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Application of the oxo reaction to various carbohydrate derivatives Koch, Hans J. 1967

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The U n i v e r s i t y of B r i t i s h Columbia FACULTY OF GRADUATE STUDIES PROGRAMME OF THE FINAL. ORAL EXAMINATION FOR THE DEGREE OF DOCTOR OF PHILOSOPHY OF HANS J . KOCH B.Sc. (Hons.). The Univ e r s i t y of B r i t i s h Columbia TUESDAY, MAY 30, at 3:30 P.M. IN ROOM 261, CHEMISTRY BUILDING COMMITTEE IN CHARGE Chairman: B.N. Moyls Q.LTeHefele J. Trotter C A . McDowell L.D. H a l l G.G.S .. Dutton N. Paddock External Examiner: J.K.N.. Jones Department of Chemistry Queen's U n i v e r s i t y Kingston, Ontario Research Supervisor:. A. Rosenthal APPLICATION OF THE OXO REACTION TO VARIOUS CARBOHYDRATE DERIVATIVES ABSTRACT 3,4, 6-Tri-0_-acetyl-D-glucal (1) reacted with carbon monoxide and hydrogen i n the presence of dicobalt octacarbonyl to y i e l d a mixture of two epimeric anhy-drodeoxyheptitols, namely, 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-D-manno-heptitol (2) and 4,5,7-tri-jJ)-acetyl-2,6-anhydro-3-deoxy-D-gluco-heptitol (3). De-O~acetylation of the mixture, followed by chroma-tographic separation, yielded 2,6-anhydro-3-deoxy-D-manno- h e p t i t o l (4) and 2,6-anhydro-3-deoxy-D-gluco-h e p t i t o l (5) .. Compounds (4) and (5) were oxidised with periodate to y i e l d dialdehydes which on reduction with sodium borohydride afforded enantiomeric t e t r o l ethers. Reaction of 3,4,6-tri^O-acetyl-D-glucal (1) with carbon monoxide and deuterium, followed by de-0_-acetylation and chromatographic separation gave 2,6-anhydro-3-deoxy-D-manno-heptitol-1,1, 3-2]i3(cis) (6) and 2,6-anhydro-3-deoxy-D-gluco-heptitol-1,1,3-2H^(CJS)(7). Examination of. the proton- magnetic resonance spectra of the normal (4,5) and deuterated anhydrodeoxy h e p t i t o l s (6,7) revealed t h e i r structures and showed that c i s -addition of carbon monoxide and hydrogen to the double bond of (1) had taken place. Reaction of the mixture of p a r t i a l l y acetylated h e p t i t o l s (2) and (3) with j>-toluenesulphonyl chloride followed by f r a c t i o n a l c r y s t a l l i s a t i o n of the products gave pure 4,5, 7-tri-()-acetyl-2, 6-anhydro-3-deoxy-l-()-(p-toluenesulphonyl)-D-glueo-heptitol (8).. S i m i l a r l y , the mixture of (2) and (3) reacted with _p_-bromoben-zenesulphonyl bromide to give 4,5,7-tri~()-acetyl-2, 6-anhydro-l-()- (j>-bromobenzenesulphonyl) -3-deoxy-D-gluco - h e p t i t o l (11), the structure of which was confirmed by X-ray structure analysis"by A. Camerman and J . T r o t t e r . Therefore, the absolute structures of compounds (4) and (5) were ascertained. Compounds (8) and (11) were converted to (5) by a series of reactions. Comparison of the exchange reaction of sodium iodide with 4,5, 7-tri-()-acetyl-2, 6-anhydro-3-deoxy-1- 0-(p-toluenesulphonyl)-D-gluco-heptitol (8) and with 4,5, 7-tri-()-acetyl-2, 6-anhydro-3-deoxy-l-()- (p_-toluene-sulphonyl)-D-manno-heptitol (14) revealed that the equatorial primary ]3-toluenesulphonoxy group of (8) was exchanged more r e a d i l y than that of (14). The hydroformylation of (1) yielded two enantio-meric aldehydes (16a,16b) which were separated chromatographically v i a t h e i r 2,4-dinitrophenyl-hydrazones (16b) and (17b) . Both (16b) and (17b) were degraded to (4) and (5) r e s p e c t i v e l y . 3,4-Di-O-acetyl-D-arabinal (18) reacted with carbon monoxide and hydrogen i n the presence of dicobalt octacarbonyl to y i e l d , upon de-O-acetylation and chromatographic separation, a mixture of two epimeric anhydro-deoxyhexitols, namely, 1,5-anhydro-4-deoxy-L-ribo-hexitol (21) and 1,5-anhydro-4-deoxy-D-iLyxo-hexitol (22) . Compounds (21) ans (22) were converted into enantiomeric 2-deoxy-3-JD-(2-hydro-xyethyl) - L - g l y c e r o - t e t r i t o l (23) and 2-deoxy-3-£)-(2-hydroxyethyl)-D-glycero-tetritol (24). Compound (23) was i d e n t i c a l to an authentic sample of 2-deoxy-3-0-(2-hydroxyethyl)-L-glycero-tetritol. 1,2,4,6-Tetra-O-acetyl-3-deoxy-ol-D-erythro-hex-2- enopyranose (29) reacted with carbon monoxide and hydrogen i n the presence of dicobalt octacarbonyl to y i e l d 1,2, 3 1,4, 6-penta-0-acetyl-3-deoxy:;3-C-(hydro-xymethyl)-W-D-gluco-pyranose (31) besides hydro-genolysed hydrohydroxymethylated products, a s i m i l a r reaction of (29) with deuterium instead of hydrogen gave 1,2,3 1,4,6-penta-j)-acetyl-3-deoxy-3-C-(hydro-xymethyl) -tt-D-gluco-pyranose-2, 3^ , 3^- ^ ( c i s ) (33) . The structures of (31) and (33) were established by p.m.r. spectroscopy. 2,3,4, 6-Tetra-0~acetyl-«.-D-glucosyl bromide (26) reacted with sodium tetracarbonylcobaltate under compressed carbon monoxide followed by treatment with triphenylphosphine to a f f o r d 2,3,4,6-tetra-^-acetyl-^-D-glucosyl t r i c a r b o n y l triphenylphosphine cobaltate (39) and 3,4,5,7-tetra-0-acetyl-2,6-anhydro-D-glycero-D-gulo-heptosoyl t r i c a r b o n y l triphenylphosphine cobal-tate (41). Reduction of (39) and (41) with sodium borohydride followed by a c e t y l a t i o n gave 2,3,4,6-tetra-0-acetyl-l,5-anhydro-D-glucitol (40) and 1,3,4,5, 7-penta-0-acetyl-2,6-anhydro-D-glycero-D-gulo-hep-t i t o l (42). Both (40) and (42) were compared with authentic samples and shown to be the same. GRADUATE STUDIES F i e l d of Study: Chemistry Topics i n Physical Chemistry Seminar i n Chemistry Topics i n Inorganic "Chemistry J.A.R. Coope,'W.C. L i ' -J.P. Kutne H.C. Clark, W.R. Cull;. Advanced Inorganic Chemistry Topics i n Organic Chemistry Organic Stereochemistry Carbohydrates A l k a l o i d Chemistry Physical Organic Chemistry Organic Reaction Mechanisms Recent Synthetic Methods i n Organic Chemistry Chemistry of Polysaccharides Organic Medicinal Products (Pharmacy) PUBLICATIONS A. Rosenthal, H.J. Koch Can. J. Chem., 42,2025 (1964). A. Camerman; H.J. Koch, A. Rosenthal, Can. J. Chem., 42,2630 (1964) A. Rosenthal, H.J. Koch Can. J. Chem., 43,1375 (1965) A. Rosenthal, H.J;.Koch Tetrahedron L e t t e r s , 871 (1967). A. Rosenthal, D. Abson, T.D. F i e l d , H.J. R.E.J. M i t c h e l l Can. J. Chem., i n press (1967) N. B a r t l e t t H.C. Clark, W.R.. Culle. F. McCapra-, A.E. Scott J.P. Kutney L.D. Hayward L.D. Hayward, A. Rosenthal G.G.S. Dutton J.P. Kutney R. Stewart R.E. Pincock G.G.S .. Dutton, A. Rosenthal G.G.S. Dutton T.H. Brown J. T r o t t e r Koch, THE APPLICATION OF THE OXO REACTION TO VARIOUS CARBOHYDRATE DERIVATIVES by HANS J . KOCH Sc., The U n i v e r s i t y of B r i t i s h Columbia, 1962 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n the Department of Chemistry We accept t h i s t h e s i s as conforming to the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA May, 1967 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 an 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 nd 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 by t h e H e a d o f my D e p a r t m e n t o r by 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, C a n a d a r Date /vT'/zf. %Ui^L /96 > ABSTRACT 3,4,6-Tri-O-acetyl-D-glucal (1) reacted with carbon monoxide and hydrogen i n the presence of dicobalt octacarbonyl to y i e l d a mixture of two epimeric anhydrodeoxyheptitols, namely, 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-D-manno-heptitol (2) and 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-D-gluco-h e p t i t o l (3). De-O-acetylation of the mixture, followed by chromatographic separation, yielded 2,6-anhydro-3-deoxy-Q-manno-heptitol (4) and 2,6-anhydro-3-deoxy-Q-gluco-heptitol (5). Compounds (4) and (5) were oxidised with periodate to y i e l d dialdehydes which on reduction with sodium borohydride afforded enantiomeric t e t r o l ethers. Reaction of 3,4,6-tri-O-acetyl-D-glucal (1) with carbon monoxide and deuterium, followed by de-O-acetylation and chromatographic separation gave 2,6-anhydro-5-deoxy-D-manno-heptitol-1,1,3- 2H3(cis)(6) and 2,6-anhydro-3-deoxy-jj-gluco-heptitol-l, 1,3- 2 H 3 ( c i s ) (7) . Examination of the proton magnetic resonance spectra of the normal (4,5) and deuterated anhydrodeoxy h e p t i t o l s (6,7) revealed t h e i r structures and showed that c i s - a d d i t i o n of carbon monoxide and hydrogen to the double bond of (1) had taken place. Reaction of the mixture of p a r t i a l l y -acetylated h e p t i t o l s (2) and (3) with p_-toluenesulphonyl chloride followed by f r a c t i o n a l c r y s t a l l i s a t i o n of the products gave pure 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-l-0-(p_-toluenesul-phonyl)-D-gluco-heptitol (8). Similarly,, the mixture of (2) and (3) reacted with p_-bromobenzenesulphonyl bromide to give 4,5, 7-tri-C^-acetyl-2,6-anhydro-l-0-(p_-bromobenzenesulphonyl)-3-deoxy-D-gluco-heptitol (11), the structure of which was confirmed by X-ray structure analysis by A. Camerman and J . T r o t t e r . Therefore, the absolute structures of compounds (4) and (5) were ascertained. Compounds (8) and (11) were converted to (5) by a s e r i e s of reactions. Comparison of the exchange reaction of sodium iodide with 4,5,7-tri-£-acetyl-2,6-anhydro-3-deoxy-l-()- (p-toluenesulphonyl)-D-gluco-heptitol (8) and with 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-l-0-(p_-toluenesulphonyl)-D-manno-heptitol (14) revealed that the equatorial primary p_-toluenesulphonoxy group of (8) was exchanged more r e a d i l y than that of (14). The hydroformylation of (1) y i e l d e d two enantiomeric aldehydes (16a, 16b) which were separated chromatographically v i a t h e i r 2,4-dinitrophenyl-hydrazones (16b) and (17b). Both (16b) and (17b) were degraded to (4) and (5), r e s p e c t i v e l y . 3,4-Di-()-acetyl-D-arabinal (18) reacted with carbon monoxide and hydrogen i n the presence of dicobalt octacarbonyl to y i e l d , upon de-O-a c e t y l a t i o n and chromatographic separation, a mixture of two epimeric anhydro-deoxyhexitols, namely, 1,5-anhydro-4-deoxy-L-ribo-hexitol (21) and 1,5-anhydro-4-deoxy-Q-lyxo-hexitol (22). Compounds (21) and (22) were converted in t o enantiomeric 2-deoxy-3-0-(2-hydroxyethyl)-L-glycero-tetritol (23) and 2-deoxy-3-0-(2-hydroxyethyl)-D-glycero-tetritol (24). Compound (23) was i d e n t i c a l to an authentic sample of 2-deoxy-3-0-(2-hydroxyethyl)-L-glycero-t e t r i t o l . 1,2,4,6-Tetra-O-acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose (29) reacted with carbon monoxide and hydrogen i n the presence of dicobalt octa-carbonyl to y i e l d 1,2,3 1,4,6-penta-0^acetyl-3-deoxy-3-C-(hydroxymethyl)-a-D-gluco-pyranose (31) besides hydrogenolysed hydrohydroxymethylated products, a s i m i l a r reaction of (29) with deuterium instead of hydrogen gave 1,2,3*,4,6-penta-(D-acetyl-3-deoxy-3-C- (hydroxymethyl) -ct-D-gluco-pyranose-2,3 1,3 1 - 2H 3 (cis) (33). The structures of (31) and (33) were established by p.m.r. spectroscopy. 2,3,4,6-Tetra-O-acetyl-a-D-glucosyl bromide (26) reacted with sodium tetracarbonylcobaltate under compressed carbon monoxide followed by treatment with triphenylphosphine to a f f o r d 2,3,4,6-tetra-O-acetyl-g-D-glucosyl t r i -carbonyl triphenylphosphine cobaltate (39) and 3,4,5,7-tetra-0_-acetyl-2,6-anhydro-D-glycero-D-gulo-heptosoyl t r i c a r b o n y l triphenylphosphine cobaltate (41). Reduction of. (39) and (41) with sodium borohydride followed by ac e t y l a t i o n gave 2 33,4,6-tetra-0_-acetyl-l,5-anhydro-D-glucitol (40) and l,3,4,5,7-penta-0-acetyl-2,6-anhydro-D-glycero-D-gulo-heptitol (42). Both (40) and (42) were compared with authentic samples and shown to be the same. - V -TABLE OF CONTENTS Page A b s t r a c t . i i Table o f Contents v L i s t of Figures • • • x i Acknowledgements . . . . . . . . x i i INTRODUCTION . . 1 The Oxo Reaction • 1 The c a t a l y s t , 2 The e f f e c t of s t r u c t u r e on the hydro f o r m y l a t i o n r e a c t i o n . . 7 The mode of a d d i t i o n to the double bond 8 The e f f e c t of f u n c t i o n a l groups 10 Hydroformylation of c y c l i c v i n y l ethers 11 Reaction c o n d i t i o n s . . . . . . . . . . . . . . . . 13 General c o n s i d e r a t i o n s 13 Side r e a c t i o n s 14 The g l y c a l acetates .• • 14 The formation of g l y c a l s 16 The mode of a d d i t i o n to g l y c a l double bonds • 17 C i s - a d d i t i o n 18 Trans- a d d i t i o n 21 The A c e t y l a t e d G l y c o s y l Halides 22 Pr e p a r a t i o n . . .' 23 Reactions 24 A c e t y l a t e d 2-hydroxyglycals 27 - v i -TABLE OF CONTENTS (cont'd) Page A c e t y l a t e d 3-deoxy-hex-2-enopyranoses . . . . 27 Cobalt carbonyl d e r i v a t i v e s . . . . . . . . . . . 29 Tet r a c a r b o n y l c o b a l t a t e s 30 A l k y l c a r b o n y l c o b a l t a t e s . . . . . . . . . . . . . . . . . . 31 Branched-chain carbohydrates . . . . . 33 K i l i a n i Synthesis . . . . . . . . . . . . . . . . . . . . . 33 Grignard Reaction 34 The a c t i o n of dialkylmagnesium . . . . . . . . . . . . . 34 The a c t i o n of diazocompounds . • • 34 A l d o l condensations 34 Nomenclature 35 DISCUSSION . , 36 Reaction c o n d i t i o n s 36 The p r e p a r a t i o n of a c e t y l a t e d g l y c a l s 36 The Oxo Reaction of a c e t y l a t e d g l y c a l s 37 Hydrohydroxymethylation of 3 , 4 , 6 - t r i - O - a c e t y l - Q - g l u c a l . . 38 Proton-magnetic resonance s p e c t r a o f the anhydrodeoxy-h e p t i t o l s • 41 Chemical s e p a r a t i o n o f the isomers 44 Hydroformylation of 3 , 4 , 6 - t r i - O - a c e t y l - D - g l u c a l . . . . . The hydrohydroxymethylation o f 3,4-di-O-acetyl-D-arabinal ... 51 The Oxo Reaction of l,2 )4,6-tetra-0-acetyl-3-deoxy-a-D-erythro-hex-2-pyranose . . . 54 : The low-pressure hydroxymethylation o f 2,3,4,6-tetra-O-acetyl-a-Q-g l u c o s y l bromide v i a c o b a l t carbonyl complexes . 62 - v i i -TABLE OF CONTENTS (cont'd) Page EXPERIMENTAL 70 General considerations . . . . 72 Dicobalt octacarbonyl . . . . . . . . 72 3.4.6- Tri-O-acetyl-D-glucal . 72 Hydrohydroxymethylation of 3,4,6-tri-O-acetyl-D-glucal . . . . . 73 Ac e t y l a t i o n of the hydrohydroxymethylation product of 3,4,6,-tri-O-acetyl-D-glucal . . . . . 74 De-O-acetylation of the hydrohydroxymethylation product . . . . 74 Preparative separation by paper chromatography of the anhydrodeoxy-h e p t i t o l s . 75 1,4,5,7-Tetra-0-acetyl-2,6-anhydro-3-deoxy-D-manno-heptitol • ... 76 1,4,5,7-Tetra-0-acetyl-2,6-anhydro-3-deoxy-D-gluco-heptitol . . . 