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Conformational studies of furanosyl fluorides by proton and fluorine nuclear magnetic resonance spectroscopy Steiner, Paul Robert 1969

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CONFORMATIONAL STUDIES OF FURANOSYL FLUORIDES BY PROTON AND FLUORINE NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY by PAUL ROBERT STEINER B . S c , U n i v e r s i t y of B r i t i s h Columbia, 1966 A THESIS SUBMITTED IN FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the department of CHEMISTRY We accept t h i s t h e s i s as conforming to the required' standard THE UNIVERSITY OF BRITISH COLUMBIA January, 1969 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r a n a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e a n d S t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d b y t h e Head o f my D e p a r t m e n t o r b y h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . D e p a r t m e n t o f The U n i v e r s i t y o f B r i t i s h C o l u m b i a V a n c o u v e r 8, Canada ( i i ) ABSTRACT Proton and f l u o r i n e nuclear magnetic resonance spectroscopy was used to in v e s t i g a t e the favoured forms of several furanosyl f l u o r i d e s . The low energy b a r r i e r to pseudo-r o t a t i o n i n these systems precludes the assignment of only one favoured conformation f o r each molecule. A systematic study of f i v e membered r i n g sugar conformations was undertaken by examining three types of systems, varying from a r e l a t i v e l y r i g i d molecule i n v o l v i n g three fused r i n g s , to more f l e x i b l e molecules i n v o l v i n g a "free"•furanosyl f l u o r i d e r i n g . The s p e c t r a l assignment was greatly f a c i l i t a t e d by heteronuclear f l u o r i n e decoupling and computer a n a l y s i s . 5-fluoro-3^-anhydro-^-L-idofuranose was synthe-siz e d i n good y i e l d from several precursors and the molecule's 3 furanose r i n g conformation of was assigned on the basis of v i c i n a l ''"H-1H coupling constants. Using the values 1 19 f o r v i c i n a l H- F couplings obtained from t h i s molecule, together with data from other workers,, a p a r t i a l Karplus 1 19 type curve was constructed r e l a t i n g v i c i n a l H- F couplings to d i h e d r a l angles. This curve - which was found to be more asymmetric than the Karplus relationshp f o r v i c i n a l Hl-^H ' couplings - was then used, together with the known ( i i i ) Karplus curve f o r v i c i n a l "Hl-^ II couplings, to determine the conformations of the t r i e s t e r furanosyl f l u o r i d e s of r i b o s e , 3 arabinose and xylose. Assuming pure sp h y b r i d i z a t i o n and maximum r i n g puckering, the conformations f o r most of the sugars studied were found to involve the displacement of C 0 and/or C po s i t i o n s out of the plane of the r i n g formed by the other atoms. The conformation f o r a - f l u o r o - r i b o -• 4 furanosyl t r i e s t e r ( T ) was found to be d i f f e r e n t than that o of the S-fluoro-ribofuranosyl t r i e s t e r (^T^). A s i g n i f i c a n t 4 and apparently s t e r e o s p e c i f i c long-range J coupling through oxygen of ca. .6.5 Hz, i s observed when H and F are i n a trans arrangement, while a much smaller coupling f o r 4 J„ _ of ca. 1.0 Hz. i s observed when these two n u c l e i are V F ~~~ i n a c i s or approximately "planar H" arrangement. On the H other hand, J couplings were found to have a value of ca. 2.2 Hz. i n the c i s or "planar M" geometry, while i n the H trans geometry, J„ i s ca. 0.5 Hz. • H 3 ' F ~ ( i v ) TABLE OF CONTENTS INTRODUCTION . . 1 RESULTS AND. DISCUSSION 11 Section A: Three fused f i v e membered rings .'. 12 Section B: Furanosyl f l u o r i d e s containing two fused r i n g s . . . . 32 Section C: F l e x i b l e furanosyl f l u o r i d e s 42 EXPERIMENTAL . . . . 69 General Methods 70 5-fiuoro-3,6-anhydro-l,2-0-isopropylidene-=-L-idose(VI) 73 Other F l u o r l n a t l o n Procedures 75 F l u o r i n a t i o n with Hydrogen Fluoride 78 APPENDIX.. 82 Appendix A: Computer programming........ 83 Appendix B: Heteronuclear decoupling 85 REFERENCES 88 (v) LIST OF TABLES TABLE I F i r s t order coupling constants f o r three fused r i n g systems 18 TABLE II F i r s t order chemical s h i f t s f o r three fused r i n g systems 19 .TABLE III Comparison of coupling constants and chemical s h i f t s from f i r s t order a n a l y s i s and computer an a l y s i s f o r compound VI 23 TABLE IV F i r s t order coupling constants f o r two fused r i n g systems 34 TABLE V F i r s t order chemical s h i f t s f o r two fused r i n g systems 35 TABLE VI F i r s t order coupling constants f o r furanosyl f l u o r i d e s 43 TABLE VII F i r s t order chemical s h i f t s f o r furanosyl f l u o r i d e s 44 TABLE VIII Evaluation of the favoured conformation of compound XVIII.. 61 TABLE IX Favoured conformations f o r f l e x i b l e furanosyl f l u o r i d e s 62 TABLE X Comparison of conformational assignments 63 ( v i ) LIST OF FIGURES Figure 1 The Karplus curve f o r v i c i n a l "Hi-Si couplings 4 Figure 2 100 MHz. spectra of (A) 5-fluoro-3,6-anhydro-1 J2-0-isopropylidene- a :-L-idofuranose (VI) and (B) 5-0-benzoyl-3 ,6-anhydro-l,2-0-isopropylidene-a-L-idofuranose (iXa) 24 Figure 3 P a r t i a l 100 MHz. spectrum f o r (VI) computer an a l y s i s 25a Figure 4 94 MHz. f l u o r i n e spectra of (VI) 25b Figure 5 100 MHz. proton spectra of 2 ,5-di-0-benzoyl-3-fluoro-D-glucuronolactone (XIV); (A) normal spectrum,(B) -^F decoupled spectrum 40 Figure 6 100 MHz. spectra of 2,3,5-tri-0-benzoyl-B-D-ribofuranosyl f l u o r i d e (XVIII); (A) normal ipectrum, (B) ^ ^F decoupled spectrum 45 Figure 7 P a r t i a l 100 MHz. spectra of (XVIII); (A) computer simulation, (B) normal spectrum, (C) -^F decoupled spectrum and (D) l ^ F and H decoupled spectrum .46 Figure 8 100 MHz. spectra of 2,3,5-tri-0-benzoyl-°=-D-ri b o f u r a n o s y l f l u o r i d e (XIX); (A) normal spectrum, (B) ^ F decoupled spectrum 49 Figure 9 P a r t i a l 100 MHz. of compound (XIX); (A) computer simulation, (B) normal spectrum, (C) l ^ F decoupled spectrum and (D) l ^ F and H decoupled spectrum -50 Figure 10 Pseudorotation cycle of envelope and twist conformations 55 1 19 Figure 11 The r e l a t i o n s h i p between v i c i n a l H- F coupling constants and dihedral angles f o r f l u o r i n a t e d sugars 58 (vxi) LIST OF FLOW SHEETS Flow Sheet 1 13 Flow Sheet 2 33 ( v i i i ) • ACKNOWLEDGEMENTS I would l i k e to express my sincere gratitude to Dr. L. D. H a l l f o r h i s patient guidance during the course of t h i s i n v e s t i g a t i o n . The free atmosphere of discussion between fellow graduate students i n t h i s laboratory also encouraged the progression of t h i s study to i t s ultimate aim. Sp e c i a l thanks are extended to Dr. C. Pedersen f o r providing several compounds which added s i g n i f i c a n t l y to the scope of t h i s study. INTRODUCTION - 2 -In the past two decades organic chemists have become i n c r e a s i n g l y interested i n the f i e l d of conformational a n a l y s i s . Such i n t e r e s t a r i s e s from the seemingly close r e l a t i o n s h i p between molecular conformation and the chemical and thermodynamical properties of a molecule. This present study was undertaken with the object of determining the favoured conformation of various furanose sugars by u t i l i z -1 19 ing proton ( H) and f l u o r i n e ( F) nuclear magnetic reson-ance spectroscopy. The e l u c i d a t i o n of the conformation of pyranose carbohydrates and other saturated s i x membered ring s by proton magnetic resonance ("Hi n.m.r.) has i n recent years demonstrated the strength of t h i s spectroscopic t o o l (1,2). • Most of these studies have been based on the use of v i c i n a l coupling constants, however, the observations of chemical s h i f t between a x i a l and eq u a t o r i a l protons (A ) i s also important. I n i t i a l l y , i t was concluded that the proton of an e q u a t o r i a l l y oriented hydrogen resonates at lower f i e l d by ca. 0.5 p.p.m. than that of a chemically s i m i l a r but a x i a l l y oriented hydrogen (17). However, more recent studies have shown several cases where t h i s trend i s r e -versed (18). In 1959 Karplus determined the now famous - 3 -semi-theoretical relationship between v i c i n a l proton coupling constants and d i h e d r a l angles f o r ethane type molecules (3). The generalized Karplus equation has the form where J i s the v i c i n a l coupling constant due to the i n t e r -a c t i o n between two hydrogen atoms bound to adjacent carbon atoms and separated by a d i h e d r a l angle of ej>. J 0 and K are c o e f f i c i e n t s which have a value of K = -0.28 and J Q = 8.5 o o o o f o r 0 «f><90 and J Q = 9.5 f o r 90 <4><180 . A p l o t of v i c i n a l coupling constant against d i h e d r a l angle (Figure 1) gives an unsymrnetrical curve about the negative coupling at <j> = 90 . This r e l a t i o n s h i p has been applied to other molecular systems by s l i g h t l y modifying the parameters J D and K (4,5,6). Recently Williams and Bhacca (7), when i n v e s t i g a t i n g a s e r i e s of s t e r o i d a l a l c o h o l s , observed a c o n f i g u r a t i o n a l dependence (as shown i n A and B) f o r v i c i n a l coupling constants where J = J c c o s <J> + K o electronegative substituents are involved. This dependence H, La A B R = H or Ac R = H or Ac •J«,e - 5.5 ± 1.0 Hz. J c , a = 2.5—3.2 Hz. - 4 -Dihedral Angle (Degrees) FIG. 1 The Karplus curve f o r J = J Q c o s <j> + K; the r e l a t i o n s h i p f o r ethane with K = -0.28 and J 0 = 8.5 f o r 0 <<J)<90° and J 0 = 9.5 f o r 90°«j><180° . --- the modified r e l a t i o n s h i p f o r carbohydrates (See Reference 1) with K = -0.28 and J D = 9.5 f o r 0°<$<90° and J 0 = 10.5 f o r 90°<<J.<180°. - 5 -also has been reported i n pyrai.'ose sugars (8,9). This c o n f i g u r a t i o n a l dependence appeals to be maximal when the electronegative substituent i s co-planar with one of the protons involved i n the v i c i n a l coupling (10) as i n B. Indeed several authors have suggested that a l i n e a r r e l a -t i o n s h i p e x i s t s between v i c i n a l coupling constants and the e l e c t r o n e g a t i v i t y of substituents on these centres (19). However, by using a la r g e r range of electronegative sub-s t i t u e n t s , t h i s r e l a t i o n s h i p now appears to be exponential, that i s , as the e l e c t r o n e g a t i v i t y of the substituent increases, the J's decrease sharply (20). Although most conformational studies have been based on "^H n.m.r. spectroscopy, such spin ^/ n u c l e i as 19 13 31 F, C and P also have been u t i l i z e d f o r conformational studies (11). In a recent communication (9) H a l l and Manville have shown that f l u o r i n e can be used as a probe to determine the conformations of g l y c o s y l f l u o r i d e s . This concept now has been applied to other s p e c i f i c a l l y f l u o r i n a t e d carbohydrates (12). Introduction of a f l u o r i n e substituent provides increased s e n s i t i v i t y since the order of magnitude of v i c i n a l fluorine-hydrogen coupling constants are three to four times greater than the v i c i n a l proton-proton J's (21). - 6 -Roberts has shown from h i s i n v e s t i g a t i o n of 1,1 d i f l u o r o c y -clohexanes that a large chemical s h i f t d i f f e r e n c e of 15 to 20 p.p.m. e x i s t s between the a x i a l and equatorial f l u o r i n e s . S i m i l a r observations have been reported f o r pyranose sugars (9). This chemical-shift d i f f e r e n c e i s almost f o r t y times that observed f o r hydrogen. Studies to determine the precise dihedral angle dependence of v i c i n a l have involved several groups (9,23). Recently Williamson (24) reported the angular dependence of J^p using a s e r i e s of compounds with "minimized substituent e f f e c t s " . From several b i c y c l i c compounds which are assumed to have f i x e d dihedral angles, Williamson found the v i c i n a l J^P to dihedral angle dependence to have the same shape o curve as that f o r v i c i n a l J,,,,, with a maximum at 0 of 31 Hz., nn o o a minimum at 90 (ca. 0 Hz.) and a maximum of 44 Hz. at 180 . However, as pointed out i n the author 7's di s c u s s i o n , these coupling constants seem to be extremely dependent on bond angle and since one i s dealing c h i e f l y with strained systems, 3 the assumption of sp h y b r i d i z a t i o n and i n t e r p o l a t i o n of dih e d r a l angle from X-ray data may not be v a l i d i n many of these cases. The primary concern of t h i s study was a conforma-t