  F t r a n s i t i o n s 3S4; (C) Hi spectrum showing e f f e c t o f  19 irradiating  5.5  5.0  F t r a n s i t i o n s 152.  -109-  and the power output J + J2 j ), that field  transitions  (H^) was  (Ik,) > (Jp 2)  14 $ 16) o f the \\^ resonance.  ( F i g . 14C) , i r r a d i a t i o n o f t r a n s i t i o n s  in collapse of transitions s t a t e assignments  such t h a t  (^2  +  F  +  i s (H^) > 12 Hz; t h i s e f f e c t e d c o l l a p s e o f the h i g h (10 ?, 12 and  sequent experiment  are  selected  (9 f» 11 and 13 f, 15) .  shown i n T a b l e XIX  c o n s i s t e n t with J  , and J b,J  In a sub-  (1 £) 2) r e s u l t e d  I n s p e c t i o n o f the s p i n -  i n d i c a t e that the above experiments  h a v i n g the same r e l a t i v e s i g n s .  Since  —  1,2  homonuclear d e c o u p l i n g had a l r e a d y i n d i c a t e d that Jp ^ and Jp ^ had the same r e l a t i v e s i g n s , and i t Lis known t h a t v i c i n a l absolutely positive positive. to  No  *H-*H c o u p l i n g s are  , i t f o l l o w s t h a t Jp ^ and Jp ^ are a l s o  attempt was  absolutely  made to a p p l y t h i s h e t e r o n u c l e a r d e c o u p l i n g method  o t h e r d e r i v a t i v e s and i t has been assumed i n n o r m a l i z i n g a l l the v a l u e s  given i n T a b l e XVIII t h a t a l l o t h e r c o u p l i n g s f o l l o w the p a t t e r n observed f o r XXXV.  *See F i g . 15 f o r a f u l l  assignment  o f the  H transition  numbers.  * * I t can be seen from F i g s . 14R $ 14C t h a t the H t r a n s i t i o n s are more s t r o n g l y p e r t u r b e d i n the f i r s t experiment ( F i g . 14BJ than i n the second ( F i g . 14C) : t h i s o b s e r v a t i o n i s c o n s i s t e n t with the assignment made above f o r the two s e l e c t i v e i r r a d i a t i o n experiments. C o n s i d e r the s i t u a t i o n i n these f i e l d - s w e e p experiments as the change i n magnetic f i e l d (H ) b r i n g s H^ towards t h e l 9 F resonance and Hj^ towards the iH spectrum. In the case o f the experiment designed to i r r a d i a t e t r a n s i t i o n s 3 § 4, w h i l s t o b s e r v i n g H2, i t i s c l e a r l y p o s s i b l e f o r !1 to p e r t u r b the F s p i n - s t a t e s w h i l s t the H^ resonance i s b e i n g o b s e r v e d : " i t can be imagined that Hj reaches the ^H spectrum as Jj^ approaches the ^ F spectrum, and thus Hj w i l l d e t e c t a l l p o s s i b l e p e r t u r b a t i o n s o f the spectrum, i n c l u d i n g the d e s i r e d d e c o u p l i n g . However, when i s chosen f o r the i r r a d i a t i o n o f t r a n s i t i o n s 1 5 2, Hj has a l r e a d y been swept through the 1-H spectrum as f a r as the H2 resonance i t s e l f , b e f o r e {^2 reached the ^ F spectrum, and i s thus never i n p o s i t i o n to d e t e c t the s p u r i o u s p e r t u r b a t i o n s induced i n the h-l spectrum. J 9  7  n  a  s  -110-  TABLE XVTII 19  The Signs o f the  1 F- H C o u p l i n g Constants o f a S e r i e s o f G l y c o p y r a n o s y l Fluorides.  Signs and magnitudes o f Relevant C o u p l i n g C o n s t a n t s (Hz).  Derivative  2-bromo-2-deoxy-3-D-glucopyranosyl fluoride  triacetate  (XXXVI)  Jj  0  2-bromo-2-deoxy-a-D-mannopyranosyl fluoride  triacetate  (XXXV)  F  + 50.3  J  1,F  +  5  ° -  J  1,F  +  5 3  ; J  2  +  F  10.0  2 5  J  2,F  +  2  '  ;  J  2,F  +  2 4  8 5  C  2,3-di-0-acetyl-4,6-0-benzylidene-a-Dglucopyranosyl  fluoride  (XI)  -°  -  6  2,3-di-0-acetyl-4,6-benzylidene-3-Dglucopyranosyl f l u o r i d e  a-D-glucopyranosyl  (XII)  fluoride  J  a  J  fluoride  acetate  (XXX)  x  p  1,F  J  fluoride  + 52.8  (XXXVIII)  =  acetate  (XXIII)  3  2  +  F  > 2,F J  5 4  -°  C  1,F  +  5 1  -  J  • 2a,F 7  1,2a  fluoride  ; J  5  +  3  B-D-ribopyranosyl  -  5 2  • 1,F T  3  triacetate  11.6  23.8  +  -°  1 2  tri-  2-deoxy-a-D-arabino-hexopyranosyl fluoride  +  Z , r  tetra-  acetate (III)  B-D-arabinopyranosyl  ; J_  tetra-  a c e t a t e (I)  B-D-glucopyranosyl  + 53,4  i ,r  J  2e,3  J  1,F  +  3 8  +  2  +  5  ;  J  +  -° 8 5 ;  '  2  -  5 :  J  J  J  l,2e  2e  ) 2  9  *  J  5  '  2 Z  > 2e,F  4  '  2,F  +  a  2a,3  " +  1 0  1  '  3  ^  8  tri+  4 9  J  2,F  +  1  A  1  -111-  TABLE X V I I I ( c o n t ' d )  a-D-xylopyranosyl  fluoride triacetate . (XXI)  B-D-allopyranosyl f l u o r i d e  (x)  1.F  J  +  S 3  triacetate  J  J . _ + 53.6 3,F +  J  Jj  fluoride triacetate  J ;  +  2 3  -  ?  ; J . _+  12.0  (XLV)  b  3  3-deoxy-3-f luoro-B-D-xylopyranose". (CXIII)  3.6  + 51.1  f  p  -  V  ; J  0  +  4 9  '  6  9  + 10.6  ; VplO.91  0.8 I ' ':  \,V  ;  J  J  I ' '  5.F  4.F  0  +  1 2  '  7  4  a J  3-deoxy-3-f louro-B-D-glucopyranor>e tetraacetate  ' 2,E  8  a  2-chloro-2-dcoxy-B-D-glucopyranosyl  triacetate  -  a  J  (CXIV)°  J  Measured i n c h l o r o f o r m - d Measured i n a c e t o n e - d ,  5e,F 6.,F 5,F  solution.  solution.  6 Measured i n benzene-d..  +  solution  4  '  l°l  2  '> 6 , F J  ?  I " ' 1  5  -112-  TABLE XIX  S p i n - S t a t e Assignments f o r the  F, M  and It., Resonances o f 2-bromo-  2-deoxy- -D-Mannopyranosyl F l u o r i d e T r i a c e t a t e a  1 2  3  4  5  H  8  9  10  a  a B  a  8  R  F  2  13  12  14  15  16  a  8  a '  g  8.  2  H  3  Nci ehbouring  a  8  3  a  8  a  8  a  a  B  8  a  8  TO  H  of  a  fl  l  TO  H  R  States  Nucleii  11  ] q  TO  Spin  No.  "l 6 7  R  Transition  p  TO  19  (XXXV).  a  a  a  B  a  8  3  3  -113-  It 19 vicinal as  can  be  i n f e r r e d from t h e  above d i s c u s s i o n t h a t the s i g n s  of  1 F- II c o u p l i n g s  are not  f a r as angles o f ca. 60°  have shown t h a t the  and  subject 180°  same i s t r u e  to an a n g u l a r dependence, at l e a s t  are concerned.  Further  studies* '' 3  f o r d i h e d r a l angles o f ca. 0° and  120°,  The  p o s i t i v e s i g n i s c o n s i s t e n t with p r e v i o u s r e l a t i v e s i g n d e t e r m i n a t i o n s 136 o f non-carbohydrate d e r i v a t i v e s and with a r e c e n t a b s o l u t e s i g n d e t e r 39 137 m i n a t i o n on C H F C l j and another on CH^F " . I t would s t i l l be o f i n t e r e s t 19 1 to determine the s i g n o f a v i c i n a l F- H c o u p l i n g between substituents 2 6 separated  by  ca. 90°  f o r which t h e r e  remains the p o s s i b i l i t y  '  of a sign  change. All  o f the homonuclear s i g n d e t e r m i n a t i o n s d e s c r i b e d  S e c t i o n have u t i l i z e d  the  frequency-sweep method.  However, at t h i s  many c a r b o h y d r a t e l a b o r a t o r i e s o n l y have access to 60 MHz apparatus and be  in this time  field-sweep  n.m.d.r.  i t seemed worthwhile to demonstrate t h a t r e l a t i v e s i g n s  performed q u i t e r e a d i l y with such equipment.  The  r e s u l t s of  can  field-sweep  homonuclear s i g n d e t e r m i n a t i o n s on the a-mannosyl f l u o r i d e (XXXV) are shown in  F i g . 15.  T r a n s i t i o n s 5-8  s i t i o n s 9-16  correspond to the 1!^ resonance, w h i l s t  correspond to H j , t h e s p i n s t a t e s o f these resonances have  a l r e a d y been a s c r i b e d  i n T a b l e XIX  t r a n s i t i o n s o f VI  higher  field  i n the  c o l l a p s e o f the h i g h e r  field  This conclusion  .  I t can be  seen that  field  t r a n s i t i o n s o f V\^ (11,12 and  Thus J  is verified  p  ^ and  i n F i g . 15C  J  p  2  have the  13 S 14) .  i s that there  i s no  i r r a d i a t i o n ; thus,  The  the  considerable  spectrum i t s e l f  care must be  same r e l a t i v e lower .  lower f i e l d t r a n s i t i o n s  p r i n c i p a l disadvantage o f t h i s  i n d i c a t i o n on the  15,16)  where i r r a d i a t i o n o f the  t r a n s i t i o n s 5 5 6 r e s u l t s i n a c o l l a p s e o f the  (9 f, 10 and  i r r a d i a t i o n of  (7 5 8 ) , which correspond to F = 8 , r e s u l t s  which a l s o have F = g , F i g . 15B. sign.  tran-  exercised  field-sween  method  o f the p r e c i s e p o i n t  of  i n s e l e c t i n g the f r e -  -114-  A  i  _j  4.0  F i g u r e 15.  4.5  P a r t i a l 60 MHz  fluoride triacetate  ,  i  1  5.0  5.5  r  1  6,0  s p e c t r a o f 2-bromo-2-dcoxy-a-D-mannopyranosyl  (XXXV) i n c h l o r o f o r m s o l u t i o n ;  with simultaneous i r r a d i a t i o n of t r a n s i t i o n s radiation of t r a n s i t i o n s  •—  556.  (A) normal-spectrum,  (B)  7fj8 and (C) w i t h s i m u l t a n e o u s i r -  Both (B) and (C) a r c f i e l d - s w e p t d e c o u p l e d spectv  -115-  quencies o f the a u d i o - o s c i l l a t o r s used i n such experiments t o generate the decoupling  f i e l d (H^). I t i s now worthwhile t o comment on the o r i e n t a t i o n a l dependence o f  vicinal  ester substituents  on the magnitude o f geminal c o u p l i n g s . 19  e a r l i e r noted  (p. 25), geminal  ester substituent  information  i s any e l e c t r o n e g a t i v e  nuclei involved  either trans  i s a x i a l l y oriented  are cji. 53 Hz when the C j  (see below).  o f the c o n f i g u r a t i o n a l dependence  t h a t , i f there  itive.  F- 1-1 c o u p l i n g s  i s o n l y ca_. 49  In view o f the s i g n  now a v a i l a b l e , the above r e s u l t s are e a s i l y r a t i o n a l i z e d through 8 9  consideration  two  1  i s e q u a t o r i a l l y o r i e n t e d , w h i l s t the v a l u e  Hz when t h i s s u b s t i t u e n t  As was  i n the c o u p l i n g , 19 1  Thus the p o s i t i v e  group  ' , which i n e f f e c t s t a t e s  (eg. -OAc) t r a n s  t o e i t h e r o f the  then i t w i l l make that c o u p l i n g  F- H c o u p l i n g  l e s s pos-  (C) (manno-tyne), i s s m a l l e r than  (A) o r (B) s i n c e these l a t t e r two have no e l e c t r o n e g a t i v e  groups i n a  OAc  configuration.  AcO  AcO  (A) J  -53  H,F,  The  Hz  above r e s u l t s seem at f i r s t  73 ported  ~53Hz  1 f o r geminal  substituent  with those re-  1  H- H c o u p l i n g s  and indeed f o r those r e s u l t s p r e s e n t e d i n  t h i s t h e s i s f o r geminal *H~*H c o u p l i n g s . negative  t o be at v a r i a n c e  - 4 9 Hz  I t i s noted t h a t when the e l e c t r o -  i s t r a n s t o the c o u p l i n g n u c l e i , the magnitude o f t h i s  -116coupling i s larger.  Mien the s i g n o f H- M 1  s i d e r a t i o n the r e s u l t s are found 15)  l  1  c o u p l i n g s i s taken  groups i n a t r a n s  con-  found f o r  coupling i s less positive  l  n e g a t i v e ) when the c o u p l i n g n u c l e i are a s s o c i a t e d with negative  into  t o be i n agreement w i t h those  Thus the U- \i  I - M geminal c o u p l i n g s . ;  1  (larger  one o r more e l e c t r o -  orientation.  Ac 0'  OAc  J  = c a . - ] l Hz  gem  The Signs o f Long-Range  ( J) 4  1 9  F- li i  couplings  4  Again  i n s i g n (ca.+4 }\ ) z  there i s l i t t l e  Table  X,XLV,CXIII)  whilst  evidence  4  of J 4  XVIII.  Thus,  s i g n depen-  couplings are e, e J couplings are negative ( c a . - l Hz). e, a " — a, a  in  (compounds  t h a t these c o u p l i n g s a l s o e x h i b i t the same s t e r e o s p e c i f i c  dence found p r e v i o u s l y f o r J *H-*H c o u p l i n g s . positive  c.a.-13 Hz —  Couplings.  A study o f long-range revealed  gem  —  couplings. • °  4  J  These r e s u l t s a r e l i s t e d  -117-  EXPERIMENTAL  For convenience  and  b r e v i t y t h i s s e c t i o n has been arranged so  t h a t syntheses which have a common format  a r e grouped t o g e t h e r .  erences between these groups a r e g i v e n where  SECTION A:  ref-  necessary.  GENERAL METHODS  (a)  A l l e v a p o r a t i o n s were c a r r i e d out under reduced  (b)  Most o p t i c a l Polarimeter All  Cross  pressure.  r o t a t i o n s were measured on a Bendix ETL-NPL Automatic (Type 143A) u s i n g e i t h e r a 4 cm. o r a 0.5 cm. c e l l .  o p t i c a l r o t a t i o n s were measured u s i n g c h l o r o f o r m  (ethanol-free)  solutions. (c)  M e l t i n g p o i n t s were determined apparatus  (d)  on a F i s h e r - J o h n s m e l t i n g p o i n t  and a r e u n c o r r e c t e d .  