77 «' P e r i o d i c acid oxidation of 2,6-anhydro-3-deoxy-D-manno-heptitol to give 2-deoxy-3-0-(1,3-dihydroxy-2-propyl)-D-glycero-tetritol . 77 Tetra-0-(p_-nitrobenzoyl)-2-deoxy-3-0-(1,3-dihydroxy-2-propyl)-D-g l y c e r o - t e t r i t o l . . . 77 Peri o d i c a c i d oxidation of 2,6-anhydro-3-deoxy-D-gluco-heptitol to give 2-deoxy-3-0-(1,3-dihydroxy-2-propyl-L-glycero-tetritol . . 78 Tetra-0- (p_-nitrobenzoyl) -L-deoxy-3-0_-(l, 3-dihydro-2-propyl) -L-g l y c e r o - t e t r i t o l 78 4.5.7- Tri-0-acetyl-2,6-anhydro-3-deoxy-l-0_- (p_-toluenesulphonyl) -g-g l u c o - h e p t i t o l 79 2,6-Anhydro-3-deoxy-l-0-(p-toluensulphonyl)-D-gluco-heptitol . . 80 4,5,7-Tri-0-acetyl-2,6-anhydro-l-0- (p_-bromobenzenesulphonyl) -3-deoxy-gluco-heptitol 80 - v i i i -TABLE OF CONTENTS (cont'd) Page 4.5.6- Tri-O-acetyl-2,6-anhydro-1,3-dideoxy-l-iodo-D- gluco-heptitol from 4,5,7-tri-O-acety 1-2,6-anhydro-3-deoxy-l-0_-(p_-toluenesulphonyl) -g - g l u c o - h e p t i t o l . . . . . . . . . 81 4.5.7- Tr i - Q - a c e t y l - 2 , 6 - a n h y d r o - l , 3 - d i d e o x y - l - i o d o - D - g l u c o - h e p t i t o l from 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-l-0_-(p_-bromobenzene-sulphonyl) - j j - g l u c o - h e p t i t o l . . 81 4,5,7-Tri-O-ace.ty 1- 2,6-anhydro-3-deoxy-l-O-nitro-D-gluco-heptitol 82 4,5,7-Tri-O-acety1-2,6-anhydro-3-deoxy-D-gluco-heptitol 82 2,6,-Anhydro-3-deoxy-D-gluco-heptitol . . . . . 82 l-Acetamido-4,5,7-tri-0-acety1-2,6-anhydro-1,3-dideoxy-D-gluco-h e p t i t o l 83 Attempted p r e p a r a t i o n of l-acetamido-4,5,7-tri-0_-acetyl-2,6-anhydro-1.3- didoexy-D-giuco-heptitol v i a the azide . . . . . . . . . . . . 83 The r e a c t i o n of 3 , 4 , 6 - t r i - O - a c e t y l - g - g l u c a l w i t h carbon monoxide and deuterium 84 4,5,7-Tri-0_-acetyl-2 ,6-anhydro-3-deoxy-1-0- (p_-toluenesulphonyl) -D-manno-heptitol ' • . 85 Comparison of the e x c h a n g e a b i l i t y of the p_-toluenesulphonoxy groups by i o d i d e f o r 4,5, 7-tri-0-acetyl-2,6-anhydro-1-0- (p_-toluenesulphonyl) -3-deoxy-D-gluco- and manno-heptitols . 86 Hydroformylation of 3 , 4 , 6 - t r i - 0 - a c e t y l - Q - g l u c a l . . . . . . . . . 88 2.4- Dinitrophenylhydrazones of the hydroformulation product and t h e i r s e p a r a t i o n . • 89 Conversion o f 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-D-gluco-heptose 2,4-dinitrophenylhydrazone to 2,6-anhydro-3-deoxy-Q-gluco-heptitol 90 - i x -TABLE OF CONTENTS (cont'd) Page Conversion of 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-D-manno-heptose 2,4-dinitrophenylhydrazone to 2,6-anhydro-3-deoxy-D-manno-heptitol . 90 3.4- Di-0-acetyl-D-arabinal ... . 91 The hydrohydroxymethylation of 3,4-dl-0-acetyl-D-arabinal . . . 91 1.5- Anhydro-2,3,6-tri-0-benzoyl-4-deoxy-Q-lyx6-hexitol. . . . . . 92 l,5-Anhydrd-2,3,6-tri-0-benzoyl-4-deoxy-L-ribo-hexitol . . . . 92 Periodic acid o x i d i a t i o n of l,5-anhydro-4-deoxy-D-lyxo-hexitol to give 2-deoxy-3-0-(2-hydroxyethyl)-D-glycero-tetritol . . . . 92 Per i o d i c acid oxidation of 1,5-anhydro-4-deoxy-L-J_ibo-hexitol to give 2-deoxy-3-0-(2-hydroxyethyl)-L-glycero-tetritol 93 2,3,4,6-Tetra-O-acetyl-a-Q-glucosyl bromide 93 2,3,4,6-Tetra-0-acetyl-2-hydroxy-Q-glucal . . . . . . . . . . . . 94 l,2,4,6-Tetra-0-acetyl-3-deoxy-D-erythro-hex-2-enopyranose . . . 94 The hydrohydroxymethylation of l,2,4,6-tetra-0-acetyl-3-deoxy-Q-D-erythro-hex-2-enopyranose 95 The hydrohydroxymethylation of 1,2,4,6-tetra-0-acetyl-3-deoxy-ct-D-erythro-hex-2-pyranose with carbon monoxide and deuterium . . 96 Preparation of sodium tetracarbonylcobaltate . . . . . . . . . . ^ The reaction of 2,3,4,6-tetra-0-acetyl-a-D-glucosyl bromide with sodium tetracarbonylcobaltate . . . 99 Ga s - l i q u i d p a r t i t i o n chromatographic separation of the acetylated polyols derived from the cobalt complexes . 99 Reduction of 2,3,4,6-tetra-0_-acetyl-D-glucosyl t r i c a r b o n y l t r i -phenylphosphine cobaltate . . . . . . . . . . 100 - X -TABLE OF CONTENTS (cont'd) Page Reduction of impure 1,3,4,5,7-penta-0-acetyl-2,6-anhydro-D-glycero-D-gulo-heptosoyl t r i c a r b o n y l triphenylphosphine cobaltate 100 Decarbonylation of 3,4,5,7-tetra-Q-acetyl-2,6-anhydro-D-glycero-D-gulo-heptosyl t r i c a r b o n y l triphenylphosphine cobaltate . . . . , 101 Attempted carbonylation of 2,3,4,6-tetra-0_-acetyl-D-glucosyl t r i c a r b o n y l triphenylphosphine cobaltate . . . . . . . . . . 101 2,3,4,6-Tetra-O-acetyl-D-polygalitol . 102 BIBLIOGRAPHY 103 - x i -LIST OF FIGURES Page Figure 1 P.M.R. Spectra o f 2,6-anhydro-3-deoxy-D-manno-heptitol and i t s p a r t i a l l y deuterated analogue 42 2. P.M.R. Spectra of 2,6-anhydro-3-deoxy-D-gluco-heptitol and i t s p a r t i a l l y deuterated analogue . . . . . . . . . . . . 43 3. Deuterium decoupled s p e c t r a of 2,6-anhydro-3-deoxy-D-g l u c o - h e p t i t o l - 1 , l , 3 - 2 H 3 ( c i s ) and 2 J6-anhydro-3-deoxy-Q-manno-heptitol-1,1,3- 2H 3(cis) 44 4 Gas l i q u i d p a r t i t i o n chromatography o f the a c e t y l a t e d hydrohydroxymethylation product of l , 2 , 4 , 6 - t e t r a - 0 -acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose 56 5. P.M.R. Spectrum of 1,2,3 1, ^ ^-Penta-O-acetyl-S-deoxy-S-C- (hydroxymethyl)-a-D-glucose 57 :. 6. P.M.R. Spectrum of 1,2,31,4,6-penta-0-acetyl-3-deoxy-3-£-(hy d r o x y m e t h y l ) - a - D - g l u c o s e - 2 , 3 1 3 1 - 2 H 3 ( c i s ) . . . . . . 58 7. P.M.R. Spectrum o f gas l i q u i d p a r t i t i o n chromatography zone A . . . . . . . . . . . . . . . . . . 59 8. ' Comparison of the e x c h a n g e a b i l i t y of the p_-toluene-sulphonoxy groups by Iodide 87 - x i i -ACKNOWLEDGEMENTS The author i s greatly indebted to Professor A. Rosenthal f o r hi s help, encouragement, and guidance throughout t h i s i n v e s t i g a t i o n . The author i s also g r a t e f u l to other members of the Department of Chemistry who have a s s i s t e d him i n many ways, i n p a r t i c u l a r to Dr. L.D. H a l l and Mr. J . Manville f o r the i n t e r p r e t a t i o n of nuclear magnetic resonance spectra and valuable discussions. Appreciation i s also expressed to Professor G.G.S. Dutton, Dr. D. Abson and Dr. J.N.C. Whyte of t h i s Department and to Dr. P. Reid of the Department of Pathology. F i n a n c i a l assistance from Canadian Industries Limited and the B r i t i s h Columbia Sugar Refining Company i n the form of fellowships and from the Department of Chemistry i n the form of teaching a s s i s t a n t s h i p s i s g r a t e f u l l y acknowledged. The author also wishes to record h i s gratitude to h i s parents and friends outside the Uni v e r s i t y f o r t h e i r help. Admiration i s due to Miss B.M. Dominique f o r typing a somewhat i l l e g i b l e manuscript. - 1 -INTRODUCTION  The Oxo Reaction S h o r t l y a f t e r the F i r s t World War Franz F i s c h e r and Hans Tropsch of the Kaiser-Wilhelm I n s t i t u t at MUhlheim found that carbon monoxide i s reduced t o methanol by hydrogen i n the presence o f a mixed metal oxide c a t a l y s t c o n s i s t i n g of 31.5% c o b a l t , 1.8% thorium oxide, 3.7% magnesium oxide, and 63% k i e s e l g u r . CO + H 2 — • CH3OH Since the process i s accompanied by a volume r e d u c t i o n , high pressures (ca 200 atm.) favour the formation o f methanol. The temperatures used are about 450°C. One of the main by-products i s i s o b u t y l a l c o h o l . In 1938 Otto Roelen made the.valuable disc o v e r y t h a t o l e f i n s add carbon monoxide and hydrogen i n the presence of Fischer-Tropsch c a t a l y s t s to y i e l d s a t u r a t e d aldehydes. Ethylene, f o r example, gives as the main product propionaldehyde. CH 2 = CH 2 + CO + H 2 • CH3-CH2-CHO The importance of t h i s r e a c t i o n l i e s not only i n the p r e p a r a t i o n of aldehydes but a l s o i n the syn t h e s i s o f a l c o h o l s formed by t h e i r r e d u c t i o n . The use of l a r g e r amounts o f hydrogen leads d i r e c t l y t o a l c o h o l s and i n the presence of ammonia or amines to amines v i a t h e i r corresponding S c h i f f ' s bases. In the l a b o r a t o r y d i c o b a l t octacarbonyl i s best used as the c a t a l y s t d i s s o l v e d i n the s o l v e n t , although l y o p h i l i c or h y d r o p h i l i c cobalt s a l t s show s i m i l a r e f f e c t s . The autoclave, which, should be able to withstand i t l e a s t 300 atmospheres pressure can be made of s t a i n l e s s s t e e l because of the u s u a l l y short r e a c t i o n times. For extended use s t e e l s , or l i n i n g s r e s i s t a n t to carbon - 2 -monoxide and hydrogen should be used. Carbon monoxide and hydrogen are used as the hydroformylation reagents at about 300 atm. pressure and 160°C. Because of the e x t r a o r d i n a r i l y poisonous c h a r a c t e r of hydrogen t e t r a c a r b o n y l c o b a l t a t e and carbon monoxide s p e c i a l precautions t o prevent leaks i n the apparatus are necessary and good v e n t i l a t i o n o f the working space i s mandatory. The C a t a l y s t . A v a r i e t y of c a t a l y s t s were used when the Oxo Reaction was f i r s t i n troduced. The usual one being a mixture of c o b a l t , thorium oxide, magnesium oxide, and k i e s e l g u r . The most a c t i v e c a t a l y s t s c o n t a i n c o b a l t i n some form, although i r o n and manganese compounds a l s o show a c t i v i t y . Since m e t a l l i c c o b a l t r e a c t s w i t h carbon monoxide under pressure to form d i c o b a l t o c t a c a r b o n y l , 1 i t appeared t h a t t h i s compound i s i n v o l v e d i n the hydr o f o r m y l a t i o n r e a c t i o n . 2Co + 8CO • C o 2 ( C 0 ) 8 2 This was confirmed by the work of Adkins and Krsek, and Wender, Orchin, 3 and Storch. The use of d i c o b a l t octacarbonyl i n s o l u t i o n was described 4 f i r s t by Roelen. . The r e l a t i v e i n s e n s i t i v i t y of the c a t a l y s t to p o i s o n i n g e s p e c i a l l y by sulphur compounds f u r t h e r suggested t h a t i t must act i n s o l u t i o n and not as a c a t a l y t i c s u r f a c e . ^ The f a c t t h a t the form i n which c o b a l t i s used i s not very important a l s o supports t h i s assumption. In the presence of compressed hydrogen and carbon monoxide at e l e v a t e d temperatures, c o n d i t i o n s used i n the Oxo Process, c o b a l t s a l t s are reduced and carbony-l a t e d . H 2 + C o + + —> Co + 2H + , : : . . 2Co + 8C0 y C o 2 ( C 0 ) 8 In the l a b o r a t o r y d i c o b a l t octacarbonyl i s o f t e n prepared by the r e a c t i o n o f cobaltous carbonate w i t h hydrogen and carbon monoxide under pressure.^ 2CoC0 3 + 2H 2 + 8C0 • Co 2(CO) 8 + 2H 20 +• 2C0 2 D i c o b a l t octacarbonyl i s r e a d i l y reduced to hydrogen t e t r a c a r b o n y l -7 c o b a l t a t e by hydrogen under h y d r o f o r m y l a t i o n c o n d i t i o n s . C o 2 ( C O ) 8 + H 2 — — > 2HCo(CO) k I f , however, an o l e f i n i s present the hydrogen t e t r a c a r b o n y l c o b a l t a t e appears only a f t e r h y d r o f o r m y l a t i o n i s complete. This suggests s t r o n g l y t h a t the a c t u a l c a t a l y s t i s the hydrocarbonyl of c o b a l t . E a r l y i n t e r -p r e t a t i o n s o f the mechanism o f the h y d r o f o r m y l a t i o n r e a c t i o n seem to be 2 8 9 completely obsolete s i n c e they d i d not take t h i s compound i n t o account, ' ' Much i n f o r m a t i o n about the mechanism has been obtained from the i n t e r a c t i o n o f o l e f i n s and hydrogen t e t r a c a r b o n y l c o b a l t a t e under carbon monoxide at atmospheric pressure and at room temperature, assuming a s i m i l a r behaviour under usual h y d r o f o r m y l a t i o n c o n d i t i o n s . Orchin and co-workers*^'** reacted 1-pentene under carbon monoxide (1 atm.) w i t h hydrogen t e t r a c a r b o n y l c o b a l t a t e and obtained n-hexaldehyde. They a l s o .examined the s t o i c h i o m e t r y o f the r e a c t i o n . 2HCo(C0) l + + CO •+ CH 3-(CH 2) 2-CH=CH 2 - > C o 2 ( C O ) 8 + CH 3-(CH 2)^-CHO The r e l a t i v e r a t e s of r e a c t i o n of v a r i o u s o l e f i n s under these c o n d i t i o n s . . 11 12 are s i m i l a r t o those under h y d r o f o r m y l a t i o n c o n d i t i o n s . '; In a mechanism 13 suggested by Sternberg and Wender the f i r s t step i s the formation of an intermediate i n which the o l e f i n has d i s p l a c e d a carbonyl group of the hydrogen t e t r a c a r b o n y l c o b a l t a t e . R H R H \ / \ • / H C + HCo^O)^ > C I II • ' . . ( I—> Co (CO) 3 + CO C C -R H R H This step i s almost c e r t a i n l y an e q u i l i b r i u m r e a c t i o n and e x p l a i n s why a high p a r t i a l pressure of carbon monoxide re t a r d s the normal hydroformy-l a t i o n r e a c t i o n . 1 4 A high carbon monoxide pressure would d i s f a v o u r the l i b e r a t i o n o f a molecule of carbon monoxide. There i s ample evidence f o r the replacement of carbonyl ligands by o l e f i n s . 1 * ' ^ The next step i s 13 a t r a n s f e r o f hydrogen from c o b a l t to carbon, f o l l o w e d by the a d d i t i o n o f a carbon monoxide molecule to the c o b a l t to form an a l k y l c o b a l t t e t r a -carbonyl d e r i v a t i v e . A carbonyl group from the cobalt i s then i n s e r t e d R H * \ : \ q y H f"2 |H 2 J — Co(CO) 3 • ^ C H-Co(CO) 3 C H - C o ( C O ) H R ^ N i R R between the a l k y l group and the cobalt atom to form an a c y l c o b a l t t e t r a -carbonyl d e r i v a t i v e . Although there seems to be no d i r e c t evidence i n the case of c o b a l t that the a c y l carbonyl group o r i g i n a t e s from the coba l t moiety, evidence has been obtained with analogous complexes of manganese usin g l l +C l a b e l l e d carbon monoxide, which i n d i c a t e s that the i n s e r t e d 21 carbonyl was o r i g i n a l l y bonded t o the metal. One can a l s o look upon t h i s r e a c t i o n as a m i g r a t i o n of the a l k y l group from the coba l t atom to a carbonyl l i g a n d . R R R ^ CH ? CO ^ CH 2 0 ^ CH 2 0 I * \ * CO I S ,CH - Co(CO) 3 v CH-C ' CH-C / y I / \ R R Co(CO) 3 R C O ( C 0 ) ^ The c o b a l t atom then captures another carbon monoxide molecule. Reduction by the hydrogen present under hyd r o f o r m y l a t i o n c o n d i t i o n s y i e l d s the aldehyde and l i b e r a t e s hydrogen t e t r a c a r b o n y l c o b a l t a t e . R X CH 2 I CH 0 I! • C-CoCCO)^ + H2 X CH 2 I CH - CHO HCo(C0) 4 A very s i m i l a r mechanism would explain the carbonylation of alcohols and ethers. It may also explain the appearance of a l k y l formates during 22 - 26 most hydroformylation reactions i n alcohol s o l u t i o n . 