i o n a l i n v e s t i g a t i o n of s p e c i f i c a l l y f l u o r i n a t e d furanoses. The conformations of f i v e membered rings are of general i n t e r e s t since, next to s i x membered rings they comprise the second most abundant r i n g form i n organic compounds. For example: r i n g D of s t e r o i d s , nucleotides and many h e t e r o c y c l i c compounds a l l contain f i v e membered r i n g s . Indeed the presence of furanose forms of ribose and 2-deoxy-ribose i n RNA and DNA r e s p e c t i v e l y - two very important molecules i n the l i f e process - has i n i t i a t e d many of the conformational i n v e s t i -gations of the f i v e membered r i n g forms (25). In the case of cyclopentane, P i t z e r (26) has shown by thermodynamical c a l c u l a t i o n s that the repulsion of the neighbouring hydrogen atoms w i l l favour a puckering of the r i n g at the expense of deviating from the normal tetrahedral angles. In e f f e c t , t h i s puckering i s not f i x e d but rotates around the r i n g by an up and down motion often r e f e r r e d to as "pseudorotation". Hendrickson (27), using a computer program which e s s e n t i a l l y ignored symmetry r e s t r i c t i o n s , c a l c u l a t e d the preferred conformation of cyclopentane by minimization of the t o t a l energy with respects to bond angle s t r a i n , t o r s i o n a l s t r a i n , non-bonding repulsions and non-bonding a t t r a c t i o n s . His r e s u l t s confirmed P i t z e r ' s pseudorotation concept. Hence i n contrast to the two stable c h a i r forms - 8 -of cyclohexane where both angle and t o r s i o n a l s t r a i n are minimum, cyclopentane has numerous possible conformations with .similar energies and low energy b a r r i e r separations. I f only the two symmetric forms - envelope and twist -are used , twenty conformations are p o s s i b l e . In order to f a c i l i t a t e a meaningful, dis c u s s i o n of furanose conformations - one which allows a workable concept of f i v e membered r i n g forms - the envelope and twist conforma-t i o n s w i l l only be considered here. Such a r e s t r i c t i o n has been applied s u c c e s s f u l l y by other workers (28). In cyclopentane the conformations can be described i n the following manner: the envelope form (C) has one carbon above or below the plane of the ring- defined by the other four carbon atoms. Five types of bonds are present i n t h i s conformer: ' Alternate designations of C f o r envelope' and f o r twist a r i s e from the presence of a'plane of symmetry and a two f o l d axis f o r these respective forms i n cyclopentane. s - 9 -a x i a l ( a ) , eq u a t o r i a l ( e ) , q u a s i - a x i a l ( a ' ) , quasi-equator'.al (e') and b i s e c t i o n a l (b), the l a t t e r which assumes a p o s i t i o n be-tween the a x i a l and equa t o r i a l bonds. The twist form (D) has one carbon above and an adjacent carbon below the plane a b of the r i n g defined by the other carbon atoms. This form contains the same bonds as present i n the envelope structure. In order to apply the apparent advantages of 19 f l u o r i n e magnetic resonance ( F n.m.r.) f o r conformational an a l y s i s of furanoses i t was desi r a b l e to learn more about 19 1 the r e l a t i o n s h i p between "F and H n.m.r. with respect to angular dependences. To accomplish t h i s aim a project was undertaken to synthesize r i g i d , s p e c i f i c a l l y f l u o r i n a t e d furanose sugars using "^H -n.m.r. to define t h e i r conformations and then to r e l a t e the v i c i n a l H-F couplings obtained from such conformations to dih e d r a l angle. - 10 -It was thought that this, constructed "Karplus curve" f o r might l a t e r be applied to the examinations of furanosyl f l u o r i d e s which are expected to tdopt more f l e x i b l e conformations. Primary sugar f l u o r i d e s are synthesized r e a d i l y from n u c l e o p h i l i c displacements of sui t a b l e d e r i v a t i v e s by metal f l u o r i d e s (13). Secondary carbohydrate f l u o r i d e s have been synthesized from the opening of s u i t a b l e sugar epoxides with hydrogen f l u o r i d e (14) or potassium f l u o r i d e (15). Recently Foster and co-workers have used tetra-n-butylammonium f l u o r i d e i n a c e t o n i t r i l e to synthesize 3-deoxy-3-fluoro-1,2:5,6-di-0-isopropylidene-^-D-glucofuranose v i a n u c l e o p h i l i c displacement of a tosyloxy group. Pedersen has made extensive use of hydrogen f l u o r i d e to replace anomeric acetates or benzoates with f l u o r i n e (29) and this. a r e a has been reviewed by Hicheel and Klemer (30). 19 1 The concept of applying F and H n.m.r. together f o r s t r u c t u r a l e l u c i d a t i o n of r i n g systems has been shown to be successful f o r pyranosyl f l u o r i d e s (31). In the case of furanosyl f l u o r i d e s a s i m i l a r approach can be applied but the problem JLs inherently more d i f f i c u l t due to the abundance of possible.conformations having almost i d e n t i c a l energy minima. This t h e s i s shows that systematic treatment of n.m.r. data makes i t possible to a r r i v e at reasonably d e f i n i t i v e conclusions about the conformation of furanosyl f l u o r i d e s i n s o l u t i o n . . RESULTS AND DISCUSSION - 12 -The low energy b a r r i e r to pseudorotation i n f i v e membered r i n g s has made a d e f i n i t i v e study of these r i n g forms d i f f i c u l t (28b ,32 ,33 ,34) . 'In attempting a conforma-t i o n a l study of the favoured forms of furanosyl f l u o r i d e s we undertook to examine f i r s t , the r e l a t i v e l y r i g i d molecules and then to proceed to the more f l e x i b l e forms . Each of the three furanose sj'stems studied w i l l be discussed separately i n Sections A, B and C, proceeding from a conformational e l u c i d a t i o n of high confidence ( i . e . r i g i d structures) to one which i s more speculative ( i . e . f l e x i b l e s t r u c t u r e s ) . General f a c t o r s involved i n a l l the compounds studied w i l l be discussed i n the l a t t e r portion of Section C. SECTION A: 5-FLU0R0-3,6-ANBYDR0-l ,2-0-IS0PR0PYLIDENE-«-L-IDOFURANOSE; THREE FUSED FIVE MEMBERED RINGS. In studying a molecule with three connected f i v e membered r i n g s some r i g i d i t y i s introduced into the molecular system. Each r i n g shares two mutual centres with the other, In t h i s t h e s i s the terms " r i g i d " or "n o n - f l e x i b l e " designate a molecule which can have a s e r i e s of possible conformations of s i m i l a r minimum energy, but ex i s t as one s p e c i f i c conformation due to a high energy b a r r i e r to mobility and/or a large population of that molecule being maintained i n the one s p e c i f i c conformation. Non-flexible forms include molecules with fused rings which introduce r i g i d i t y into the system. On the other hand, the term " f l e x i b l e " w i l l designate molecules whose representative form cannot be described by a sing l e conformer, but'instead reside i n a r e s t r i c t e d portion of the pseudorotation c y c l e . Here, t h i s l a t t e r term applies to the free furanose rings described i n Section 'C of the discussion. 13 -FLOW SHEET 1 - 14 -thus r e s t r i c t i n g the pseudorotation c y c l e . In essence the presence of more than one f i v e membered r i n g i n the molecule provides the p o s s i b i l i t y of overdefining the system. Since several coupling constants are i n t e r r e l a t e d to mutually fused r i n g s , one can i n e f f e c t , observe deformations i n two rings by looking at one coupling constant (a common bond e x i s t s between two r i n g s ) . The 3 ,6-anhydro-l ,2-0-isopropylidene furanose system was chosen as the conformationally r i g i d model f o r several reasons. F i r s t l y , the synthesis of these compounds i s well known and can e a s i l y be accomplished (5). Secondly, the s t a b i l i t y of the 3,6-anhydro r i n g allows one to apply various harsh reagents, such as potassium f l u o r i d e . i n the f l u o r i n a t i o n procedure which would degrade most sugars (35). Indeed, once the 3,6-anhydro bond i s formed under moderately' a l k a l i n e conditions, i t w i l l remain r e s i s t a n t to both base and a c i d . The 3,6-anhydro portion of the r i n g forms a c y c l i c ether and i n t h i s regard i s more'stable than the furanose sugar r i n g (36). T h i r d l y and most importantly, the n.m.r. spectra of these d e r i v a t i v e s are usually f i r s t order (5). The 1 • ' ' H n.m.r. spectrum of 5-0-tosyl-3,6-anhydro-l,2-0-isopropylidene-<*-D-glucofuranose has been extensively studied by Abraham, The term " f i r s t order a n a l y s i s " indicates that the chemical s h i f t s and coupling constants are 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 . H a l l and co-workers (5). Detailed examination of the v i c i n a l coupling constants provided these workers with enough informa-t i o n to make d e f i n i t i v e statements about the conformation of t h i s molecule. By using the Karplus equation and the concept that "symmetry i n r i n g buckling i s r e f l e c t e d i n the eq u a l i t y . o f c e r t a i n coupling constants", they r a t i o n a l i z e d the conforma-t i o n of t h i s molecule (H). The very.small value of J -i s conclusive that the dihe d r a l angle between these two o hydrogen bonds I s near 90 (Table I ) . The approximately equal TSO value of J 0 and J suggests a symmetrical deformation of the furanose r i n g . This can occur when the r i n g i s i n the twist form with the puckering of C and C centres r e s p e c t i v e l y below and above the r i n g plane. The twist arrangement of the main sugar r i n g implies that the 16 isopropylidene group i s non-pianar due to the a x i a l and quasi-e q u a t o r i a l r i n g linkages. However, no s p e c i f i c conformation i s assigned to the isopropylidene moiety. The conformation of the 3,6-anhydro portion of the molecule was suggested from the observation that J^. ^  and ^ are approximately equal and d i f f e r e n t from J r . and Jc . . This s i t u a t i o n occurs only i n the envelope form i n which i s displaced below the plane of the other four r i n g atoms. By t r e a t i n g the 5-0-mesyl or 5-0-tosyl-3,6-anhydro-1,2-0-isopropylidene-a:-D-glucofuranose (V and X r e s p e c t i v e l y ) with sodium benzoate, the C centre i s r e a d i l y inverted to obtain 5-0-benzoyl-3,6-anhydro-l ,2-isopropylidene-oc-L-idofuranose ( i X a ) . ' The-n.m.r. data (Table I) indicates that the coupling constants 2' ^2 3 a n ^ ^3 1 a r e s^ m^- I- a r t o the gluco isomer previously discussed, but the other couplings have now changed due to the inversion of the C,. centre. 5-0-mesyl-3 ,6-anhydro-l,2-isopropylidene- o c-L-idofuranose (IXc) exh i b i t s s i m i l a r "^H n.m.r. data. The small value of. J u _ and J,. . i n these L-ido d e r i v a t i v e s suggests an angle * O approaching 90 . This i s s t i l l i n agreement with an envelope conformation where i s bent down out of the plane formed by the four atoms of the 3,6-anhydro r i n g . Hence, a l t e r i n g - 17 -the C,. epimer, does not change the conformation of the 3,6-anhydro furanose system. With the high degree of confidence i n the conforma-tio n s of these m u l t i - r i n g compounds there i s now the question of introducing f l u o r i n e into t h i s model system. F o r t u i t o u s l y , the s p e c i f i c f l u o r i n a t i o n of the 3,6-anhydro r i n g was achieved to give good y i e l d s of 5-fluoro-3,6-anhydro-l,2-0-isopropyli-dene- a-L-idofuranose (VI) from three glucofuranose d e r i v a t i v e s . A l l these reactions involved r e f l u x i n g the glucofuranose d e r i v a t i v e i n ethylene g l y c o l f o r 1.5 hours. Indeed, at high enough temperatures, the c r y s t a l l i n e product w i l l sublime out of the re a c t i o n mixture and onto the condenser walls. The use of potassium f l u o r i d e as a f l u o r i n a t i n g agent has been known f o r some time. Primary deoxy-fluoro sugars such as, 6-fluoro-6-deoxy-D-galactose (37) and 6-fluoro-6-deoxy glucose (38) have been synthesized by the d i r e c t displacement of the terminal O-mesyl or O-tosyl group using potassium f l u o r i d e . Reactions of halo sugars with t h i s reagent has been reported to give anomalous r e s u l t s , with an oxide being the usual i s o l a t e d material (39). Synthesis of secondary sugar f l u o r i d e s with potassium f l u o r i d e has usua l l y occured by the opening of epoxides, however, low y i e l d s and much degradation r e s u l t (13a). 