Micro-analyses  were c a r r i e d out by Mr. P. P.orda o f t h i s  (e) ' A l l a c e t y l a t i o n s were performed at ca_. 0° u s i n g excess anhydride/pyridine  Department. acetic  (1:1); b e n z o y l a t i o n s and t o s y l a t i o n s were a l s o  c a r r i e d out at ca_. 0° by adding, a s o l u t i o n o f e i t h e r benzoyl (1.1 mole) i n dichloromethane. aqueous sodium b i c a r b o n a t e  t o a s o l u t i o n o f the a l d o s e i n p y r i d i n e ,  c h l o r i d e or p-toluenesulfonyl c h l o r i d e Excess  reagent  was decomposed by adding  (ca_. 5 ml.); t h e s o l u t i o n was then  diluted  with c h l o r o f o r m and e x t r a c t e d with aqueous sodium b i c a r b o n a t e , water  -118-  and d r i e d (Na^SO^) . taminated  E v a p o r a t i o n u s u a l l y r e s u l t e d i n a syrup  by p y r i d i n e ; t h i s p y r i d i n e was  d i s s o l v i n g the syrup  con-  e f f e c t i v e l y removed by  i n t o l u e n e and e v a p o r a t i n g  to dryness.  The  p y r i d i n e f r e e syrup g e n e r a l l y c r y s t a l l i z e d from an aqueous e t h a n o l solution. (f)  Glycopyranosyl  bromides were prepared  by d i s s o l v i n g the f u l l y e s t e r -  i f i e d a l d o s e i n excess hydrogen b r o m i d e / a c e t i c A f t e r the s t a r t i n g m a t e r i a l had  a c i d (35%, w/w) .  a l l d i s s o l v e d , the s o l u t i o n was  at room temperature f o r ca. 2 h r .  T h i s r e a c t i o n m i x t u r e was  then  d i l u t e d with dichloromethane,  washed w i t h water u n t i l n e u t r a l , d r i e d  (Na^SO^) and e v a p o r a t e d .  syrupy  The  g l y c o p y r a n o s y l bromide was  r e a c t e d d i r e c t l y o r c r y s t a l l i z e d from d i e t h y l e t h e r at ca_. (g)  left  Most p.m.r. s p e c t r a were measured w i t h a V a r i a n HA-100  either  -5°.  spectrometer  o p e r a t i n g i n e i t h e r the "frequency-sweep" or " f i e l d - s w e e p " mode, u s i n g t e t r a m e t h y l s i l a n e (TMS)  as i n t e r n a l r e f e r e n c e ; chemical  shifts  are g i v e n on the t - s c a l e . (h)  Most f.m.r. s p e c t r a were measured w i t h a V a r i a n HA-100 at 94.071 MHz, reference.  The  using trichlorofluoromethane spectrometer  was  spectrometer,  (Freon-11) as  internal  used i n e i t h e r the " u n l o c k e d "  or i n the " l o c k e d " " f i e l d - s w e e p " mode u s i n g the " i n f i n i t e  HR-mode  offset"  138 m o d i f i c a t i o n o f Douglas Burton  , (which was  f u r t h e r m o d i f i e d by Mr.  and b u i l t i n the department's e l e c t r o n i c shop).  s h i f t s are i n p.p.m.; <f>^ v a l u e s r e f e r t o a c h l o r o f o r m c ca_. 20% Ereon-11 as i n t e r n a l r e f e r e n c e .  R.  Chemical s o l u t i o n with  *  (i)  R o u t i n e p.m.r. s p e c t r a were run i n e t h a n o l f r e e c h l o r o f o r m s o l u t i o n  on a. V a r i a n A-60 spectrometer. *The c h l o r o f o r m was s t o r e d o v e r s e l f - i n d i c a t i n g s i l i c a g e l which e f f e c t i v e l y removed the t r a c e o f e t h a n o l which i s used as an a n t i - o x i d a n t .  -119-  SECTION B:  THE  The  GLYCOPYRANOSYL FLUORIDES  compounds i n t h i s  s e c t i o n were e i t h e r p r e p a r e d  l i t e r a t u r e methods o r were generous g i f t s  from Dr.  C.  T e c h n i c a l U n i v e r s i t y o f Denmark, L y n g b y , Denmark. 1 in this assigned  structures.  standard  (see T a b l e s  procedures  example o f each procedure  from the  fully  acylated  d i s s o l v e d i n anhydrous l i q u i d  left  into a mixture  ether  l a y e r was  listed  be  f o l l o w s one 20  and  given.  g,  7 4 % ) , m.p.  afforded  pure  ( I ) , m.p.  another  ), only  A l l syntheses  HF  (20 m l )  w h i c h had  one  started  ( c a . 20 min)  been c o o l e d  The  resulting  and  was  dried  (NajSO^).  107-111°.  110-112°, [a]^  as n e e d l e s  in a  dir-  solution.  from  of  (lit.  1  9  The this  ethanol  from aqueous  +91.0° ( c , 2 . 9 3 ) .  g)  solution  Evaporation  Recrystallization  (5  then poured  aqueous sodium b i c a r b o n a t e  a c l e a r syrup which c r y s t a l l i z e d  (3.3  Klemer  or  ( I ) : - D-Glucose p e n t a a c e t a t e  (solid-COj/acetone).  o f e t h e r and  solution  their  Fluorides  w a s h e d w i t h w a t e r and  s o l u t i o n produced  ethanol  m.p.  108°,  +90.1°) A sample  and  will  t o warm t o room t e m p e r a t u r e  ectly  [a)l°  derivatives  Fluoride Tetraacetate  p o l y e t h y l e n e v e s s e l t o --78° was  A l l compounds  sugar.  Hexopyranosyl  was  the  I , I I , I V £- V f o r t h e i r n.m.r. p a r a m e t e r s )  ( r e v i e w e d by M i c h e e l  detailed  a-D-Glucopyranosyl  Pedersen of  F n.m.r. p a r a m e t e r s i n a c c o r d w i t h  Since the p r e p a r a t i o n of a l l of these  o f two  standard  19 II and  s e c t i o n had  by  (3.3  sodium mcthoxide  g) o f  (2.4 m l ,  ( I ) was  d i s s o l v e d i n a b s o l u t e methanol  1%)  added.  was  After  20 m i n  (12  the b a s i c s o l -  ml)  -120-  u t i o n was n e u t r a l i z e d w i t h i o n exchange r e s i n  (Amberlite-IR-120-H),  f i l t e r e d and e v a p o r a t e d t o g i v e a - D - g l u c o p y r a n o s y l f l u o r i d e a f l u o r i n e chemical s h i f t p.p.m. and  53.0 Hz; J  p  8-D-Glucopyranosyl bromide  .  26.8 Hz.  2p  Fluoride Tetraacetate ( I I I ) : -  a-D-Glucopyranosyl  ' t e t r a a c e t a t e (5 g ) , p r e p a r e d i n t h e u s u a l manner from  s i l v e r m o n o f l u o r i d e (5 g ) . overnight.  I t had  (aqueous s o l u t i o n ; e x t e r n a l Freon-11) o f +149.7  p e n t a a c e t a t e , was d i s s o l v e d i n a c e t o n i t r i l e  was  (II)  D-glucose  (25 ml) c o n t a i n i n g powdered  L i g h t was e x c l u d e d and t h e m i x t u r e was shaken  The r e s u l t i n g s o l u t i o n was f i l t e r e d and aqueous sodium  added t o p r e c i p i t a t e any s i l v e r i o n s from s o l u t i o n .  chloride  T h i s m i x t u r e was  f i l t e r e d and c o n c e n t r a t e d t o a m o b i l e syrup which was d i s s o l v e d i n c h l o r o form, e x t r a c t e d w i t h w a t e r , d r i e d b o i l i n g diethyl ether. l i g h t petroleum  (Na^SO^), evaporated and d i s s o l v e d i n  C r y s t a l l i z a t i o n was completed by t h e a d d i t i o n o f .  (b.p. 65-110°) t o g i v e (3.5 g, 80%) o f ( I I I ) as s t u r d y  p r i s m s , m.p. 86-89°; r e c r y s t a l l i z a t i o n from d i e t h y l e t h e r a f f o r d e d pure ( I I I ) , m.p. 89°.  (lit.  1 4 0  m.p. 88°, [ a ] + 2 0 ° ; Q  141  m . p . 98°, [a] +21.9°).  A sample o f ( I I I ) was de — a c e t y l a t e d t o g i v e B - D - g l u c o p y r a n o s y l 19 fluoride was  (IV).  The " F c h e m i c a l s h i f t  +142.9 p.p.m. and J  52 Hz; J 1 ,r  (aqueous s o l u t i o n e x t e r n a l Freon-11) 12.5 Hz.  Z , I*  a-D-Mannopyranosyl F l u o r i d e T e t r a a c e t a t e ( V ) : - S y n t h e s i s by t h e method used for  the preparation o f e i t h e r  (n.m.r.).  ( I ) o r ( I I I ) a f f o r d e d t h e same syrupy product  T h i s c r y s t a l l i z e d a f t e r s e e d i n g w i t h a sample p r o v i d e d by  C. Pedersen,  The p r o d u c t (V) had m.p. and mixed m.p. 69-71°.  (lit.  3 0  m.p.  68-69°) A sample o f (V) was d e — a c e t y l a t e d t o g i v e a-D-mannopyranosyl  -121-  fluoride was  (VI).  The  "F chemical  +138.8 p.p.m. and  shift  50.0  p  Hz; 3  2  (aqueous s o l u t i o n ; e x t e r n a l F r e o n - l i ) p  c a . 1.5  a-D-Galactopyranosyl F l u o r i d e Tetraacetate r i v a t i v e f o l l o w e d the method d e s c r i b e d  Hz.  (VII):- Preparation of t h i s  for (I).  y i e l d e d a syrup which f a i l e d t o c r y s t a l l i z e .  de-  However, the r e a c t i o n  The  syrupy p r o d u c t  was  chromatographed on a column o f s i l i c a g e l , u s i n g 1% methanol i n d i c h l o r o methane as e l u a n t .  The  f a s t e s t moving component was .  j  by i n s p e c t i o n o f b o t h i t s  shown t o be pure 25  ig  H and  (VII),  "F n.m.r. s p e c t r a .  i -)^' +106.6°. 0  ( c , 0.84). Anal. Calc. C, 48.2;  H, 5.6;  F,  for C^H^OgF:  C, 48.0;  H, 5.45;  F, 5.45.  Found:  5.7.  Dr. C. P e d e r s e n , has  a l s o mentioned ( p r i v a t e communication) t h a t  the above compound i s n o n - c r y s t a l l i n e . B-D-Galactopyranosyl F l u o r i d e Tetraacetate d e r i v a t i v e f o l l o w e d the c o n v e r s i o n  (VIII):-  The  preparation of t h i s  of D-galactose pentaacetate  s y r u p y cx-Fl-galactopyranosyl bromide t e t r a a c e t a t e  1 4 2  which was  p u r i f i c a t i o n , with s i l v e r monofluoride i n a c e t o n i t r i l e .  (5 g)  to  reacted,  Inspection  without  (f.m.r.)  o f the c r u d e , syrupy f l u o r i d e showed the presence o f ca_. 5% o f the a-anomer, which was  not i s o l a t e d i n the work up.  from d i e t h y l e t h e r t o y i e l d m.p.  103-104°.  (lit.  a-D-Allopyranosyl Tetraacetate  (X):-  1 4 3  m.p.  1.7  The  crude p r o d u c t was  g (40% from the p e n t a a c e t a t e ) ,  98-99°; [ a ] J  Fluoride Tetraacetate  8  crystallized of  (VIII)  +22°)  (IX) and  When D - a l l o s e p e n t a a c e t a t e  B-D-Allopyranosyl  (0.75  the c o n d i t i o n s d i s c u s s e d above, f o r the f o r m a t i o n  g) was  Fluoride  subjected  to  o f ( I ) , an almost e q u i -  -122-  •molar mixture  o f ( I X ) and (X)  was  obtained,  (X) was a l s o p r o d u c e d f r o m t h e s y r u p y ethyl  ether.  needles  Recrystallization  (m.p. 149 - 151°,[o]  ( 0 . 6 3 g, ' 9 1 % ) .  a - b r o m i d e and c r y s t a l l i z e d  from aqueous e t h a n o l  -1.3°  The 6 - f l u o r i d e  afforded  from d i -  (X) a s  fine  ( c . 1.55).  A n a l . C a l c . f o r C ^ H ^ O g F ; C, 4 8 . 0 ; H,5.45; F, 5.45.  Found:  C, 4 7 . 8 ; II, 5.4; F, 5.2. N.M.R. D a t a  (chloroform-d solution)  Chemical  H  l  H  4.45  Shifts  2  H  4.97*  (T v a l u e s )  3  H  4.31  Coupling Constants l,2  J  J  7.3  2,3 3.1  graphed ca.  5  \  ' 4.97*  \  -°  5.7  J  4,5  J  5,6  J 1  5,6  J 2  6  1 5  6  J 2  crystallization  mainly  7.91  7.99  1.F  J  2,F  2  (IX).  o f methyl  3,F 3.6  chromato-  spot.  Fluoride  ot-D-altropyranoside t e t r a a c e t a t e with  HF y i e l d e d a m i x t u r e  to crystallize.  J  I t contained  F l u o r i d e T e t r a a c e t a t e and 8 - D - A l t r o p y r a n o s y l  Reaction  146.6  12.0  t h e a-anomer w h i c h was  2 5 % i m p u r i t i e s b y p.m.r., T.L.C. showed o n l y one  failed  7.94  o f t h e 8-anomer f r o m t h e m i x t u r e  2  anhydrous l i q u i d  7.86  53.6  ( s i l i c a g e l , 1% MeOH i n C H C 1 ) t o g i v e i m p u r e  Tetraacetate:-  A C  (Hz)  f r o m t h e HF r e a c t i o n l e f t  a-D-Altropyranosyl  far  3,4  H  2.6  Successive obtained  J  4  o f t h e a- and 8 - f l u o r i d e s , w h i c h s o  T h e s e f l u o r i d e s h a v e b e e n c h a r a c t e r i z e d on t h e  19 basis of their  F n.m.r. p a r a m e t e r s w h i c h a r e g i v e n  a-anomer <j> +134.9; C 8-anomer <J> +138.5; C Dr.  C. P e d e r s e n ,  J  below.  _ 48.3 H z ; J„ "2.7 Hz 1,1* /., r . 54 1,1 r  H z ; J . _ 20 -.Hz 2,F  has a l s o mentioned  the benzoate analogues are n o n - c r y s t a l l i n e .  (private  communication) t h a t  -123-  2,3~Di-0-Acetyl-4,6~0-Benzylidene-a-D-Glucopyranosyl F l u o r i d e  (XI) and  2,3-Di-0_-Acetyl-4 ,6-£-Benzylidene-3-D-Glucopyranosyl  (XII) : -  Fluoride  144 These two  compounds were o b t a i n e d by a c e t y l a t i o n of the c o r r e s p o n d i n g  4,6-0-benzylidene compounds. sufficient  These compounds were n o t , however, o b t a i n e d i n  q u a n t i t y or p u r i t y f o r d e t a i l e d p h y s i c a l c h a r a c t e r i z a t i o n .  had m.p.  137-143°  a f t e r two r e c r y s t a l l i z a t i o n s from aqueous e t h a n o l .  had m.p.  142-148°, a l s o a f t e r r e c r y s t a l l i z a t i o n from aqueous e t h a n o l .  (XI) (XII)  N.m.r. showed them t o be at l e a s t 95% pure as no i m p u r i t y peaks were d i s cernable. a-D-Mannopyranosyl F l u o r i d e T e t r a b e n z o a t e  (XIII)^  a-L-Rhamnopyranosyl F l u o r i d e T r i b e n z o a t e (XIV)  45  145  a-D-Glucopyranosyl F l u o r i d e T e t r a b e n z o a t e  (XV)  6-D-Glucopyranosyl  (XVI)  Fluoride Tetrabenzoate  AS  46  2-0-Methyl-a-D-Glucopyranosyl  F l u o r i d e T r i b e n z o a t e (XVII)  2-0-Methyl-B-D-Glucopyranosyl  F l u o r i d e T r i b e n z o a t e (XVIII)  3-0-Methyl-a-D-Glucopyranosyl  F l u o r i d e T r i b e n z o a t e (XIX)  3-0-Methyl-8-D-Glucopyranosyl  F l u o r i d e T r i b e n z o a t e (XX)  47  47  46  -124-  Compounds' (XTII) - (XXII) were g i f t s their receipt  i s g r a t e f u l l y acknowledged. 1  r e c e i v e d and i n s p e c t i o n o f t h e i r  from C. Pedersen  These  samples  and  were used as  19 H and  *F s p e c t r a c o n s t i t u t e d  evidence f o r t h e i r a s s i g n e d s t r u c t u r e s and Pentopyranosyl  further  purity.  Fluorides  a-D-Xylopyranosyl F l u o r i d e T r i a c e t a t e  (XXI):-  A sample o f t h i s  derivative  19 was  s y n t h e s i z e d by the method o f Brauns  .  The  crude r e a c t i o n product con-  t a i n e d ca_. 5% o f the c o r r e s p o n d i n g B-isomer was  not i s o l a t e d  (XXII) as shown by f.m.r, which 19 (XXI) had m.p. 86-88°. ( l i t . " m.p. 87°)  i n the work up.  3-D-Xylopyranosyl F l u o r i d e T r i a c e t a t e derivative  (XXII):-  The p r e p a r a t i o n o f t h i s  f o l l o w e d the method o f Lundt and Pedersen  45  , except t h a t  crystal-  146 l i n e a - D - x y l o p y r a n o s y l bromide 52-55°.  (lit.  4 S  m.p.  8-D-Ribopyranosyl  56-57°  triacetate  [a]  2 3  was  used.  (XXII) had  m.p.  -56.4°)  Fluoride Triacetate  (XXIII):-  The p r e p a r a t i o n o f t h i s 45  d e r i v a t i v e a l s o f o l l o w e d the method o f Lundt and Pedersen ".  Examination  (f.m.r.) o f the crude r e a c t i o n product showed the presence o f a second component which we  a s s i g n e d to the a - D - r i b o p y r a n o s y l f l u o r i d e  (XXIV) on the b a s i s o f i t s c h e m i c a l s h i f t  T h i s compound was measured and had m.p.  not i s o l a t e d ; however, i t s  found t o be: 4>  94-96°.  and f i r s t 19  c  (lit'!  5  m.p.  +147.7, 93-95°).  p  52.1  triacetate  order coupling constants,  F n.m.r. parameters were Hz, J  2  , 26.3  f  Hz.  (XXIII)  -125-  a-D-Ribopyranosyl Tribenzoate Pedersen  F l u o r i d e T r i b e n z o a t e (XXV) and 8-D-Ribopyranosyl  (XXVI):-  These d e r i v a t i v e s were p r e p a r e d by the method o f  and F l e t c h e r . 3 4  (XXVI) had m.p.  (XXV) had m.p.  135-137°.  cc-D-Lyxopyranosyl  Fluoride  34  ( l i t . m.p.  Fluoride Triacetate  202-204°.  (lit.  m.p.  3 4  205-206°)  139-140°).  (XXVII):-  This  compound was syn-  45 thesized  i n the manner o f Lundt  ( l i t ' ' m.p. 4  and Pedersen  (XXVII) had m.p.  85-87  87-89°) .  a-D-Xylopyranosyl  Fluoride Tribenzoate  B-D-Xylopyranosyl  F l u o r i d e T r i b e n z o a t e (XXIX)  (XXVIII)  49  49  8-D-Arabinopyranosyl  Fluoride Triacetate  a-D-Arabinopyranosyl  F l u o r i d e T r i b e n z o a t e (XXXI)  a-D-Arabinopyranosyl  Fluoride Triacetate  a-D-Lyxopyranosyl  Compounds (XXVIII)  Fluoride Tribenzoate  (XXX)* ' 9  (XXXII)  (XXXIII)  - (XXXIII) were generous  and t h e i r r e c e i p t i s g r a t e f u l l y acknowledged. 1 received  .  and i n s p e c t i o n o f t h e i r  II and  4 3  45  45  48  gifts  from C.  Pedersen,  These samples were used as  19 F n.m.r. s p e c t r a  f u r t h e r evidence f o r t h e i r a s s i g n e d s t r u c t u r e s  and p u r i t y .  constitutes  -126-  SECTION C:  ELECTROPHILIC ADDITION REACTIONS OF D-GLUCAL TRIACETATE  (XXXIV)  A d d i t i o n o f the elements o f " B r F " (a)  Generated from B r  (1.36 g) i n d r y a c e t o n i t r i l e  2  and AgF:-  ( c a . 25 ml) was  powdered s i l v e r m o n o f l u o r i d e * * (4 g ) . w/v  ( c a . 10 m i n ) , the s o l u t i o n was  (XXXIV)*  s t i r r e d vigorously with  A s o l u t i o n o f bromine  i n benzene) was then added d r o p w i s e .  addition  D-Glucal t r i a c e t a t e  (0.85 g, 10%  A f t e r c o m p l e t i o n o f the bromine s t i r r e d f o r a f u r t h e r 20 min  then f i l t e r e d from the c o p i o u s p r e c i p i t a t e o f s i l v e r h a l i d e .  and  To t h i s  sol-  u t i o n was added 5 ml o f s a t u r a t e d aqueous sodium c h l o r i d e , the p r e c i p i t a t e d s i l v e r c h l o r i d e was removed, the f i l t r a t e was c o n c e n t r a t e d t o ca_. 10 ml and c h l o r o f o r m (30 ml) was  added.  The c h l o r o f o r m s o l u t i o n was  extracted  s u c c e s s i v e l y w i t h aqueous sodium t h i o s u l p h a t e , aqueous sodium b i c a r b o n a t e and water. 97%).  A f t e r d r y i n g (Na^SO^), e v a p o r a t i o n produced a c l e a r s y r u p (1.8 g,• I n s p e c t i o n (p.m.r.) o f the crude r e a c t i o n p r o d u c t showed t h a t no 19  s t a r t i n g m a t e r i a l remained and  "F n.m.r. showed the presence o f t h r e e  g l y c o p y r a n o s y l f l u o r i d e s which were s u b s e q u e n t l y i d e n t i f i e d 2-bromo-2-deoxy-a-D-mannopyranosyl f l u o r i d e t r i a c e t a t e +123.2,  p 50.2 Hz; J  fluoride triacetate  2  , 2.85  {  Hz; c  2-bromo-2-deoxy-a-D-glucopyranosyl  1>r  (XXXV) 70%, $  2-bromo-2-deoxy-8-D-glucopyranosyl  (XXXVI) 21%, 4>  + 144.9, .7, • 51.5 Hz; J _ _ 25.2  ( v i d e i n f r a ) as:-  +136.0, J  ]  p  50.3 Hz; J  fluoride triacetate  2  p  10.0 Hz and  (XXXVII) 9%, <j>  Hz.  2,1"  *(XXXIV) was a commercial sample from the A l d r i c h Chemical Co., M i l w a u k e e , W i s c o n s i n , which was p u r i f i e d by r e c r y s t a l l i z a t i o n from aqueous ethanol. **The s i l v e r m o n o f l u o r i d e was a commercial sample from Harshaw C h e m i c a l Co., C l e v e l a n d , Ohio, and was ground t o a f i n e powder b e f o r e use.  -127-  A f t e r work up, the r e a c t i o n mixture was  dissolved  in boiling  d i e t h y l e t h e r and on c o o l i n g the s o l u t i o n d e p o s i t e d c r y s t a l s m.p.  (0.98 g) ,  137-142°; a d d i t i o n o f l i g h t petroleum a f f o r d e d a second crop o f the  same m a t e r i a l  (0.13 g ) , t o t a l y i e l d  1.11  g; 56%.  Recrystallization  from 22  e t h a n o l a f f o r d e d pure -32.0°  (XXXV) as p r i s m a t i c c r y s t a l s ; m.p.  138-140°, [ ] a  D  ( c , 2.06). Anal. Calc. f o r C  C, 39.0:  H, 4.5;  F,  1 2  H  1 6  0 BrF: ?  C, 38.8; H, 4.3;  F, 5.1.  Found:  5.0.  The mother l i q u o r s r e m a i n i n g a f t e r i s o l a t i o n o f (XXXV) were evaporated and the r e s u l t i n g syrup d i s s o l v e d a f t e r s e v e r a l weeks an impure  sample  i n e t h a n o l and c o o l e d t o - 5 ° ;  o f (XXXVII) was  o b t a i n e d (0.12 g, 6%).  R e c r y s t a l l i z a t i o n , t w i c e from aqueous e t h a n o l a f f o r d e d pure f i n e n e e d l e s ; m.p.  120-121°,  [a]  2 2  +134.5°  Anal C a l c . f o r C H . 0 B r F : 1 2  C, 39.0;  H, 4.45;  F,  The r e s i d u a l  1 (  7  (XXXVII)  as  (c, 1.80).  C, 38.8; H, 4.3;  F, 5.1.  Found:  4.95. syrup from above was  shown (n.m.r.) t o c o n t a i n  mainly the 8 - g l u c o isomer (XXXVI) t o g e t h e r w i t h s m a l l e r q u a n t i t i e s o f the o t h e r isomers (XXXV) and  (XXXVII)  F o r t u n a t e l y t h i s syrup was  pure f o r d e t a i l e d n.m.r. a n a l y s i s ; i t has so f a r f a i l e d  sufficiently  to c r y s t a l l i z e .  R e i n v e s t i g a t i o n o f the above r e a c t i o n , u s i n g o n l y benzene s o l v e n t , y i e l d e d the same t h r e e isomers, but i n q u i t e d i f f e r e n t the o v e r a l l y i e l d o f adducts was  Generated from N-bromosuccinimide  F o l l o w i n g the procedure o u t l i n e d by Kent, Robscn was  ratios  and  o n l y 83%; the q-manno isomer (XXXV) 42%,  the 8-gluco isomer (XXXVI) 42% and the a - g l u c o isomer (XXXVII) (b)  as  and anhydrous 33 and Welch  16%. liquid  , this  reaction  repeated several times, using s l i g h t l y d i f f e r e n t r e a c t i o n times.  y i e l d s r e p o r t e d are average r e s u l t s .  Anhydrous  hydrogen ' f l u o r i d e  HF:-  The  (10 g)  was  -128-  added to anhydrous d i e t h y l e t h e r cji_. -78°  (solid-C0 /acetone).  b o t t l e cooled  N-Bromosuccinimide (4.0 g) and  o  triacetate  (18 g) i n a p o l y t h e n e  D-glucal  (XXXIV) (5.0 g) were added, p o r t i o n w i s e , t o the s t i r r e d  o v e r the course  o f ca. 10 min.  A f t e r 1/2-2  r a i s e d t o 0° f o r a f u r t h e r 1/2-2 the s o l u t i o n was  hr.  h r at -78°,  The  A f t e r d i l u t i o n with d i e t h y l  e t h e r e a l l a y e r was  t r a c t e d w i t h w a t e r , d r i e d (Na^SO^) and e v a p o r a t e d . o f the crude r e a c t i o n product  solution,  the temperature  was  ether,  decomposed by p o u r i n g d i r e c t l y i n t o an i c e - c o l d ,  s o l u t i o n o f sodium b i c a r b o n a t e .  to  saturated  subsequently  ex-  I n v e s t i g a t i o n (p.m.r.)  showed t h a t no s t a r t i n g m a t e r i a l remained  and  19 F n.m.r. showed the presence o f f o u r g i y c o p y r a n o s y l f l u o r i d e s which were 19 1 19 i d e n t i f i e d , on the b a s i s o f t h e i r "F c h e m i c a l s h i f t s and HF coupling c o n s t a n t s , as the a-manno isomer (XXXV) ca_. 55%, the B-gluco isomer (XXXVI) c a . 30%,  the a - g l u c o isomer (XXXVII) ca_. 9%;  the f o u r t h resonance has  been  84 identified acetate 38.0  (see p.139)  as 2-deoxy-a-D-arabino-hexopyranosyl f l u o r i d e  (XXXVIII) ca. 7%,  cj> +131.1, J j c  51.2  p  Hz; J  2q  p  5.0  Hz; J  2  g  tri-  p  Hz. The  syrupy m i x t u r e was  the s o l u t i o n d e p o s i t e d  d i s s o l v e d i n d i e t h y l e t h e r and on c o o l i n g ,  (XXXV) (1.85  g, 3 2 % ) .  R e c r y s t a l l i z a t i o n from  v/v c h l o r o f o r m - l i g h t p e t r o l e u m a f f o r d e d pure (XXXV) m.p. 140°,  w i t h the compound o b t a i n e d  above.  The  remaining  1:5  and mixed m.p.  139-  compounds from t h i s  r e a c t i o n were not i s o l a t e d as they were p r e v i o u s l y c h a r a c t e r i z e d . The a-manno isomer (XXXV) was  r e f l u x e d f o r 24 h r . i n a c e t o n i t r i l e  containing a m o l a r excess o f s i l v e r w o n o f l u o r i d e I t was and  and was  a l s o u n a f f e c t e d when resubjectc-d t o treatment  recovered  unchanged.  w i t h N-bromosuccinimide  anhydrous HF as d e s c r i b e d above. P a r t i a l hydrogenolysis  palladium-charcoal  o f (XXXV) , at a t m o s p h e r i c p r e s s u r e  c a t a l y s t , diethylamine  as a c i d a c c e p t o r )  (10% .  i n methanol  -129-  solution  gave (n.m.r. e v i d e n c e ) the 2-deoxy f l u o r i d e  with unreacted s t a r t i n g material The manno d e r i v a t i v e anol s o l u t i o n  (XXXVIII) t o g e t h e r  (XXXV) and D - g l u c a l t r i a c e t a t e  (XXXIV).  (XXXV) was u n a l t e r e d when h e a t e d under r e f l u x i n meth-  c o n t a i n i n g d i e t h y l a m i n e and p a l l a d i u m - c h a r c o a l  catalyst.  A d d i t i o n o f the elements o f " I F "  (a)  Generated from 1^  a r ,  d A R ^ : - F o l l o w i n g t h e same p r o c e d u r e  (as d e s c r i b e d above f o r t h e g e n e r a t i o n o f " B r F " from B r ^ and AgF), glucal  triacetate  (XXXIV)  (1.36 g) was  r e a c t e d w i t h I ^ (1.25 g) and  (2 g) t o form a c l e a r syrup i n 98% y i e l d . three glycopyranosyl f l u o r i d e s : triacetate  (XXXIX.) 60%, <j>  51.7 Hz; J  i  C  ,r  9.3 L.  acetate  ... , r  ether solution  2 2  §^ 139.8, J j  50.5 Hz; J  p  2  p  132.3, J 1,1, .,  (XXXIX) as p r i s m a t i c c r y s t a l s  27.8  Hz.  o b t a i n e d c r y s t a l l i n e from an  o f t h e r e a c t i o n m i x t u r e and was  c r y s t a l l i z e d from e t h a n o l t o  ( y i e l d 1.0  g, 4 7 % ) ; m.p.  155-156°,  -46.1° ( c , 2.54). Anal. Calc. for C  C,  Hz; 2*deoxy-2-  Hz and 2 - d e o x y - 2 - i o d o - a - D - g l u c o p y r a n o s y l f l u o r i d e t r i -  The ot-D-manno isomer (XXXIX.) was  [a]  r  fluoride  ,F  ( X L l ) 6%,  g i v e pure  3.9  (XL) 34%,' 6c  i o d o - 8 - _D - .g.l u c o p .y r a n o s.y l f l u o r i d e t r i a c e t a t e 49.9 Hz; J  AgF  T h i s s y r u p c o n t a i n e d (f.m.r.)  2-deoxy-2-iodo-a-D-mannouyranosyl  116.9, J  D-  34.7; H,4.0; F,  H  0 PI: y  C, 34.45; H, 3.85;  F, 4.55.  