0 ROH HCoCCO)^ + CO •—• H-C0-Co(C0)4 HC - OR 27 Heck and Breslow , however, believe that hydrogen tetracarbonyl-cobaltate decomposes r e v e r s i b l y i n t o hydrogen t r i c a r b o n y l c o b a l t a t e which then complexes with the o l e f i n . They base t h e i r mechanism upon evidence that the formation of a l k y l tetracarbonylcobaltates i s i n h i b i t e d by carbon monoxide, which means that the i n i t i a l complexing with the o l e f i n would presumably require the p a r t i c i p a t i o n of a co-ordinately unsaturated carbonyl. I t i s , however, d i f f i c u l t to see where t h i s evidence c o n f l i c t s 13 with the mechanism proposed by Sternberg and Wender, Methyl tetracarbonylcobaltate i n an atmosphere of carbon monoxide absorbs exactly one mole of the gas to give acetyl tetracarbonylcobaltate indicated by the strong i n f r a r e d absorption band at 1728 cm - 1, which was 28 assigned to the a c y l carbonyl group. They also observed the same band at reduced i n t e n s i t y i n s o l u t i o n s of a l k y l tetracarbonycobaltates indicating the existence of an equilibrium between the a l k y l and acyl forms. R-CH^CoCCO)^ — > R-CH2-CO-Co(CO)3-CO R-CH2-CO-Co(CO)k As was mentioned e a r l i e r , Orchin and co-workers 1^' 1 1 had found that two moles of hydrogen tetracarbonylcobaltate react with an o l e f i n and carbon monoxide to y i e l d an aldehyde and dicobalt octacarbonyl. Breslow - 6 -28 and Heck found that the second mole of hydrogen tetracarbonylcobaltate Is involved i n the decomposition of the acyl complex to the aldehyde. 0 - II R-C-CoCCCOi, + HCoCCOK »- R-CHO + Co 2(CO) 8 29 Support i s also given by the observation by Heck that epoxyacrolein reacts with hydrogen tetracarbonylcobaltate under carbon monoxide to give dicobalt octacarbonyl. CH 2 2HCo(C0)i+ + f ^ TCH-CHO • Co 2(CO) 8 + HO-(CH2)2-CHO o ^ Presumably one molecule of the hydrocarbonyl opens the epoxide r i n g forming an a l k y l complex which then reacts with another molecule of the hydrocarbonyl before carbonylation can occur. This l a s t step must be ruled out under 28 hydroformylation conditions since i t i s completely i n h i b i t e d by carbon monoxide. Under pressure the acyl complex can be reduced by hydrogen alone. Since carbon monoxide i n h i b i t s the decomposition of the acyl complex i t i s believed that the acyl tetracarbonylcobaltate i s converted to the t r i -28 carbonyl which i s then reduced. This would also explain the adverse 14 e f f e c t of carbon monoxide upon the course of the hydroformylation reacti o n . It may also mean that the r e s u l t s obtained from the low-pressure reactions of o l e f i n s with carbon monoxide and hydrogen t e t r a c a r b o n y l c o b a l t a t e 1 ^ 1 2 cannot be applied i n d i s c r i m i n a t e l y to hydroformylation conditions. R-CH 2-C0-Co(C0) 3 + H 2 • R-CH2-CH0 + HCo(C0) 3 + 4-C0 R-CH^CO-CotCO)^ HCo(C0) 3+ CO ^ HCofCO)^ Under elevated temperatures and extended periods of time, and e s p e c i a l l y i n the carbohydrate f i e l d , the Oxo Reaction tends to give alcohols and not t h e i r corresponding aldehydes as products. - 7 -R-CH=CH2 + CO + 2H 2 R-CH2-CH2-CH20H For the sake of b r e v i t y , t h i s reaction i s c a l l e d hydrohydroxymethylation since i n essence i t represents the addition of the elements of methanol 30 across the double bond. Marko has proposed a mechanism f o r the hydro-hydroxymethylation of o l e f i n s which i s very reminiscent to those just discussed. R-CHO + HCo(C0) 3 > R-CH == 0 • R-CH2-0-Co(CO) 3 H—Co(CO) 3 H 2 R-CH 2-0-Co(C0) 3 — * R-CH20H + HCo(C0) 3 + 4- CO +4- CO R-CH 2-0-Co(C0) L f HCo(C0K ' The E f f e c t of Structure on the Hydroformylation Reaction The hydroformylation reaction i s applicable to a l l simple unsub-s t i t u t e d o l e f i n s . However., the rate of reaction and the types of products formed are greatly influenced by the structure of the substrate, but 12 c e r t a i n general rules have been found. Wender, Sternberg, and associates have made a thorough study of the influence of structure on the rate of hydroformylation. Of major importance i s the s t e r i c hindrance encountered about the double bond. Presumably, the reaction rate i s proportional to the ease of formation of a cobalt complex. Straight chain terminal o l e f i n s react most r e a d i l y and h i g h l y hindered ones not at a l l , or only a f t e r extensive rearrangements have occurred. Also, terminal s t r a i g h t - c h a i n o l e f i n s react more readily.than i n t e r n a l ones, the l a t t e r a l l reacting at approximately the same rate. A branching a l k y l group, even when remote from the o l e f i n i c bond decreases the rate markedly. A branching methyl group at one end of an i n t e r n a l double bond decreases the reaction rate about t e n - f o l d . Internal o l e f i n s bearing a branching a l k y l function on - 8 -both sides of the double bond react exceedingly slowly and often only a f t e r rearrangements have occurred. C y c l i c o l e f i n s having a strained r i n g system react more r e a d i l y than t h e i r corresponding s t r a i g h t chain i n t e r n a l o l e f i n s , whereas cyclo-hexene reacts more slowly. Since s t r a i n e d o l e f i n i c r i n g systems are ' 3 1 generally b e t t e r electron donors than unstrained ones, one might postulate that the more strained the r i n g the more r e a d i l y i t can complex to the cobalt atom. The Mode of Addition to the Double Bond Normal st r a i g h t - c h a i n o l e f i n s with a terminal double bond form the two expected isomeric aldehydes i n approximately equal amounts, the s t r a i g h t - c h a i n isomer usually predominating somewhat. CH3-CH =CH 2 + CO + H 2 > CH3-CH-CH3 + C H 3 - ( C H 2 ) 2 - C H 0 3 2 CHO 40% 60% 33 CHO CH3-CH2-CH = CH 2 + CO + H 2 > CH 3-(CH 2) 3-CH0 + CH3-CH2-CH-CH3 50% 50% In general the aldehyde group i s attached to the least hindered side of the double bond, although t h i s i s not necessary f o r the reactions of 27 hydrogen tetracarbonylcobaltate at room temperature. Under hydro-formylation conditions i t seems that an equilibrium i s established and that the thermodynamically more stable^product i s formed predominantly. Hence terminal o l e f i n s having a branch on the double bond give predom-33 34 i n a n t l y terminal aldehydes. ' CH 3 CHo ^ C = CH 2 + CO + H 2 ^CH-CH 2-CH0 CH 3 CH 3 - 9 CH3-CH2 • CH 2 + CO + H 2 C ° > CH3-CH2-CH-CH2-CH05 CH, + CO + H 2 .CH2-CH0 35 Straight-chain o l e f i n s having an i n t e r n a l double bond give approximately equal amounts of both expected products. A s i m i l a r behaviour has been found for c y c l i c o l e f i n s . S t e r i c hindrance about the double bond i s again important. Cyclohexene and cyclopentene give cyclohexanaldehyde and cyclo-36 37 pentanaldehyde re s p e c t i v e l y . ' C y c l i c o l e f i n s with a hindered double bond give the least hindered product. For example, A 1-p-menthene gives 38 p r i m a r i l y 2-methyl-5-isopropylcyclohexanaldehyde.' + CO + H5 Co CHO Ar y l substituted o l e f i n s react normally to give a mixture of aldehydes. Styrene, for instance, gives a mixture of 2- and 3-phenylpropionaldehydes. Aromatic compounds do not usu a l l y react and are often used as solvents (benzene, toluene). Dienes generally react v i a the less hindered double bond, the other one being only reduced as i s i l l u s t r a t e d by the hydroformylations of , . . . 5,40 . 41 butadiene and limonene. 39 CH 2 = CH-CH = CH 2 + CO + 2H 2-^°—*• CH 3- (CH 2) 3-CHO + CH3-CH2-CH-CH3 CHO + CO + 2H 2 Co CHO An exception are a,6-unsaturated aldehydes and ketones which are 42 very r e s i s t a n t to hydroformylation and are generally only reduced. 10 -CH3-CH = -CH-CHO + 2H 2 Co, CO CH3-(CH 2) 2-CH 20H '0' CHO + 2H : Co CO — CH20H The E f f e c t of F u n c t i o n a l Groups F u n c t i o n a l groups i n the o l e f i n molecule o f t e n have a d i r e c t i n g i n f l u e n c e upon the mode of a d d i t i o n t o the double bond during hydroformy-l a t i o n . ' Terminal o l e f i n s possessing a cyanide group give p r i m a r i l y t e r m i n a l aldehydes, the p o s i t i o n o f the cyanide.group i s unimportant. The cyanide group i s q u i t e u n r e a c t i v e under c o n d i t i o n s necessary f o r hy d r o f o r m y l a t i o n . NC-CH = CH 2 + CO + H 2 ——>• NC-CH 2-CH 2-CH0 4 3 , 4 4 NC-CH2-CH=CH2 + CO + H, Co NC-CH2-CH2-CH2-CH0 36,37 NC-(CH 2) 3-C = CH 2 + CO + H 2 C ° > NC-(CH 2) 3-CH-CH 2-CHO 4 5 CH: CH ^3 A carboxy group adjacent t o a double bond u s u a l l y d i r e c t s the e n t e r i n g formyl group to the g-position.' 0 Co 5,46,47 CH30-C-CH = CH 2 + CO + H 2 0 0 II CH30-C-CH2-CH2-CH0 0 " Co U C 2H 50-C-CH = CH-CH3 + CO + H 2 ^ > C 2H 50-C-CH 2-CH-CH 3 CHO However, diet h y l f u m a r a t e can be hydroformylated. 5 Adkins and Kr s e k 5 have found t h a t , w h i l e a l l y l i c ethers give mainly products b e a r i n g the formyl group i n the g - p o s i t i o n , v i n y l a l c o h o l e s t e r s and v i n y l aldehyde e s t e r s react i n the opposite way. - 11 C 2H 5-0-CH 2-CH = CH 2 + CO + H 2 C 2H 5-0-CH 2-CH-CH 3 • CHO' 75% + C2H5-0-(CH2)3-CHO 10% V i n y l e t h e r s , i n c o n t r a s t to v i n y l e s t e r , appear t o form mainly -alkoxy aldehydes. nBu-O-CH = CH 2 + CO + H 2 0 II CH3-C-0-CH=CH2 + CO + H 2 -*• n-Bu-0-CH2-CH2-CH0 0 CH3-C-0-CH-CH3 + some CH3-C-0-CH2-CH2-CHO The Hydroformylation o f C y c l i c V i n y l Ethers The behaviour o f the c y c l i c v i n y l ethers under hydroformylation c o n d i t i o n s i s of p a r t i c u l a r i n t e r e s t s i n c e they are s t r u c t u r a l l y r e l a t e d t o the g l y c a l s . The most i n t e r e s t i n g , of course, i s 2,3-dihydro-4H-pyran 48 (3,4-dideoxypental), which has been i n v e s t i g a t e d by Falbe and Korte. They used c o n d i t i o n s s u f f i c i e n t l y vigorous t o reduce the aldehydes t o a l c o h o l s , thus the r e a c t i o n a c t u a l l y c o n s t i t u t e d a hydrohydroxymethylation. In c o n t r a s t to a c y c l i c v i n y l ethers 2,3-dihydro-4H-pyran gives p r i m a r i l y 2-hydroxymethyltetrahydropyran and i n a d d i t i o n s m all amounts of 3-hydroxy-methyltetrahydropyran and tetrahydropyran. + CO + 2H 2 Co .CH2OH CH20H 0 • 78% 8% 3% Under s i m i l a r c o n d i t i o n s 2-hydroxymethyl-2,3-dihydro-4H-pyran (3,4-dideoxy-hexal) gives only 2,6-bis-hydroxymethyltetrahydropyran. - 12 -H0H2C •+ CO + 2H 2 Co •0 H0H2C *CH20H When the 2 - p o s i t i o n of the double bond i s blocked by an a l k y l group the mode o f a d d i t i o n i s reversed, but more d r a s t i c c o n d i t i o n s are r e q u i r e d and the y i e l d i s lower. -+ CO + 2H 2 Co H 3C 0 VCH 3 0 CH 20H C H c 42 The d i r e c t i o n of a d d i t i o n i n furan i s the same as f o r hydropyran but i t a l s o reacts l i k e a t y p i c a l conjugated diene. One double bond i s hydrogenated while the other one undergoes normal hydrohydroxymethylation, + CO + H; Co 42 CH 20H H,C CH: + CO + H 2 Co H 3 C •CH20H •CHo Few workers have i n v e s t i g a t e d whether the hydrof o r m y l a t i o n represents a c i s or trans a d d i t i o n t o the double bond. The hydrohydroxymethylation o f s t e r o i d s having a double bond i n the A 5 - p o s i t i o n y i e l d s i n each case a 6 - a - h y d r o x y m e t h y l a l l o s t e r o i d , 5 ^ ' 5 * hence the r e a c t i o n i s a c i s - a d d i t i o n . 5 ^ This mode of a d d i t i o n i s a l s o supported by work i n t h i s l a b o r a t o r y . 13 -Reaction Conditions The composition of the products from the hydroformylation reaction can be somewhat influenced by the experimental conditions. High pressure 52 (above 500 atm.) favours the formation of s t r a i g h t - c h a i n aldehydes. The same r e s u l t can be apparently obtained by using ether as a solvent. The normal hydroformylation of propylene y i e l d s a mixture c o n s i s t i n g of 60% n-butyraldehyde and 40% isobutyraldehyde, i f ether i s present only n-butyraldehyde i s formed. The product composition i s pressure dependent. Ethylene at 125 atmospheres gives a mixture of 50% propionaldehyde and 22% diethylketone, whereas at 500 atm i t gives 92% propionaldehyde. At high temperatures only diethylketone, a true Oxo product, i s formed. General Considerations The amount of c a t a l y s t required f o r t h i s reaction i s very small, i t i s s u f f i c i e n t to pass the reacting gases over c o b a l t . 5 3 , 5 4 In contrast to the Fischer-Tropsch synthesis the Oxo Reaction i s favoured by small amounts of sulphur compounds. The reaction i s generally performed at temperatures of 100°C to 200°C and pressures of 20 to 300 atm. These conditions may be mainly required f o r the formation of hydrogen tetracarbonylcobaltate and not n e c e s s a r i l y f o r the actual hydroformylation. A maximum y i e l d of aldehydes i s favoured at high pressures (500 atm.) and low temperatures; temperatures o 37 above 180°C favour reduction to alcohols. The solvents used most often are benzene, toluene, alcohols, e t h e r s , 5 52 55 a c e t i c anhydride, and water. 1 The reaction can also be performed i n the gas phase. Alcohols have been used as solvents to capture s e n s i t i v e aldehydes as the acetals and thus prevent further r e d u c t i o n . 4 3 A c e t i c anhydride, which gives the geminal diacetate i s used f o r a s i m i l a r purpose. 5^ - 14 -According to Pino orthoformates are the best agents to capture aldehydes. An i n t e r e s t i n g r e a c t i o n i s a l s o the hyd r o f o r m y l a t i o n of a c e t a l s i n a l c o h o l s o l u t i o n . 