187 -. . •• ' "'*' .T/.RLE L. ' "'" .... -• F i r s t Order Coupling Constants f o r Three Fused Ring Systems. (Hz) The-compounds above are measured i n (a) acetone-d^, (b) benzene-dg, and (c) chloroform-d. 60 MHz. data from Reference 5. - 19 -TABLE II \,^i3^%J^^r^h^mX^X^ifXs.Xx.jaxid^.) for.JThr.ee~.Fused-. Ring-Systems-COMPOUND F Hi H 2 H 3 H 4 H 5 "6, H6, R (b) i' VI 189.7 4.41 5.68 5.41 5.29 5.30 6.25 6.41 — r (c) IXa — 4.10 5.34 5.29 5.09 4.53 5.79 6.01 1.9-2.9 (OBZ) /VpMS (a) IXc — 4.12 5.41 5.38 5.12 4.92 5.90 5.96 6.97 \ / °—/iVie A Me MSO / \ ^ • (OMS) V — 4.02 5.38 5.43 5.03 4.95 5.92 6.20 6.92 -(OMS) X Me (c) • — 4.12 5.48 5.56 5.33 5.18 6.08 6.31 7.57 X .- (OTS^) /-Me Me — 4.06 5.45 5.54 5.27 4.98 6.37 6.90 7.51 The compounds above are measured i n (a) acetone-d (b) benzene-dg, and (c) chloroform-d. 60 MHz. data from Reference 5. - 20 -The probable mechanism; f o r the r e a c t i o n of potassium f l u o r i d e with 5,6-di-0-mesyl-3-0-acetyl-l^-O-isopropylidene-*-D-glucofuranose (IVa) involves the displacement of the a c e t y l group by base (potassium f l u o r i d e ) and the backside attack of t h i s formed 0^ anion onto C &, d i s p l a c i n g the mesyloxy group and forming a 3,6-anhydro r i n g . The d r i v i n g force behind t h i s r e a c t i o n appears to be the formation of t h i s new f i v e membered r i n g which decreases the energy of the molecular system . The newly formed 5-0-mesyl-3,6-anhydro-l,2-0-isopropylidene-«-D-giucofuranose (V) now undergoes a SN displacement r e a c t i o n of mesyloxy by F to give the desired product. The y i e l d of t h i s r e a c t i o n can be increased from 48% to 75% by i n i t i a l l y r e a c t i n g V with potassium f l u o r i d e . That t h i s l a t t e r r e a c t i o n proceeds r e a d i l y , seems added proof to the above stated mechanism. It might also be noted that the attack of F ion to give the 5-fluoro-L-ido anomer has l i t t l e s t e r i c hinderance, since the anion attacks from the outer-side of the molecule. However, i n the case of synthesizing the 5-fluoro-D-gluco anomer from the 5-0-mesyl-L-ido s t a r t i n g m a t e r i a l , much more s t e r i c hinderance i s present, since the anion must now attack from the inner Lee and Sawi (See Reference 13a) found that on t r e a t i n g methyl-6-0-tosyl- a-D-glucoside with KF, the only product formed was methyl-3jB-anhydro-^-D-glucoside. They r a t i o n a l i z e d t h i s s i t u a t i o n by saying, "In a l k a l i n e medium i o n i z a t i o n of the hydroxyl group i s favoured and t h i s w i l l tend to s t a b i l i z e the form showing the widest charge separation Attack by f l u o r i d e ion i s strongly hindered i n t h i s form; oxide formation i s strongly favoured." - 21 -"V" p o r t i o n of the molecule. This can e a s i l y be seen by constructing a simple "framework" model. The t h i r d d e r i v a t i v e used f o r the preparation of VI was 5,6-di-0-mesyl-3-0-benzyl~l ,2-0-isopropylidehe - c c -D-glucofuranose (IVb) Indeed, i t was i n i t i a l l y thought that .» the benzyl ether would be r e s i s t a n t to base , but the 45% y i e l d of VI on r e a c t i o n with potassium f l u o r i d e , indicated' such not to be the case. A communication published a f t e r the above observation indicated a s i m i l a r c y c l i z a t i o n i n the case of methyl-2 ,3-di-0-benzyl-6-6-mesyl-«-D-galacto-pyranoside (40). Benzyl ethers have been used extensively as protecting groups and only r e c e n t l y have been shown to provide anichimeric assistance i n the s o l v o l y s i s of 2,3,4 t r i - 0 - b e n z y l - l , 5 - d i - 0 -toluene-p-sulphonylpentitols (G.R. Gray, F.E. Hartman and R. Baker, J . Org. Chem. 30, 2020 (1965)). .»..». Following the completion of t h i s study, Brimacombe (See Reference 41) published a paper proposing the following mechanism f o r the c y c l i z a t i o n • i n v o l v i n g benzyl group p a r t i c i -pation i n compound IVb. - 22 -The n.m.r. spectra of VI i s shown i n Figure 2a. Analysis was assigned i n the following manner: the anomeric . hydrogen i s observed as a doublet at lowest f i e l d (x 4.41), since i t i s attached to a carbon centre bonded to two oxygen atoms. I r r a d i a t i o n of the doublet collapses the doublet at T 5.58, thus i d e n t i f y i n g the H 2 resonance. H 5 i s assigned from the expected large geminal hydrogen-fluorine coupling constant which i s present i n the m u l t i p l e t at x 5.30. The assignment of and can be r a t i o n a l i z e d on the basis that H„ should at most be a broad doublet, since J . 0 = 0 and thus any s p l i t t i n g s should be from and minor long-range couplings. On the otherhand i s expected to be at l e a s t a quartet with possible couplings from H , H and F. Thus i s assigned to the quartet at x 5.29 and to the broad doublet at x 5.41. The two Hg protohs can now be assigned by f i r s t f i n d i n g the geminal coupling constant which i s repeated eight times. The assignment i s complicated, however, by the overlap of two Hg resonances due to the large v i c i n a l hydrogen-fluorine coupling. In Figure 3 an^expanded sweep width of the Hg region shows these two protons i n more d e t a i l . A A The i n i t i a l assignment was based on f i r s t order a n a l y s i s ; however, due to the large coupling constants and the small chemical s h i f t s i n the Hg region, t h i s p ortion of the spectra 5 : ; ' A This coupling has been observed to be of the order of 50 Hz. at the anomeric centre of pyranose sugars and 60 Hz. at furanose anomeric centres, while primary f l u o r i d e s have geminal coupling constants of 50 Hz. See footnote Page 14. i s t r u l y an AB of an ABMY spectra. The computer program TW0SUH (See Appendix A) was used to perform i t e r a t i v e - f i t c a l c u l a t i o n s of t h i s region to give the true chemical s h i f t s and coupling constants. These values are compared with the f i r s t order values i n Table I I I . TABLE I I I . Comparison of Computer Analysis to F i r s t Order Analysis f o r Coupling Constants and Chemical Shif Involving the H,. Protons of Compound VI. F i r s t Order Values TW0SUM Values 2.9 Hz. 2.8 Hz. 5 » 6 2 1.1 Hz. 0.8 Hz. V* -11.3 Hz. - l l . l Hz. J5,F 50.1 Hz. 50.4 Hz. V 26.5 Hz. 26.1 Hz. v 37.6 Hz. 38.3 Hz. T 5.30 T 5.30 <j>.H 6 1 T 6.22 T 6.25 <j> H 62 T 6.48 T 6.41 A histogram p l o t of these i t e r a t i v e values (Figure 3) gives a p e r f e c t f i t with the experimental spectra. .1.. ••. I . •• I I : , 1.:.: I , I • 1 ., I I.... Me 4.00 4.50 5.00 5.50 6.00 T FIG. 2 100 MHz. proton magnetic resonance spectra.of (A) 5-fluoro-3,6-anhydro-l ,2-0-isopropylidene-«-L-idofuranose (VI) i n benzene-d g s o l u t i o n and (13) 5-0-bon/.oyl-3,G-.anhydro-l,2-0-i.sopropyl.Wone-«r.L-5.dofuranor;e (IXa) FIG. 3 Spectra of the H protons f o r compound VI i n benzene-d s o l u t i o n (100 MHz.) with a matching h i s t o -gram of t h i s region simulated using mode C of TW0SUM (See Appendix A). - 25b -FIG. 4 The F n.m.r. spectra of VI .in benzene-dg (top spectra) r e s u l t i n g from the i n t e r a c t i o n s of one f l u o r i n e atom with a l l protons except H . A simula-ted spectra (bottom) was computed using "LAC00N I I I . The discrepancy between the l e f t hand quintet of the observed and computed spectra a r i s e s from second order e f f e c t s i n the proton spectra (See Text). 26 -As can be seen from Table I I I , the f i r s t order couplings and chemical s h i f t s f o r VI are within 5% of those values obtained by d e t a i l e d a n a l y s i s . Hence, even when dealing with spectra e x h i b i t i n g some second order e f f e c t s , the coupling constants obtained from the routine f i r s t order a n a l y s i s are close enough to be used i n conformational e l u c i -dations . Organic chemists.find t h i s approximation to the f i r s t order case u s e f u l , since without spending much of t h e i r time on n.m.r. a n a l y s i s , they can be confident of obtaining values which are close to the r e a l values. Most of the furanosyl f l u o r i d e s studied here were analyzed on a f i r s t order b a s i s . However, a l l the obtained coupling constants and chemical s h i f t s were checked by computer techniques and the values considered r e a l only i f the computed and experimental spectra matched. It i s i n t e r e s t i n g to note the s i m i l a r i t i e s of the f l u o r i d e d e r i v a t i v e (Figure 2a) with that of the O-benzoyl d e r i v a t i v e (Figure 2b). The only di f f e r e n c e s are due to extra s p l i t t i n g s from f l u o r i n e i n a l l but H^ of the f l u o r i d e d e r i v a t i v e VI. These s i m i l a r i t i e s f u r t h e r support the concept that changing from a benzoate to a f l u o r i n e substituent at does not d r a s t i c a l l y a l t e r the conformation of the 3,6-anhydro monoacetone furanoses. -Since the Karplus curve i s cal c u l a t e d formally f o r ethane, the accuracy i n applying t h i s r e l a t i o n s h i p to other systems i s l i k e l y to be at most, within *5% of the true angle or coupling constant. (See Reference 1 page 7 5 ) This approximation w i l l not hold f o r highly coupled systems; that i s , one that can be described as an ABCD or AA'BB'. - 27 -The f l u o r i n e spectrum of VI (Figure 4) consists of 46 l i n e s which can r e a d i l y be assigned on a f i r s t order basis from the coupling constants determined i n the proton * spectrum. A spectrum simulated by using a p l o t t i n g program SMASH i n conjunction with LAC00N III i s shown at the bottom of Figure 4. Indeed, the spectrum i s symmetrical except f o r the region of the two quintets. This apparent abnormality has been observed i n other systems (42) and can be r a t i o n a l i z e d i n the following manner: In the "^"H n.m.r. spectra the Hg 1 19 region has two large v i c i n a l H- F couplings (Figure 3). This region can be analyzed as two subspectra corresponding to the o r i e n t a t i o n of the f l u o r i n e spin i n the « or 3 spin 1 19 sta t e s . Assuming that the signs of a l l v i c i n a l H- F coupling constants are the same , one can a r b i t r a r i l y set = f l u o r i n e spin states to the f i r s t h a l f of each Hg See Appendix A. Art 1 19 The signs of v i c i n a l . H- F coupling are p o s i t i v e as j n the case of v i c i n a l H- H couplings, while geminal H- F couplings^arj also p o s i t i v e i n contrast to the negative sign of geminal H- H coupling (See Reference.-43'). -28.-and H 6 m u l t i p l e t . Correspondingly, the l a t t e r h a l f of. the 2 two Hg m u l t i p l e t s i s assigned the t' f l u o r i n e spin s t a t e . Hence, the Hg l i n e assignments f o r f l u o r i n e spin states are: « e« 8B B B 8 B ft and the overlap, of « and 8 states makes the e f f e c t i v e chemical s h i f t s of Hg . and Hg almost equal i n one part of the subspectra, while d i f f e r e n t i n another. This overlap gives r i s e to large second order e f f e c t s - often r e f e r r e d to as " v i r t u a l coupling" (44) which are r e f l e c t e d i n the f l u o r i n e spectrum. The l i n e s of the f l u o r i n e spectra w i l l be af f e c t e d to d i f f e r e n t degrees de-pending on which t r a n s i t i o n the l i n e i s associated with ( i . e . d i f f e r e n t s p i n state t r a n s i t i o n s associated with overlapping l i n e s i n the Hg proton region w i l l show more second order 19 e f f e c t s ) . The computer simulated F spectrum (Figure 4), matches well with the observed spectrum, except i n the region - 29 -of the left-hand-side quintet. In the observed spectra, the two t r i p l e t s forming t h i s quintet are s h i f t e d f u r t h e r apart than i n the computed spectra where the two l i n e s of each t r i p l e t overlap to give a quartet. . The. f l u o r i n e spectrum i s very s e n s i t i v e to second order e f f e c t s and the discrepancy i n the observed and computed spectra a r i s e s from the s l i g h t e rrors (±0.005 p.p.m.) in assigning one of the proton s h i f t s . This d i f f e r e n c e probably a r i s e s from the small errors involved i n matching observed frequencies to l i n e assignments i n the computer a n a l y s i s . An i n t e r e s t i n g aspect of the spectrum of 5-fluoro-3,6-anhydro-mono-acetone idose i s the presence of a multitude 1 19 . of long-range H- F couplings. Indeed, as the number of l i n e s 19 i n the F spectra i n d i c a t e s , f l u o r i n e i s coupled s i g n i f i c -a n t l y to every proton except . As subsequently w i l l be seen, these long-range couplings were observed i n a l l sugars studied here and t h e i r magnitude appears to be dependent on the con-f i g u r a t i o n and/or conformation of the molecule (45). It i s important to note the large values of 38 Hz. 1 19 and 26 Hz. f o r the Hg-. F couplings i n VI. One has d i f f i c u l t y r a t i o n a l i z i n g these two large values on the basis of what Is presently known of the Karplus r e l a t i o n s h i p of " v i c i n a l " 1 19 H- F couplings. In other words, these couplings should be - 30 - . o due to a di h e d r a l angle of';6 and 120 + 6, i f we assume tet r a h e d r a l symmetry at the carbon centre. Since the d i h e d r a l angles are somewhat defined from the proton couplings, these o o o o angles should be approximately 150 -170 and 30 -50 . This would make the curve r e l a t i n g dihedral angle to v i c i n a l 1 19 H- . F constant much more asymmetric than presently thought (46) This point w i l l be considered fur t h e r i n Section C. From an examination of the coupling constant data f o r the 3,6-anhydro-l,2-0-isopropylidene d e r i v a t i v e s studied (Table I ) , i t i s evident that the replacement of the substituent from f l u o r i n e to benzoate to mesyl does not . s i g n i f i c a n t l y change the conformation of the furanose of anhydro r i n g . On the basis of v i c i n a l ^H-Hl couplings the conformation of VI i s shown i n I. The changes i n J and J,. . going - 31 -from f l u o r o to other C,. d e r i v a t i v e s , i s a t t r i b u t e d to the d i f f e r e n c e s i n e l e c t r o n e g a t i v i t y of these substituents. As wa.s previously shown, the inversion of the substituent a l s o does not a l t e r the conformation of the molecule. These two observations fur t h e r support the contention of r i g i d i t y i n t h i s molecular system. - 32 -SECTION B: FURANOSYL FLUORIDES CONTAINING TWO FUSED RINGS. A s e r i e s of compounds having l e s s r i g i d f i v e membered ring s were investigated by synthesizing f l u o r i n a t e d d e r i v a t i v e s of furanose sugars i n v o l v i n g two fused r i n g s . Furanosyl f l u o r i d e s XII, XIV and XVII were prepared by re a c t i n g a tri-O-benzoyl or t r i - O - a c e t y l precursor with anhydrous hydrogen f l u o r i d e . The 3 f l u o r i d e anomer was the major product, however, i n the case of XII, during a r e a c t i o n which was quenched i n h a l f the usual time, the « anomer was observed 19 by F n.m.r., but could not be i s o l a t e d . The <* anomer consisted of two doublets with couplings of 61 Hz. and 18 Hz. at + 139 p.p.m. from freon 11, while the 8 anomer was two sextets separated by 60 Hz. with a chemical s h i f t of + 120 p.p.m. u p f i e l d from freon 11. As w i l l be subsequently seen i n Section C, the chemical s h i f t s of the « f l u o r i d e s appear to be 10-15 p.p.m. higher than those of the 6 anomer i n furanose sugars. The n.m.r. data f o r XII, XIV and XVII i s shown i n Tables IV and V. F i r s t , i t should be noted that i n a l l cases, the proton coupling constant J, „ and J „ are ca.. 0. o This i s c h a r a c t e r i s t i c of dih e d r a l angle approaching 90 - 33 -XV F L O W S H E E T 2 - 34 -TABLE IV F i r s t Order Coupling Constants for Two Fused Ring Systems. (Hz) COMPOUND HlF HiH 2 H 2F H 2H 3 H 3 F H 3 H 4 Hi*F H14H5 H 5 F H s H 5 l H 5 H 6 2 H 5 H 6 1 2 62.3 0.8 5.8 <0.5 <0.5 4.8 4.8 <1.0 - 4.0 1.5 1.5 -10.6 9 A C Q /I M ^ J f \ v i ! ' OAC 60.1 0.6 4.5 <0.5 <0.5 4.6 H3H5 <0.5 4.4 6.3 <o.s - *- -BZO / | ' ^ ^ J f ^ XIV OBZ 60.1 <o.s 4.0 <0.5 0.5 4.6 H 3H 5 <0.5 4.6 6.3 0.3 - ' - -OAC - <0.5 - <0.5 - 4.5 - • <0.S - 4.1 1.0 -10.6 The compounds above are measured i n (a) acetone-d 6 and (c) chloroform-d. - 35 -TABLE V F i r s t Order Chemical Shifts (t and $) for Two Fused Ring Systems COMPOUND F Hi. H 2 H 3 ' H 4 H 5 \ OAC OBZ 119.8 4.28 4.72 4.94 5.28 4.44 5.58 5.94 7.93 1.9-2.8 o ACOyA OACV 118.3 4.09 4.65 4.77 4.64 4.37 - - 7.14 -BZO. / V < ^ ^ X ° N ^ ^ XIV OBZ 118.5 3.80 4.30 4.44 4.29 4.02 - - - 1.8-2.7 v / AoBZ \ y \ ) S > s s . / 0 A C ( ', ^ L , / ^ VII OAC - 3.79 4.76 5.00. 5.23 4.48 5.29 5.95 7.98 8.04 1.9-2.8 The compounds above are measured i n (a) acetone-dg and (c) chloroform-d. The s h i f t s of the CH3 groups were a l l i n the range 8.5-8.7T. -• 36 - . • which can r e a d i l y be accomplished by depressing the centre downward out of the plane defined by the other carbon centres. J„ . i s generally l a r g e r i n these moleculesthan i n compound VI, suggesting the p o s s i b i l i t y the has l e s s puckering - a concept r e c e n t l y l a b e l l e d " p s e u d o l i t e r a t i o n " (47) - than i n the case of the three fused r i n g molecules. On t h i s basis one could suggest an envelope conformation f o r the furanose " 1 1 portion of the 3,6-anhydro molecule . The H- H couplings i n the 3,6-anhydro r i n g are almost i d e n t i c a l f o r the two and three fused r i n g systems, suggesting that the envelope conformation i s retained i n t h i s portion of the molecule. Hence, the conformation of these 3,6-anhydro deriva-t i v e s are s i m i l a r to that of the three fused r i n g molecules with the p o s s i b i l i t y that the furanose r i n g may be favouring the envelope form i n the former case, rather than a twist form as the l a t t e r Recently, Pedersen and co-workers have examined the intermediates and products a r i s i n g from the rea c t i o n of A l t e r n a t i v e l y , the increase of ^ may be due to the reduction of r i n g s t r a i n r e s u l t i n g from the removal of the isopropylidene group. In t h i s case the twist form could s t i l l be the dominant conformation. As w i l l be discussed subsequently (Section C), the n.m.r. technique i s not s u f f i c i e n t l y s e n s i t i v e to d i f f e r e n t i a t e a twist form in v o l v i n g C and C„ from an envelope form inv o l v i n g C 2 ° r V - 37 -ribofuranose and arabinofuranose sugar esters with hydrogen f l u o r i d e (48). They found b r i e f treatment of acetylated or benzoylated D-ribofuranoses with hydrogen f l u o r i d e gave e x c l u s i v e l y 8 f l u o r o t r i - e s t e r s of ribofuranose,; while s i m i l a r treatment of the e s t e r i f i e d D-arabinofuranose gave the « f l u o r o t r i - e s t e r of arabinofuranose. These observations were consistent with t h e i r proposed mechanism i n v o l v i n g the formation of a 1,2 oxonium ion (observed by n.m.r.). In t h i s present i n v e s t i g a t i o n the r e a c t i o n of precursors with hydrogen f l u o r i d e gave almost e x c l u s i v e l y ft . the "trans product" . Only i n one instance (Xb), i n v o l v i n g a r e a c t i o n quenched i n h a l f the usual time, was the formation ft of the a anomer ("cis product" ) observed. However, upon repeating the f l u o r i n a t i o n f o r the normal r e a c t i o n time, only the 8 anomer was observed. Pedersen found that prolonged t r e a t -ment of the ribofuranose and arabinofuranose d e r i v a t i v e s l e d to the formation of a 2,3 oxonium ion which r e s u l t e d i n a mixture of °c and 8 f l u o r i d e s on work up. To r a t i o n a l i z e the formation of the « f l u o r i d e from Xb, ft In t h i s context the term "trans product" i s used to i n d i c a t e a molecule where the f l u o r i n e at i s trans to the substituent at C^; s i m i l a r l y , the term " c i s product" w i l l be used to designate a molecule where the f l u o r i n e at C, i s c i s to a substituent at C_. - 38 -one could suggest the following equilibrium: ides The i n i t i a l formation of the carbonium ion A, followed by the possible SN^ attack of f l u o r i d e i o n , seems reasonable when one considers that the r e a c t i o n of some e s t e r f i e d pyranose sugars with hydrogen f l u o r i d e gives a mixture of anomeric f l u o r i d e s . Presumably, the s t e r i c influences of the 3,6-anhydro system D-ribopyranose tetraacetate and D-altropyranose pentaacetate are reported to give a mixture of °- and 8 f l u o r i d e s upon r e a c t i o n with HF f o r ca_. 20 min. (Ph.D. t h e s i s of J.F. Manville (U.B.C. ,1967)). - 39 -causes the non-cyclic carbonium ion (See A) to be i n i t i a l l y formed. With longer r e a c t i o n times the equilibrium s h i f t s to tha more stable c y c l i c carbonium ion B, gi v i n g the 8 anomer e x c l u s i v e l y . An i n t e r e s t i n g "^H n.m.r. spectrum which demonstrates is the a p p l i c a t i o n of heteronuclear decoupling occurs i n the case of XIV (Figure 5a). This molecule shows a highly coupled system, since a l l f i v e protons have chemical s h i f t s within a 100 Hz. sweep range. H^ i s r e a d i l y i d e n t i f i e d 1 19 from the large geminal H- F coupling. The resonance of the other n u c l e i are complicated, however, by the presence of the couplings from f l u o r i n e . I n i t i a l l y , the spectra could not be analyzed by computer techniques, since good f i r s t order approximations could not be obtained. Selective "^H-^ "H decoupling proved somewhat inconclusive because of the highly coupled nature of the system. The•spectrum was f i n a l l y analyzed by a p p l i c a t i o n of heteronuclear f l u o r i n e decoupling (Appendix B) i n combination with s e l e c t i v e proton decoupling. The m u l t i - t r a n s i t i o n spectrum .'is g r e a tly s i m p l i f i e d by i r r a d i -a t i o n of f l u o r i n e (Figure 5b). The doublet at T 4.H4 and -T 4.02 remain unperturbed and hence cannot be H^ or H^, since the former should have a f l u o r i n e coupling and the l a t t e r should be at l e a s t a quartet (due to coupling form H and H ). See Appendix B. FIG. 5 100 MHz. proton spectra of 2,5-di-0-benzoyl-B-fluoro-D-glucuronolactone (XIV) i n acetone-dg. (A) normal spectra (B) " F decouDled S D e n t y s . - 41 -From the presence of a carbonyl and 0-benzoyl group near H^, one expects t h i s proton to be deshielded. I n i t i a l assignment of the doublet at T 4.02 to Hj., followed by i r r a d i a t i o n of t h i s doublet collapsed a m u l t i p l e t at T ,4.29 which was assigned to H^. From the i n t e n s i t y b u i l d up, the doublet at T 4.30 i n the undecoupled spectra was thus assigned to U^. (This 19 resonance was observed to collapse to a s i n g l e t i n the F decoupled spectrum. I r r a d i a t i o n of the highest f i e l d doublet-was found to collapse ; thus t h i s doublet at T 4.44 was as-signed t O 19 F i r s t order values obtained from the F decoupled spectra of XIV were now entered into TW0SUM and a spectrum simulated which matched both the experimental f l u o r i n e and proton spectra. This f u r t h e r v e r i f i e d the above assignment. It should be noted f o r t h i s s e r i e s of compounds that a s i g n i f i c a n t long-range coupling i s present f o r J^, ^ ' 4 (4.8-6.3 Hz.) while J _ i s very small (ca. 0.5 Hz.). r , o This important observation w i l l be discussed i n greater d e t a i l i n Section C. - 42 -SECTION C: FLEXIBLE FURANOSYL FLUORIDES A s e r i e s of f l e x i b l e furanosyl f l u o r i d e s (XVTII-XXIV) 1 19 were now extensively examined by H and F n.m.r. (Tables VI £ VII) Their synthesis was i n i t i a l l y attempted i n our-laboratory, however t h i s proved somewhat unsuccessful .. F o r t u i t o u s l y , a number of the desired sugar f l u o r i d e s were made av a i l a b l e to us by Dr. C. Pedersen, allowing t h i s study to proceed more r a p i d l y to the ultimate aim. Subsequently, some of the other desired f l u o r o sugars were synthesized i n our laboratory by applying the hydrogen f l u o r i d e r e a c t i o n . Much of the pertinent information i n t h i s s e r i e s a r i s e s from the two anomeric tri-O-benzoyl-D-ribofuranosyl f l u o r i d e s XVIII and XIX (Table VI). The spectrum of the B anomer (XVIII) i s shown i n Figure 6A together with i t s f l u o r i n e decoupled spectrum (Figure 6B). was r e a d i l y assigned from the c h a r a c t e r i s t i c 60 Hz. coupling with f l u o r i n e and i t s low f i e l d chemical s h i f t . The H^ and two H<_ protons, as expected, are to highest f i e l d , while H and H are highly coupled at x 4.04 and x 3.96 r e s p e c t i v e l y . The H^ resonance was i d e n t i f i e d by spin decoupling both f l u o r i n e and H u, while observing that the See footnote on page 12. J.J. D i f f i c u l t i e s were encountered because methods employed to synthesize these furanosyl f l u o r i d e s involved the preparation of a furanosyl bromide or choride from the 0-acetyl or 0-benzoyl d e r i v a t i v e and then replacing t h i s halide by f l u o r i n e using s i l v e r f l u o r i d e . However, the intermediate halides were found to be highly l a b i l e and often hydrolyzed before the exchange could take place. - 43 -TABLE VI Firs t Order Coupling Constants for Fuisnosyl Fluorides (Hi) COMPOUND H1 H2 H2F 2 3 V 1 •• H3 H4 H,F H 4 H S j H H 51 52 BZOC .F ^ ( XVIII 61.5 <0.5 4.8 4.8 2.2 S.fc 6.6 3.9 5.2 -12.2 61.2 <0.S 4.9 4.9 2.2 6.2 7.3 3.9 5.2 -11.9 O B Z O B Z B Z O y ( x i x 64.4 3.2 20.6 6.9 -0 2.3 1.0 3.1 3.5 -12.1 W Cc) 63.6 3.5 20.6 6.9 ."» 