Found:  4.65.  The mother l i q u o r s r e m a i n i n g from c r y s t a l l i z a t i o n o f (XXXIX) were c o n c e n t r a t e d t o a syrup which was ( X L l ) was  o b t a i n e d from t h i s s o l u t i o n  Recrystallization 4.8%); m.p.  dissolved i n ethanol.  The a - g l u c o isomer  a f t e r s e v e r a l weeks o f s t a n d i n g at 0°  from aqueous e t h a n o l a f f o r d e d f i n e n e e d l e s ( y i e l d 0.10  143-144°, [ c c ] ^  2  +180.5° ( c . 2 . 7 2 ) .  g,  -130-  A n a l . C a l c . f o r C" H_,0„FI: 12 16 7 C, 34.60; H, 4.0; F,  C, 34.45; H, 3.85;  F, 4.55.  Found:  4.65.  The mother l i q u o r s were found (n.m.r.) t o c o n t a i n mainly- the B-gluco isomer ( X L ) .  Column chromatography  ( s i l i c a g e l , 1% MeOH i n C H ^ C l j  as e l u a n t ) y i e l d e d a c l e a r syrup which was s u f f i c i e n t l y pure f o r d e t a i l e d n.m.r. a n a l y s i s .  To d a t e , t h i s compound has not been o b t a i n e d c r y s t a l l i n e .  Upon r e i n v e s t i g a t i o n o f t h i s r e a c t i o n , u s i n g o n l y benzene f o r s o l v e n t , the same t h r e e isomers wei-e o b t a i n e d ( y i e l d 79%) i n the f o l l o w i n g ratio:  the a-manno isomer (XXXIX) 33%, the B-gluco isomer (XL) 45% and the  a - g l u c o isomer (XLI) 22%.  (b)  Generated from N - i o d o s u c c i n i m i d e and anhydrous  l i q u i d IIP:—  81 F o l l o w i n g the procedure o f Wood, Kent and F i s h e r  0  , a partially  crystal-  l i n e mass was o b t a i n e d which c o n t a i n e d (f.m.r.) the same t h r e e g i y c o p y r a n o s y l f l u o r i d e s , i n the f o l l o w i n g r a t i o s :  the a-manno isomer  (XXXIX)  71%, the B-gluco isomer (XL) 3% and the a - g l u c o isomer (XLI) 23% t o g e t h e r with a small  (3%) u n i d e n t i f i a b l e resonance at <j>  +125.3.  None o f the deoxy  isomer (XXXVIII) c o u l d be d e t e c t e d . A d d i t i o n o f the elements o f  "C1F" *  (a)  Generated from C l j / A g F : - F o l l o w i n g c l o s e l y  the procedure  o u t l i n e d above f o r the a d d i t i o n o f " B r F " from Br^/AgF, an amber syrup was o b t a i n e d i n 91% y i e l d which c o n t a i n e d (f.m.r.) a l l f o u r i s o m e r i c adducts.  These were shown t o . b e :  "OF"  2-chloro-2-cleoxy-a-D-mannopyranosyl  ''The o n l y m o d i f i c a t i o n r e q u i r e d was t h a t benzene (20 ml) was added to the a c e t o n i t r i l e s o l u t i o n and the c h l o r i n e gas was bubbled i n t o the s t i r r e d s o l u t i o n . Excess c h l o r i n e was s u b s e q u e n t l y removed w i t h a stream o f dry a i r .  -131-  fluoride triacetate  ( X L l I ) .16%, 4> +127.8 c  chloro-2-deoxy-8-D-mannopyranosyl +118.6, J  49.4  Hz; J  1,1"  3.6  49.5  Hz; J  fluoride triacetate Hz;  2  p  2 Hz;  (XLV)  2-  16%, cj>  2-chloro-2-dcoxy-a-D-glucopyranosyl  ^ , r  fluoride triacetate  (XLIV) 6%,  <j> +147.6, ^ c  2-chloro-2-deoxy-8-0-glucopyranosyl +13S.9, J  p  _ 51.0 1,r  Hz; J _  10.6  p  51.2  Hz; J  fluoride triacetate  2  p  24.0  Hz;  (XLHI)62%, <j>  Hz.  ,r  Over the course o f s e v e r a l days at c a . 0 ° , an e t h a n o l i c o f the r e a c t i o n p r o d u c t p r e c i p i t a t e d 10%).  Recrystallization  120-121°,  [a]  2 5  the ct-manno isomer  H, 5.1;  F,  1 6  7  C, 44.1;  (see p.141) y i e l d e d  which when r e c r y s t a l l i z e d 77-78°,  [a]  2 5  0.83  5.1;  The crystalline  H, 4.9;  F, 5.9.  Found:  with an a u t h e n t i c sample o f  g (51%) o f the g-gluco isomer  from aqueous e t h a n o l a f f o r d e d  (XLlIT),  crystalline  plates:  +1.24° ( c , 1.13).  Anal. Calc. f o r C^II^OyClF: C, 44.15; H,  m.p.  5.6.  The mother l i q u o r s , when seeded  m.p.  (XLII);  g,  -23.4° ( c , 0.96). 2  (XLIII)  solution  (XLII) (0.17  from aqueous ethanol a f f o r d e d pure  Anal C a l c . f o r C H 0 C 1 F : C, 44.3;  and  F,  C, 44.1;  H, 4.9;  F, 5.9.  Found:  5.8.  r e m a i n i n g compounds  (XLIy ) and  (XLV  ) were not o b t a i n e d  from t h i s r e a c t i o n ; however, see p.141 f o r the p r e p a r a t i o n of  (XLIV).  (b) HF:  - The  G e n e r a t i o n from N - c h l o r o s u c c i n i m i d e and anhydrous  reaction of D-glucal t r i a c e t a t e  liquid  (XXXIV) with anhydrous l i q u i d  and N - c h l o r o s u c c i n i m i d e d i d not lead t o any  HF  fluorine containing material.  -132-  A d d i t i o n o f t h e elements o f "BrOBz"  D-Glucal t r i a c e t a t e  (XXXIV)  (1.36 g) was d i s s o l v e d i n benzene *  (25 ml) t o which was added s i l v e r benzoate solution  (2.5 g ) ; 8.5 ml o f a bromine  (10% w/v i n benzene) was added dropwise t o t h e s t i r r e d s u s p e n s i o n .  A f t e r a f u r t h e r 20 min, t h e s u s p e n s i o n was f i l t e r e d and t h e f i l t r a t e was then e x t r a c t e d s u c c e s s i v e l y w i t h aqueous sodium t h i o s u l f a t e , aqueous sodium b i c a r b o n a t e and water.  The benzene s o l u t i o n was d r i e d  (Na,S0^) and evap-  o r a t e d t o a c l e a r s y r u p (2.32 g ) . I n s p e c t i o n (p.m.r.) o f t h i s crude r e a c t i o n p r o d u c t i n d i c a t e d f o u r anomeric r e s o n a n c e s , which were a t t r i b u t e d t o t h e f o u r i s o m e r i c "BrOBz" adducts. (XLVI)  They were formed i n t h e f o l l o w i n g y i e l d s :  3.1% T  3.43, J j  2  U  l  = 3.44,  J  l  2  1.8 Hz; a-gluco isomer  3.5 Hz; g-gluco isomer  B-manno isomer  (XLIX)  < 2%  t h e a-manno isomer  (XLVII)  T HJ  ( X L V I I I )  26%  T HJ  =  42% t Hj = 3.94, J j 9.1 Hz; and 2  = 3.56, J j  2  3.5 Hz.  T h i s crude r e a c t i o n p r o d u c t was d i s s o l v e d i n a minimum o f b o i l i n g ethanol. and l e f t a t room temperature o v e r n i g h t , d u r i n g which time c r y s t a l s (1.61 g, 68%) were d e p o s i t e d . These were shown (p.m.r,) t o be an almost equal m i x t u r e o f t h e two t r a n s isomers  (XLVI)  and  ( X L V I I ) .  The mother l i q u o r s were c o o l e d t o c a . 0° and a f t e r s e v e r a l weeks f i n e n e e d l e shaped c r y s t a l s were d e p o s i t e d (0.55 g 2 3 % ) ; r e c r y s t a l l i z a t i o n from aqueous e t h a n o l a f f o r d e d pure pyranose t r i a c e t a t e  (XLVIII):  l-0-benzoyl-2-bromo-2-deoxy-a-D-gluco-  m.p. 112-113° [ a ]  2 5  +213° ( c , 0.89).  • S i l v e r benzoate was formed by r e a c t i n g e q u i - m o l a r aqueous s o l u t i o n s o f s i l v e r n i t r a t e and sodium b e n z o a t e ; t h e crude p r e c i p i t a t e was washed w i t h c o p i o u s amounts o f w a t e r , f i l t e r e d ( s u c t i o n ) and d r i e d a t 120^ for 8 hr.  -133-  Anal. Calc. C,  for  c 1  g  H  i 9 0  2  ! 7 ; r :  C  >  4 8  - ; 2  H  > 4.45;  B r , 17.  Found:  48.0; II, 4.5; B r , 17. The  m i x t u r e o f ( X L V I ) and  (XLVII)  w e r e s e p a r a t e d i n t h e manner  29 o f L e m i e u x and  Levine  and w e r e e a c h  recrystallized  from aqueous e t h a n o l .  1-0_-Benzoyl-2-bromo-2-deoxy-a-D-mannopyranose t r i a c e t a t e  168-169°, [ a ]  m.p.  +62.3° (c_, 1.54).  2 8  Anal. Calc. C, 48.0;  (XLVI) had  11, 4.5,  for C.gll^O^r:  Fl, 4.45;  C, 48.2;  B r , 17.0  Found:  17.1.  Br.  l-0-Benzoyl-2-bromo-2-deoxy~ B-D-glucopyranose  h a d m.p. 161-162°, [ a ] Anal Calc.  2 8  triacetate  (XLVII)  B r , 17.0.  Found:  +15.3° ( c , 0.72).  f o r C H 0 15r: 1 9  2 1  g  C,  48.2;  H,  4.45;  C, 48.05; H, 4.6; B r , 17.1. 'Alien t h e a b o v e r e a c t i o n was solve the D-glucal t r i a c e t a t e  ( X X X I V ) , t h e same f o u r p r o d u c t s w e r e  (n.m.r.) i n t h e f o l l o w i n g r a t i o s ; isomer  ( X L V I I ) 55%,  (XLIX)  t h e a-manno i s o m e r  the a-gluco isomer  ( X L V I I T ) 40%  (XLVI.) 20%, and  dis-  observed  the  B-gluco  t h e B-ma.nno i s o m e r  6%.  A d d i t i o n o f the elements • The acetates  repeated using acetonitr.i l e to  two  ( L ) and  of  "IOBz"  isomeric trans  l-0_-benzoyl-2--deoxy-2-iodo-pyranose  tri-  ( L I ) were o b t a i n e d by a v a r i a n t o f t h e method d e s c r i b e d  29 b y L e m i e u x and L e v i n e and  the i o d i n e  (1.35  wise to the s t i r r e d  :  1.36  g) was  g o f ( X X X I V ) , i n b e n z e n e s o l u t i o n , was  dissolved  i n benzene  (10%  w/v)  and a d d e d  used drop-  solution.  Investigation  (n.m.r.) o f t h e c r u d e r e a c t i o n p r o d u c t showed t h e  presence o f a third anomeric  p r o t o n , n o t r e p o r t e d b y L e m i e u x and  Levine.  -134-  I t was a s s i g n e d t o 1-^0-benzoyl-2-deoxy-2--iodo-a-D-glucopyranose  triacetate  (1,11) (-r " J - 3.42; J j ^ 3.0 H z ) . The p r o d u c t r a t i o as determined by p.m.r. was t h e -manno isomer (L) 46%, t h e a - g l u c o isomer (LIT) 8% and t h e 8-gluco a  isomer  (LT) 46%. T h i s r e a c t i o n was r e p e a t e d , u s i n g an a c e t o n i t r i l e s o l u t i o n o f  D-glucal t r i a c e t a t e lowing r a t i o s :  (XXXIV).  The same p r o d u c t s were observed i n t h e f o l -  t h e a-manno isomer (L) 64%; t h e B-gluco isomer ( L I ) 28%,  and t h e q-gluco isomer ( L I I ) 8%. The  q-gluco isomer (L1I) was not i s o l a t e d from the mother l i q u o r s .  The -manno isomer (L) had m.p. a  160-161°, l i t .  m.p.  159.5-160°, [a]  +45.3  29 and t h e B-gluco isomer ( L I ) had m.p.  150-151°, l i t .  ~ m.p.  150-151.5°, [a]  +2.2°. A d d i t i o n o f t h e elements o f "ClOBz" D-Glucal t r i a c e t a t e  (XXXIV) (5.6 g) was d i s s o l v e d i n d r y benzene  (70 ml) c o n t a i n i n g s i l v e r benzoate  (5.6 g) and c h l o r i n e gas was bubbled i n  u n t i l an excess was p r e s e n t as e v i d e n c e d by t h e c o l o u r o f t h e s o l u t i o n . A f t e r 20 min t h e excess c h l o r i n e was removed by a stream o f d r y a i r .  The  r e s u l t i n g s o l u t i o n was f i l t e r e d and s u c c e s s i v e l y e x t r a c t e d w i t h aqueous sodium t h i o s u l p h a t e , aqueous sodium b i c a r b o n a t e and water. s o l u t i o n was d r i e d  The benzene  (Na S0^) and e v a p o r a t e d t o a c l e a r s y r u p . ?  (8.9 g, 105%).  The r e a c t i o n p r o d u c t was d i s s o l v e d i n e t h a n o l and a f t e r s t a n d i n g at -5° o v e r n i g h t , d e p o s i t e d c r y s t a l s  (1.3 g, 15%) m.p.  150-153°.  Recrystal-  l i z a t i o n t w i c e from e t h a n o l a f f o r d e d l-0-benzoyl-2-chloro-2-deoxy--a-D-gluco28  pyranose t r i a c e t a t e  ( L I I I ) as n e e d l e s , m.p.  Anal, Calc. f o rC H i g  C, 53.3; H, 5.05; C I , 8.25.  0 CI  :  c  >  153-154°, p]  - '> > -°'>  S7,  2  H  4  C1  >  +195.0° ( c , 0.50). 8  - 5  F o u n c i :  -135-  Th e mother l i q u o r s r e m a i n i n g a f t e r i s o l a t i o n o f (IJIT) d e p o s i t e d l i g h t n e e d l e s (0.37 g, 4.2%) o f l-0_-benzoyl-2-chloro-2-deoxy-a-D-mannopyranose t r i a c e t a t e  (LTV).  R e c r y s t a l l i z e d from e t h a n o l a f f o r d e d pure  ( L I V ) , m.p. 169-170°, [ a ] " +79.3° ( c , 0.52). Anal C a l c . f o r C  1 9  H  2 1  0 Cl: g  C, 53.2; H, 4.9; C I , 8.3;  Found:  C, 53.0; II, 4.95; C I , 8.4. P.m.r. a n a l y s i s o f t h e above mother l i q u o r s showed t h a t a major component was 2 - c h l o r o - 2 - d e o x y - a - D ~ g l u e o p y r a n o s y l c h l o r i d e t r i a c e t a t e (LV) I t was i d e n t i f i e d from comparison o f i t s *H n.m.r. spectrum w i t h t h a t 2 8b p u b l i s h e d by Lemieux and F r a s e r - R e i d  .  No attempt was made t o i s o l a t e t  compound.' The n.m.r. d a t a f o r t h e "XOBz" a d d i t i o n p r o d u c t s a r e l i s t e d i n T a b l e s XX f, X X I .  -136-  FIRST ORDER CHEMICAL SHUTS (ivah.cs) OF THE "XOBz" ADDUCTS TO GLUCAL TRIACETATE  TAB1.E XX.  (XXXIV).  -OAc  COMPOUND  3.42 (LH)  \  (XLV [XLVIII)Br  OBz (L1I1)  (LI)  I \  ....-<i* ^ ^  I  c 3.43  5..81  4.,33  4 .85 ,  a 3.41  5,.S3  ' 4.21  4,.84  b 3.46'  6,.24  4..18  4,.84  I  (XLVII) Pi > B z  CI  (XLV1)  (L1V)  I  Br  CI  The benicnc-d  (b)  8.05  8.20  8.26  8.26  - S,.75-  7.90  7,,9S  7 .95  - 5,.8 —  7.45  7,.50  7 .55  8,.28  8 .28  5..80  4 .38  4.84  5,.52  4 .36  4.84  _  b  5,.49  6,,31  4..20  4.84  5.S3  5,.73  6.12  8.22  C  3.,85  5,,S2  4 .55  4 .92  6..00  5,.61  S.84  7,.89  7.95  7.97  3  3..68  5,.69  4..46  4 .96  5,.SO -  7,.97  8.04  8.05  b  3..98  6 .12  4 .66  4 .92  6 .78  5,.75  8 .23  8.32  8.32  C  .90  7. 94  7.96  5.9  .98  8.03  8.05  .20  8.32  8.32  3,.94  5,.92  4 .58 .  4 .91  a 3..75  5,.85  4 .46  4 .94  —  , b •1.03  6,.18  4..64  4 •1.96 .96  6.80  4.,0)  5.,95  4.62  4 .90  a 3,.81  5,.76  4.49  4 .91  b 4,.09  6..IS  4.65  4,.90  c 3.36 (L)  7.97  S.Ol  3,.43  C  (LVI)  7.97  7.96  a 3,.41  C  CI  7.31 5.8  5.3 • 5.11  5.23  4.48  b 3.36  5.59  5.11  4.29  c J.44  5.41  4.61  4.42  a 3.50  5.19  4.60  4.44  b 3.42  5.73  4.52  4.19  c 3.53  5.43  —  4 .49  a 3.58  5.20  —  4 .45  b 3.55  5.67  4.41  c6":;)ounds  listed  solutions.  above  .92  7. 96  7.98  .96  8.00  8.03  6.15  .25  8.31  8.31  .88  7. 90  7.92  5.90  .97  7. 93  8.02  .27  8.,30  8.30  .90  7..94  7.94  .96  7,.97  8.03  5.9  .32  8..34  8.34  5.8  .89  7,.93  7.93  —  .94  7.96  8.02  .26  8,.27  8.30  5.75 5 . 87  S.8 5.67  5.84  6.00  5.81-  5.9  cr.ch n e a s u r c d  cslcr  6.16  5.8 5.64  5.64  were  5.76  5.8  4.26  The b e n z o a t e  6.14  5.90  4.48  a 3.33  — 5 .,75  protons  in chloroforn-d  resonated  at  ca_.  fc),  acctcnc-d,  2T and c a ,  2.5x.  (a)  and  -137-  TARLE  XXI.  FIRST  0RI1F.R COUPLING  C  (LII)  OBl (LIII) CI  (LI)  I  10.9  9.1  9.9  3.6  a  3.5  10.8  9.1  9.8  -  -  -  b  3.5  11.0  9.2  3.6  1.8  11.8  c 3.6  10.7  9.2  9.8  a  3.6  10.6  9.4  9.7  b  3.S  10.6  9.5  9.6  3.9  1.5  11.8  c 9,.6 a 9..3  10.8  9.0  9.7  4.5  12.5  9.1  9.1  -  2.3  11.2  9,.5  10.8  9.0  9.8  4.0  2.0  12.4 12.4  CI  r  (XLVI) Hr  (LIV)  CI  The benzene-d^  (b)  -  12.5  -  10.J  9..0  9.8  4.4  2.1  9,.0  10.4  9..0  9.5  -  -  -  b  9..1  10.2  .9, .0  9.6  4.3  2.1  12.4  C  iS.7  9.0  9.6  4.6  12.5  !1.6  9.0  9.3  -  2.6  a  9.0  9.5  4.1  C  1  10.1  ' 1.8  a  9.9 10.1  b fS.6  (L)  (XXXIV).  5,6,  c 3.5  c 9.,1 (XLVII) Br  (LVI)  5,6,  GLUCAL TR1ACKTATE  3.0  b  \  "3,4  TO  I  (XLVIII)Br  J  2.3  >,2  COMTOUND  THE "XOBs" AODUCTS  CONSTANTS OF  9.5  2.0 '  -  12.5  M  a  1 .6  4.3  9.0  9.7  b  i.6  4.2  9.6  9.6  12.2  3.7S  9.75  9.5  -  -  -  a  1.6  3.5  9  9  4.0  2.5  12.0  b  1.5  3.6  10  10  -  -  -  c 1.8  3.1  a  1.8  3.2  b  1.8  3.4  9.5  9.5  c 1 .8  coTipountls  listed  solutions.  above  were  each  incisured  in chloroform-d  (c) ,  acctonc-d^  and  (Hz)  -138-  SECTION I):  STEREOSELECTIVE SYNTHESES OF PRODUCTS FORMED DURING  THE  ADDITION REACTIONS OF D-GLUCAL TRIACETATE.  2-Bromo-2-deoxy-a-D-Mannopyranosyl F l u o r i d e T r i a c e t a t e (XXXV):-1-Q-benzoyl-2-bromo 2-deoxy-a-D-mannopyranose t r i a c e t a t e  (XLVI) (0.25  g) was  converted  t o the  83 2-bromo-2»deoxy-ct-D-mannopyranosyl broinide t r i a c e t a t e " which was dissolved in acetonitrile The  s o l u t i o n was  (20 ml) c o n t a i n i n g s i l v e r m o n o f l u o r i d e  then shaken f o r c a . 20 min  a f t e r c a . 15 min).  immediately (1 g ) .  (no more p r e c i p i t a t e was  formed  Work up, f o l l o w i n g the procedure d e s c r i b e d p r e v i o u s l y  f o r halogen exchange r e a c t i o n s , produced a c l e a r syrup which c o n t a i n e d (f.m.r.)  o n l y one  fluoride  (XXXV); however, p.m.r. showed the presence o f  ca. 20% o f the s t a r t i n g m a t e r i a l ( X L V I ) . T h i s syrup was precipitated,  d i s s o l v e d i n e t h a n o l and  (0.050 g, m.p.  the benzoate (XLVI)  was  171-174) l e a v i n g a c o l o u r l e s s s o l u t i o n which  c o n t a i n e d m a i n l y the d e s i r e d f l u o r i d e .  T h i s s o l u t i o n was  evaporated,  s o l v e d i n 3 ml o f c h l o r o f o r m , p e t r o l e u m  e t h e r (20 ml) was  added and the  u t i o n cooled to ca. 5 . C  C r y s t a l s o f (XXXV) m.p.  which were r e c r y s t a l l i z e d from aqueous e t h a n o l The  fluoride  (XXXV) was  dissol-  137-142° were d e p o s i t e d (0.102 g, 51%)  also prepared,  m.p.  138-140°.  as d e s c r i b e d f o r the f o r -  I mation o f the a-D-gluco isomer ( I ) , from the benzoate (XLVT) (0.05 a c t i o n o f anhydrous l i q u i d HF. i n 63% y i e l d ; m.p.  and mixed m.p.  The  d e s i r e d compound (XXXV) was  g) by  obtained  w i t h samples o b t a i n e d p r e v i o u s l y (see p. i 2 6  and p.128) 139-140°. T h i s compound was  i d e n t i c a l i n every r e s p e c t w i t h the  o b t a i n e d i n the b r o m o f l u o r i n a t i o n r e a c t i o n s d e s c r i b e d above.  product  !  -139-  NBromo-2-Deoxy-B-D-Glucopyranosyl  Fluoride Triacetate  Benzoyl-2-bromo-2-deoxy-8T)-glucopyranose  triacetate  (XXXVI):-  (XLVII]  1-0-  (0.250 g)  was c o n v e r t e d as d e s c r i b e d above t o t h e 2-bromo-2-deoxy-a-P-glucopyranosyl bromide t r i a c e t a t e , which was i m m e d i a t e l y d i s s o l v e d i n a c e t o n i t r i l e c o n t a i n i n g s i l v e r m o n o f l u o r i d e (1 g ) . S t a r t i n g m a t e r i a l  (0.055 g, 21%) was  i s o l a t e d from t h i s r e a c t i o n t o g e t h e r w i t h t h e d e s i r e d f l u o r i d e (0.095 g, 6 2 % ) .  (20 ml)  (XXXVI)  T h i s product,, however, ha*s n o t been o b t a i n e d c i t h e r pure 19  or  crystalline.  F n.m.r. showed o n l y t h e d e s i r e d f l u o r i d e , none o f t h e  c o r r e s p o n d i n g c i s isomer (XXXVII) c o u l d be d e t e c t e d . 2-brono-2-Deoxy-a-D-Ghicopyranosyi  Fluoride Triacetate  Benzoy'l-2-brono-2-deoxy-8-D-g, 1 ucopyranose t r i a c e t a t e  ( X X X V I I ) : - 1-0-  (XLVIi)  (0.25 g) was  c o n v e r t e d , i n t h e manner d e s c r i b e d f o r t h e f o r m a t i o n o f t h e n-D-gluco ( I ) , w i t h anhydrous hydrogen f l u o r i d e , i n t o t h e d e s i r e d f l u o r i d e (0.11 g, 58%) m.p. mixed in.p. w i t h sample o b t a i n e d p r e v i o u s l y  isomer  (XXXVII)  (see p.127)  120-121°. 2-Deoxy-a-D-arahino-hexopyranosyl F l u o r i d e T r i a c e t a t e D-arabino-hexopyranose t e t r a a c e t a t e hydrogen f l u o r i d e  1 4 7  ( X X X V I I I ) : - 2-Deoxy-  (0.20 g) was added t o anhydrous  ( c a . 5 ml) a t c a . -70°.  The s o l u t i o n was kept a t t h i s  t e m p e r a t u r e f o r 5 min and t h e n poured d i r e c t l y i n t o an ether-aqueous bicarbonate mixture.  The e t h e r l a y e r was washed s u c c e s s i v e l y w i t h aqueous sodium  • b i c a r b o n a t e and w a t e r , d r i e d was d i s s o l v e d i n C l i C U  (Na SO^), and c o n c e n t r a t e d .  The r e s u l t a n t s y r u p  (5 m l ) , l i g h t p e t r o l e u m (60 ml) was added, and t h e  s o l u t i o n was l e f t o v e r n i g h t a t - 5 . s  Long f l a t n e e d l e s (0.10 g) were o b t a i n e d ,  m.p.'73-74°; a f u r t h e r c r o p (0.035 g) was o b t a i n e d from t h e mother a f t e r s e v e r a l weeks. acetate  sodium  liquors  The 2-dcoxy-ct-D-a r a b i n o - h c x o p y r a n o s y 1 f l u o r i d e t r i -  23 ( X X X V I I I ) (0.135 g, 77%) had ro.n. 73-74° and [ a ] ' +67° ( c , 2.15).  -140-  Th e m e l t i n g p o i n t was unchanged a f t e r two r e c r y s t a l l i z a t i o n s . Anal. Calc. f o r Cj H 2  7  0 F : C, 49.3; Ii, 5.8; F, 6.5.  Found:  ?  C, 49.4; H, 6.0; F, 6.4. 19 The  F spectrum o f the mother l i q u o r s showed an a d d i t i o n a l r e -  sonance, which was a s s i g n e d  t o 2-deoxy-B-p-arabino-hexopyranosyl  t r i a c e t a t e ( C X V ) on t h e f o l l o w i n g b a s i s .  fluoride  I t s s h i f t o f +125.33 p.p.m. was  s i g n i f i c a n t l y t o l o w - f i e l d o f t h a t o f the -anomer, which i s i n a c c o r d a  with  82 previous  findings  .  F u r t h e r m o r e , t h e o b s e r v a t i o n o f s p l i t t i n g s o f 15.3  and 1.0.7 Hz i s o n l y c o n s i s t e n t w i t h a gauche r e l a t i o n s h i p between t h e f l u o r i n e s u b s t i t u e n t and both o f t h e  protons.  The anomeric  proton  resonance o f t h i s anomer was a s s i g n a b l e as an o c t e t , c e n t e r e d a t 4.45T, w i t h a geminal II c o u p l i n g o f 51.9 Hz, a v i c i n a l H I L c o u p l i n g o f 6.5 l,f' *~ l, / a * Hz, and an H^,H c o u p l i n g o f 3.0 Hz. These l a t t e r two c o u p l i n g s a r e a g a i n 82 c h a r a c t e r i s t i c o f a 8-hexopyranosyl f l u o r i d e 2e  2-Peoxy-ct-D-arabino-hexopyranosyl F l u o r i d e T r i b e n z o a t e (CxVI) : -  The r e a c t i o n  148 o f 2-deoxy-3 -Ij-arabino-hexopyranose  tetrabenzoate  w i t h HF, as d e s c r i b e d 23  o  above gave, i n about a 95% y i e l d , t h e a - f l u o r i d e ( C X V I ) , m.p. 112-114 +41.6° (c_, 2.3).  ,[ ] a  The m e l t i n g p o i n t was unchanged by r e c r y s t a l l i z a t i o n and  was n o t depressed on admixture w i t h a sample p r o v i d e d by Dr. C. Pedersen. Anal. Calc. f o r  C  H 2 7  22 7 0  F :  C  »  6  7  ,  8  ;  H  '  4  ,  8  ;  F  ' ' 3  9 5 ,  F  o  u  C, 67.7; H, 5.1; F, 3.8. None o f t h e c o r r e s p o n d i n g 8-anomer c o u l d be d e t e c t e d l i q u o r s by n.m.r.  spectroscopy.  n  d  :  i n t h e mother  -141-  2-Deoxy-2-Iodo-ct-D-Mannopyrancsyl  F l u o r i d e T r i a c e t a t e (XXXIX):- 1-0-Benzoyl  2-deoxy-2-iodo-a-D-mannopyranose t r i a c e t a t e  (L) (0.25 g) was r e a c t e d  u s u a l manner w i t h anhydrous hydrogen f l u o r i d e t o g i v e t h e d e s i r e d (XXXIX).  i n the  fluoride  (0.10 g, 50%) m.p. mixed m.p. w i t h a sample p r e v i o u s l y  obtained  (see p. 129) 153-155° .  2-Deoxy-2-Iodo-a-D-Glucopyranosyl 2-deoxy-2-iodo-B-D-glucopyranose  F l u o r i d e T r i a c e t a t e ( X L l ) : - 1-0-Benzoyl triacetate  ( L I ) (0.25 g) was s u b j e c t e d , i n  the u s u a l manner, t o r e a c t w i t h hydrogen f l u o r i d e .  The d e s i r e d f l u o r i d e ( X L l )  was formed i n a y i e l d o f 60%; m.p. mixed m.p. w i t h a sample o b t a i n e d viously  (see p. 129) 142-144°.  2-Chloro-2-Deoxy-a-D-Clucopyranosyl F l u o r i d e T r i a c e t a t e ( X L I V ) : 2-chloro-2-deoxy-ct-D-glucopyranose t r i a c e t a t e to the d e s i r e d f l u o r i d e ( y i e l d 0.23 g, 60%) m.p. aqueous e t h a n o l [cjp  5  pre-  (LI 11)  1-0-Benzoyl-  (0.50 g) was c o n v e r t e d  (XLIV) by t h e a c t i o n o f anhydrous hydrogen 87-95°.  fluoride,  R e c r y s t a l l i z a t i o n , t h r e e times from  a f f o r d e d n e e d l e - l i k e c r y s t a l s o f t h e f l u o r i d e ; m.p.  95-97°,  +203° ( c , 1.13). A n a l . C a l c . f o r C^H^O-^CIF:  C, 44.1; H, 4.9; F, 5.9.  Found:  C, 44.05; H, 5.1; F, 5.65.  2-Chloro-2-Deoxy-3-D-Ci.ucopyranosyl  F l u o r i d e T r i a c e t a t e (XLILT): - 1-0-Benzoyl-  2-chloro-2-deoxy- -D-glucopyranose t r i a c e t a t e a  (LT) (0.50 g) was c o n v e r t e d t o  the c o r r e s p o n d i n g bromide i n t h e manner p r e v i o u s l y d e s c r i b e d .  Hi n.m.r.  showed t h a t t h e d e s i r e d bromide had formed i n c a . 8 6 % y i e l d , and t h a t t h e r e mainder was u n r e a c t e d s t a r t i n g m a t e r i a l .  The crude bromide was d i s s o l v e d  i n a c e t o n i t r i l e (25 ml) and s i l v e r m o n o f l u o r i d e (1 g) was added.  T h i s mix-  -142-  t u r e was  shaken  itated) .  f o r ca_. 20 min  ( u n t i l no more s i l v e r h a l i d e was  Standard work up produced  g ) , which was  found  a p a r t i a l l y c r y s t a l l i n e product  (p.m.r.) t o c o n s i s t o f t h r e e components.  i d e n t i f i e d as s t a r t i n g m a t e r i a l  precip(0.38  They were  ( L I I T ) , the c o r r e s p o n d i n g 8-benzoate (LVI) 19  and the d e s i r e d f l u o r i d e ( X L I I I ) .  