5 ^ ' " ^ The hydro f o r m y l a t i o n of methanol gives a large number o f products, mainly various e s t e r s o f a v a r i e t y of f a t t y a c i d s . Side Reactions Various s i d e r e a c t i o n s have been observed during Oxo c o n d i t i o n s . Aldehydes may undergo a l d o l condensations. Lower o l e f i n s tend to po l y -merise and rearrange under the i n f l u e n c e of the a c i d i c hydrogen t e t r a -c a r b o n y l c o b a l t a t e , hydrogenation may a l s o be observed. Reduction of the aldehydes gives r i s e to a l c o h o l s which i n t u r n react w i t h unreduced aldehydes to form a c e t a l s . ^ 3R - CH = CH 2 + 3C0 + 5H 2 C ° > R-(CH 2) 3-0 ^CH-(CH) 2-R R - ( C H 2 ) 3 - 0 ^ Extremely s l o w l y r e a c t i n g o l e f i n s can undergo rearrangements to more r e a c t i v e s p e c i e s . T h u s , the hydro f o r m y l a t i o n of tetramethylethylene gives only 3,4-dimethylpentanaldehyde as the product. CH 3 CH 3 CH 3 CH 2 CH 3 CH2-CH0 C = C • CH - C + CO + H 2 CH - CH / \ / X / \ CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 The G l y c a l Acetates The g l y c a l s represent the best known group o f unsaturated carbohydrates. The most common one, 3 , 4 , 6 - t r i - O - a c e t y l - D - g l u c a l , was prepared by E. F i s c h e r i n 1913 by the dehydrobromination and r e d u c t i o n of 2, 3 , 4 , 6 - t e t r a - 0 - a c e t y l -q-D-gluco-pyranosyl bromide, commonly known as acetobromoglucose, w i t h z i n c i n 62 a c e t i c a c i d . The name o r i g i n a t e d because of the o r i g i n a l erroneous b e l i e f that glucaL contained an aldehyde group. CHxOAc 0 A C AcO Oflc A :0 Since C-2 loses i t s asymmetry during double bond formation, two C-2 epimeric sugars y i e l d the same g l y c a l ; both mannose and glucose give glucal (mannal). The mechanism for the formation of acetylated glycals from acetylated ft ^ glycosyl halides seems to be uncertain. According to Overend the formation of t r i a c e t y l - D - g l u c a l from tri-0_-acetyl-a-D-glucosyl bromide begins with the loss of a bromide ion from the g l y c o s y l h a l i d e to give a carbonium ion which i s reduced to a carban ion by z i n c . E limination of the C-2 acetoxy group as an acetate ion gives the g l y c a l . The carbonium ion i s presumably s t a b i l i s e d by acetoxonium ion formation with the C-2 acetate function . Ofk. \ Br fitO O f l c 4-OPK. A AcO De-0_-acetylation of the acetylated g l y c a l s does not disturb the o l e f i n i c bond. The glycals undergo most o f the standard reactions of unsaturated compounds and hence are very useful substrates f o r the preparation of a - 16 -v a r i e t y of carbohydrate d e r i v a t i v e s . Hydration i n the presence of s u l p h u r i c a c i d o f D-glucal r e s u l t s i n 2-deoxy sugars and small amounts of furan d e r i v a t i v e s . ^ 4 ^ Hr.0 > u o 6 9 C a t a l y t i c hydrogenation of D-glucal gives the corresponding dihydro d e r i v a t i v e . OH HO Both c h l o r i n e and bromine add r e a d i l y t o form the dihalogeno derivative.62,64,68 69 Iodine does not seem to r e a c t . The Prevost reagent adds r e a d i l y t o g l y c a l s . O z o n i s a t i o n leads t o aldose d e r i v a t i v e s of one l e s s carbon atom. The o x o n i s a t i o n of 3 , 4 , 6 - t r i - O - a c e t y l - D - g l u c a l gives 2,3,5-tri-O-acetyl-D-arabinofuranose. Hydroxylationsof the g l y c a l double bond with perbenzoic a c i d or hydrogen peroxide i n the presence o f osmium t e t r o x i d e proceed normally; depending on the reagent the C - l and C-2 hydroxyl groups are v i r t u a l l y c i s or trans. D-Glucal gives Q-mannose^5 when t r e a t e d w i t h perbenzoic a c i d , 70 w h i l e 3 , 4 , 6 - t r i - O - a c e t y l - D - g l u c a l y i e l d s the D-glucose d e r i v a t i v e . The Conformation of G l y c a l s The g l y c a l r i n g i s f o r c e d i n t o a h a l f - c h a i r conformation because o f the c o n s t r a i n t imposed upon the molecule by the 1,2-double bond;- the oxygen atom and carbon atoms 1,2 and 3 l i e roughly i n a plane. Two h a l f -c h a i r conformations are p o s s i b l e , depending upon the p o s i t i o n s of c o n s t i t u e n t s . - 17 -3,4,6-tri-0_-acetyl-D-glucal can exi s t i n one h a l f - c h a i r conformation where a l l acetoxy groups are i n a pseudo-equatorial p o s i t i o n , or one where they are a l l pseudo-axial. OAc A l l acetoxy groups A l l acetoxy groups pseudo-equatorial pseudo-axial 71 H a l l has investigated the conformation of 3,4,6-tri-0_-acetyl-D-glucal i n so l u t i o n . The r e s u l t s showed that the dihedral angle between C-3-H' and C-4-H i s roughly 140°, and that between C-4-H and C-5-H i s about 150° and hence confirmed that the conformation with a l l acetoxy groups pseudo-equatorial i s preferred. The Mode of Addition to Glycal Double Bonds In most cases additions to glycals are greatly influenced by the r i n g oxygen. In general they react l i k e v i n y l ethers and e s p e c i a l l y 2,3-dihydro-4H-pyran. The p o l a r i t y of the double bond explains the mode of addition of water, 63 alcohols or hydrogen h a l i d e s . -.18 -ROM > / \ . — O R R = H or a l k y l C l , Br, I Cis-Additions to the Glycal Double Bond The most important c i s - a d d i t i o n s i n respect to the hydroformylation reaction are those i n v o l v i n g the reaction of a whole molecule with the o l e f i n , representing molecular additions. Examples of molecular additions are the hydroxylations of o l e f i n s with osmium tetroxide or potassium 72 73 permanganate. I f the oxidation with osmium tetroxide ' i s conducted i n a non-hydrolytic solvent the osmate ester can be i s o l a t e d . R \ R \ R \ CH XCH — 0 CHOH « + OsO, • C H - 0 - 0 s 0 2 — ^ CHOH + H 2 ° s 0 « R R R ^ Traces of osmium tetroxide i n the presence of other strong o x i d i s i n g agents 74 75 are usually s u f f i c i e n t . ' The permanganate hydroxylation follows a . „, 76 s i m i l a r path. . . R \ R R CH ^ C H 0 ^ C H O H J H + M n ° ^ — C H - 0 > n ° 2 \ CHOH Another method f o r synthesising c i s - g l y c o l s from o l e f i n s i s the reaction 77 with iodine and s i l v e r acetate, which involves an orthoester intermediate. - 19 -R CH I! CH + I. R CH I ' ,CH' 0 OAc CH I CH I OAc H,0 'CH i CH CH: OH H,0 CHOH I CHOH An i n t e r e s t i n g molecular a d d i t i o n i s the r e a c t i o n of c h o l e s t e r y l benzoate with iodobenzenedichloride which gives r i s e to 5a, 6 a - d i c h l o r o c h o l e s t a n -79 33-yl benzoate. The att a c k i s from the l e s s hindered s i d e of the molecule. Hydroboration o f o l e f i n s a l s o gives c i s - a d d i t i o n products. Thus the hydroboration of-1-methylcyclohexene gives pure trans-2-methylcyclo-hexanol 80 -> 81 Meinvvrald a n d co-workers suggest a four centre mechanism with l i t t l e or no carbonium ion character f o r the intermediates formed on the a d d i t i o n o f n i t r o c h l o r i d e to norbornadiene. - 20 -This r e a c t i o n has been a p p l i e d t o 3 , 4 , 6 - t r i - O - a c e t y l - D - g l u c a l to a f f o r d 82 3 >4,6-tri-0-acetyl-2-depxy-2-nitroso-cc-D-gluco pyranosyl c h l o r i d e . NO The r e a c t i o n o f 3,4-di-O-acetyl-D-arabinal w i t h n i t r o s y l c h l o r i d e gives the g- g l y c o s y l h a l i d e . I t appears that the C-3 acetoxy group exerts a d i r e c t i n g i n f l u e n c e , an e f f e c t which w i l l be di s c u s s e d l a t e r . The l i g h t - c a t a l y s e d molecular a d d i t i o n o f phenanthrenequinone to 83-84 g l y c a l s i s w e l l known. The r e a c t i o n had f i r s t been a p p l i e d to other . ... 86 o l e f i n s . - 21 -Trans-Addition to the Glycal Double Bond The majority of trans-additions to double bonds are the r e s u l t of e l e c t r o p h i l i c attack. The addition of halogens, hydrogen hal i d e s , hypo-halous acids, water i n the presence of acids, sulphenyl h a l i d e s , and the Prins Reaction, among many others, are of t h i s type. In most cases where the stereochemistry has been studied a trans-addition was found. For instance,the addition of bromine to maleic a c i d y i e l d s (+)-2,3-dibromo-87 88 su c c i n i c a c i d by the following reaction path. R c 6 ^ The hydroxylation of o l e f i n s by peracids also produces trans 89 g l y c o l s . The f i r s t product i s the epoxide which i s subsequently opened 90 by rearward attack to give the monoester of a g l y c o l . In c y c l i c systems the preferred s t e r i c path of trans-addition i s such as to 91 favour a t r a n s - d i a x i a l product. Hence g l y c a l s can give r i s e to two series - 22 -of. compounds upon t r a n s - d i a x i a l opening of a c y c l i c i n t e r m e d i a t e . M e r c u r i c acetate i n methanol s o l u t i o n adds t o 3 , 4 , 6 - t r i - 0 - a c e t y l -92-94 D-glucal t o g i v e a trans product. I t appears t h a t the l a r g e C-3 acetoxy group prevents attack from the B-side of the molecule, an assumption supported by d i s c o v e r y t h a t the r e a c t i o n of D-glucal under s i m i l a r c o n d i t i o n s may give methyl 2-acetoxymercuric-2-deoxy-92 « q-D-manno-pyranoside. The A c e t y l a t e d G l y c o s y l Halides G l y c o s y l h a l i d e s are carbohydrate d e r i v a t i v e s i n which the hemiacetal hydroxyl group i s r e p l a c e d by a halogen atom. They are prepared as acetates benzoates; only p e r a c e t y l g l y c o s y l f l u o r i d e s are s u f f i c i e n t l y s t a b l e to s u r v i v e d e - O - a c e t y l a t i o n , the others lose the halogen atom. They are very r e a c t i v e compounds and hence q u i t e s u i t e d as substrates f o r f u r t h e r r e a c t i o n s . Both furanose and p y r a n o s e : r i n g systems are encountered. In g e n e r a l , both • - 2 3 - ' the "a- and B-anomers can be formed although they may d i f f e r g r e atly i n s t a b i l i t y . The most important f a c t o r i n f l u e n c i n g the s t a b i l i t y of acetylated glycosyl halides seems to be the p o s i t i o n of the halogen atom i n r e l a t i o n to the lone electron p a i r s of the r i n g oxygen atom (the anomeric e f f e c t ) . That isomer whose usual conformation permits the greater distance between the halogen and the lone electron p a i r s of the r i n g oxygen i s generally the more stable one. Hence the more stable isomer has the halogen atom i n an a x i a l o r i e n t a t i o n . Thus, i f the acetoxy substituents and the C-5 acetoxy methyl group are i n a configuration supporting a conformation which allows the halogen to be a x i a l , then the compound w i l l be more stable than i t s anomer. For example, 2,3,4,6-tetra-O-acetyl-oi-D-glucosyl bromide i s more stable than the 8-anomer. Indeed, t h i s c r i t e r i o n becomes so important for acetylated and benzoylated pentopyranosyl f l u o r i d e s , : that the f l u o r i n e atom . , . 9 5 always assumes an a x i a l o r i e n t a t i o n . 96 The empirical rules which have been promulgated to explain the s t a b i l i t i e s of substituted g l y c o s y l halides can be explained i n t h i s manner. The cc-isomer i s usually found to be more stab l e , because t h i s permits the C-5 acetoxymethyl to assume an equatorial p o s i t i o n i n the stable conformer. For s i m i l a r reasons the same holds true f o r the furanosyl s e r i e s . Among acetylated penta-pyranosyl halides the stable isomer has a trans-re1ation-ship between the C-3 acetoxy group and the halogen atom. The s t a b i l i t y of the acetylated glycosyl halides increases markedly from the iodides to the f l u o r i d e s . The Preparation of Acetylated Glycosyl Halides Most procedures f o r the preparation of peracetyl g l y c o s y l halides begin with the completely acetylated sugar which i s halogenated. The - 24 -halogenating agent i s frequently the hydrogen halide which i s added as 97-100 ' such, or i s prepared i n s i t u by the action of water upon the phosphorus t r i h a l i d e (bromide). 1^ 1' Hydrogen iodide i n g l a c i a l a c e t i c a c i d i s used 103 to prepare peracetyl glycosyl iodides. S i m i l a r l y , acetofluoro sugars are prepared with hydrogen f l u o r i d e i n a c e t i c a n h y d r i d e . ^ 4 ' S e n s i t i v e halides can be prepared by the action of hydrogen chloride i n ethyl e t h e r 1 ^ ' 108 or hydrogen bromide i n benzene. A f t e r the reaction i s complete, the solvent and excess hydrogen halide may be d i s t i l l e d o f f . Reaction with anhydrous hydrogen halides has also been used f o r s e n s i t i v e sugar acetates such as t r i - O - a c e t y l r i b o f u r a n o s e . 1 ^ The t e t r a c h l o r i d e s of titanium and t i n are useful as c h l o r i n a t i n g agents. Titanium t e t r a c h l o r i d e reacts r e a d i l y with penta-0_-acetyl-B-D-gluco pyranose to y i e l d the B - c h l o r i d e . 