2.S 1.8 3.2 3.8 -12.3 O B Z O B Z B Z O C«) N. if .Xxx 60.9 <0.S 4.7 4.7 2.4 6.9 6.7 3.5 4.6 -11.9 61.4 <0.5 4.8 4.7 1.9 6.7 6.8 3.8 5.6 -12.S . O B Z OAC B Z O \S2 , y ( , x x i ^ (c) 61.6 61.1 <0.S 4.S 5.0 1.7 5.0 7.9 4.5 5.4 -12.4 OAC O B Z A.CXX ^(XXII 61.3 <0.5 4.9 4.9 2.1 4.9 7.2 3.6 5.3 -12.1 3[ CO 61.4 <0.5 _ _ 3.S 5.3 -12.2 O B Z O B Z BZOC CO S8.4 0.9 6.4 <0.S <0.7 4.4 l . S 3.3 5.8 -12.1 K B Z O > ( X X I 1 1 S8.1 <0.S 6.1 1.0 0.5 3.5 . i.o 3.0 6.5 -12.1 O B Z A C O ( .00 N. F V ? A C V x x i v Sf Cc) OAC 60. S 1.0 5.2 <0.S <0.5 S.S 5.2 5.3 7.1 -11.4 The compounds above are measured in (•) *cetone-d^ and (c) cMoroform-d solutions. - 44 -TABLE VII First Order Chemical Shifts (T and $) for Furanosyl Fluorides C0MP01KD p H l H2 H3 H4 \ \ 08Z OAC (») .f ( XVIII 115.9 3.82 4.04 3.98 4.89 5.11 S.31 1.9-2.8 -CO | 116.1 4.04 4.S4 4.43 S.10 5.26 S.43 1.9-2.8 -O B Z O B Z B20CHj/°> 00 133. J S.70 4.49 4.14 5.07 5.24 5.39 1.9-2.8 -( x i x ' O 133.6 3.86 4.53 4.16 5.10 5.23 5.41 1.9-2.8 O B Z O B Z (•) if ( x x US.8 4.20 4.4S 4.26 5.21 5.32 5.49 1.9-2.7 7.8S (c) 116.0 4.21 4.24 4.38 5.23 5.29 5.48 1.9-2.7 7.95 O B Z O A C B Z O C H 2 / ° ^ Ca) \XXI 115.5 4.OS 4.30 4.38 5.26 S.32 5.58 1.9-2.7 6.98 CO 115.7 - - . _ O A C O B Z ACOCH2/^*\ F ( " XXII 115.7 3.96 4.19 4.2S ' S.18 5.39 5.75 2.0-2.8 ,95 Cc) . 4.09 - - 5.32 S.38 5.75 2.0-2.8 7.90 O B Z 0 B Z B Z O C H j / ° % CO 123.8 3.83 4.26 4.2S 5.05 5.12 S.27 1.9-2.8 -A 'zo i XXIII P CO 124.7 4.01 4.35 4.43 5.IS 5.20 S.31 1.1-2.1 -O B Z A C O C H J -. CO f -. - - - ' - - - -/\u O A C XXIV C<=) 113.2 4.37 4.82 4.66 S.30 S.71 S.80 7.95 7.98 TJio compounds abovo aro measured In (a) acetona-dg and (c) chloroform-d. . - 45 -J4 3 rV\rS j 5.2 5.4 5.6 FIG. 7 P a r t i a l 100 MHz. spectra of H^ and H region of XVIII i n acetone-dg with (A) computer simulated spectra using LAC0/5N, (B) normal spectra, (C) 1 9 F decoupled spectra and (D) I 9 F and H 3 decoupled spectra. The beat pattern in the top spectra i s due to a noise beat a r i s i n g from the proton decoupler. - 47 -heptet at T 3.96 collapses to a doublet. It should be noted here that - 0 and J = 4.8 Hz; both coupling constants are i n d i c a t i v e of the 8 anomer of a i l r i b o f u r a n o s y l f l u o r i d e d e r i v a t i v e s studied here. At t h i s stage a comment should be made concerning the f l u o r i n e decoupled spectrum of t h i s compound. An ambiguity appears to be present i n the and.Hg region of the decoupled spectrum (Figure 6B). H should collapse to a o quartet and ]{ to a doublet when f l u o r i n e i s decoupled. Instead, one sees a m u l t i p l e t which cannot be analyzed by simple f i r s t order a n a l y s i s and a r i s e s from an e f f e c t i v e decrease i n the chemical s h i f t d i f f e r e n c e between H and H„. This change i n chemical s h i f t s comes from an increase i n the temperature of the sample due to the power of the heteronuclear decoupling 19 f i e l d . Such temperature s h i f t s were observed i n a l l F decoupling experiments and are reproducible. Furthermore, the complication a r i s i n g from these .temperature s h i f t s could be'readily simulated by TW0SUM. Returning now to compound XVIII, the most informative portion of the proton spectrum i s the H^ region. Figure 7B shows the H^ and Hg protons at expanded sweep width. Upon i r r a d i a t i o n of f l u o r i n e the H^ m u l t i p l e t collapses with the band width at h a l f height decreasing by 6.6 Hz. (Figure 7C), V 19 By simultaneously i r r a d i a t i n g H_ and' F (Figure 7D), H An al t e r n a t e designation of t h i s region as part of a "deceptively simple" ABX spectrum (See Reference 72), i s pre-cluded on the basis that a s i m i l a r d e r i v a t i v e , XX, i n which \\^  and H^ are s h i f t e d well apart, e x h i b i t s the same f i r s t order coupling constants as t h i s compound. f u r t h e r collapses into a broad quartet whose s p l i t t i n g a r i s e s from the coupling to the two H,. protons. The broadening of these t r a n s i t i o n s can be a t t r i b u t e d to both long-range "^H-^ "H coupling and second order e f f e c t s a r i s i n g from the small J / A r a t i o f o r the two. protons. Thus, i t becomes apparent from these i r r a d i a t i o n experiments that a s u p r i s i n g l y large coupling'of 6.6 Hz. e x i s t s f or a four bond coupling through oxygen between -fluorine and H^. This coupling was r e a d i l y 19 observed i n the F spectrum. Computer analysis of XVIII was used to check the f i r s t order values given i n Table VI. A computer simulation of the u p f i e l d region of the B anomer (Figure 7A) shows a perfect f i t with the experimental observations. 19 The normal and F decoupled spectra of tri-0-benzoyl- r e-D-ribofuranosyl f l u o r i d e (XIX),are shown i n Figure 8A £ 8B. Again note the temperature s h i f t s of and Hg i n the f l u o r i n e decoupled spectrum. The assignment of H^, H^ and H^ are straightforward. Values of 3.2 Hz. and 20.6-Hz. f o r J and J„ r e s p e c t i v e l y (checked by computer analysis),, are s i g n i -f i c a n t l y d i f f e r e n t than those of the 8 anomer. Hence J 1 and J may be taken as c h a r a c t e r i s t i c f o r d i f f e r e n t i a t i n g between the « and B anomers i n furanosyl f l u o r i d e s . Further d i f f e r e n t i a t i o n a r i s e s from the observation that the chemical s h i f t of f l u o r i n e i s over 17 p.p.m. greater i n the case'of the 49 -F I G . 8 . 1 0 0 MHz. proton spectra of 2 , 3 , 5 - t r i - O - b e n z o y l - o c - D -r i b o f u r a n o s y l f l u o r i d e (XIX) i n chloroforrn-d. (A) normal spect ( B ) 1 9 F decoupled s p e c t r a . (See Text f o r d e t a i l s ) - 50 -5.0 5.2 B 5.0 5.2 A 5.4 r J 5.4 T 5 25, 5 24 i 5.4. T 5.4 r FIG. 9 P a r t i a l 100 MHz. spectra of H and H region of compound XIX i n chloroform-d with (A) c3mputer 5simulated spectra using LAC00N, (B) normal spectra, (C) 1 9 F decoupled spectra and (D) and H decoupled spectra. - 51 -°- anomer compared to that of the 6 anomer. This d i f f e r e n c e i n chemical s h i f t seems to be a c h a r a c t e r i s t i c of anomeric co n f i g u r a t i o n i n a l l the p a i r s of anomeric furanosyl f l u o r i d e s examined i n t h i s i n v e s t i g a t i o n . The u p f i e l d region of XIX i s shown on expanded sweep width i n Figure 9B. Fluorine decoupling (Figure 9C) decreases the band width of , however t h i s decrease i s s i g n i f i c a n t l y smaller than that observed i n the f l u o r i n e i r r a d i a t i o n of the $ anomer. This coupling i s ca_. 1.0 Hz. The assignment of couplings i n H^ can be f u r t h e r v e r i f i e d by the similtaneous i r r a d i a t i o n of f l u o r i n e and H (Figure 9D) which leaves H^ e s s e n t i a l l y as a broad quartet, the couplings of which a r i s e from the two H^ protons. The l i n e broadening observed here.. probably a r i s e s from incomplete 19* F decoupling due to the l a r g e r band width of the f l u o r i n e spectrum(See Appendix B). Long-range coupling could also account f o r some of the l i n e width. F i n a l l y , using the values derived from f i r s t order a n a l y s i s , a simulated spectrum could be computed which f i t the experimental H^ and H^ region (Figure 9A). By comparing the data obtained f o r the two anomeric f l u o r i d e s XVIII and XIX (Table VI), i t becomes evident that not only do the couplings i n v o l v i n g the n u c l e i at and d i f f e r , but those couplings i n v o l v i n g H^ and H^ are also s i g n i -f i c a n t l y changed. Notably, on i n v e r t i n g f l u o r i n e from the 6-- 52 -to the « p o s i t i o n , the coupling J changes from 5.8 Hz. o ,4 to 2.3 Hz. This i s i n d i c a t i v e of an a l t e r a t i o n i n the dihedral angle between H^ and H^ a r i s i n g from the anomerization of the sugar and s i g n i f i e s a conformational change i n the molecule. The nature of t h i s conformational change w i l l be subsequently discussed. ' Several other B-ribofuranosyl fluoride, d e r i v a t i v e s (compounds XX, XXI and XXII) were studied and these r e s u l t s are given i n Tables VI £ VII. E s s e n t i a l l y , the coupling constants and chemical s h i f t s are very s i m i l a r to the tri-O-benzoyl-B-D-ribofuranosyl f l u o r i d e discussed previously. Any minor changes i n coupling constants i s a t t r i b u t e d to the e l e c t r o -n e g a t i v i t y e f f e c t of the acetate group i n the r i n g and not to any conformational changes. These d e r i v a t i v e s a l s o show the 4 large long-range J of ca. 7 Hz. 4> F  In most cases these f l e x i b l e furanosyl f l u o r i d e s were dissolv e d i n acetone-d c f o r n.m.r. studies. This solvent D produced chemical s h i f t s which reduced the second order e f f e c t s i n many spectra. Several d e r i v a t i v e s were examined i n more than one solvent to determine i f s p e c i f i c s o l v a t i o n could a l t e r the conformation of the molecule. However, i n no case was there any evidence of solvent e f f e c t s changing conformation. - 53 -Other furanose sugars, such as, tri-0-benzoyl-#-D-arabinofuranosyl f l u o r i d e (XXIII) and t r i - 0 - a c e t y l - 8 - D -xylofuranosyl f l u o r i d e (XXIV) also were studied i n order to observe the e f f e c t s of i n v e r t i n g and i n the furanose 1 19 r i n g on the conformation and H-. F coupling constants. Considering the C^ and C^ p o s i t i o n s of XXIII, the configu-r a t i o n around these two centres i s the same as i n XIX, however, the respective coupling J_ . of 4.4 Hz. and 2.3 Hz. are considerably d i f f e r e n t . S i m i l a r l y , the long-range coupling J„ i s d i f f e r e n t i n both these molecules. This i s i n d i c a t i v e of a conformational change between compounds XXIII and XIX. In the case of XXIV, the C^ and C^ centres have the same configuration as that.of XVIII and the r e l a t e d J's are s i m i l a r , i n d i c a t i n g at most, a minor a l t e r a t i o n i n the conformation. It should be noted here that the J i s smaller i n the xylo case than i n that of the ribo^sugar. This may be due e i t h e r to the s l i g h t conformational change or to the e f f e c t of the 3-acetoxy group which i s trans to H^ i n the xylofuranose sugar. As mentioned previously, the concept of pseudorotation Is prevalent i n any study of furanose conformation. R e s t r i c t i n g our discussion only to the envelope and twist conformations, allows twenty d i f f e r e n t forms which are represented i n the - 54 -pseudorotation c i r c l e i n Figure 10 . The energy b a r r i e r betwetn each e q u i l i b r a t i n g " form i s the same order of magnitude as that of the r o t a t i o n a l b a r r i e r i n ethane (50) and w i l l e s s e n t i a l l y depend on the substituents present i n the r i n g . Due to the highly substituted nature of furanoses used i n t h i s study, i t was expected that the e n e r g e t i c a l l y favoured forms would be r e s t r i c t e d to a small portion of the pseudo-r o t a t i o n c y c l e . It should be noted here that the assignment 1 19 of conformations to a molecule by H and "F n.m.r. w i l l be l i m i t e d at best to part of the pseudorotation c y c l e (usually three e q u i l i b r a t i n g forms). For instance, due to the l i m i t a t i o n s of the Karplus curve, n.m.r. could not d i f f e r e n t i a t e between •*- 3 •*- 3 a s p e c i f i c conformation i n the r e s t r i c t e d cycle ^2 ~* 2^ ^ ' The l i m i t i n g of conformation to only part of the pseudorotation c y c l e , instead of one d i s t i n c t form, should not g r e a t l y hinder t h i s study. It appears l i k e l y that the molecule w i l l e x i s t to some degree i n a l l forms of the r e s t r i c t e d c y c l e , since the energy d i f f e r e n c e s between these forms are expected to be very low, even i n highly substituted r i n g s . Using the system proposed by L.D. H a l l (See Reference 49), the envelope and twist form w i l l be designated by V and T r e s p e c t i v e l y with subscripts and superscripts used to i n d i c a t e respective displacements below or above the reference plane. For example, i n the D serie s a twist conformation with^ below and C 3 above the reference plane i s designated , while an envelope form with C^ below the plane of the r i n g , w i l l have the notation V„. - 55 -Pseudorotation Cycle FIG. 10 Cycle of the Pseudorotation Scheme (CYCLOPS) fo r furanose sugars with T and V r e s p e c t i v e l y , designa-t i n g twist and envelope conformations. R e s t r i c t e d pseudorotation cycles are represented at the top and bottom of the c i r c l e . - 56 -It i s proposed to make the following assumptions before proceeding to apply the n.m.r. data obtained i n t h i s study to the conformational analysis of furanose sugars: (a) The arrangement around the carbon centres can be described as approximately te t r a h e d r a l , even though s l i g h t deviations from an angle of 109° 28' w i l l occur f o r the molecule to be non-planar. (The dihedral angles were measured using frame-work models.) (b) Only the envelope and twist conformations are considered.