P n.m.r. showed t h a t o n l y one  (XLITT) had formed, rone o f the c o r r e s p o n d i n g c i s f l u o r i d e  fluoride  (XLTV) c o u l d be  detected. The above syrup was d i s s o l v e d i n e t h a n o l (20 ml) and c o o l e d t o c a . 5°; a f t e r 3 2 h r the l-0-benzoyl-2-chloro-2-deoxy-B--D-glucopyranose a c e t a t e (LVI) c r y s t a l l i z e d , and was  removed from s o l u t i o n .  tri-  Recrystal-  25 l i z a t i o n from e t h a n o l a f f o r d e d f i n e n e e d l e s , m.p. (c,  160-161°, [ a ] ^  +35.5  1.46). Anal. Calc. f o r C  C, 53.1; H, 5.1; C I ,  i g  H  2 1  0 Cl: g  C, 53.2; II, 4.9; C I , S.3.  Found:  8.1.  The mother l i q u o r s , a f t e r removal o f ( L V I ) , were l e f t a f u r t h e r 24 h r at c a . 5°, d u r i n g which time the a-benzoate T h i s f i l t r a t e was  (L111) was  then d i l u t e d w i t h p e t r o l e u m e t h e r (15 ml) and c o o l e d t o  ca. -5° and a f t e r s e v e r a l days impure c r y s t a l s o f the d e s i r e d (XLHI)were  precipitated.  obtained.  fluoride  These c r y s t a l s were r e c r y s t a l l i z e d from aqueous e t h a n o l  t h r e e times but were not o b t a i n e d pure  (m.p.  75-82°); p.m.r. showed t h a t  they, were contaminated w i t h c h l o r o b e n z o a t e ( L I I I ) .  These c r y s t a l s were  n e v e r t h e l e s s s u i t a b l e f o r s e e d i n g the s o l u t i o n o b t a i n e d from the c h l o r o f l u o r i n a t i o n r e a c t i o n (see p . ] 3 0 ) l-0-Benzoyl.-2-Chloro-2-I)eoxy-g-D-Glucopyranose triacetate  (XXXIV) (1.36 g) was  T r i a c e t a t e (LVI) :- D - G l u c a l  d i s s o l v e d i n 25 ml C C l ^ and c o o l e d t o 0°.  C h l o r i n e was bubbled i n t o the s o l u t i o n u n t i l an excess was p r e s e n t ; a f t e r  -143-  -25 min a i r was passed through the s o l u t i o n t o remove the excess  chlorine.  T h i s s o l u t i o n was then heated under r e f l u x f o r 45 min w i t h s i l v e r (2 g ) .  Only s t a r t i n g m a t e r i a l The d i c h l o r i d e was  (35% w/v/)  was observed (p.m.r. e v i d e n c e ) .  then d i s s o l v e d  i n hydrogen b r o m i d e / a c e t i c a c i d  and l e f t f o r 4 h r at room t e m p e r a t u r e .  S t a n d a r d work up  a syrup which was heated under r e f l u x w i t h AgOBz i n C C l ^ f o r 1 h r . s o l u t i o n was  f i l t e r e d and c o n c e n t r a t e d .  Crystals  previously  benzoate  o b t a i n e d , 160-161°.  ( L V I ) ; m.p.  yielded The  (1.50 g, 70%) were ob-  t a i n e d which were r e c r y s t a l l i z e d from aqueous e t h a n o l . proved t o be the d e s i r e d  benzoate  These l i g h t n e e d l e s  and mixed m.p.,  w i t h a sample  -144-  SECTION E:  ELECTROPHILIC ADDITION REACTIONS OF OTHER GLYCALS  The c l o s e l y those  r e a c t i o n s t h a t v/ere performed f o r t h i s reactions already described  f o r the E l e c t r o p h i l i c  Reactions  o f D-Glucal  Reactions  of D-Calactal T r i a c e t a t e (LVII).  (a)  (LVII)  (1.36  g) was  monofluoride. has  failed  f o r "BrF" reacted  A 98%  "BrF"  with  <*>  values  and  the products  first  (LIX)  Hz,  J ^ p 4.6  43%,  *  c  yield  25.1  H-  assigned,  which so f a r  on the b a s i s of  F coupling constants,  from D - g l u c a l  triacetate  49.7  Hz,  J  those  2  p  10.0  (LX)  Hz  24%,  and  and  by  (XXXIV), as:  (LVTTI) 34%,  analogy 2-bromo-2-  <£> +121.4, J^ p c  fluoride  triacetate  2-bromo-2~deoxy-a-D-  +145.0, J j p 50.5 Hz, 80 r e s u l t s r e p o r t e d by Kent et a l .)  Hz.  (compare with  (b)  T o d o f l u o r i n a t i o n , " I F " generated was  silver  19  fluoride triacetate  o f a c l e a r syrup  obtained,  2-bromo-2-deoxy-B-D-galactopyranosyl p  triacetate  s o l u t i o n with bromine and  amber syrup was  fluoride triacetate  +135.6, J j  galactopyranosyl J  Hz,  In  f.m.r. showed t h a t t h r e e g i y c o p y r a n o s y l f l u o r i d e s  order  obtained  from Br^ and AgF:-  (XXXIV), D - g a l a c t a l  T h e i r s t r u c t u r e s were t e n t a t i v e l y  deoxy-ct-D-talopyranosyl 49.8  generated  in acetonitrile  1 their  *  a d d i t i o n to  y i e l d of a l i g h t  to c r y s t a l l i z e ;  were formed.  Addition  T r i a c e t a t e (Section C).  Bromofluorinaticn,  the manner d e s c r i b e d  section followed  obtained,  which has  f.m.r. shewed t h a t t h r e e g i y c o p y r a n o s y l  <j>  from I^ and AgF:failed  f l u o r i d e s had  A  96%  to c i ' y s t a l l i z e . been formed.  Again  Tenta-  * U - G a l a c t a l T r i a c e t a t e ( L V I I ) , was a commercial sample from Koch L i g h t L a b o r a t o r i e s L t d . , England and was used as r e c e i v e d .  -145-  tively,  these have the s t r u c t u r e s , 2-deoxy-2-iodo-cc-P-talopyranosyl  triacetate  (LXT) 25%, <j>  +114.6, J . „ 50.5  C  Hz and  (LXIII) 34%,  (LXTI) 41%,  <b +139.4 J  1  c  p 50.0  Hz, J  Hz;  2-deoxy-2-iodo-  <j> +130.8, c  2-deoxy-2-iodo~a-D-galactopyranosyl  R e a c t i o n s o f D - X y l a l D i a c e t a t e (LXTV)  (a)  6.3  2, r  1,r  B-D-galactopyranosyl f l u o r i d e t r i a c e t a t e p 10.2  Hz, ,7  fluoride  2  p  27.6  fluoride  49.8  p  Hz,  triacetate  Hz.  *  B r o m o f l u o r i n a t i o n "BrF" generated  from B r  and  2  AgF:-  F o l l o w i n g the e s t a b l i s h e d procedure a c l e a r syrup.was o b t a i n e d from  (LXlV)  19 i n 91% y i e l d which has to date f a i l e d  to c r y s t a l l i z e .  that a l l four_ i s o m e r i c "BrF" adducts were formed. are  tentative):-  55%,  c  l  fluoride diacetate  p 50.1  J  2 ) F  Hz, J  (LXVI) 32%,  l y x o o r the a - x y l o isomer and  They are  2-bromo-2-deoxy-a-D-lyxopyranosyl  <J> +126.7, J  2  p  4>  c  3.5  Hz;  the a - x y l o o r the 8-lyxo isomer  ^  (the s t r u c t u r e s  fluoride diacetate  (LXV)  2-bromo-2-deoxy~8-D-xylopyranosyl  +128.0, J  (LXVII) 5%,  "F n.m.r. showed  1  p  51.0  +144.1, J  (LXVIII) 8%,  Hz, J 1  p  2  50.8  „ 9.0 Hz, J  <f> +146.5, J j c  Hz; 2  p  p  the 26.8  50.3  8Hz  Hz,  25.1Hz. (b)  l o d o f l u o r i n a t i o n , " I F " generated from I  the .established procedure  a c o l o u r l e s s syrup was  2  and AgF:-  Following  o b t a i n e d , which has  failed  19 crystallize. were  F n.m.r. again showed t h a t a l l f o u r i s o m e r i c " I F " adducts  formed. The  resonances were t e n t a t i v e l y a s s i g n e d as:- 2-deoxy-2-iodo-a-D-  * D - X y l a l D i a c e t a t e (LXIV), was prepared with the a s s i s t a n c e o f Mrs. Liane E v e l y n f o l l o w i n g the procedure o f W e y g a n d l . . .(LXIV) h ad m.p. 37-39°; l i t . m.p. 40°, [ a ] -314.7°. 49  D  to  -146-  l y x o p y r a n o s y l f l u o r i d e d i a c e t a t e (LXIX) 46%,  $  +120.4, J , „ 50.0 C  3.5  Hz;  2-deoxy-2-iodo-3-D-xylopyranosyl  +122.5, J  (j> +138.0, J c  3%,  51.1  1, h x  p  Hz, J . _ 9.2 I, h  50.8  Hz, J  <f> +141.1, J , _ 50.8 c 1 ,F  (c)  2  p  Hz;  Hz,  (LXXI)  (2.1  Hz.  When "IOBz" was  r e a c t e d with  (LXIV)  (XXXIV) i n a c e t o n i t r i l e s o l u t i o n , a l i g h t y e l l o w syrup was  g, 94%).  I t was  t h i s r e a c t i o n and  not p o s s i b l e t o o b t a i n any  o f f o u r anomeric  from res-  (LXXIII)  B r o m o f l u o r i n a t i o n , "BrF" generated  the e s t a b l i s h e d procedure,  obtained  assigned.  Reactions of D-Arabinal Diacetate  (a)  tri-  c r y s t a l l i n e products  although p.m.r. showed the presence  onances, they c o u l d not be  8%,  (LXXII)  (1.0 g) i n the manner d e s c r i b e d above f o r the r e a c t i o n with D - g l u c a l acetate  , r  43%, 4>  29 Hz and the 8-lyxo o r a - x y l o isomer  Iodobenzoylation: -  2  1,1'  f l u o r i d e d i a c e t a t e (LXX)  the g-xylo or a-lyxo isomer  Hz, J_ _ 29 2,F  J„ ,.  a syrup was  from  o b t a i n e d from  Br^ and AgF:-  (LXXIII)  Following  (1.0 g) i n 93%  19 y i e l d , which has not c r y s t a l l i z e d . f l u o r i n e resonances. D-arabinopyranosyl J  „• • 3.5  y  <J> +127.9, c  Hz;  'F n.m.r. showed o n l y t h r e e anomeric  They were t e n t a t i v e l y  a s s i g n e d as:  f l u o r i d e d i a c e t a t e (LXXIV) 62%,  4>  c  2-bromo-2-deoxy-a-  +126.4,  p  50.5  Hz,  2-bromo-2~deoxy-3-D-ribopyranosyl f l u o r i d e d i a c e t a t e (LXXV) F  50.4  Hz, J ^  p  3.4  f l u o r i d e d i a c e t a t e (LXXVI) 1.8%,  Hz and <<>  2-bromo-2-deoxy-a-D-ribopyranosyI  +147.6, ,T  C  (compare with the r e s u l t s o f Kent et a l  79  51.5  v  J ,  i'  Hz, J  25.1  Hz.  , t  .)  * D - A r a b i n a l D i a c e t a t e (LXXIII1, was prepared by Miss Z i n a t Mia, a c c o r d i n g to the procedure o f H u m o l l e r ^ . (LXXIII) had b.p. (1 mm.) 90°; lit.. b.p. (0.3 mm.) 79°; [ a ] +266°. j U  1 5 0  1 }  20%;  -147-  (b) yield  I o d o f l u o r i n a t i o n , " I F " generated from I ^ and AgF:-  An 82%  o f a c l e a r syrup was o b t a i n e d from ( L X X I I I ) (1.0 g) which so f a r has 19  f a i l e d to c r y s t a l l i z e .  "F n.m.r. showed o n l y t h r e e anomeric  These resonances were t e n t a t i v e l y a s s i g n e d as: pyranosyl fluoride diacetate  resonances.  2-deoxy-2-iodo-ct-D-arabino  (LXXVII) 49%, 4> +121.6, J j c  c a . 50 Hz, J  p  2  p  ca. 5 Hz; 2 - d e o x y - 2 - i o d o - 8 - D - r i b o p y r a n o s y l f l u o r i d e d i a c e t a t e ( L X X V I I I ) 58%, •tj) +123.9, J . 51.0 Hz, J 6.5 Hz and 2 - d e o x y - 2 - i o d o - a - D - r i b o p y r a n o s y l C 1» 2 , r — f l u o r i d e d i a c e t a t e (LXXIX) 13%, <}> +141.9 3 c  (c)  p  50.7 Hz, J  2  p  27.6 Hz.  I o d o b e n z o y l a t i o n : - F o l l o w i n g the same procedure as d e s c r i b e d  f o r D-glucal t r i a c e t a t e to  y  (XXXTV), M i s s Z i n a t M i a e f f e c t e d t h e a d d i t i o n "IOBz"  ( L X X I I I ) i n benzene s o l u t i o n and o b t a i n e d a s e m i - c r y s t a l l i n e syrup which  was found (p.m.r.) t o c o n t a i n t h r e e anomeric  resonances.  One isomer was o b t a i n e d c r y s t a l l i n e ,  from an e t h a n o l s o l u t i o n and  was r e c r y s t a l l i z e d t w i c e from aqueous ethanol. t o a f f o r d hard n e e d l e s o f 1-0-benzoyl- 2-deoxy-2- i o d o - 3-D-ribopyranose 27  .5° ( c ,  42.6;  16"l7°7  I:  C, 42.85; H, 3. 8; I , 28 3.  (LXXX) accounted f o r 4 5% o f the Chemical S h i f t s (T v a l u e s )  T h i s component Compound  H  l .  H  2  H  4  3  reaction product.  5e  "5a  OAc  c  3.77  5.58  4 .36  4.83  5.91  6.03  7.80  7. 98  a  3.72  5.22  4.36  4.79  5.87  6.01  7.91  8. 03  b  3.60  6.05  4 .43  5.00  6.32  5.89  8.23  8. 34  Co- i p l i n g C o n s t a n t s (Hz)  (LXXX)  Found:  3.9; I , 28 .1 .  TABU; XXII  (LXXX)  129-130  1.46) •  Anal. Calc. for C  C,  d i a c e t a t e (LXXX) , m.p.  A,5c  4,5a  ' 5c, 5a  •'1.2  •'2.5  c  8.2  3.0  3.0  6.5  8.0  -  a  8.4  5.1  3.1  5.6.  8.8  11.5  b  S.3  3.0  3.0  6.4  S. 3  10.4  3  J  -148-  Th e above h a l o g e n o f l u o r i n a t i o n s (Bromine and I o d i n e ) were a l s o p e r formed on the f o l l o w i n g model compounds; v i n y l a c e t a t e (LXXXI),  3,4-dihydro-  2M-pyran (LXXXI1), the • a c e t a t e o f 3,4-dihydro-2H-pyran-2-methanol and the  (LXXXIII)  p _ - t o l u e n e s u l f o n a t e o f 3,4-dihydro-2H-pyran-2-methanol (LXXXIV) . *  each c a s e , the p r o d u c t had halogen o f the t o s y l a t e  at  However, i t was  p o s s i b l e to  determine  r a t i o s by f.m.r..  Reactions of V i n y l Acetate  (a)  w i t h the e x c e p t i o n  (LXXXIV) , the p r o d u c t s were u n s t a b l e l i q u i d s o r o i l s which  c o u l d not be i s o l a t e d i n a pure s t a t e . t h e i r product  and f l u o r i n e at C^:  In  (LXXXI)  B r o m o f l u o r i n a t i o n , "BrF" generated  The b r o m o f l u o r i n a t i o n o f (LXXXI) a f f o r d e d o n l y one +121.9, ( d o u b l e t t e d t r i p l e t ) J  from Wv^ and  AgF:-  fluorine containing  product  (LXXXV) ; ^  ca. 50 Hz,  15 Hz.  S o l e l y on the b a s i s o f t h i s f.m.r. d a t a , i t was  ca.  concluded  t h a t the  p r o d u c t had the s t r u c t u r e CH^BrCHFOAc.  