1 1 1 1 1 3 Benzoylated chlorides may also be made t h i s way. 1 1 4 Other c h l o r i n a t i n g reagents are aluminum and t . . j 115,116 phosphorus t r i c h l o r i d e s . Acetylated 2-deoxy gly c o s y l halides may be r e a d i l y prepared by the 117 addition of hydrogen halides to acetylated g l y c a l s i n an i n e r t solvent. The action of hydrogen bromide on 3,4,6-tri-O-acetyl-D-glucal leads to 3,4,6-tri-O-acetyl-2-deoxy-a-D-glucosyl bromide.64,118 The Reactions of Acetylated Glycosyl Halides Of p a r t i c u l a r i n t e r e s t are the n u c l e o p h i l i c s u b s t i t u t i o n reactions of acetylated glycosyl h a l i d e s . A well studied example i s the displacement of one halid e atom by another. This reaction can occur with and without inversion at C - l . In general, the reaction occurs with inversion i f the halide atom and the C-2 acetoxy group are i n a c i s - configuration and with retention i f they are trans- oriented. - 25 -OAc. 119 Lemieux has p o s t u l a t e d an acetoxonium i o n as an intermediate. Heyns and co-workers have sy n t h e s i s e d such acetoxonium i o n s t r u c t u r e s . ' 1 2 1 -119 By Lemieux's mechanism, the a c t i o n of s i l v e r c h l o r i d e upon 2,3,4,6-tetra-O-acetyl-a-Q-glucosyl bromide to give 2,3,4,6-tetra-0_-acetyl-g-D-glucosyl c h l o r i d e , can be r e a d i l y e x p l a i n e d . The a c e t y l a t e d a-Q-g l u c o s y l bromide molecule loses a bromide i o n to give a carbonium ion which i n t e r a c t s i n t r a m o l e c u l a r l y w i t h the C-2 acetoxy group to produce an acetoxonium i o n . This c y c l i c acetoxomium i o n i s opened by the c h l o r i d e i o n to give the product i n v e r t e d at C - l . AcO ^ °flt S i m i l a r l y , 2,3,4,6-tetra-0 :acetyl-a-D-mannosyl bromide r e a c t s w i t h c h l o r i d e 122 i o n without i n v e r s i o n . - 26 -cu 5 Likewise 2,3,4-tri-O-benzoyl-g-D-ribo-pyranosyl bromide r e a c t s w i t h s i l v e r c h l o r i d e without i n v e r s i o n . S i l v e r f l u o r i d e i n a c e t o n i t r i l e s o l u t i o n reacts 123-125 wi t h p e r a c e t y l g l y c o s y l h a l i d e s t o y i e l d f l u o r i d e s i n the same manner. The a c t i o n of s i l v e r acetate on a c e t y l a t e d g l y c o s y l h a l i d e s gives the 1-acetate. OA. oAc Moist s i l v e r carbonate i n acetone replaces the halogen atom by a hyd r o x y l 127,128 group. CUxoAc The a c t i o n o f Grignard reagents upon p e r a c e t y l g l y c o s y l h a l i d e s y i e l d s a mixture of products; thus the r e a c t i o n of t e t r a - O - a c e t y l - a - D - g l u c o s y l bromide w i t h phenylmagnesium bromide gives 25% of the a-anomer and 75% of 129 130 the g-anomer ' (see below). - 27 -The A c e t y l a t e d 2-Hydroxyglycals 2-Hydroxyglycals or 1,2-glycoseens are d e r i v e d from the c y c l i c sugar molecule by the l o s s of the elements of water from C - l and C-2. They are known only as d e r i v a t i v e s , such as a c e t a t e s , benzoates, and methyl e t h e r s . They are prepared by the e l i m i n a t i o n o f hydrogen h a l i d e from the a c y l g l y c o s y l bromides by the a c t i o n of a base such as diethylamine i n an i n e r t s o l v e n t , or by the a c t i o n of sodium hydroxide i n the case of O-methylated d e r i v a t i v e s . * " ^ 4 ' * ^ 5 2, 3,4,6-Tetra-0_-acetyl-a-D-glucosyl bromide reacts with diethylamine i n benzene t o give 2,3,4,6-tetra-0_-acetyl-2-hydroxy-D-. ,122,131,132 g l u c a l . ' ' OAc 133 The corresponding benzoates r e a c t i n the same way. The A c e t y l a t e d 3-Deoxy-hex-2-enopyranoses The i s o m e r i s a t i o n of a c e t y l a t e d g l y c a l s has r e c e i v e d considerable a t t e n t i o n . The ready d i s s o c i a t i o n o f the C-3 acetoxy group r e s u l t s from the a c t i v a t i o n of the 3 - p o s i t i o n towards carbonium i o n formation by the a l l y l i c double bond. The r i n g oxygen can a l s o p a r t i c i p a t e i n the charge d e l o c a l i s a t i o n . - 28 -CH^OAc CHLOAc The c l a s s i c a l example i s the isomerisation of 3,4,6-tri-0_-acetyl-D-glucal 62 135-139 to 4,6-di-O-acetyl-iJj-D-glucal by the action of hot water. ' AcO OAc CU2OAc CUtOAt. Aco >H,OH AcO The base hydrolysis of 4,6-di-O-acetyl - i J j - Q-glucal with barium methoxide 140 y i e l d s i s o g l u c a l as one of the products. 136 CUxOAc AcO AcO 141 Lemieux, Wolfrom, and co-workers have performed s i m i l a r isomerisation on the 2-acetoxy-l-enose s t r u c t u r e . The acid catalysed rearrangement of 2,3,4,6-tetra-0-acetyl-2-hydroxy-D-glucal y i e l d s the isomeric tetra-0-141 142 acetyl-Q-erythro-hex-2-enopyranose i n high y i e l d . ' Zinc c h l o r i d e , sulphuric a c i d and p-toluenesulphonic a c i d i n a c e t i c anhydride are good ." . _ 141,143 cat a l y s t s ' • . 29 -Extended treatment with zinc chloride i n a c e t i c anhydride converts 2,3,4,6-tetra-0-acetyl-2-hydroxy-D-glucal into 1,2,4,6-tetra-0-acetyl-3-deoxy-a-D-t h r e o - h e x - 2 - e n o p y r a n o s e , 1 4 1 , 1 4 3 a material r e a d i l y prepared by the acid 143 144 catalysed isomerisation of 2,3,4,6-tetra-0-acetyl-2-hydroxy-D-galactal. ' Cobalt Carbonyl Derivatives Carbon monoxide commonly acts e i t h e r as a monodentate ligand or a bi v a l e n t bridging group. In both cases two electrons are involved i n bond formation. In a few examples carbon monoxide i s bound to three metal atoms. In the metal carbonyls the metal atom normally attains the e f f e c t i v e atomic number of the next noble gas. Hence metals of even atomic number can form simple carbonyls, while those of odd atomic number cannot form monomeric carbonyls. Thus the carbonyls formed by cobalt, manganese and vanadium are dimeric, Co 2(CO) 8, Mn 2(Co) 1 0, and V 2 ( C O ) 1 2 r e s p e c t i v e l y . Metal carbonyls having other ligands besides carbon monoxide may lead to compounds which do not obey the noble gas r u l e . Manganese, f o r example forms a mono-145 146 meric tetracarbonyl tricyclohexylphosphine d e r i v a t i v e . ' This compound i s , of course, paramagnetic. In the dimeric carbonyls the two metal atoms are bonded by a metal-metal bond, with or without the a i d of bridging carbonyl groups. X-ray measurements on c r y s t a l l i n e d i c o b a l t octacarbonyl indi c a t e two bridging and s i x terminal carbonyl groups. The bridging groups are 147 l y i n g i n two i n t e r s e c t i n g planes. In s o l u t i o n t h i s compound may e x i s t ; - ' 3 0 - ' • • •'". " 148 i n two isomeric forms, one of which does not contain bridging carbonyls. Upon reaction with triphenylphosphine dicobalt octacarbonyl changes to a 149 dimeric complex having only a metal-metal bond and no b r i d g i n g ligands. o c {CC} r j V C C " • r ° \ + 2 P ( b <f>3P(OC)3Co — Co(CO) 3P^ 3 0 Besides t r i a l k y l and triarylphosphines, triphenylphosphite also displaces 150 two carbonyl ligands without disproportionation, phosphites being more reac t i v e than phosphines. Tetracarbonylcobaltates Hydrogen tetracarbonylcobaltate may be r e a d i l y synthesised by reducing 7 d i c o b a l t octacarbonyl with a v a r i e t y of agents such as hydrogen or l i t h i u m aluminum h y d r i d e . 1 5 1 It i s a poisonous l i q u i d of remarkably bad odour. It i s very a c i d i c , and i s completely i o n i s e d i n water. In the absence of o x i d i s i n g agents, hydrogen tetracarbonylcobaltate i s stable i n aqueous s o l u t i o n . Oxidising agents react with hydrogen tetracarbonylcobaltate to form dicobalt 152 octacarbonyl. The reducing properties are due to the cobaltate anion. 2Co(C0)J" > Co t(C0) g + 2e~ ( E 0 = -0.4 Volts at 20°) Upon warming the hydrocarbonyl decomposes to hydrogen and the octacarbonyl. ^HCoCCO)^ — C o 2 ( C 0 ) 8 + H 2 In the presence of grease i t decomposes to m e t a l l i c cobalt, carbon monoxide, i n and hydrogen. The composition of the grease i s unknown. It i s a good 153 reducing agent capable of hydrogenating o l e f i n s . <j)-C=GH2 + 2HCo(C0)i+ + (j,-CH-CH3 + C o 2 ( C 0 ) 8 ; CH 3 •• CH 3 -• 31 -In the presence of hydrogen^dicobalt octacarbonyl i s a good reducing agent; 153 154 presumably hydrogen tetracarbonylcobaltate i s the actual reagent. ' Co 2(CO) 8 + 2H 2 • Co 2(CO) 8 <j)-CHOH-(j) + H 2 y <j)-CH2-<j) The c a t a l y t i c e f f e c t of hydrogen tetracarbonylcobaltate i n the Oxo Reaction has been discussed previously. Hydrogen tetracarbonylcobaltate gives i o n i c soluble s a l t s with the a l k a l i metals, while some metals such as mercury give covalent compounds. The sodium and potassium carbonylcobaltates are soluble i n many solvents, in c l u d i n g water and ethyl ether. A determining f a c t o r for a choice of method of preparation i s the solvent i n which they are formed and i t s subsequent usefulness. The reduction of cobalt s a l t s by carbon monoxide i n the presence of a l k a l i i n the aqueous phase leads to the a l k a l i metal carbonyl-cobaltate. 1 5 5 ' 1 5 ^ An elegant method f o r the preparation of a l k a l i carbonyl-cobaltates i s the reduction of d i c o b a l t octacarbonyl by the a l k a l i metal or i t s amalgam i n tetrahydrofuran or ethyl ether at room temperature i n an i n e r t u 'A 4 - u 151,157,158 or carbon monoxide atmosphere. / Co 2(CO) 8 + 2Na y ZNaCoCCO)^ Reduction of cobaltcarbonyl by l i t h i u m aluminum hydride y i e l d s the l i t h i u m 152 carbonylcobaltate. A l k y l Carbonylcobaltates Sodium tetracarbonylcobaltate reacts r e a d i l y with methyl iodide i n ethyl ether to a f f o r d methyl t e t r a c a r b o n y l c o b a l t a t e . 1 5 ^ ' 1 5 9 NaCoCCCO^ +• CH 3I y CH 3Co(CO)^ + Nal 158 ' Other a l k y l d e r i v a t i v e s are prepared analogously. While the coba l t compounds are unstable (methyl t e t r a c a r b o n y l c o b a l t a t e decomposes at -35°C),*^ 21 the corresponding manganese compounds are s t a b l e . The replacement of a carbonyl l i g a n d by triphenylphosphine or t r i p h e n y l p h o s p h i t e s t a b i l i s e s the a l k y l c a r b o n y l c o b a l t a t e c o n s i d e r a b l y . * ^ CH 3Co(CO)i t_ CH3Co(CO)3P(0<f0 3 CH3Co(CO) 3P<f>3 Decomposition temperature -35°C 0°C 20°C M e l t i n g p o i n t -44°C 10°C 30°C I t was i n d i c a t e d e a r l i e r t h a t a l k y l carbonyl c o b a l t a t e s can undergo c a r b o n y l a t i o n to an a c y l d e r i v a t i v e i n the presence of carbon monoxide. I t 28 i s b e l i e v e d t h a t the a l k y l t e t r a c a r b o n y l c o b a l t a t e i s converted to the a c y l t r i c a r b o n y l which absorbs carbon monoxide to form a c y l t e t r a c a r b o n y l c o b a l t a t e . R-CoCCCO^ • R-CO-Co(CO) 3 — R - C O - C o (CO) h The a c t u a l mechanism f o r the carbonyl i n s e r t i o n step i s not known; sin c e c o b a l t c a r b o n y l d e r i v a t i v e s exchange t h e i r ligands r a p i d l y with the carbon monoxide atmosphere,*^* i t has not been p o s s i b l e to employ t r a c e r s . Since manganese d e r i v a t i v e s undergo s i m i l a r i n s e r t i o n s the mechanism may be the same. The a l k y l and a c y l pentacarbonylmanganates can be i n t e r c o n v e r t e d i n t o , 21 each other. 0 <|>-C-Mn(CO) 5 n ) (j>-Mn(CO)5 + CO <j> = phenyl *~C0 Tracer experiments w i t h r a d i o - a c t i v e carbonyls show th a t the carbon monoxide evolved does not o r i g i n a t e from the a c y l group; s i m i l a r l y the absorbed carbon monoxide does not become the a c y l group. - 33 -Mn(CO)5 heat <j)-Mn(CO)ttCO + CO * CO R OC oc CO CO Branched-Chain Carbohydrates The branched-chain carbohydrates have, as the name suggests a branched carbon atom skeleton. Although the chemistry of the n a t u r a l l y occurring branched-chain sugars i s r e l a t i v e l y recent, that of the synthetic ones i s quite old, the f i r s t one having been reported i n 1885 by H. K i l i a n i . ^ The n a t u r a l l y occurring branched-chain . carbohydrates can be c l a s s i f i e d into two groups; those where the branch substitutes a hydrogen atom and those where i t substitutes a hydroxyl group. Plant branched-chain sugars are of the 163 f i r s t kind while those produced by micro organisms are of both types. The branching groups u s u a l l y encountered i n nature are: methyl, hydroxy methyl, f o r m y l , 1 ^ 3 and h y d r o x y e t h y l . ^ 4 Examples have been l i s t e d by Overend. The structures of synthetic branched-chain carbohydrates show great v a r i e t y . The most frequently encountered methods are l i s t e d below. cyanide group as a branch. Hydrolysis leads to acids which can be reduced. The K i l i a n i Synthesis 162,165-167 The action of hydrogen cyanide on ketoses affords compounds with a - 34 -I I H 20 | C=0 + HCN >• C(OH)CN > C(OH)COpH I I t Z C C C r p i „ . , D • , . 168,168 The Grignard Reaction The Grignard r e a c t i o n has been a p p l i e d to s u i t a b l y s u b s t i t u t e d keto-sugars by Overend. C C I I C=0 + RMgX ) C(OH)R I I C . C . Dialkylmagneslum Overend and co-workers have employed diethylmagnesium to open the epoxide r i n g i n order to synthesise branched-chain carbohydrates. C C 1 I CH HCR + R ^ HOCH I I C C 171 172 Diazo Compounds ' The a c t i o n o f diazomethane on carbohydrate d e r i v a t i v e s w i t h a keto group gives an epoxide grouping as a branch. A c i d h y d r o l y s i s forms a hydroxymethyl group. I C\^0 ' H 20 C C=0 + CH 2N 2 > C | H0-C-CH20H C I C H 2 C c A l d o l Condensations*^^ * ^ S c h a f f e r and I s b e l l have used the a l d o l condensation r e a c t i o n to obtain branched chain sugars of e x t r a o r d i n a r y chain lengths. Nomenclature o f Branched-Chain Carbohydrates The nomenclature o f these compounds i s somewhat confused because of the wide spread use of common names. They can be named s y s t e m a t i c a l l y as s u b s t i t u t e d d e r i v a t i v e s o f t h e i r s t r a i g h t - c h a i n parent compound, f o r example hamamelose would be 2-C-(hydroxymethyl)-D_-ribose. CHO I HOH,C-.COH z I HC'OH HCOH CH2OH Hamamelose The numbering of the carbon atoms of the s i d e chain begins at the f i r s t carbon atom adjacent to the s t r a i g h t - c h a i n s k e l e t o n . The number of the.carbon atoms of the branch being used as a s u p e r s c r i p t of the number of the.carbon atom at the p o i n t o f attachment. 1 CHO I - 36 -DISCUSSION Reaction Conditions w i • *u- i v * 181,185,190,191, , , Work i n t h i s laboratory has established s a t i s f a c t o r y conditions f o r the Oxo Reaction of acetylated g l y c a l s . General laboratory scale experimentation has been standardised by Adkins and Krsek. 