* (c) The conformations are defined with maximum puck-ering, such that the bonds can be described as ei t h e r equatorial (e) , a x i a l (a), quasi-equatorial (e*), q u a s i - a x i a l (a') and b i s e c t i o n a l (b). These l a t t e r three bonds are defined i n the following manner:, qu a s i - a x i a l - 10° less than a x i a l quasi-equatorial - ± 10° from equatorial b i s e c t i o n a l - ± 30° from a x i a l or equatorial ( i . e . b i s e c t s 60° angle between v i c i n a l a x i a l and equatorial bonds). '. *The d e f i n i t i o n of envelope and twist was based on the pre-sence of and C 2 symmetry r e s p e c t i v e l y i n cyclopentanes. The furanoses however, have an oxygen r i n g atom and a substituent at each carbon centre, making i t impossible f o r these pentose sugars to e x i s t i n a conformation with two-fold r o t a t i o n symmetry. - 57 -Assumption (a) i s e s s e n t i a l - both (b) and (c) are dependent on i t - since a deviation i n the i n t e r n a l angle from tetrahedral h y b r i d i z a t i o n can s i g n i f i c a n t l y a l t e r both the geminal and v i c i n a l coupling constants of a molecule (24). Notably, 3 the Karplus curve i s based on sp h y b r i d i z a t i o n only. Previous i n v e s t i g a t i o n s of the r e l a t i o n s h i p between 1 19 dihed r a l angle and v i c i n a l H- F couplings have attempted to use molecules of known conformation and have applied the experimental values thus obtained to produce a Karplus type curve (21,23,24). However, e l e c t r o n e g a t i v i t y or d i s t o r t i o n e f f e c t s have often been ignored. Indeed, many of the dihedral angles have been taken from X-ray data(24) and some of the coupling constants have been taken from low temperature studies, using techniques which are now under dispute (20,55). This study attempts to a r r i v e at conformations f o r furanosyl f l u o r i d e s by using a combination of the Karplus curve f o r v i c i n a l ^H-^H couplings, together with a v i c i n a l 1 19 H- F Karplus type curve constructed from values obtained i n studies of carbohydrates. From the data a v a i l a b l e (11a,31,51) and r e a l i z i n g the above limitations',- a Karplus type comparison 1 19 was plo t t e d f o r v i c i n a l H- F couplings (Figure 11) i n which trends could be observed. As can be seen, the absence of values f o r c e r t a i n regions of the curve does not allow one to draw a - 58 -4 0 -3 2 -N c co 2 4 -CO c o O * U) c 75. O o 1 6 -8-0 -0 6 0 1 2 0 Dihedral 'Angle (Degrees) 1 8 0 1 19 FIG. 11 The r e l a t i o n s h i p between v i c i n a l H- F coup-l i n g constants and dihe d r a l angles, using values taken from studies i n v o l v i n g f l u o r i n a t e d carbohydrates: j © - Ref. 11a - 2 and 3 f l u o r o furanoses. A '- Ref. 5 1 - 3 f l u o r o pyrarior.es. V - Ref. 5 1 - 3 f l u o r o furanoses.. B - Ref. 31 - pyranosyl f l u o r i d e s . • - compound VI - present work. - 59 -continuous l i n e through the points. Notably, t h i s p l o t appears to be more asymmetrical than that of the Karplus curve f o r v i c i n a l ^H-^H couplings. The v i c i n a l J couplings ri , r obtained from the f l u o r i n a t e d d e r i v a t i v e VI (whose conformation 1 1 was based on v i c i n a l H- H couplings) f i t s reasonably well on t h i s curve. A c t u a l l y , the r e l a t i o n s h i p i s probably not a s i n g l e curve, but a family of curves best represented by a band, which depends on the environment of the f l u o r i n e atom. This band e f f e c t does not a l t e r the use of t h i s curve f o r conformational determinations, since the r e s t r i c t e d pseudo-r o t a t i o n cycle consists of a family of conformations whose accuracy i n d i h e d r a l angle determinations w i l l generally be 1 19 of the same magnitude as the band present i n our H- F Karplus curve. The dihedral angles f o r compounds XVIII-XXIV were ca l c u l a t e d f o r a l l possible twenty conformations using "framework models" and the above stated assumptions. From the Karplus 1 1 ° r e l a t i o n f o r H- H couplings, a d i h e d r a l angle range (ca. 20 ) was assigned to each of the coupling constants used f o r deter-1 1 19 mining the r i n g shape. The H- F couplings were a l s o assigned a d i h e d r a l angle range using the rough curve determined from the data a v a i l a b l e (Figure 11). Conformations were chosen which best f i t the observed couplings . By a process of A No account was taken of e l e c t r o n e g a t i v i t y e f f e c t s on coupling constants except i n the case where a substituent was co-planar with one of the n u c l e i involved i n the v i c i n a l coupling. In t h i s l a t t e r case the coupling was a r b i t r a r i l y considered to be ca. one-half of the normal coupling. - 60 -e l i m i n a t i o n , only two or three l i k e l y conformations remained. For example, Table VIII shows the c h a r a c t e r i s t i c data f o r compound XVIII. A "X" i n the l a s t column, ind i c a t e s the e l i m i n a t i o n of that conformer from consideration, while a darkened c i r c l e beside one of the corresponding d i h e d r a l angles of that conformer, gives the angle i n v o l v i n g l a r g e s t d e v i a t i o n , which l e d to the el i m i n a t i o n of t h i s conformer. The most o c h a r a c t e r i s t i c d i h e d r a l angle i n t h i s procedure i s 90 (0 Hz. cou p l i n g ) , while any large couplings can be a t t r i b u t e d to o o an angle of 0 or 180 . As seen from t h i s example (Table V I I I ) , V"*", and V^ are c l e a r l y the most favoured conformations f o r XVIII . Table IX shows the favoured conformations f o r the other f l e x i b l e furanosyl f l u o r i d e s studies here. The presence of oxygen i n the furanose r i n g skeleton makes i t highly probable that t h i s heteroatom w i l l remain i n the plane of the r i n g . The absence of substituents on oxygen removes any s t r a i n due to e c l i p s i n g with groups on adjacent carbons, making i t very l i k e l y that , 0 and w i l l be i n the planar portion of the favoured conformation, while and Cg are displaced out of the plane. Hence, a l l conforma-ti o n s i n v o l v i n g a displacement of oxygen out of the r i n g plane,, w i l l be considered thermodynamically unfavoured. - 61 -TABLE VIII Data f o r the Evaluation of the Favoured Conformations of Compound XVIII. J Observed Couplings (Hz.) Dihedral Angle Ranges Hi H 2 H 2 F H 2 H 3 H 3 H„ <0.S 4.8 4.8 6.0 80°-100° 30°-S0°; 140°-150° 30°-50°; 130°-150° 20°-40°; 140o-160o Conformation Dihedral Ang le (degrees) Evaluation H1H2 H2F H2H3 H3H1, Vi 170 O 50 30 120 X IT 2 180 O 60 50 100 X V 2 170 0 50 SO 90 0 X 2 T 3 170 © 50 60 90 O X v3 150 O 20 50 70 X 140 © 20 SO 60 X 120 0 © • 30 70 X 100 20 20 50 X* v5 90 20 0 O 90 © X ST1 70 50 20 100 © X V» 70 50 .30 120 60 6 0 . SO 140 V2 70 50 SO ISO 2T* 70 50 60 170 O X V 3 90 20 50 170 © X 100 20 SO 180 © X V* 120 0 © -30 • 170 e X • J 5 140 O 20 20 170 O X V 5 150 © 20 0 ISO X 5 T i 170 © 50 30 ISO X See Footnote Page 60." - 62 -TABLE IX COMPOUND FAVOURED FORMS XVIII 2' XIX U 1 1 V T V T v 3 ' 3 ' ' 2 XXIII V V 1' 3' 3 XXIV V 3 XII,XIV 2' 2 In most cases the favoured forms involve r i n g puckering at C and/or C . X-ray d i f f r a c t i o n studies of the furanose rings i n n u c l e i c acids (52) conclude that the sugar r i n g involves only the puckering of C^ and C^. Although t h i s i s i n agreement with the present study, i t appears questionable, because of the low b a r r i e r to pseudorotation, whether one can r e l a t e the conforma-t i o n a l r e s u l t s obtained f o r s o l i d s to the conformation i n s o l u t i o n A recent paper by Stevens and Fletcher (28b) examined a se r i e s of pentofuranose d e r i v a t i v e s . Using "^H n.m.r. and a co r r e c t i o n f a c t o r f o r J n „ - to take i n account that C. i s attached to two oxygen atoms, while the other carbon atoms of the r i n g bear only one oxygen - t h e y a r r i v e d at conformations f o r furanose d e r i v a t i v e s of ri b o s e , arabinose and xylose, which d i f f e r e d from the furanosyl f l u o r i d e s discussed here. To evaluate the r e l a t i o n s h i p between t h i s present study and that of Stevens and Fle t c h e r , the data obtained from these worker's i n v e s t i g a t i o n was applied to conformational studies using the methods adopted i n t h i s t h e s i s . The r e s u l t s are shown i n Table X. 1,2 1 .-63 -TAL'LE X COMPOUND CONFORMATION (t a t r a e s t e r ) Stevens i Fletcher Present Study °--Ribofuranose v 2 2 2 V • T 3 ' V3 8-Ribofuranose v 2, 2i». v 3 6-Xylofuranose v 3 n n V T V V 3 ' ' "--Arabinofuranose 2 4 T V T V V 3 In the f i r s t three compounds agreement i s reasonably c l o s e , e s p e c i a l l y f o r the 8-ribofuranose. A major d i f f e r e n c e , however, i s evident i n the a-arabinofuranose d e r i v a t i v e . The conformation f o r t h i s l a t t e r compound predicted by the present study, i s supported by Bishop and Cooper (32). S i g n i f i c a n t l y , conformations f o r the te t r a e s t e r s d i f f e r from those favoured by the f l u o r i n a t e d d e r i v a t i v e s . This i s not su p r i s i n g , since the low pseudorotation b a r r i e r makes conforma-t i o n a l m o b i l i t y - which i s governed by the non-bonded i n t e r -actions - very s e n s i t i v e to changes i n substituents at a carbon centre of the furanose r i n g . See Reference 28b. - 64 Assignment of a r e s t r i c t e d conformation cycle to these~ molecules allows one to c o r r e l a t e the observed long-range 1 19 H- F coupling constants with the s t e r e o s p e c i f i c i t y of i n t e r a c t i n g n u c l e i (45). For 8-ribofuranosyl f l u o r i d e (XVIII) with a c o n f ° r m a t i o n , a long-range four bond coupling 4 i s observed following the geometry shown i n C f o r J ' and' o ,r i n D f o r J . H , r - 65 -On the other hand cc-ribofuranosyl f l u o r i d e (XIX) with conforma-nt 4 t i o n T has geometries corresponding to E and F f o r J o 3 ,F 4 and r e s p e c t i v e l y . H B Z O C H 2 O B Z H,F = 0 Hz, J.. r = 1.0-1.8 Hz. H,r E and F are also i d e n t i c a l to geometries observed f o r the same 4 p couplings i n °--arabinof uranosyl f l u o r i d e (XXIII). The 3 2T conformation of 8-xylofuranosyl f l u o r i d e (XXIV) has a 4 4 geometry f o r J s i m i l a r to E, while J i s i d e n t i c a l o,i 4 ,F to D. The long-range coupling J through oxygen i s co n s i s t e n t l y l a r g e , when the two coupled groups are i n a trans o r i e n t a t i o n (as i n D), while t h i s coupling i s small, when the i n t e r a c t i n g groups are i n a c i s o r i e n t a t i o n (as i n F ) . The l a t t e r o r i e n t a t i o n approaches a "planar M - 66 -r e l a t i o n s h i p " (57). Hence, f o r the D-ribofuranose sugars the B f l u o r i d e e x h i b i t s t h i s long-range coupling, while the « f l u o r i d e does not. The magnitude of these long-range couplings leads one to be o p t i m i s t i c of t h e i r a p p l i c a t i o n to configura-t i o n a l and conformational e l u c i d a t i o n of furanosyl f l u o r i d e s . 