R e a c t i o n s_ o f 3,4-0i.hydro-2ll-Pyran ( L X X X I I ) * * *  (a)  B r o m o f l u o r i n a t i o n , " B r F " generated  from Br^ and  AgF:-  The b r o m o f l u o r i n a t i o n o f (LXXXII) a f f o r d e d two f l u o r i n e c o n t a i n i n g p r o d u c t s :  *The r e a c t i o n p r o d u c t s i n the remainder of t h i s s e c t i o n are g i v e n t r i v i a l , names. I t i s f e l t t h a t these t r i v i a l names unambiguously d e s c r i b e the r e a c t i o n p r o d u c t s and f a c i l i t a t e g r e a t l y the comparison between these r e a c t i o n p r o d u c t s and those d e s c r i b e d p r e v i o u s l y f o r the D - g l u c a l t r i a c e t a t e adducts. Chemical  * * V i n y l A c e t a t e (LXXXI) was a commercial sample from the A l d r i c h Co., I n c . , Milwaukee, W i s c o n s i n .  ***3 ,4-Dihydro--2H-Pyran (LXXXTI), was a commercial sample from Eastman O r g a n i c C h e m i c a l s , R o c h e s t e r , New York.  -149-  the  t r a n s isomer (LXXXVI) 84%, £  +122.8, J . _ 51.3 Hz, J _ _ 4.6 Hz and the C  cis  isomer (LXXXVII) 16%, «Ji +149.4, J j c  (b) and anhydrous the  1 , r p  2,1'  52.2 Hz, .1  2  26.3  p  B r o m o f l u o r i n a t i o n , " B r F " generated from l i q u i d HF:-  Hz.  N-bromosuccinimide  F o l l o w i n g the g e n e r a l p r o c e d u r e as o u t l i n e d f o r  reaction of D-glucal t r i a c e t a t e  (XXXIV), (LXXXII) a f f o r d e d a y e l l o w syrup  which c o n t a i n e d (f.m.r.) the same two f l u o r i n e r e s o n a n c e s :  t h e s e were  a s s i g n e d t o the t r a n s isomer (LXXXVI) 55-60% and the c i s isomer  (LXXXVII)  40-45%.  (c)  I o d o f l u o r i n a t i o n " I F " , generated from I ^ and AgF:-  The  i o d o f l u o r i n a t i o n o f (LXXXII) a l s o y i e l d e d two compounds; the t r a n s isomer ( L X X X I I I ) c a . 95%, ^ (LXXXIX) c a . 5%,  +117.5,  anhydrous  51.3 Hz, J  2  p  Hz and t h e c i s isomer  <h +143.5, J . _ 51.1 Hz, J _ _ 27.2 C  (d)  p  Hz.  c , r  1,r  I o d o f l u o r i n a t i o n , " I F " g e n e r a t e d from N - i o d o s u c c i n i m i d e and  l i q u i d IIP r— V/hen t h i s i o d o f l u o r i n a t i o n r e a c t i o n was attempted, a  .black t a r was o b t a i n e d , which d i d not c o n t a i n any o r g a n i c f l u o r i n e p r o d u c t s .  *  R e a c t i o n s o f the ' A c e t a t e o f 3,4-Dihydro-2H-Pyran-2-Methanol  (a)  Bromof l u o r i n a t i o n , " B r F " generated from B r  The b r o m o f l u o r i n a t i o n o f the trans-diaxial  New  and AgF:'-  a c e t a t e ( L X X X I I I ) l e d t o the f o r m a t i o n o f the  ( -manno) isomer (XC) 57%, a  2  (LXXXIII)  cj>  c  +119.7, ..^  p  51.1 Hz, J ,  p  4.0  Hz;  *3,4-Dihydro-2H-Pyran-2-Methanol was a g i f t from S h e l l Chemical Co. York and was used as the a c e t a t e ( L X X X I I I ) (b.p. 104-106°, 15 mm.)  the t r a n s d i e q u a t o r i a l  (B-gluco)  isomer (XCI) 20%, <() +126.9 and t h e c i s  (a-gluco isomer (XCII) 18%, <|> +147.1, J .  r  51.6 Hz, J„ _ 26.0 Hz. 2,  I, r  C  —•  ( a  r  minor u n i d e n t i f i e d resonance a t d> +121.9 was a l s o d e t e c t e d ) . c ' (b)  I o d o f l u o r i n a t i o n , " I F " generated from  and AgF:- The i o d o -  f l u o r i n a t i o n o f (LXXXIII) r e s u l t e d i n t h e f o r m a t i o n o f t h e t r a n s (a-manno) isomer ( X C I I I ) 78%, <J> +114.5, J diequatorial  (B-gluco)  51.4 Hz, J  5.0 Hz; t h e t r a n s  isomer (XCIV) 17%, <\> + 122.3 and t h e c i s  isomer (XCV) ca_. 5%, <J> ca_. +141. c  diaxial  (a-gluco)  ( T h i s resonance was t o o weak f o r an a c c u r a t e 19  determination  o f <j> o r o f the c o u p l i n g c o n s t a n t s . )  No o t h e r  F resonances  were d i s c e r n a b l e . Reactions  o f t h e : -p-Toluenesulfonate  (a)  o f 3,4-Dihydro-2H-Pyran-2-Methanol (LXXXTV)*  B r o m o f l u o r i n a t i o n , " B r F " generated from B r ^ and AgF:-  b r o m o f l u o r i n a t i o n o f (LXXXIV) a f f o r d e d t h e t r a n s d i a x i a l (XCVI) 66%, 4> +120.1, J c  1  v  50.5 Hz, J  2 p  The  (a-manno) isomer  3.7 Hz; t h e t r a n s d i e q u a t o r i a l  ( B - g k i c o ) isomer (XCVII) 25%, <|> +125.8 and t h e c i s (q-gluco)  isomer  (XCVIII)  6%, $> +147.5, J , ,.. 52.0 Hz, J , „ 26.0 Hz, t o g e t h e r w i t h two o t h e r very m i n o r , ' c J , !• I Au n i d e n t i f i e d resonances.  (b)  B r o m o f l u o r i n a t i o n , "BrF" g e n e r a t e d from N-bromosuccinimide and  anhydrous l i q u i d HF:-  The b r o m o f l u o r i n a t i o n o f (LXXXIV) (5 g) a f f o r d e d a  c r y s t a l l i n e mass (1.4 g, 2 0 % ) : m.p. 106-110".  "F n.m.r. showed t h i s  reaction  *3,4-Dihydro-2H-Fyran-2-Methano1 was a g i f t from S h e l l Chemical Co.. New York and was as the p - t o l u e r . e s u l f o n a t e (LXXXIV) (m.p. 46.5-47.5°) .  -151-  p r o d u c t t o c o n s i s t o f almost e q u a l p o r t i o n s o f the t r a n s d i a x i a l isomer  (XCVI) c t i . 5 5 % , and t h e c i s (ot-gluco) isomer  Successive r e c r y s t a l l i z a t i o n s m.p.  (a-manno)  ( X C V I I I ) c a , 45%.  (7 t i m e s ) f a i l e d t o s e p a r a t e t h e s e two i s o m e r s ;  121-122.5°. Anal. Calc. f o r C^H^C^BrFS:  C, 4 2.4;  C, 42.5; H, 4.35; F, 5.2.  Found:  I i , 4.4: F, 5.25.  (c)  I o d o f l u o r i n a t i o n , " I F " generated from I ^ and AgF:-  f l u o r i n a t i o n o f (LXXXIV) a f f o r d e d o n l y t h r e e p r o d u c t s . (f.m.r.) as t h e t r a n s d i a x i a l 51.5 Hz, J  (a-manno) isomer  5.1 Hz; t h e t r a n s d i e q u a t o r i a l  They were  identified  (XCIX) 76%, <J> +114.8, J j c  ( B-gluco)  isomer  p  (C) 18%, <j> c  /. , 1'  +121.0 and t h e c i s ( u - g l u c o ) isomer  The i o d o -  (CI) 5%, §  c a . +141.  -152-  •SECTION F:  THE SIGN'S 0F CARBOHYDRATE PROTON-PROTON and PROTON-FLUORINE COUPLING CONSTANTS  With t h e e x c e p t i o n o f those d e r i v a t i v e s whose p r e p a r a t i o n s have been d e s c r i b e d p r e v i o u s l y , t h e f o l l o w i n g were p r e p a r e d by s t a n d a r d  lit-  e r a t u r e p r o c e d u r e s o r were generous g i f t s from o t h e r l a b o r a t o r i e s . 5,6-Dideoxy-l,2-0_-isopropylidene-a-D-xyl_o_--hex--5-enofuranose  (CII) ,  the c o r r e s p o n d i n g a c e t a t e ( C H I ) ' ' ' and 5 , 6 - a n h y d r c - 1 , 2 - 0 - i s o p r o p y l i d e n e - a 15  D-glucofuranose  (CIV).  These samples were g i f t s from P r o f e s s o r A. R o s e n t h a l 152  and Mr. G. Kan o f t h i s department. and  (CIV) m.p. 130-132°, l i t  ( C I I I ) m.p. 56-58°, l i t "  m.p. 61-65°  m.p. 133.5°.  1,6-Anhydro-3-D-idopyranose t r i a c e t a t e  (CV) and t h e c o r r e s p o n d i n g  D-manno isomer (CVI) were g i f t s from Dr. N.K. Richtmeyer. 5 ,6-Dideoxy-5 , 6 - e p i t h i o - l ,2-0_-isopropyl jdene-8--L-idofuranose  (CVII)  T h i s compound was p r e p a r e d by Mrs. L i a n e E v e l y n , f o l l o w i n g t h e method o f 152 H a l l , Hough and P r i t c h a r d M e t h y l 3-D-glucopyranosidc  tetraacetate  (CVIII).  A commercial  sample o f t h e g l y c o s i d e ( P f - m s t i e h l Lab. I n c . , Waukegan, I l l i n o i s ) was a c e t y l a t e d i n t h e u s u a l manner.  Tt had m.p. 106-107°, l i t .  1 5 4  m.p. 104°.  6-D-Ribopyranose t e t r a a c e t a t e ( C I X ) , had m.p. 112°, l i t  1  5  5  m.p.  110° . 2-Deoxy-B-D-arahino--hexopyrano.se t e t r a a c e t a t e lit  1  5  6  (CX) , had m.p. 93",  m.p. 92.2-93.2°. 8-D-xylopyranose  tetraacetate  157 ( C X I ) , had m.p. 127 , l i t m.p.  -153-  M e t h y l - B - D - g l u c u r o n a t e t e t r a a c e t a t e (CXII) was k i n d l y p r o v i d e d by D r s . G.O.  D u t t o n , P. R e i d and Mr. K. Gibney, o f t h i s  department.  3-deoxy-3-fluoro-B--D-xylo pyranose t r i a c e t a t e  ( C X I I I ) and 3-deoxy-  3 - f l u o r o - g - D - g l u c o p y r a n o s e t e t r a a c e t a t e (CXIV) were k i n d l y p r o v i d e d by Dr. A.B.  Foster. Most homonuclear magnetic double resonance  (*H-{ *H}) experiments  were performed on a V a r i a n HA-100 s p e c t r o m e t e r u s i n g a H e w l e t t Packard 204B 87 and/or a m o d i f i e d decoupling f i e l d  Hewlett Packard 200AB audio o s c i l l a t o r t o generate the (H^). 1  The h e t e r o n u c l e a r double resonance  19  ( H-{  F}) experiments o f  compound ( X X X I I I ) were performed on a V a r i a n Dual-Purpose V-4311 r a d i o f r e q u e n c y u n i t tuned t o 60 MHz Decoupler f o r b a s e - l i n e s t a b i l i z a t i o n .  spectrometer with  and a V a r i a n V-3521A I n t e g r a t o r / 19  The  F d e c o u p l i n g frequency was  o b t a i n e d from a N u c l e a r Magnetic Resonance S p e c i a l t i e s S.D.-60 Decoupler using a basic c r y s t a l o s c i l l a t o r frequency o s c i l l a t o r  (25.547 MHz)  i n conjunction with a variable  (V.F.O.) o f c a . 5.350 MHz..  The o v e r a l l output frequency  o f t h i s u n i t was m o n i t o r e d i n d i r e c t l y by b e a t i n g the output o f the V.F.O. a g a i n s t a s t a n d a r d 5.365 MHz  crystal oscillator  (N.M.R.S. E l e c t r o n i c Counter  Adaptor EC-60) and c o u n t i n g the r e s u l t a n t audio frequency " b e a t " s i g n a l w i t h a Hewlett Packard 3734A frequency c o u n t e r .  D i r e c t measurement o f the r a d i o  f r e q u e n c i e s o f the v a r i o u s o s c i l l a t o r s and r a d i o f r e q u e n c y u n i t s used a H e w l e t t - P a c k a r d 524B r a d i o f r e q u e n c y c o u n t e r , f i t t e d w i t h a 10-100  MHz  c o u n t e r - a d a p t o r (No. 525A) . The 60 MHz  f i e l d swept homonuclear d e c o u p l i n g experiment' (*H-{*ll})  o f d e r i v a t i v e (XXXV) u t i l i z e d the V a r i a n V-3521A I n t e g r a t o r / D e c o u p l e r as i n s t r u c t e d by  Johnson "'^. 1  -154-  REFERENCES  1.  R.U. Lemieux, R.K. K u l l n i g , H.J. B e r n s t e i n and W.G. J . Am. Chem, Soc. 8£, 6098 (1958).  2.  M. K a r p l u s .  3.  K.L. W i l l i a m s o n .  4.  R.J. Abraham, L.D, H a l l , L. Hough and K.A. McLauchlan. 213 (1962).  5.  R.U. Lemieux, J.D. Stevens and R.R. F r a s e r .  6.  M. K a r p l u s .  7.  L.D. H a l l . therein.  8.  N.S.. Bhacca and D.H. W i l l i a m s .  9.  H. Booth.  J . Chem. Phys. 30,  Schneider.  11 (1959).  J . Am. Chem. Soc. 85_, 516 (1963). Chem. I n d . ,  Can. J . Chem. 40, 1955 (1962),  J . Am. Chem, Soc. 85_, 2870 (1963). Advan. Carbohydrate Chem. 19, 51 (1964) and r e f e r e n c e s g i v e n J . Am. Chem. S o c , 8S_, 2742 (1964).  T e t . L e t t e r s 7_, 411 (1965).  10.  F.A.L. Anet, M. Ahmad and L.D. H a l l .  P r o c . Chem. S o c , 145 (1964).  11.  F.A. Bovey, E.W. Anderson, S o c , 146 (1964).  12.  F.R. J e n s e n , D.S. Noyce, C H . Sederholm and A . J . B e r l i n . S o c , 82_, (1960) .  13.  G.V.D. T i e r s .  14.  F.A. Bovey, E.W. Anderson, 40_, 3099 (1964) .  15.  J.D. R o b e r t s .  16.  N.F. T a y l o r and P.W.  17.  N.F. T a y l o r .  18.  P.W.  19.  D.H. Brauns.  20.  F. Mich e e l and A. Klemer, references given t h e r e i n .  21...  J . Feeney and L.F. S u t c l i f f e . T r a n s . Farad. Soc. 56, 1559 (1960), J . Phys. Chem. 65, 1894 (1961).  F.P.iHood and R.L. Kornegay.  Proc. Chem. J . Am. Chem.  P r o c . Chem. S o c , 389 (1960). F.P. Hood and R.L. Kornegay.  J . Chem. Phys.  Chem. i n B r i t a i n 2, 529 (1966) and r e f e r e n c e s g i v e n t h e r e i n . Kent.  J . Chem. S o c , 872 (1958).  Nature 182_, 660 (1958).  Kent, A. M o r r i s and N.F. T a y l o r .  J . Chem. S o c , 298 (1960).  J . Am. Chem. Soc. 45, 833 , 2381 (1923); 46_,.14S4 (1924). Advan. Carbohydrate Chem. _16_, 85 (1961) and  -155-  22.  J . Homer and L.F. Thomas. Proc. Chem. S o c , 139 (1961), T r a n s . Farad. Soc. 59_, 2431 (1963).  23.  R.J. F e r r i e r . Advan. Carbohydrate given t h e r e i n .  24.  0. Morton and W.N. T u r n e r .  25.  E, Aibano, D. Morten and T. T s u c h i y a .  Chem. 2J3, 67 (1965) and r e f e r e n c e s  Carbohydrate  Research  1, 444 (1966).  Carbohydrate Research  2_, 349 (1966).  26a. D.S. T a r b e l l and P.D. B a r t l e t t .  J . Am. Chem. S o c 58, 466 (1936).  26b. D.H.R. B a r t o n and R.C. Cookson.  