5 The acetylated g l y c a l s react at approximately 130°C to give mainly hydrohydroxy-methylated products, although most common o l e f i n s would y i e l d aldehydes at t h i s temperature. The pressures of carbon monoxide and hydrogen used r o u t i n e l y were i n a r a t i o of 1:3 to 1:1 at a t o t a l pressure of about 200 atmospheres. The reaction time varied from one to three hours. The removal of the ca t a l y s t from the reaction s o l u t i o n can be achieved i n various ways. Refluxing the s o l u t i o n decomposes most of the dicobalt octacarbonyl, but i t i s very tedious to remove the la s t traces. A g i t a t i n g the benzene s o l u t i o n with d i l u t e mineral acids removes the cobalt carbonyl as the corresponding cobaltous s a l t . Another procedure, when working with carbohydrate material i s the p r e c i p i t a t i o n of the reaction product by the addition of petroleum ether, leaving the cobalt carbonyl i n s o l u t i o n . However, some c a t a l y s t i s usually occluded i n the syrupy p r e c i p i t a t e . The most convenient way i s the p r e c i p i t a t i o n of the carbohydrate material into a s o l i d support such as magnesol, c e l i t e , or f l o r i s i l by the addition of petroleum ether, and then washing the s o l i d thoroughly with petroleum ether i n a sintered-glass funnel. A f t e r a l l c a t a l y s t has been removed, the support i s extracted with acetone, benzene, or an alcohol benzene mixture (1:20 V/V). The Preparation of Acetylated Glycals 62 The f i r s t acetylated g l y c a l was prepared by Fischer and Zach. The desired p e r a c e t y l g l y c o s y l bromide i s reduced with zinc dust i n a c e t i c a c i d . In general, t h i s reaction i s s t i l l used although i t has been t e c h n i c a l l y improved. The procedure now employed, an improved version of Fischer's method, proceeds from the free sugar to the acetylated g l y c a l without i s o l a t i o n of 179 intermediate compounds. The sugar i s O-acetylated by a c e t i c anhydride i n the presence of p e r c h l o r i c acid. The s o l u t i o n i s then treated with hydrogen . bromide generated i n s i t u by the action of water upon phosphorus tribromide, which i n turn i s synthesised i n the mixture from red phosphorus and bromine. The acyl g l y c o s y l bromide i s then reduced with z i n c . A small amount of copper sulphate may be added before the reduction step, since t h i s compound 192 193 f a c i l i t a t e s the formation of glycals. ' I f the temperature i s not kept s u f f i c i e n t l y low, appreciable quantities of peracetylated sugars are formed by the attack of acetate ion on the glycosyl h a l i d e . P u r i f i c a t i o n of the acetylated glycals i s e i t h e r by r e c r y s t a l l i z a t i o n or f r a c t i o n a l d i s t i l l a t i o n under vacuum. Peracetyl glycals r e a d i l y form from the corresponding acetylated 2-deoxy glycosyl h a l i d e s , however the d i f f i c u l t y encountered i n preparing these material decreases the usefulness of t h i s r e a c t i o n . Some glycosides undergo 194 elimination to give free g l y c a l s . The Oxo Reaction of Acetylated Glycals The reaction of carbon monoxide and hydrogen i n the presence of cobalt c a t a l y s t s has been'thoroughly investigated and has been discussed i n the introductory part of t h i s t h e s i s . The reactions of acetylated glycals under hydroformylation conditions were f i r s t described by Rosenthal and . 191,195,196 .. , „ * i * J •. v. i A co-workers. The major products are acetylated alcohols and a smaller amount of sugars having one more carbon atom than the o r i g i n a l peracetyl g l y c a l . Hence, the reaction follows the a n t i c i p a t e d course. The o r i g i n a l compounds were acetylated hexals with a dihydropyran structure, - 38 -183 197 however acetylated pentals were also examined. ' The object of the work discussed i n t h i s section was to e s t a b l i s h the structure of the products of the reactions of 3,4,6-tri-0_-acetyl-D-g l u c a l (1) and 3,4-di-O-acetyl-D-arabinal (18) with carbon monoxide and hydrogen i n the presence of dicobalt octacarbonyl and to study the mode of addition of the elements of methanol to the g l y c a l double bond. Since generally sugar alcohols form under Oxo conditions, the influence of reaction conditions upon the product was b r i e f l y studied. The Hydrohydroxymethylation of 3,4,6,-Tri-O-acetyl-Q-glucal (1) 3,4,6-tri-0_-acetyl-D-glucal (1) undergoes the Oxo Reaction at about 130°C to give an almost quantitative y i e l d of a mixture of 4,5,7-tri-0_-acetyl-2,6-anhydro-3-deoxy^Q-manno-heptitol and 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-g-gluco-heptitol (3). This mixture could not be induced to c r y s t a l l i s e . (» (3) 12) Indication that the hydroformylation reaction has taken place was given by the disappearance of the strong i n f r a r e d absorption at 1640 cm - 1, c h a r a c t e r i s t i c of the g l y c a l double bond, and the appearance of a previously absent band at 3400 cm - 1, c h a r a c t e r i s t i c f o r a hydroxyl function. The proton magnetic resonance spectrum shows a wide and complex pattern at approximately 2 p.p.m. which indicates the presence of two methylenic protons. ' Thin layer chromato-graphy shows the absence of 3,4,6-tri-O-acetyl-D-glucal (1) and the presence of two new major zones accompanied by a v a r i e t y of minor ones. The two major - 39 -zones were not well resolved on several adsorbents using d i f f e r e n t solvent systems, and f r a c t i o n a t i o n of the mixture as such appeared unpromising. However, column chromatography on f l o r i s i l and neutral alumina using ethanolic benzene as a solvent was attempted but no s a t i s f a c t o r y separation could be achieved. It seems c e r t a i n however, i n the l i g h t of present experience that g a s - l i q u i d p a r t i t i o n chromatography would have been succ e s s f u l . Acetylation with a c e t i c anhydride and zinc chloride gave a c r y s t a l l i n e tetra-0-acetat.e, which could not be separated by thi n layer chromatography or f r a c t i o n a l c r y s t a l l i s a t i o n . The hydrohydroxymethylation product (2 and 3) was deacetylated with 198 a d i l u t e s o l u t i o n of sodium methoxide i n anhydrous methanol. This reaction i s a t r a n s - e s t e r i f i c a t i o n . 0 0 II Q Q II R-O-C-CH3 + OCH3 > R-0 + CH3-O-C-CH3 The s o l u t i o n was then n e u t r a l i z e d by passing carbon dioxide gas into i t or by adding clean s o l i d carbon dioxide. A f t e r evaporation under vacuum and d i s s o l u t i o n i n water, the sodium ions were removed by passage through Amberlite IR-120-H cation exchange r e s i n . The i n f r a r e d spectrum of the p a r t i a l l y c r y s t a l l i n e product confirmed the complete removal of the ester groups and a strong broad hydroxyl band appeared. Preliminary descending paper chromato-graphy of the deacetylated material, using water-saturated 1-butanol as eluant, revealed the presence of two major compounds i n addition to a number of minor ones. The detecting spray reagent was the periodate - S c h i f f reagent. The chromatography paper i s sprayed with an aqueous s o l u t i o n of sodium periodate, which o x i d a t i v e l y cleaves the v i c i n a l hydroxyl groups to give at least one aldehyde molecule. I I H - C - O H T n 0 H - C = 0 I + 10^ „ H - C - O H H - C=0 - 40 -The wet paper i s then exposed to sulphur dioxide which reduces iodate and excess periodate to iodide. A f i n a l spray with S c h i f f ' s reagent produces _y 178 purple spots where the o r i g i n a l carbohydrate was located. The p o l y o l mixture was separated preparatively by applying i t i n methanol s o l u t i o n to several large sheets of Whatman No.l chromatography paper. The eluant used was water saturated 1-butanol containing 5% ethanol to prevent the formation of two separate phases should the temperature of the chromatography cabinet f a l l below that at which the butanol was saturated with water. Several narrow control sheets to which the same mixture had been applied were also hung into the tank and sprayed a f t e r c e r t a i n time i n t e r v a l s , so one would be able to follow the progression of the development. A f t e r about f o r t y hours the zones were s u f f i c i e n t l y f a r apart to allow t h e i r separation. Three narrow s t r i p s were cut from each sheet and sprayed with the periodate S c h i f f reagent to locate the zones. The zones' were then cut from the sheet and extracted exhaustively with methanol. Rechromatography of the i n d i v i d u a l zones showed that they were pure. Both could be r e a d i l y c r y s t a l l i s e d . As much as 100 mg of the mixture could be applied to a large sheet (48 x 64 cm) of chromatography paper. The t o t a l recovery of the two zones was about 80 mg. I f one assumes a 90% recovery f o r the chromatographic separation, then the two polyols represented about 90% of the o r i g i n a l mixture. Both were i s o l a t e d i n roughly equal quantity. Separation could also be achieved on a c e l l u l o s e column, however there was no advantage over paper chromatography since i t was rather tedious to f i n d the wanted zones among the larger number of f r a c t i o n s c o l l e c t e d . The slower running isomer, 2,6-anhydro-3-deoxy-D-manno-heptitol (4) and the f a s t e r one 2,6-anhydro-3-deoxy-D-gluco-hep'titol (5) were charac-t e r i s e d i n the usual way. Both polyols were acetylated with a c e t i c anhydride and pyridine to give the c r y s t a l l i n e tetra-O-acetyl d e r i v a t i v e s . r 41 -i7J In order to be able to examine the proton-magnetic resonance spectra of these polyols more e f f e c t i v e l y , the hydrohydroxymethylation of 3, 4 , 6 - t r i -O-acetyl-D-glucal (1) was repeated with deuterium instead of hydrogen. The polyols obtained were 2,6-anhydro-3-deoxy-Q-manno-heptitol-1,l,3- 2H3(cis) (6) and 2,6-anhydro-3-deoxy-Q-gluco-heptitol-l,1,3- 2H 3(cis) (7). Proton-Magnetic Resonance Spectra For these four polyols (4,5,6,7) the protons on C-3 are unique i n that t h i s carbon atom i s not bonded to oxygen, hence these protons are more highly shielded than a l l others. Their chemical s h i f t i s about 2 p.p.m. For the following discussion i t i s assumed that a l l four polyols (4,5,6,7) are i n a C - l conformation. This appears reasonable since t h i s would permit a l l substituents i n polyols (5) and (7) to take an equatorial p o s i t i o n and a l l but the C-2 hydroxymethyl group i n polyols (4) and (6) to take an equatorial p o s i t i o n . The C-3 proton signals i n the spectra of polyols (4) and (5) are too complex to be analysed e f f e c t i v e l y , but t h e i r width allows a te n t a t i v e assignment of configuration about C-2. Comparing the methylene sig n a l s of - 42 -o 2,6-anhydro-3-deoxy-D-manno-heptitol (4) and 2,6-anhydro-3-deoxy-D-gluco-h e p t i t o l (5) one finds that they are much wider i n the case of (5), h e p t i t o l (4) and i t s p a r t i a l l y deuterated analogue (6) i n deuterium oxide at 2 p.p.m. (60 MHz). since the a x i a l C-3 proton couple with the a x i a l C-4 and C-2 protons. In po l y o l (4) the C-2 proton i s equatorial and hence the methylene signal i s somewhat narrower. A d e f i n i t e assignment of structure i s poss i b l e i n the case of the p a r t i a l l y deuterated polyols 2,6-anhydro-3-deoxy-D-manno-heptitol 1,1,3- 2H 3 (6) and 2,6-anhydro-3-deoxy-D-gluco-heptitol 1,1,3- 2H 3 (7). The chemical s h i f t and quartet structure (width 17.7 Hz) of the s i g n a l of i n t e n s i t y one at 1.7 p.p.m. require the C-3 proton of po l y o l (6) to be i n an a x i a l o r i e n t a t i o n and to be coupled with the C-4 a x i a l and C-2 equatorial protons. On the other hand, the corresponding narrower quartet (width 7.3 Hz) of i n t e n s i t y one at 1.94 p.p.m. necessitates that the C-3 proton of compound (7) i s i n an equatorial o r i e n t a t i o n and i s coupled with the C-4 and C-2 a x i a l hydrogens. Therefore, compounds (6) and (7) are 2,6-anhydro-3-deoxy-D-manno-heptitol - 43 -J _ _ : 1 L . (7) 3.0 2.0 1.0 pp-m Figure 2. P.M.R. Spectra of 2,6-anhydro-3-deoxy-g-gluco-h e p t i t o l (5) and i t s p a r t i a l l y deuterated analogue i n deuterium oxide at 2 p.p.m. (60 MHz) l , l , 3 - 2 H 3 ( c i s ) , (6)and 2,6-anhydro-3-deoxy-D-gluco-heptitol-1,1,3- 2H 3 ( c i s ) (7), r e s p e c t i v e l y . Evidently, the deuterated polyols must have been formed by a c i s addition of the hydroxymethyl group and of the deuterium atom to the 1,2-unsaturated bond of 3,4,6-tri-0-acetyl-D-glucal. Deuterium decoupling was used to improve the methylenic s i g n a l q u a l i t y f o r compounds (6) and (7) (Figure 3). An independent proof of structure of 2,6-anhydro-3-deoxy-D-gluco - h e p t i t o l (5) was provided by an X-ray c r y s t a l l o g r a p h i c a n a l y s i s 1 8 2 of a-derivative, namely, 4,5,7-tri-0-acetyl-2,6-anhydro-l-0- (p_-bromobenzene-sulphonyl)-3-deoxy-D-gluco-heptitol (11). - 44 -Figure 3. Deuterium decoupled spectra of 2,6-anhydro-3-deoxy-D-gluco-heptitol-1,1, 3- 2H 3 (cis)(7) and 2,6-anhydro-3-deoxy-D-manno-heptitol-1,1, 3- 2H/cis) (6) i n deuterium oxide (60 MHz) Chemical Separation of Isomers In an attempt to separate the hydrohydroxymethylation products of 3, 4,6-tri-0_-acetyl-D-glucal (1) v i a t h e i r p_-toluenesulphonates i t was found that mild p_-toluenesulphonation gave only the desired d e r i v a t i v e f or 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-D-gluco-heptitol (3), while the manno isomer (2) did not react. More vigorous conditions were necessary to obtain both d e r i v a t i v e s . Reaction of the hydrohydroxymethylation product with p_-toluenesulphonyl chloride i n pyridine at room temperature gave an amber syrup upon work-up. Upon addit i o n of d i e t h y l ether, a c r y s t a l l i n e mass developed which was shown to be - 45 4,5,7-tri-0_-acetyl-2,6-anhydro-l-0- (p_-toluenesulphonyl) -3-deoxy-D-gluco-h e p t i t o l (8). The remaining syrupy material showed a strong hydroxyl absorption i n i t s i n f r a r e d spectrum and upon deacetylation gave paper chromatograms which were i d e n t i c a l to the o r i g i n a l mixture except f o r a fast running zone due to the de-O-acetylated p_-toluenesulphonate. The spot due to p o l y o l (3) was weak i n d i c a t i n g that the p_-toluenesulphonate corresponded to i t . Deacetylation of the acetylated sulphonate gave a c r y s t a l l i n e material which gave the f a s t running spot. •0 CUtpTs, (8) For a d e f i n i t e s t r u c t u r a l assignment the p_-toluenesulphonate (8) was degraded to the corresponding anhydro p o l y o l . The c r y s t a l l i n e p_-toluenesulphonate (8) was treated with sodium iodide i n acetone to obtain 4,5,7-tri-O-acetyl-199 2,6-anhydro-l,3-dideoxy-l-iodo-D-gluco-heptitol (9]. This reaction proceeds best i n a sealed tube (Carius tube) at 100°C, under these conditions the reaction time i s a f r a c t i o n of that necessary at the b o i l i n g point of acetone. The iodo compound (9) i s c r y s t a l l i n e . Treatment with s i l v e r n i t r a t e 200-203 m a c e t o n i t r i l e y i e l d e d the b e a u t i f u l l y c r y s t a l l i n e n i t r a t e ester (10). K u h n ^ 4 and Hayward^ 5 reported the removal of n i t r a t e groups by the low pressure hydrogenation over a palladium-on-charcoal c a t a l y s t . However, t h i s p a r t i c u l a r n i t r a t e ester i s r e a d i l y hydrogenated at atmospheric pressure over palladium black. The absorption of gas was almost q u a n t i t a t i v e following the equation. 