4 I n t e r e s t i n g l y , when examining the J couplings, an opposite t , o -e f f e c t i s observed. The "planar M" or c i s geometry of the i n t e r a c t i n g groups has a l a r g e r coupling than the trans arrangement. H a l l has shown from a study of pyranosyl f l u o r i d e s 4 (45) that J couplings through carbons only, are l a r g e r n ,r when i n the "planar M" configuration than when i n the non-planar arrangement . To r a t i o n a l i z e t h i s reverse e f f e c t 1 19 observed here f o r long-range H- F couplings through oxygen, • 4 one can suggest the p o s s i b i l i t y that the signs of these J couplings have changed and the "planar M" arrangement s t i l l has a l a r g e r coupling (-1.0 to -1.8 Hz.) than the coupling through the "trans arrangement" (-6.6 to -7.3 Hz.). Although t h i s suggestion leads to some consistency i n the observations 4 of J couplings, the signs of these four bond couplings n ,r through oxygen must be proven c o n c l u s i v e l y before any d e f i n i t i v e statements can be made about the s t e r i c requirements of these •; 1 19 :• ^ In pyranosyl f l u o r i d e s f o r H- F couplings, jt^ he sign of the. J coupling i s p o s i t i v e , while that of the J i s negative 6(§ee Reference 45). ' - 67 -couplings . F i n a l l y , some comments should be made about the geminal 1 19 H- F coupling. The range of 58 to 64 Hz. f o r the anomeric 1 19 H- E couplings f o r furanosyl f l u o r i d e s i s s i g n i f i c a n t l y 2 l a r g e r than the same J., coupling of ca. 50 Hz. f o r H,F •— pyranosyl f l u o r i d e s (9,31). Furthermore, the observation 1 19 ' that the geminal H- F coupling i n the 3,6-anhydro r i n g of compound VI - where no hetero-atom i s adjacent to the carbon containing the n u c l e i involved i n the coupling - i s 50.4 Hz., suggests that r i n g s i z e alone does not account f o r the d i f f e r e n c e 1 19 i n geminal H- F couplings between furanose and pyranose r i n g s . A possible explanation f o r the change i n s i z e of these geminal couplings may a r i s e from the o r i e n t a t i o n of the oxygen lone p a i r s to the anomeric f l u o r i d e (54). The l i m i t e d ' number of compounds a v a i l a b l e f o r t h i s study r e s t r i c t e d one .from making i n c i s i v e statements about the e f f e c t of substituents at the p o s i t i o n of the geminal 1 19 H- F coupling. S u f f i c e to say that an acetoxy or benzoyloxy group at C^, which i s trans to the f l u o r i n e atom on the anomeric 1 19 carbon, tends to decrease the s i z e of the geminal H- F coupling. For instance, g - r i b o f u r a n o s y l f l u o r i d e has a 2 . smaller J coupling than a - r i b o f u r a n o s y l f l u o r i d e , while n, r For l a , 2°--0-isopropylidene-38-0-acetyl-4B-cyano-tetrahydrofuran-l«, 2«, 3 6 - t r i o l , Pachler has shown (See Reference 58) that „ and ^ - the l a t t e r of which involves a long-range coupling'through 6xygen - are both small and have a negative sign. - 68 -the ^-arabinofuranosyl f l u o r i d e geminal coupling i s smaller than both of the r i b o anomers. This present i n v e s t i g a t i o n attempted to assign conformations to furanosyl f l u o r i d e s by a p p l i c a t i o n of both 19 1 F and H n.m.r. By using several basic assumptions, together with heteronuclear decoupling and computer programming, t h i s o bjective was achieved to the extent of assigning a r e s t r i c t e d number of conformers to each molecule. However, i t has become very evident that previous i n v e s t i g a t i o n s added confusion to matters because of oversights i n d e f i n i n g the l i m i t a t i o n s of t h e i r studies. I t i s hoped that t h i s t h e s i s , by s t a t i n g d e f i n i t i o n s and assumptions used i n t h i s i n v e s t i g a t i o n , demonstrates some of the l i m i t s i n assigning conformations to furanose sugars. Indeed, since the energy b a r r i e r to pseudorotation f o r f i v e membered rings i s of the same order as that f o r the r o t a t i o n of ethane, i t i s questionable - f o r the case of f i v e membered rings - whether one should even use the term "conformation" i n the same sense as i t i s applied to cyclohexane (53). Instead, one should be considering . furanose forms i n the same terms as that of ethane, where rotamers are somewhat analogous to pseudorotational forms. EXPERIMENTAL 70 -GENERAL METHODS (a) The s t r u c t u r a l formula associated with each compound are given on flow sheets i n Sections A and B. (b) O p t i c a l r o t a t i o n s were measured i n a Bendix ETL-NPL Automatic Polarimeter (type 143A) using a 4.0 cm. or a 0.5 cm. c e l l . A l l o p t i c a l r o t a t i o n s were measured using chloroform s o l u t i o n s . (c) Micro-analysis was c a r r i e d out by Mr. P. Borda of the U.B.C. Chemistry Department. (d) Melting points were measured on a Fisher-Johns melting point apparatus and are uncorrected. (e) A l l "*"H n.m.r. spectra were measured with a Varian HA-100 spectrometer operating i n ei t h e r the frequency sweep or f i e l d sweep mode using tetramethylsilane (T.M.S.) as i n t e r n a l reference. Proton chemical s h i f t s are a l l reported i n the T s c a l e . 19 ( f ) A l l F n.m.r. spectra were measured at 94.071 M.Hz. using a Varian HA-100 spectrometer with t r i c h l o r o f l u o r o -methane (freon 11) as i n t e r n a l reference. The spect-rometer was used i n e i t h e r the HR-mode or i n the locked f i e l d sweep mode using the " i n f i n i t e o f f s e t " m o d i f i c a t i o n of Douglas (59) - further modified by Mr. 71 -R. Burton of t h i s Department. Chemical s h i f t s are reported i n p.p.m. from freon 11. 3-_Q-acetyl-l ,2 : 5 ,6-di-^.-isopropylidene- c c-D-glucofuranose ( I l a ) : -150 g. of glucose (anhydrous) vras shaken with 1 1. of acetone, 120 g. of zinc c h l o r i d e and 15 ml. of 85% phosphoric acid f o r 30 hours, and worked up i n the usual manner (60) to give 85 g. (57%) of l,2:5,6-di-0-isopropylidene- a-D-glucofuranose ( I ) ; m.p. 112° ( l i t . (60) 112°-113°). A c e t y l a t i o n was c a r r i e d out by shaking 70 g. of I, 50 ml. pyridine and 45 ml. of a c e t i c anhydride f o r several minutes. The s o l u t i o n was allowed to stand at room temperature f o r 10 hours then poured into ice-water, extracted t h r i c e with chloroform and the extracts dri e d over Na^SO^. Evapora-t i o n at reduced pressure y i e l d e d a l i g h t yellow syrup which c r y s t a l l i z e d i n aqueous ethanol to give.63 g. of I l a ; m.p. 53°-54° ( l i t . (61) 55°). 3-0-acetyl-l ,2-0-isopropylidene- t t-D-glucose ( I l i a ) : - 40 g. of o I l a and 75 ml. of 20% a c e t i c a c i d were heated at 60 . Thin l a y e r chromatography ( t . l . c . ) was used to follow the r e a c t i o n . A f t e r 4 hours, the r e a c t i o n was completed. Work-up involved the evaporation of the r e a c t i o n mixture at reduced pressure, o c c a s i o n a l l y adding ethanol to ensure the removal of a l l the - 72 -a c e t i c a c i d . C r y s t a l l i z a t i o n from aqueous ethanol afforded 32 g. (94%) of Ilia;.m . p . 124°-:.26° ( l i t . (62) 125°-126°). 5,6-di-Q^rnesyl-3-Cl-acetyl-l ,2-_Q-isopropylidene- c c-D-glucose (iVa) 20 g. of IVa were dissolved i n 25 ml. of dry methanol and heated on a steam bath. 0.1 N sodium methoxide was added u n t i l the b o i l i n g s o l u t i o n remained a l k a l i n e . The s o l u t i o n was refluxed f u r t h e r f o r 30 minutes and then poured into 250 ml. of water. o Upon standing overnight at 0 , 0.9 g. (61%) of V p r e c i p i t a t e d ; o o ]_ m.p. 114 -115 . The H n.m.r. spectra was i d e n t i c a l to that observed f o r 5-0-tosyl-3,6-anhydro-l^-O-isopropylidene-^-D-glucofuranose (X) except f o r the aromatic region. This t o s y l d e r i v a t i v e (X) was prepared i n an i d e n t i c a l manner as compound V l i s t e d above, but using 5,6-di-0-tosyl-3-0-acetyl-— l^-O-isopropylidene-^-D-glucofuranose as a precursor. Y i e l d of X was 56%; m.p. 135° ( l i t . (5) 135°-136°). 3-^-benzyl-l ,2 :5 ,6-di-0 --isopropylidene- a :-g-glucofuranose ( l i b ) : -25 g." of T, 160 ml", of "benzyl chloride and 80 g. of anhydrous o potassium hydroxide were s t i r r e d and heated at 110 f o r 4 hours. The s o l u t i o n was cooled, 300 ml. of water added, and then ex-tr a c t e d several times with col d ...water,, and evaporated at reduced pressure. Treatment with c h a r c o a l - c e l i t e r e s u l t e d i n a l i g h t orange syrup of l i b (63); y i e l d 26 g. (78%). - 73 -3-0-benzyl-l,2-0-isopropyliden^- <- c-g-glucofuranose 11 l b ) : -Using the method of Goldstein and Smith (64), 26 g. of l i b was hydrolized i n quantitative y i e l d to a colourless syrup I l l b . n.m.r. showed the removal of one isopropylidene group v i a i n t e g r a t i o n of resonances from the x 8.3-8.5 region. 5,6-di-mesyl-3-0-benzyl-l ^-^-isopropylidene-- 1-D-glucose (IVb): -1 g. of I l l b and 3 g. of mesyl choride i n 15 ml. of pyridine were allowed to stand overnight, Work-up as i n previous mesylation r e a c t i o n s , afforded 3 g. (54%) of no n - c r y s t a l l i n e IVb. n.m.r. indicated the presence of two methyl groups (from mesyl substituents) at x 6.2. SYNTHESIS OF 5-FLUORO-3,6-ANHYDRO-l,2-0-IS0PR0PYLIDENE-«-L-IDOFURANOSE (VI) (a) From 5 ,6-di-P_-mesyl-3-0-acetyl-l ,2-0-isopropylidene--*-D-glucofuranose (IVa):- 5 g. of IVa and 5 g. of anhydrous potassium f l u o r i d e were refluxed f o r 2 hours i n 50 ml. of anhydrous ethylene g l y c o l . During t h i s time, white c r y s t a l s sublimed out onto the condenser w a l l . The darkened s o l u t i o n was poured into i c e water and extracted t h r i c e with chloroform. The combined extracts were dr i e d over Na„SO u and concentrated to give crude c r y s t a l s . - 74 -The crude and sublimed c r y s t a l s from the condenser wall were placed i n a sublimation apparatus to y i e l d 1.21 g. (48.4%) of VI; m.p. 96.5°-97.5'° (Found C, 53.12; H, 6.21; 0, 31.37; F, 9.31. Calculated f o r CgH^O^F: C, 52.94; H, 6.37; 0, 31.56; F, 9.11 % ) . O ] ^ 2 = 1 3 t 5 0 1.9.7). (b) From 5-0-mesyl-3 ,6-anhydro-l ,2,-isopropylid.ene-g-D-glucofuranoside (V):- 1 g. of V and 1 g. o f anhydrous potassium f l u o r i d e i n 25 ml. of dry ethylene g l y c o l were refluxed f o r 1 hr. The reaction mixture was worked up as i n (a) above. Sublimation yielded 0.55 g. (75.3%) o o of VI; m.p. and mixed m.p. of 96.5 -97.5 . (c) From 5,6-di-0-mesyl-3-0-benzyl-l, 2-0-isopropylidene-o-^- p-glucof uranose(IVb): -- 1.5 g. of; IVb' and 1.5' g'. of potassium f l u o r i d e (anhydrous) i n 30 ml. of dry ethylene g l y c o l were refluxed u n t i l sublimed product was observed i n the condenser (1 hour). The dark s o l u t i o n was treated i n a s i m i l a r manner as (a) above. 0.25 g. of VI were recovered (45.5%); m.p. £ mixed m.p. of 96.5 -97.5 . By ^ 9 F n.m.r., another product containing f l u o r i n e was observed i n the mother l i q u o r s , but could not be i s o l a t e d . The -^F n.m.r. consisted of a t r i p l e t at +234 p.p.m. u p f i e l d from freon 11, suggesting a primary f l u o r i d e . The proton spectra indicated one mesyl group (T 6.2), an isopropylidene group (T 8.0-8.2), and the benzyl group (T 1.9-2.8) remaining. This product was t e n t a t i v e l y assigned to 6-fluoro-5-0-mesyl-3-0-benzyl-I, 2-0-isopropylidene - a - D-glucofuranose. - 75 -OTHER ATTEMPTED FLUORINATIONS OF IVa (a) Using potassium f l u o r i d e and potassium hydrogen d i f l u o r i d e 2 g. of IVa and 1 g. each of anhydrous potassium f l u o r i d e and potassium hydrogen f l u o r i d e were refluxed f o r 2 hours i n dry ethylene g l y c o l . Severe charring occurred and a white gas (presumably hydrogen f l u o r i d e ) evolved. Work-up i n the usual manner resu l t e d i n a small amount of s t a r t i n g material as the only d i s c e r n i b l e product. (b) Using tet r a - n - b u t y l ammonium f l u o r i d e : - 2 g. of IV and 4 g. of Bu^N+F (16) were refluxed f o r 2 hours i n 20 ml. of a c e t o n i t r i l e . Water was added and the p r e c i p i t a t e d c r y s t a l s f i l t e r e d . Product was i d e n t i f i e d as V (does o o not contain f l u o r i n e ) ; m.p. & mixed m.p. 114 -115 . 1,2-di-0-acetyl-5-fluoro-3 ,6-anhydro-L-idofuranose ( V I I I ) : -500 mg. of VI i n 25 ml. of 30% a c e t i c a c i d were placed on a steam bath. The hydrolysis was followed by t.I.e. (3 hours) to give a quantitative y i e l d of colourless syrup VII. "^H n.m.r exhibited no isopropylidene resonance. To 300 mg. of VII i n 10 ml. of pyridine were added 2 ml. of a c e t i c anhydride. The s o l u t i o n was l e f t at room temperature - 76 -overnight, then poured into 100 ml. of ice-water and extracted with chloroform. Evaporation of the extracts at reduced pressure afforded a l i g h t yellow syrup. T . l . c . showed only one spot i n a v a r i e t y of elutants (benzene/ether; CHC1 /MeOH; o and EtOAc/pet. eth e r ) . V.P.C. could resolve only one broad peak (column packing of 5% butanediol succinate on 60-80 Diataport S). 19 F n.m.r., however, showed two f l u o r i n e resonances at + 176.1 p.p.m. and + 180.0 p.p.m. u p f i e l d from freon 11 i n chloroform; the l a t t e r having approximately twice the area of 19 the former. Both F chemical s h i f t s are c h a r a c t e r i s t i c of secondary f l u o r i d e s . "*"H n.m.r. gave two sets of peaks i n the anomeric region; at T 3.45, a quartet having ca. twice the area of the doublet observed at T 3.65. Thus, one has an i n d i c a t i o n from the n.rn.r. that both anomeric acetates are present, however u n t i l the mixture has been separated, i t would indeed be presumptuous to assign any mu l t i p l e t s to a s p e c i f i c anomer. 