Quart. Rev. (London) 10^, 44 (1956).  27.  P.B.D. de l a Mare and R. B o l t o n i n " E l e c t r o p h i l i c A d d i t i o n s t o U n s a t u r a t e d Systems", C. Eaborn, Ed., monograph 4, " R e a c t i o n Mechanisms i n O r g a n i c C h e m i s t r y " , E l s e v i e r P u b l i s h i n g Co., New York, 1966.  28a. R.U. Lemieux and B. F r a s e r - R e i d .  Can. J . Chem. 4_2_, 532 (1964).  28b, R.U. Lemieux and B. F r a s e r - R e i d .  Can. J . Chem. 4_3, 1460 (1965).  Can. J . Chem. 4J3, 1926 (1962).  29.  R.U. Lemieux and S. L e v i n e .  30.  A. Bowers, E. Denot, L.C. Ibanez and R. B e c e r r a . J . Am. Chem. Soc. 82_, 4001 (1960) .  31.  A. Bowers, E. Denot and R. B e c e r r a .  32.  A. Bowers.  35.  P.W. Kent, F.O. Robson and V.A. Welch. Chem. S o c , 24 (1963).  34.  C. Pedersen and H.G. F l e t c h e r , J r .  35a. C. Pedersen.  J . Am, Chem. S o c 82, 4007 ( I 9 6 0 ) .  J . Am. Chem. Soc. 81, 4107 (1959). J.Chem. S o c , 3273 (1963),  Proc  J . Am. Chem. Soc. 82, 941, 945 (1960).  A c t a Chem. Scand. 2_0_, 1369 (1966); C. Pedersen  and I . Lundt.  I b i d . 21_, 1239 (1967). 35b. C. Pedersen.  T e t r a h e d r o n L e t t e r s , 511 (1967).  36.  E.D. Bergmann and I . Shahak.  37.  M. Schmidt and H. Me i n e r t .  J . Chem. S o c , 1418 (1959). Agnew. Chem, 71_, 126 (1959) ; 7_2_, 1.09, 493 ( I 9 6 0 ) .  '38,  R.H. Andreatta. and A.V. Robertson.  •39.  E.L. Mackor and C. MacLean.  A u s t . J . Chem. 19, 161. (1.966).  J . Chem. Phys. 44, 64 (1966).  40.  K.L. W i l l i a m s o n , Y.F. L i , F.H. H a l l and S. Swager. .88, 5678 (1966) .  J . Am. Chem. S o c  41,  J.A, M a r t i n , M. Chauvin and J . L e v i s a l l e a .  42..  J . F . C o d i n g t o n , I.E. Doerr and J . J . Fox. Carbohydrate Research (1966).  T e t r a h e d r o n L e t t e r s , 2879 1_, 455  (19661.  -156-  43.  I . Johansson and B. L i n d b e r g . Carbohydrate Research 1_, 467 (1966).  44.  A.B. F o s t e r .  45.  I . Lundt and C. Pedersen.  46.  C. Pedersen.  47.  I . Lundt, C. Pedersen and B. T r o n i e r .  48.  C. Pedersen.  I b i d . 1.8, 60 (1964).  49.  C. Pedersen.  I b i d . 17, 1269 (1963).  50.  C. Pedersen.  lbidL_ 17, 673  5.1.  C  I b i d . 16, .1831 (1962).  52.  J.T. Edward.  Pedersen.  Private  communication. Microchem.  A c t a 1_, 125 (1966).  A c t a Chem. Scand. 20, 963 (1966). Ibid.  1_8, 1917 (1964).  (1963).  Chem. I n d . (London), 1102 (1955).  53. ' R.U. Lemieux i n " M o l e c u l a r Rearrangements", P. de Mayo, e d . , P a r t 2, T n t e r s c i e n c e D i v i s i o n , John W i l e y and Sons, I n c . , New York, 1964, pp. 735-743. 54.  S . J . Angyal i n " C o n f o r m a t i o n a l A n a l y s i s " , E.L. E l i e l , N.L, A l l i n g e r , S..J. Angyal and C A . M o r r i s o n , I n t e r s c i e n c e D i v i s i o n , John W i l e y and Sons, I n c . , New York, 1965, C h a p t e r 6.  55.  J . A l l i n g e r and N.L. A l l i n g e r . T e t r a h e d r o n 2_, 64 (1958).  56.  0. l i a s s e l and B. O t t a r .  57.  R.E. Reeves.  Advan. C a r b o h y d r a t e Chem. 6_, 107 (1951).  58.  C S . Hudson.  J . Am. Chem. Soc. 31_, 66 (1909).  59.  L.D. H a l l .  60.  J . I . Musher and E . J . Corey.  61.  B. Coxon.  A c t a Chem. Scand.  ly 929 (1947).  Chem. and Ind. (London), 950 (1963). T e t r a h e d r o n 1_8, 791 (1962).  C a r b o h y d r a t e Research 1_, 357 (1966).  62a. J.A. P o p l e , W.C S c h n e i d e r and H.J. B e r n s t e i n , "High R e s o l u t i o n N u c l e a r M a g n e t i c Resonance", M c G r a w - H i l l Book Co., I n c . , New York, 1959. 62b. J.D. R o b e r t s , "An I n t r o d u c t i o n t o t h e A n a l y s i s o f S p i n - S p i n S p l i t t i n g i n H i g h - R e s o l u t i o n N u c l e a r Magnetic Resonance S p e c t r a , " W.A. Benjamin, I n c . , New Y o r k , 1961. 63.  L.D. H a l l and D.L. Jones. U n p u b l i s h e d r e s u l t s .  64.  B. Coxon.  65.  R.C Cookson, T.A. Crabb, J . J . F r a n k e l and J . Hudcc. Supplement 7, 355 (1967).  T e t r a h e d r o n 22, 2281 (1.966). Tetrahedron,  -157-  66.  L.D. H a l l .  T e t r a h e d r o n L e t t e r s , 1457 (1964).  67.  R.W.  68.  R..I. F e r r i e r and M.F. S i n g l e t o n . T e t r a h e d r o n  69.  R.U. Lemieux and J.U. S t e v e n s .  .70.  G. F i l i p o v i c h and G.V.D. T i e r s .  Lenz and J.P. Heeschen.  J . Polymer S c i . , 5j_, 247 (1961).  Can. J . Chem. 43_, 2059 (1965). J . Phys. Chem. 63_, 761 (1959).  71.  L.D. H a l l , I . Johnsson  72.  L.D. H a l l , R. H e m s and A.B. F o s t e r .  73.  B. Coxon.  74.  D.F. Evans.  Tetrahedron  1_8, 1143 (1962).  and B. L i n d b e r g .  To be P u b l i s h e d .  To be p u b l i s h e d .  22, 2281 (1966).  J . Chem. S o c , S77 (1960).  75a. R.K. H a r r i s and N. Sheppard.  Proc Chem. S o c , 418 (1961).  75b. J . Mushcr and R.E. R i c h a r d s .  Proc Chem. S o c , 230 (1958).  76.  L.D. H a l l and L. E v e l y n .  To be published'.  77a. G. Aranda, J . J u l l i e n and J.A. M a r t i n . (1966) .  B u l l . Soc. Chim. F r a n c e , 2850  77b. J.M. J u l l i e n and (Mrs) H. S t a h l - L a r i v i e r e . B u l l . Soc.Chim. F r a n c e , 99 (1967) . '77c  D. Morton and W.N. T u r n e r .  78.  C.V. H o l l a n d , D. H o r t o n and J.S. J e w e l l .  79.  P.W. Kent and J.E.G. B a r n e t t .  80.  P.W. Kent and M.R. Freeman. I b i d . ( C ) , 910 (1966).  81.  K.R. Wood, P.W. Kent and D. F i s h e r .  82.  L.D. H a l l and J.F. M a n v i l l e .  83.  H. Nakamura, S. T e j i m a and M. A k a g i .  84.  L.D. H a l l and J.F. M a n v i l l e .  85.  M.S. L e f a r and C E . W e i l l .  •86.  R.U. Lemieux. A.C.S., 1966.  J . Org. Chem. 30, 3387 (1965) . J . O r g . Chem. 32_, 1818 (1967).  J . Chem. S o c , Supplement 2_, 6196 (1964).  I b i d . , 912 (1966).  Chem. and I n d . , London, 991 (1965). Chem. Pharm. B u l l .  12_, 1302 (1964).  Can J . Chem. 45, 1299 (1967). J . O r g . Chem. 30, 954 (1965).  Hudson Awards A d d r e s s , A t l a n t i c C i t y , 152nd m e e t i n g ,  87.  L.D. H a l l and J.F. M a n v i l l e i n S. H a n e s s i a n ( E d . ) , "The C h e m i s t r y o f Deoxy-Sugars," Advances i n C h e m i s t r y S e r i e s , American Chemical S o c i e t y , in press.  88.  R.J. C u s h l e y , J . F . Codington  and .T.J. Fox. C a r b o h y d r a t e  R e s e a r c h , 5_, 31 (196/  -158-  89.  R . J . Abraham and L. C a v a l l i .  M o l . Phys. 9, 67 (1965).  90.  R . J . Abraham, L. C a v a l l i and K.C.R. P a c h l e r .  91.  M.L. Muggins.  92.  F. H r u s k a , H.M. Mutton and T. S c h a e f e r .  93.  J . P . Maher and D.F. Evans.  94.  R. Freeman and I). H. ' IVhif f e n .  95.  E.W. G a r b i s c h .  96.  M. B a r f i e l d .  97.  L.D. H a l l and J . F . M a n v i l l e .  98.  L.D. H a l l , D.L. J o n e s , J . F . M a n v i l l e and B. Webster.  99.  R.F. M e r r i t t  M o l . Phys.  11_, 471 (1966).  J . Am. Chem. Soc. 75, 4123 (1953). Can. J . Chem. 43_, 2392 (1965).  P r o c . Chem. S o c , 208 (1961). M o l . Phys. 4_, 321 (1961).  J . Am. Chem. Soc. 86_, 5561 (1964). J . Chem. Phys. 41_, 3825 (1964). Chem. Comm., s u b m i t t e d .  and F.A. Johnson.  Unpublished  results.  J . Org. Chem. 31_, 1859 (1966).  100.  H.M. M c C o n n e l l . J . Chem. Phys. 23, 2454  (1955).  101.  J.H. Van V l e c k and A. Sherman. Rev. Mod. Phys., 7_, 167 (1935).  102.  R. Freeman and D.H.Vhiffen.  103.  W.A. Anderson and R. Freeman. J . Chem. Phys. 37_, 85 (1962).  104.  R. Freeman and W.A. Anderson.  105.  R . J . Abraham, L.D. H a l l , L. Hough and K.A. McLauchlan. 3699 (1962) .  106.  F. Block and A. S i e g e r t .  107.  L.F. Johnson. Summer 1965.  108.  F.A.L. Anet.  109.  P.C. L a u t e r b u r and R . J . K u r l a n d .  110.  M. K a r p l u s .  111.  A.D. Buckingham and K.A. McLauchlan.  112.  R.E.J. Sears and E.L.Hahn.  113.  S. Meiboon and L.C. Snyder.  J . Am. Chem. S o c 89_, 1038 (1967).  114.  M. B a r f i e l d and D.M. G r a n t .  Advan. M a g n e t i c Resonance 1_, 149 (1965).  115.  M. K a r p l u s and D.M. Anderson.  P r o c . Phys. S o c (London), 79_, 794 (1962).  I b i d . , 37_, 2053 (1962). J . Chem. Soc.  Phys. Rev. 57_, 522 (1940).  Varian Associates Technical Information B u l l e t i n ,  J . Am. Chem. S o c , 84, 3767  (1962).  J . Am. Chem. Soc. S4, 3405 (1962).  J . Am. Chem. Soc. 84_, 2485 (1962). P r o c . Chem. S o c , 144 (1963).  J . Chem. Phys. 45_, 2753 (1966).  J . Chem. Phys. 30, 6 (1959).  -159-  116.  U.S. Gutowsky, M. K a r p l u s and D.M. G r a n t .  J . Chem. Phys. 31_, 1287 (1959).  117.  J.A. P o p l c and A.A. Bothner-Ry.  118.  A.A. Bothner-By.  119.  H. Conroy.  120.  R.C. Fahey, G.C. Graham and R.L. P i c c i o n i .  121.  S.L. Manatt, D.D. Fllemin and S.J. B r o i s .  122.  D.H. Buss, L.D. H a l l , L. Hough and J.F. M a n v i l l e .  123.  L.D. H a l l , J . F . M a n v i l l e and A. T r a c e y . 514 (1967).  124.  J . Meinwald  125.  S. S t e r n h e l l .  126.  M. B a r f i e l d .  127.  K.G.R. P a c h l e r and W.C.E. Underwood.  128.  K. T o r i and M. O h t s u r u .  129.  L.D. H a l l , J . F . M a n v i l l e and P.R. S t e i n e r . S t e v e n s . P r i v a t e communication.  130.  K.G.R. P a c h l e r and P.L. Wessels.  131.  R.R. F r a s e r , R.U. Lemieux and J.D. S t e v e n s . 3901 (1961).  132.  J.R. Dyer.  133.  R.U. Lemieux.  134.  B. Coxon, H.J. J e n n i n g s and K.A. McLauchlan.  135.  L.D. H a l l , D.L. Jones and J . F . M a n v i l l e .  136.  D.F. Evans, S.L. Manatt and D.D. E l l e m a n .  137.  R.A, Berheim and B.J. L a v e r y .  138.  A.W. Douglas, P r i v a t e  139.  F.. F i s h e r . Ber. 44_, 1898 (1911); D.H. Brauns. 1280 (1925).  140.  F. M i c h e e l , A. Klemer, M. N o l t e , H. N o r d i e k , L. Tork and I!. U'estermann. Ber.- 90, 1612 (1957) .  J . Chem. Phys. 4 2 , 1339 (1965).  Advan. M a g n e t i c Resonance 1_, 195 (1965).  Advan. O r g a n i c Chem. 2_, 265 (1965).  and A. L e w i s .  J . Am. Chem. Soc. 88, 193 (1966). J . Am. Chem.Soc. 8_7, 2220 (1965). T e t r a h e d r o n 2_1_, 69 (1965).  C a r b o h y d r a t e Research  4  t  J . Am. Chem. Soc. 83_, 2769 (1961).  Rev. Pure A p p l . Chem. 14, 15 (1964). Private  Private  communication. T e t r a h e d r o n 23, 1817 (1967).  Chem. Comm., 886 (1966). U n p u b l i s h e d r e s u l t s . J.D.  J . South A f r i c a n Chem.Soc. 19_, 49 (1966). J . Am. Chem. Soc. 83_,  communication.  A b s t r a c t s Papers Am. Chem. Soc. M e e t i n g 152, 12D (1966). T e t r a h e d r o n 23, 2395 (1967).  To be p u b l i s h e d . J . Am. Chem. Soc. 85_ 238 (1963). ;  J . Am. Chem. Soc. 89_, 1279 (1967).  communication. J . Am. Chem. Soc. 47,  -160-  "141.  R. H e l f e r i c h and R. Gootz.  B e r . 62_, 2505 (1929); V.F.. Sharp and M. S t a c e y .  J . Chem. Soc. , 285 (1951) . 142.  II. Ohle, W. Marecck and W. B o u r j a u .  143.  F. M i c h e e l . A. Klemer, G. Baun, P. R i s t i c and F. Zumbulte. Ber., 88, 4 75  Ber. 62, 833 (1929).  (1955).  144.  F. M i c h e e l .  Ber. 90, 1612 (1959).  145.  B. H e l f e r i c h , K. B a u e r l e i n and F. Wiegand.  146.  J.K. D a l e .  147.  W.G. Overend, M. Stacey and J . Stanek.  148.  M. Bergmann, H. S c h o t t e and W. L e c h i n s k y .  149.  F. Weygand.  150.  F.L. Humoller.  151.  A. R o s e n t h a l and G. Kan. U n p u b l i s h e d r e s u l t s .  152.  L.D. H a l l , L. Hough and R.A. P r i t c h a r d .  153.  H. Ohle and L. Vargha.  154.  T.L. H a r r i s , E.L. H i r s t and C H . Wood.  155.  P.A. Levene and R.S. T i p s o n .  156.  W.A.  157.  C.S. Hudson and .T.M. Johnson.  Ann. Chem. 447, 27 (1926).  J . Am. Chem. Soc. 37_, 2745 (1915).  Bonner.  158. • L.F. Johnson,  Methods i n Carbohydrate  J . Chem. S o c , 2841 (1949). Ber. 55_, 158 (1922).  Chem. 1_, 182 (1962).  Methods i n Carbohydrate Chem. 1_, 83 (1962).  J . Chem. Soc, 1537 (1961).  Ber. 62, 2435 (1929). .J. Chem. S o c , 2 1 0 8  ,T. B i o l . Chem. 92,  (1932).  109 (1931).  J . Org. Chem. 26, 908 (1961). J . Am. Chem. Soc. 37_, 2748 (191.5).  V a r i a n T e c h n i c a l I n f o r m a t i o n B u l l e t i n , V o l . 3, No. 3 (1963).  

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0062089/manifest

Comment

Related Items