2R-0N02 + 5H 2 > 2R-0H + N 2 + 4H 20 - 46 -The r e s u l t i n g p a r t i a l l y acetylated a l c o h o l , 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-D-gluco-heptitol (3) could not be obtained c r y s t a l l i n e . However, deacetylation gave the c r y s t a l l i n e 2,6-anhydro-3-deoxy-D-gluco-heptitol (5). Identity with the genuine p o l y o l was established by comparing t h e i r melting points, chromatographic behaviour, and i n f r a r e d spectra. No mixture melting point depression was observed. The p_-toluenesulphonation of the hydrohydroxymethylation product under more vigorous conditions y i e l d s 4,5,7-tri-0_-acetyl-2,6-anhydro-3-deoxy-1-0-p-tolunesulphonyl-D-gluco-heptitol (8) and 4,5, 7-tri-0_-acetyl-2,6-anhydro- — 3-deoxy-l-O-p-toluenesulphonyl-D-manno-heptitol (14). Separation can be e f f e c t e d by preparative thin layer chromatography. Since 4,5,7-tri-0- acetyl-2,6-anhydro-3-deoxy-Q-gluco-heptitol (3) and 4,5,7-tri-O-acetyl-2,6-anhydro-3-deoxy-D-manno-heptitol (2) c o n s t i t u t e about 90% of the hydro-hydroxymethylation product of 3,4,6-tri-0-acetyl-Q-glucal (1) i t appears reasonable to assume that 4, 5, 7-tri-0_-acetyl-2 ,6-anhydro-3-deoxy-l-0_-p_-toluenesulphonyl-D-manno-heptitol (14) i s formed besides the Q-gluco (8) isomer upon p_-toluenesulphonationalthough i t s structure has not been established d e f i n i t e l y . It was f e l t that a d e f i n i t e confirmation of the structures of the two polyols (4) and (5) beyond that supplied by proton magnetic resonance spectroscopy would be h e l p f u l . Hence,several compounds having a heavy atom were synthesised for X-ray a n a l y s i s . The acetylated iodide (9) described 206 above was not.suitable. p-Bromobenzenesulphonation of the hydrohydroxy-methylation mixture under conditions i d e n t i c a l to those employed for p_-toluenesulphonation y i e l d e d a c r y s t a l l i n e d e r i v a t i v e which was s u i t a b l e T 82 for X-ray analysis and was shown to be 4,5,7-tri-0-acetyl-2,6-anhydro-1 - 0_~ (£-bromo-benzenesulphonyl)-3-deoxy-D-gljjco-heptitol (11). To show that - 47 -th i s compound had the same configuration as the p_-toluenesulphonate (8) i t was converted to the iodo d e r i v a t i v e which was i d e n t i c a l to that obtained from compound (8). 4co AcO CH.OA>-Ctf.o/H CHxoA<. CH3on A(0 AcO C M 3 C 0 C M 3 c r t TI <9) CH.OH In order to show that the other isomer formed i n the hydrohydroxymethy-l a t i o n of 3,4,6-tri-O-acetyl-D-giucal (1) and i t s deacetylation product (4) was indeed the manno d e r i v a t i v e , both polyols (4) and (5) were degraded by oxidation with p e r i o d i c acid, followed by reduction with sodium borohydride. The oxidation with p e r i o d i c a c i d , discovered by Malaprade i n 207 208 1928, ' i s used to cleave 1,2-diols to the corresponding aldehydes or 209 210 ketones v i a a c y c l i c ester intermediate. ' -C-OH I -C-OH + HIO4 I -c-o. 4 _ 0 ^ I 0 3H -C-0 - - C=0 + H I ° 3 I - 48 -210 211 This reaction i s s e n s i t i v e to s t e r i c and conformational e f f e c t s . ' In general, d i t e r t i a r y alcohols are cleaved with more d i f f i c u l t y than d i -secondary ones since the c y c l i c ester formation i s more d i f f i c u l t . S t e r i c compression i s most l i k e l y responsible f o r t h i s d i f f i c u l t y . Glycals f o r which i t i s s t e r i c a l l y impossible to form a c y c l i c ester with p e r i o d i c acid 212-217 are not oxidised. HO C ^ O H Ho C H , O H O H (5) CM-OH '•ho one CHjOH / Cuo OHC. CW..OH NIIV-BH^, A — ° -HOCU. CH^OH x (IZ) O / . o H CH t©H H O C ^ 1 X MOCH,--«»• CHtOH (.11) (13) - 49 -The periodate oxidation followed by borchydride reduction of 2,6-anhydro-3-deoxy-D--gluco-heptito3 (5) and 2,6, -ar.hydro-3-deoxy-D-manno-heptitol (4) gave enantiomeric t e t r o l ethers, namely 2-deoxy-3-0-(l,3-dihydroxy-2-• p r o p y l ) - L - g l y c e r o - t e t r i t o l (13) and 2-deoxy-3-0-(1,3-dihydroxy-2-propyl)-D-g l y c e r o - t e t r i t o l (12), r e s p e c t i v e l y . These compounds are i d e n t i c a l except for t h e i r o p t i c a l rotations which are equal and opposite. They were also compared as t h e i r c r y s t a l l i n e p_-nitrobenzoates. This behaviour ascertained the point of attachment of the hydroxymethyl group to 3,4,6-tri-O-acetyl-D-glu c a l during the hydrohydroxymethylation.. These enantiomeric ethers of known absolute configuration also proved useful i n e s t a b l i s h i n g the structures of the products derived from 3,4,6-tri-0-acetyl-D-galactal by the Oxo D ' 218 Reaction. Remarkable i s the dependence upon configuration of the replacement of the p_-toluenesulphonoxy group by iodide i n acetone. A crude attempt was made to compare the rates of replacement of the l-p_-toluenesulphonoxy group by iodide by reacting 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-l-0-p-toluene-sulphonyl-D-gluco-heptitol (8) and 4,5,7,-tri-0-acetyl-2,6-anhydro-3-deoxy-l-O-p-toluenesulphonyl-D-manno-heptitol with sodium iodide i n acetone at 100°C i n sealed tubes f o r varying periods of time. The solutions were equi-molar i n respect to each other. The extent of reaction was determined by weighing the p r e c i p i t a t e d sodium p_-toluenesulphonate. The r e s u l t s c l e a r l y show that the exchange at C-l i s much more rapid, f o r the gluco isomer than f o r the manno one. However, i t i s impossible to make any generalised deductions since i t appears that no other studies of t h i s kind have been performed. From work with p o l y o l b i c y c l i c acetal d e r i v a t i v e s i t has been • ' 219 found that a x i a l l y oriented p_-toluenesulphonoxy groups react more r e a d i l y . - 50 Hydroformylation of 3,4,6-Tri-O-acetyl-D-glucal (1) 191 E a r l i e r work has shown that 3,4,6-tri-O-acetyl-D-glucal (1) and 224 3,4-di-O-acetyl-D-xylal react with carbon monoxide and hydrogen i n the presence of dicobalt octacarbonyl to y i e l d anhydrodeoxyglycoses. It has been established that once absorption of gas commences the reaction r a p i d l y evershoots the hydroformylation stage to give hydrohydroxymethylated 181 183 185 218-products. > > > T h e hydroformylation of 3,4,6-tri-O-acetyl-D-226 224 gl u c a l was performed according to the procedure of Rosenthal and Abson. The reaction was stopped a f t e r two molar equivalents of gas had been absorbed. A r e l a t i v e l y high y i e l d of aldehydes (16a, 17b) could be i s o l a t e d as t h e i r 2,4-din.i trophenyl hydra zones (16b, 17b). •':. :r.-The reaction product (16a, 17a) was treated with 2,4-dinitrophenyl-hydrazine i n methanol containing a c e t i c a c i d to obtain the 2,4-dinitro-phenylhydrazones (16b, 17b). These were separated by preparative t h i n layer chromatography into two main zones using a i r dried s i l i c a gel as absorbent and chloroform as developer. To establish'the structures of these compounds the 2,4-dinitrophenylhydrazone groups were removed by pyruvic acid i n a c e t i c 225 acid containing hydrogen/bromide. R - C H = F ( V - A I H — \ ^ \ — N O z + C H 3 R—CMo CO I COxH J V I This method i s very convenient since a l l compounds except the aldehyde can be extracted with aqueous base from a chloroform s o l u t i o n . The aldehydes were - 51 -immediately reduced to t h e i r respective polyols (4,5) with sodium borohydride. C H O CHO (16a.) (I7<x.) 1,H -J)NP H + CH toH CHxOH *> Pyavi/ic. Gap /I, . i - 7 - i (5) The polyols 2 >6-anhydro-3-deoxy-D-manno-heptitol (4) and 2,6-anhydro-3-deoxy-D-gluco-heptitol (5) were compared with authentic samples. The Hydrohydroxymethylation of 3,4-Di-O-acetyl-D-arabinal (18). The synthesis of di-O-acetyl-D-arabinal (18)was s i m i l a r to that of the g l u c a l d e r i v a t i v e using a modification of the procedure of H e l f e r i c h and 179 co-workers. This material had to be d i s t i l l e d since i t i s not known i n the c r y s t a l l i n e s t a t e . The procedure used f o r the hydrohydroxymethylation reaction and p u r i f i c a t i o n of the products was s i m i l a r to that used f o r 181 185 3,4,6-tri-O-acetyl-D-glucal (1). ' The product mixture consisted mainly of hy'drohydroxymethylated.••material- as indicated, by the proton magnetic resonance and i n f r a r e d spectra. It reduces Fehling's and Tollen's solutions which indicates the presence, of some sugar,, however any remaining cobalt carbonyls also tend to reduce these reagents. The product mixture was deacetylated with aqueous sodium borohydride to reduce any sugars which might be present . Separation of the isomers, 1,5-anhydro-^4-deoxy-L-ribo-hexitol (21) and - 52 -1,5-anhydro-4-deoxy-D-lyxo-hexitol (22) was achieved'by preparative paper chromatography or c e l l u l o s e column chromatography using water saturated 1-butanol containing 5% V/V ethanol as described previously. The pure polyols which could not be r e a d i l y c r y s t a l l i s e d were also characterized as t h e i r benzoates. A preliminary structure determination by proton magnetic resonance spectroscopy s i m i l a r to that described f o r the hydrohydroxymethylation products of 3,4,6-tri-O-acetyl-D-glucal (1) was used. Each p o l y o l has a m u l t i p l e t of peaks equivalent to two hydrogens at about 1.8 p.p.m., i t can be i n f e r r e d that each isomer possesses methylenic protons at C-4. Thus, the two polyols must be l i n e a r and d i f f e r only i n the configuration of C-5. The deuterated polyols show only one methylene proton as expected. The stereochemistry of C-5 cannot be a s c e r t a i n e d s i n c e i t appears that the two p o l y o l s are i n d i f f e r e n t conformations. In order t o e s t a b l i s h the s t r u c t u r e s o f these p o l y o l s with c e r t a i n t y both were degraded by p e r i o d i c a c i d o x i d a t i o n f o l l o w e d by sodium borohydride r e d u c t i o n . OH <ZS> The two p o l y o l ethers (23) and (24) have an equal and opposite o p t i c a l r o t a t i o n but are otherwise i d e n t i c a l (p.m.r.).. They were c h a r a c t e r i s as such and a l s o as t h e i r p_-nitrobenzoate. This c l e a r l y demonstrates that the p o l y o l s d i f f e r i n the c o n f i g u r a t i o n at C-5. The p o l y o l ether (23) obtained from the p e r i o d a t e o x i d a t i o n f o l l o w e d by r e d u c t i o n w i t h borohydride of l,5-anhydro-4-deoxy-L-rIbo-hexitol.(21) was i d e n t i c a l t o the one obtained - 54 -by periodate oxidation followed by borohydride reduction from authentic 1,4-anhydro-5-deoxy-D-arabino-hexitol (25). 185 A p p l i c a t i o n of the Oxo Reaction to 1,2,4,6-Tetra-0-acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose (29) In order'to examine the general a p p l i c a b i l i t y of the Oxo Reaction to unsaturated carbohydrate d e r i v a t i v e s other than acetylated g l y c a l s , the reaction was performed on l,2,4,6-tetra-0_-acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose (29). One of the aims of t h i s group was also the synthesis of sugars having a branched-chain carbon skeleton. This aim would.also be f i l l e d since a normal hydrohydroxymethylation of t h i s o l e f i n must give branched-chain products. 1,2,4-6-tetra-0-acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose (29) was prepared from 2,3,4,6-tetra-0-acetyl-a-D-glucosyl bromide (26) . Dehydrobromination of (26) with a base such as di.ethylamine gave 2,3,4,6-tetra-0_-acetyl-2-hydroxy-D-glucal (27). AcO (lb) ( t 7 ) oAc +- (C zH 5) 2HH-HSr -This compound (27) was then isomerised i n a s o l u t i o n of anhydrous zinc chloride i n a c e t i c anhydride. 141 A mechanism f o r t h i s isomerisation has been suggested by Lemieux, Wolfrom and co rworkers. 141 The acid abstracts the C-3 acetoxy group leaving a p o s i t i v e ion (28). - 55 -An acetate ion then attacks C-l to form the anomeric acetates (29). By r e c r y s t a l l i z a t i o n the a-isomer can be i s o l a t e d . 191 The hydrohydroxymethylation was performed under the usual conditions only a s l i g h t l y higher temperature was required. Infrared spectroscopy indicated the introduction of a hydroxyl group. The proton magnetic resonance spectrum was very poorly defined, probably i n d i c a t i n g a considerable number of components in the sample, however, i t had a wide complicated band i n the methylenic region (~2 p.p.m.). Neither the Oxo Reaction product (of 29) nor the de-O-acetylated material showed a s u f f i c i e n t l y strong anomeric proton s i g n a l i n the p.m.r. spectrum which seems to indi c a t e .that some of the C-l acetoxy group had been redu c t i v e l y removed during the Oxo Reaction. . This ready r e d u c i b i l i t y of the anomeric carbon atom may be expected since the c a t a l y t i c hydrogenation of tetra-0-acetyl-3-deoxy-a-D-erythro-hex-2-eno-pyranose (29) i n ethanol under atmospheric pressure over platinum black requires two moles of hydrogen. The product consists of 2,4,6-tri-0-acetyl-l,5-anhydro-3-deoxy p o l y o l s , a c e t i c acid and only traces of l,2,4,6-tetra-0_-144 acetyl-3-deoxy-glycoses. Since normal sugar acetates are r e s i s t a n t to c a t a l y t i c hydrogenation under these conditions i t i s obvious that the anomeric carbon atom i s reduced before the double bond i s hydrogenated. Since gas l i q u i d p a r t i t i o n chromatography of the acetylated Oxo Reaction product indicates the presence of the above mentioned compounds i t seems l i k e l y that - 56 -some reduction at C - l did indeed occur. + OA* A gas l i q u i d p a r t i t i o n chromatographic separation of the t o t a l l y . acetylated hydrohydroxymethylation products was performed. A column (3/8" x 12') having a packing of 10% s i l i c o n gum rubber SE-52 on chromosorb W operating at 280°C was used. Two major zones (Figure 4 (A, B) besides the completely hydrogenated products were observed and i s o l a t e d . The f a s t e r zone A (retention time 11 minutes) proved to be a mixture while the slower zone B (15.4.minutes) was a pure compound. The slower zone B (about 30% of the t o t a l areas of A and B on the chromatogram) was r e c r y s t a l l i z e d and i t s structure was r e a d i l y shown by p.m.r. spectroscopy to be that of 1,2,3 1,4,6-penta-0-acetyl-3-deoxy-3-£- (hydroxymethyl)-a-D-gluco-pyranose (31);. (see page . 