5-0-benzoyl-3,6-anhydro-l,2-0-isopropylidene - g - L-idofuranose (IXa) 2 g. of V were refluxed with 10 g. of sodium benzoate i n 150 ml. of dimethyl formamide i n the usual manner (65). C r y s t a l l i z a t i o n o from aqueous ethanol afforded 1.1 g. (50.3%) of IXa; m.p. 83 o O ]_ ( l i t . (65) 83 -84 ). H n.m.r. showed the removal of the mesyl - 77 -peak at i 6.2 and appearance of an aromatic resonance at T 1.9-2.8 i n chloroform. 3 , 6-anhydro-l , 2 -0-isopropylidene - cc-L-idofuranose (IXb) : -1.1 g. of IX a were dissolved i n a minimum amount of dry methanol and 0.1 N sodium methoxide added u n t i l the s o l u t i o n became ba s i c . A f t e r r e f l u x i n g f o r an hour, the s o l u t i o n was neu t r a l i z e d with s o l i d carbon dioxide and then extracted with chloroform. Evaporation at reduced pressure gave 0.6 g. (83%) of IXb; o o o 2. m.p. 105 ( l i t . (65) 105 -107 ); H n.m.r. indicated removal of the aromatic resonance. 5-0-mesyl-3 ,6-anhydro-l , 2 -0-isopropylidene - cc-L-idofuranose (IXc):-0.5 g. of IXb and 1 g. of mesyl c h l o r i d e i n 10 ml. of pyridine were allowed to stand overnight. Work-up i n the usual manner followed by r e c r y s t a l i z a t i o n from aqueous methanol afforded 0.55 g. (79.5%) of IXc; m.p. 1 2 9 ° - 1 3 0 . 5 ° (Found C, 42.69; H, 5.58; S, 11.12; Calculated f o r C^ H ^ C ^ S : C, 42.80; H, 5.70; S, 11.4 %). [<x]^2 = 31° (c. 2.25). - 78 -GENERAL FLUORINATION PROCEDURE USING HYDROGEN FLUORIDE The tetra-acetate or tetra-benzoate d e r i v a t i v e of the furanose sugar (500 mg.) was added slowly to a small amount (1 ml.) of hydrogen f l u o r i d e i n a polyethylene f l a s k surrounded by an acetone-dry ice bath. The r e a c t i o n mixture was swirled s e v e r a l times and allowed to warm to room temperature (20 Min.). The reactants were poured slowly into a beaker containing 100 ml. of super-saturated sodium bicarbonate s o l u t i o n and 100 ml. of e t h y l ether. A f t e r n e u t r a l i z a t i o n was accomplished, the ether la y e r was separated, dri e d over Na^SO^ and evaporated to give a syrup. P u r i f i c a t i o n was accomplished by column chromato- ' graphy ( S i l i c a r CC 7) using 25% eth y l acetate/75% pet. ether as e l u t a n t . In the manner described above the following furanosyl 19 1 f l u o r i d e s were prepared f o r F n.m.r. and H n.m.r. i n v e s t i g a t i o n s : (a) 5-0.-benzoyl-3 , 6-anhydro-2-0.-acetyl-B-L-idofuranosyl f l u o r i d e (XII):- prepared from a sample of 5-0-benzoyl-3,6-anhydro-l,2-di-O-acetyl-L-idofuranose (VII) kindly 19 provided by Dr. John F. Manville. F n.m.r. shows two sextets s p l i t by 60 Hz. at + 120.6 p.p.m. - 79 -u p f i e l d from freon 11. From a s i m i l a r r eaction which was quenched 19 a f t e r h a l f the usual r e a c t i o n time, F n.m.r. showed, I i n ad d i t i o n to the resonance observed f o r XII, two doublets s p l i t by 60 Hz. at +138 p.p.m. u p f i e l d from freon 11. This m u l t i p l e t was assigned to 5-0-benzoyl-3,6-anhydro-°--L-idofuranosyl f l u o r i d e (XI), In t h i s instance the r e a c t i o n mixture contained 70% of XII and 30% of XI. (b) 2,3,5-tri-0-acetyl-B-D-xylofuranosyl f l u o r i d e (XXIV). (c) 2,5-di-0-acetyl-B-D-glucuronolactone f l u o r i d e (XVII):-prepared from a sample of 1,2,5-di-0-acetyl-B-D-glucuronolactone (XVI) k i n d l y provided by Dr. John F. Manville. 2,5-di-0-benzoyl-3-fluoro-D-glucuronolactone (XIV):-( i ) 750 mg. of 1,2 ,5-tri-0-benzoyl-D-glucuronolactone (55) were reacted with anhydrous hydrogen f l u o r i d e i n the manner described above. C r y s t a l l i z a t i o n occurred ' o a f t e r two days at 0 C. i n dry Et^O/pentane. 19 F n,m.r. gave two t r i p l e t s s p l i t by 60 Hz. at - 8 0 -+ 117.9 p.p.m. u p f i e l d from freon 11. The mother l i q u o r s also showed only t h i s f l u o r i n e resonance. 290 mg. of white c r y s t a l l i n e XIV (46.2%) were i s o l a t e d ; m.p. 132°-134° (Found C, 62.18; H, 4.13; F, 5.05: Calculated f o r c 2 o H i 5 ° 7 F : C> - 5 2 ' 1 8 ; H> 3-89; F, 4.92 % ) . o o o t>]p = 64 (c. 1.28). ( i i ) 1 g. of 1,2 ,5-tri-0-benzoyl-D-glucuronolactone were added to 20 ml. of saturated B r ^ / a c e t i c a c i d s o l u t i o n . The mixture was s t i r r e d u n t i l a l l the sugar was d i s s o l v e d , then allowed to remain at room temperature f o r four hours. The r e a c t i o n mixture was slowly added to 100 ml. of saturated sodium bicarbonate s o l u t i o n and quickly extracted several times with chloroform. Drying over Na2S0^ afforded a l i g h t brown syrup from which "^H n.m.r. indicated the removal of one benzoate group. The product was t e n t a t i v e l y assigned to 2,5-di-0-benzoyl-B-bromo-D-glucuronolactone (XV). Due to the l a b i l i t y of the bromides, the syrup was reacted immediately with 0.5 g. of s i l v e r f l u o r i d e i n 20 ml. of a c e t o n t r i l e . The s o l u t i o n was s t i r r e d f o r 1 hour, f i l t e r e d and evaporated at reduced pressure. The product could not be i s o l a t e d , but from the f l u o r i n e spectra of the mother l i q u o r s , a small resonance was observed at + 118 p.p.m. u p f i e l d from freon 11 (two t r i p l e t s ) which was i d e n t i c a l to the f l u o r i n e spectra f o r compound XIV. - 81 -5-.Q_-benzoyl-3 ,6-anhydro-2-0-^cetyl-B -L-idofuranosyl f l u o r i d e (XII): -1.1 g. of VII was added to a saturated Br^/acetic acid s o l u t i o n o at 0 C. and s t i r r e d at room temperature f o r 2 hours. Five times the volume of saturated sodJurn bicarbonate s o l u t i o n was added and the mixture quickly extracted t h r i c e with chloroform. The extracts were dried over Ifc^SO^ anc1^ then evaporated at reduced pressure to y i e l d a l i g h t brown syrup XIII. Dry a c e t o n i t r i l e (20 ml.) and 0.5 g. of s i l v e r f l u o r i d e were immediately added and the mixture s t i r r e d f o r 1 hour. The s i l v e r bromide p r e c i p i t a t e d and excess s i l v e r f l u o r i d e was f i l t e r e d o f f and the c l e a r s o l u t i o n reduced to a syrup i n vacuo. 19 F n.m.r. showed two sextets separated by 60 Hz. at t 120.6 p.p.m. u p f i e l d from freon 11. The following furanosyl f l u o r i d e s were generously donated by C h r i s t i a n Pedersen (48) f o r use i n t h i s i n v e s t i g a t i o n : (a) Tri-O-benzoyl - B - g-ribofuranosyl f l u o r i d e (XVIII). (b) Tri-Jj-benzoyl - g-Q-ribofuranosyl f l u o r i d e (XIX) (c) 2-H-acetyl-3,5-di-Q-benzoyl-g-D-ribofuranosyl f l u o r i d e (XX). (d) 3-D-acetyl-2,5-di-il-benzoyl-8 - g-ribofuranosyl f l u o r i d e (XXI). (e) 5-l)-acetyl-2,3-di-Il-benzoyl-g-g-ribofuranosyl f l u o r i d e (XXII). ( f ) Tri-,Q_-benzoyl- g-D-arabinofuranosyI f l u o r i d e (XXIII). APPENDIX APPENDIX A COMPUTER PROGRAMS During the course of t h i s i n v e s t i g a t i o n , there was an increasing awareness that many of the compounds studied did not e x h i b i t s t r i c t l y f i r s t order spectra, but often involved second order e f f e c t s , which make the observed chemical s h i f t s and coupling constants d i f f e r e n t from the true values. The computer programs were used to check both the assigned analysis and a l s o i n some cases to r e f i n e the coupling constants and chemical s h i f t s to t h e i r true values.. (1) TW0SUM" This program was written i n F0RTRAN IV f o r an IBM 70-+4 computer and can handle a maximum number of s i x spins with an upper l i m i t of 100 energy l e v e l s and 600 t r a n s i t i o n s . There are two modes of operation, the f i r s t involves entering .guesses of the s h i f t s and coupling constants into the program u n t i l one achieves a computed spectrum close enough to the one observed, such that an unambiguous'assignment of observed t r a n s i t i o n s to p a i r s of energy l e v e l s can be made. The output of a histogram p l o t simulating the c a l c u l a t e d spectrum f a c i l i t a t e s t h i s stage of the operation. The second mode of operation assigns these t r a n s i t i o n s to t h e i r experimental frequencies and produces an optimum set of energy l e v e l s . Then, the s h i f t s and couplings are r e f i n e d by an i t e r a t i v e "Graciously provided by Dr. John Martin, University of A l b e r t a , Edmonton, Alberta. - 84 -.nethod to f i t these optimized energy l e v e l s . The output gives a l i s t i n g of these r e f i n e d couplings and s h i f t s together with the er r o r Involved i n matching the t r a n s i t i o n s . (2) LAC00N III ft LAC00N III was kindl y provided by Aksel Bothner-By and was written i n F0RTRAN IV and used f o r systems i n v o l v i n g up to seven spins. As with TW0SUM, the program has two opera-t i o n a l modes, one invo l v i n g the introduction of "guess" s h i f t s and couplings to generate an assigned set of frequencies and t r a n s i t i o n s . The other mode uses an i t e r a t i v e procedure to match the experimental and observed spectra by a l e a s t squares c r i t e r i o n . The core s i z e of the IBM 7044 r e s t r i c t s the number of i t e r a t i o n s i n t h i s l a s t stage. (3) SMASH . ' . A The p l o t routine SMASH was written by John Coulthart f o r the calcomp p l o t t e r and used i n conjunction with LAC00N III to provide a simulation of the ca l c u l a t e d n.m.r. spectra. A Mellon I n s t i t u t e , Pittsburgh, Pa. * I'-l l . B.C. Computing Centre, - 85 -APPENDIX B HETERONUCLEAR DECOUPLING The advantages of using f l u o r i n e as a probe f o r conformational analysis are often l i m i t e d by the presence of a multitude of couplings between f l u o r i n e and other n u c l e i i n the molecule. These extra couplings may complicate the spectrum to such an extent that analysis becomes d i f f i c u l t . In t h i s present i n v e s t i g a t i o n , such problems were overcome by a p p l i c a -t i o n of f l u o r i n e double resonance. Oreof the f i r s t successful a p p l i c a t i o n s of hetero-nuclear decoupling was made by Bloom and Schoolery (67) who observed the f l u o r i n e spectra of NagPO^F while i r r a d i a t i n g phosphorous. Conformational free energies of deuterium l a b e l l e d cyclo-octane have been determined by Anet (68) using deuterium decoupling to remove the e f f e c t s of quadrupole broadening i n the proton spectra. S i m i l a r l y , Bovey (23) s i m p l i -. 1 9 f i e d the F spectra of cyclohexyl f l u o r i d e by i r r a d i a t i n g protons and used t h i s spectra to determine the r e l a t i v e free energies of the two conformations f o r the molecule. The a p p l i c a t i o n of heteronuclear decoupling to these and other n u c l e i has been r e c e n t l y reviewed by McFarlane (69). The heteronuclear decoupler unit used f o r t h i s study - 86 -wa^ b u i l t by Mr. R. Burton of t h i s Department f o r a Varian HA-100 Spectrometer (70). E s s e n t i a l l y , the unit involved a modification of the Varian V--+333 probe, by means of a double-tuner-probe-adapter, f o r observing "^H at 100 MHz., while 19 19 i r r a d i a t i n g F. The F decoupling frequency i s produced by a Hewlett Packard Frequency Synthesiser (Model 5105A) with a maximum output frequency of 500 MHz. and which i s coupled to a Hewlett Packard Synthesiser-Driver (Model 230A). A l l heteronuclear decoupling applied to the^ molecules i n t h i s t h e s i s involves continuous wave decoupling ( i . e . using a s i n g l e coherent radiofrequency). The maximum band width, which can be e f f e c t i v e l y i r r a d i a t e d under continuous wave con-ft d i t i o n s , i s ca. 80 Hz. A t y p i c a l heteronuclear decoupling experiment was performed as follows: F i r s t , 'the correc t decoupling frequency was found by s e t t i n g the HA-100 recorder at a c e n t r a l p o s i t i o n 1 . 1 19 ( i n the H spectra) between two peaks a r i s i n g from a H- F coupling. Usually, the H^ resonance was used because of i t s 1 19 large geminal H- F coupling and i t s low f i e l d chemical s h i f t . 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Chem., 39, 216(1961). - 94 -NOTE . The naming of compound VI as 5-fluoro-3,6-anhydro-l,2-0-isopropylidene-^-L-iuofuranose i s used i n t h i s thesis and i n our laboratory as a matter of convenience f o r v i s u a l i z a t i o n of structure. However, by I.U.P.A.C. nomenclature, compound VI should be c o r r e c t l y designated as 3,6-anhydro-5-fluoro-l,2-0-isopropylidene-jS-L-idofuranose. 

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