5 7 ) . Obviously t h i s material was formed by a cis-hydrohydroxy-methylation of 1,2,4,6-tetra-0-acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose (29). I Figure 4. A c e t y l a t e d Hydrohydroxymethylation Product o f Tetra-0_-acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose. Column: 12' x 3/8", 10% S i l i c o n Gum Rubber SE-52 on Chromosorb W; column temp. 280°C; Helium flow: 200 ml/min.; d e t e c t o r temp. 310°C; in j e c t . t e m p . 280°C. f i l a m e n t c u r r e n t : 150 mA. - 57 -CH^OAc C H . o A t A<L.O 4 CO + 1 H | _ C ° * M 8 j > 4 0TMS-«5 (15) oa^ O ) (31; 1,2,4,6-Tetra-0-acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose (29) was also reacted with carbon monoxide and deuterium i n the presence of dicobalt octa-carbonyl to y i e l d deuterated products which would f a c i l i t a t e the analysis o f ' t h e p.m.r. spectra. f ' c o t i D i 0 0 1 iCOS £ \ + OTienp-(51) o f i c -( 3 3 ) By comparing the p.m.r. spectra of 1,2,3^,4,6-penta-0-acetyl-3-deoxy-C-«, (6.23) «i.(*.98) A, X,- f c(3.yH».) 6 ppm ^-5 OoHi) Y j T ^ - 3 ( " H z ) tS O/Jc prot */vi 2 pprrt Lppm 1 1 1 ' ' ' ' _i i i t i i i ' ' ! I ! ! I !_ - j _ I I I 1 i ! ! 1— • ' < Figure 5. P.M.R. Spectrum o f 1,2,3 1,4,6-Penta-0-acetyl-3-deoxy-3-C-(hydroxymethyl)-a-D-glucose (29) i n CDC1 3 at 100 MHz. - 58 -(hydroxymethyl)-a-D-gluco-pyranose (31) and i t s p a r t i a l l y deuterated analogue, 1,2,3 i^^-penta-O-acetyl-S-deoxy-S-C-(hydroxymethyl) - q - Q-gluco-pyranose 2,3*, 3 1 - 2 H 3 ( c i s ) (33), an assignment of structure i s r e a d i l y p o s s i b l e . H OAc H Ofl^, (31) T33) Compound (31) has f i v e acetate groups as i s indicated by the i n t e g r a l of i t s spectrum. There i s one anomeric proton and one methyne proton to show that the compound i s a glycose d e r i v a t i v e and must have a branched carbon skeleton. In the deuterated material (33) three protons are replaced by deuterons showing that i t i s a normal hydrohydroxymethylation product •CUD || + CO + 2QX > j R H P The chemical s h i f t of the anomeric proton (6.23 p.p.m.) of (31) and (33) suggests that they are a-anomers, which agrees well with the corres-ponding chemical s h i f t s of the 1,2,3,4,6-penta-0-acetyl d e r i v a t i v e s of a-D-141 glucose and a-D-mannose (6.31 p.p.m. and 6.07 p.p.m. r e s p e c t i v e l y ). Since the s t a r t i n g material has also an a-configuration at C-l i t i s obvious that no anomerisation has occurred. The anomeric proton of (31) i s a doublet produced by coupling with the C-2 proton. The coupling constant ( J ~ Hz) i s s i m i l a r to that of 1,2,3,4,6-penta-O-acety1-a-D-gluco-pyranose J j _ 2 = 3.5 Hz) and not to that of 1,2,3,4,6-penta-O-acetyl-q-D-manno-pyranose (J^_2 = 1.0 Hz). The large coupling constant ( J ^ _ ) shows that the C-2 proton i s i n an a x i a l p o s i t i o n thus e s t a b l i s h i n g the configuration about H,(6.2 3) A A X , _ 3 ( l l Hz) ^ ( 2 . 3 5 ) A 15 Oflc pr«4 on * i ' i » i i . • i , tpptn. i 1 I 1 I ' I ! • . • • » I • * • • Figure 6. P.M.R. Spectrum o f 1,2,3 1,4,6-Penta-0-acetyl-3-deoxy-3-C-(hydroxymethyl) -a-D-glucose-2 , 3 1 , 3 1 - 2 H 3 ( c i s ) (31) i n CDC1 3 at 100 MHz. - 59 -C-2. In the deuterated compound (33) the C-2 proton has been replaced by a deuteron and the anomeric s i g n a l becomes a s i n g l e t . The C-2-H si g n a l at 4.98 p.p.m. i s a quartet as a r e s u l t of coupling with C-l-H and C-3-H. The constant ^ - i * s °^ course equal to ^ v i r t u e of which the si g n a l can be i d e n t i f i e d r e a d i l y and ^ (12 Hz) establishes that C-2-H and C-3-H must be i n a t r a n s - d i a x i a l conformation. This fi x e s the p o s i t i o n of the hydroxymethyl group. In the deuterated compound (33) the C-2-H si g n a l i s absent, as would be expected. The C-3-proton s i g n a l i s r e a d i l y i d e n t i f i e d because of i t s high chemical s h i f t (2.35 p.p.m), expected f o r a methyne proton. The coupling constant ^ ~ ^2-3 = 1 2 ^ Z aS a^- n shows the t r a n s - d i a x i a l r e l a t i o n s h i p . Since the configuration about C-4 i s known, the coupling constant should correspond to a t r a n s - d i a x i a l arrangement, and hence be large, which indeed i t i s ( J ^ ^  = 11 Hz). The coupling constants C-3-H and the protons of the C-3 hydroxymethyl group are small (-2.5 Hz) and cause a d e f i n i t e broadening of the s i g n a l . In the deuterated compound (33) only C-4-H can couple with C-3-H giving r i s e to a doublet (Jg_4 - H Hz) the doublet i s poorly defined because of coupling with deuterons (C-2- 2H,C-3 1- 2H 2). The C-4 proton at 5.06 p.p.nn units i s coupled with both C-3-H O-^g =11 Hz) and C-4-H (J^_c - = 10 Hz). Hence H 3, H^, and H 5 a l l have a t r a n s - d i a x i a l r e l a t i o n s h i p . It seems safe to assign the gluco-configuration to the compound, ex p e c i a l l y since the configuration of C-3-H can be r e l a t e d to both that of C-4 and C-2. Hence, as was shown e a r l i e r , the Oxo Reaction constitutes a c i s - a d d i t i o n . The hydrohydroxymethylation of l,2,4,6-tetra-0_-acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose (29) followed by a c e t y l a t i o n of the products gives as the only seven carbon aldose d e r i v a t i v e 1,2,3 1,4,6-penta-0_-acetyl-3-deoxy-3-C-(hydroxymethyl)-q-D-gluco-pyranose (31). Figure 7. P.M.R. Spectrum of gas l i q u i d p a r t i t i o n chromatography Zone A i n CDClo at 100MHz. - 60 -CU^oAc crii.o/lc, CHi°Ac 0>l) Since gas l i q u i d p a r t i t i o n chromatography does not y i e l d another zone of comparable retention time besides zone B, i t appears that the other possible isomer, 1,2,3 !,4,6-penta-0-acetyl-3-deoxy-3-C_- (hydroxymethyl) -a-D-altro-pyranose (34),is not formed i n detectable amounts. The f a s t e r moving zone A consists of at least two compounds which are reduced at C-l since no anomeric proton s i g n a l i s observed i n the proton magnetic resonance spectrum. The p r e f e r e n t i a l formation of the gluco-isomer can be t e n t a t i v e l y explained by the assumption that the C - l and C-4 acetoxy groups of 1,2,4,6-tetra-0_-acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose (29) protect the a side the double bond. This compound (29) can e x i s t i n two conformations, (35) and (36 ) jOf which the one where the C-4 and C-5 acetoxymethyl groups are i n pseudo-equatorial orientations should predominate (35). In conformer (35) the C - l and C-4 acetoxy groups can protect the a side of the double bond permitting the approach of hydrogen tetracarbonylcobaltate - 61 -only from the B side giving r i s e to the gluco isomer. OAc In the other conformer (36) the C - l and C-4 acetoxy groups also protect the ct side of the r i n g ; however, the C-5 acetoxymethyl group could also prevent the 8 side,making a reaction with hydrogen tetracarbonylcobaltate d i f f i c u l t from e i t h e r side. It appears that some 1,2,4,6-tetra-0-acetyl-3-deoxy-ct-D-erythro-hex-2-enopyranose (29)' i s hydrogenolysed to 2,4,6-tri-0-acetyl-l,5-anhydro-3-deoxy-D-erythro-hex-2-enitol (37) before hydrohydroxymethylation occurs. X \ 4 - H l A c O \ / p f l c (29) o A <-In t h i s substance the pr o t e c t i v e e f f e c t of the C - l acetoxy group has been removed and hence i t might give, upon hydrohydroxymethylation, both the gluco and a l t r o isomers more r e a d i l y . It i s believed that zone A obtained by the gas l i q u i d p a r t i t i o n chromatographic separation (Figure 4) contains both 2,3 1,4,6-tetra-0-acetyl-l,5-anhydro-3-deoxy-3-C_- (hydroxymethyl)-a-D-glucitol and 2,3 1,4,6-tetra-O-acety1-1,5-anhydro-3-deoxy-3-C-(hydroxymethyl)-cx-D-a l t r i t o l . However, the composition of zone A has not been established. CH uoAc 4- MO Ac. ( 3 7 ) - 62 -The Low-Pressure Hydroxymethylation of 2,3,4,6-Tetra-0-acetyl-a-D-glucosyl bromide During the high-pressure hydroformylation of o l e f i n s , the c a t a l y s t , hydrogen tetracarbonylcobaltate adds to the double bond to form a l k y l cobalt carbonyl complexes. R H R 4- H C o {CO)Urr > I / \ / R H R These cobalt derivatives can also be synthesized by the reaction of s u i t a b l e a l k y l halides with a l k a l i - m e t a l carbonylcobaltates. Sodium tetracarbonylcobaltate may be prepared by several methods. One procedure i s that described by Blanchard and Gilmont.* 5 5 An aqueous s o l u t i o n of a c o b a l t i c s a l t containing sodium hydroxide and sodium cyanide i s agitated i n a carbon monoxide atmosphere. The r e s u l t i n g aqueous sodium tetracarbonyl-cobaltate s o l u t i o n i s then n e u t r a l i s e d with hydrochloric a c i d and the hydrogen tetracarbonylcobaltate extracted i n t o toluene, the toluene layer in turn being n e u t r a l i s e d with a l k a l i . The sodium s a l t may also be extracted d i r e c t l y i n t o ether. This l a t t e r procedure has the disadvantage of contaminating the sodium tetracarbonylcobaltate s o l u t i o n with water. Hydrogen tetracarbonyl-cobaltate can also be synthesised by the reduction of dicobalt octacarbonyl 7 with hydrogen followed by n e u t r a l i s a t i o n through a l k a l i . The simplest way i n making anhydrous sodium tetracarbonylcobaltate solutions i n ether i s the reduction of dicobalt octacarbonyl with sodium amalgam. The procedure used was a mechanical m o d i f i c a t i o n * ^ of that described by H i e b e r * 4 ^ ' * 5 * ' * 5 ^ . The procedure f o r reacting 2,3,4,6-tetra-O-acetyl-a-D-glucosyl bromide (26) 27 with sodium tetracarbonyl cobaltate i s s i m i l a r to that reported previously. ' 2 ?0 227 ' Generally the a l k y l h a l i d e i s mixed with sodium tetracarbonyl-c o b a l t a t e i n an i n e r t s o l v e n t under n i t r o g e n or carbon monoxide. T r i p h e n y l -29 221 222 phosphine or t r i p h e n y l p h o s p h i t e i s added t o s t a b i l i s e the complex. ' ' RX.+ NaCoCCO)^ >• R-CofCO),, + NaX + + P$ 3 R-Co(CO) 3P({)3 + CO Hieber and co-workers on the other hand, a l s o prepare s u b s t i t u t e d phosphine complexes by the i n t e r a c t i o n of the a l k y l h a l i d e w i t h sodium t r i c a r b o n y l -triphenylphosphine c o b a l t a t e . However i t appears t h a t the triphenylphosphine complexes undergo c a r b o n y l a t i o n l e s s r e a d i l y . The apparatus used f o r t h i s i n v e s t i g a t i o n was e s s e n t i a l l y a pressure v e s s e l f i t t e d with a manometer.;and a rubber septum through which s o l u t i o n s could be i n j e c t e d at atmospheric pressure w i t h a s y r i n g e without opening the v e s s e l . The a c t u a l s o l u t i o n was put i n t o a g l a s s or s t a i n l e s s s t e e l l i n e r . E t h y l ether s o l u t i o n s of 2,3,4,6-t e t r a - O - a c e t y l - a - D - g l u c o s y l bromide (26) and sodium t e t r a c a r b o n y l c o b a l t a t e were s u c c e s s i v e l y i n j e c t e d i n t o the carbon monoxide f i l l e d r e a c t i o n v e s s e l , which was then charged with 11 atmospheres (10 atmospheres above atmospheric pressure) of carbon monoxide gas. The autoclave was rocked f o r two days or u n t i l no more gas was absorbed. The a g i t a t i o n presented a t e c h n i c a l problem with the apparatus used and had i t been more vigorous i t i s f e l t that the r e a c t i o n would have been more r a p i d . A previous experiment performed i n a g l a s s apparatus under carbon monoxide at atmospheric pressure showed t h a t the r e a c t i o n between 2,3,4,6-tetra-O-acetyl-a-D-glucosyl bromide (26) and sodium t e t r a c a r b o n y l c o b a l t a t e in..ethyl e t h e r i s r a p i d as shown by the p r e c i p i t a t i o n of sodium bromide. - 64 -( 2 0 The gas was then allowed to escape to s l i g h t l y above atmospheric pressure and an excess of triphenylphosphine i n ether was i n j e c t e d . The autoclave was rocked to mix the solutions and was l e f t u n t i l the pressure remained constant. The carbon monoxide was then allowed to escape and the vessel was opened. The reaction material was- handled i n an i n e r t atmosphere although t h i s was not absolutely necessary. The reaction mixture was freed of sodium bromide by f i l t r a t i o n . To remove the excess triphenylphosphine, an excess of methyl iodide was added; f i l t r a t i o n removed methyl triphenylphosphonium iodide, which i s insoluble i n ethyl ether. <f>3P: + CH 3I > <j>3CH3PI The complexed triphenylphosphine does not react with methyl iodide. The s o l u t i o n was evaporated and the carbohydrate cobalt carbonyl complexes were extracted with hot petroleum ether, leaving the remaining sodium tetracarbonyl-cobaltate behind. Evaporation of the petroleum ether extract gave a yellow material which by i t s i n f r a r e d and proton magnetic resonance spectra could be t e n t a t i v e l y i d e n t i f i e d as a mixture of triphenylcarbonylcobalt complexes with an acetylated carbohydrate moiety. Thin layer chromatography showed the presence of two major zones and several very minor ones. Hence column chromatography appeared promising and the mixture was f r a c t i o n a t e d and the two major zones i s o l a t e d . The f a s t e r moving zone was i d e n t i f i e d by i t s conversion to 1,5-anhydro-D-glucitol (38) to be 2,3,4,6-tetra-O-acetyl-D-glucosyl t r i -carbonyl triphenylphosphine cobaltate (39). It .seemed that t h i s compound can be de-O-acetylated without breaking the carbon-cobalt bond. Treatment of the acetylated complexes gave D - p o l y g a l i t o l (1,5-anhydro-D-glucitol (38) which was - 65 -i d e n t i f i e d as the tetraacetate (40). This compound was compared to an authentic sample prepared by the l i t h i u m aluminum hydride reduction of 2,3,4,6-223 tetra-O-acetyl-ct-D-glucosyl bromide (26). (!(,) (38) Examination of the. slower moving zone (41) was more d i f f i c u l t since i t decomposed slowly into the f a s t e r moving one (39) as could be observed by t h i n layer chromatography. Reduction with sodium borohydride i n aqueous methanol gave a mixture of p o l y o l s , whose acetates were separated preparatively by gas l i q u i d p a r t i t i o n chromatography. The major f r a c t i o n having a higher retention time was i d e n t i c a l to an authentic sample of 1,3,4,5,7-penta-0-189 acetyl-2,6-anhydro-D-glycero-D-gulo-heptitol (42). The minor f r a c t i o n , having a lower retention time, was i d e n t i c a l to 2,3,4,6-tetra-0_-acetyl-l,5-anhydro-D-glucitol (2,3,4,6-tetra-0-acetyl-D-polygalitol) (40). The un-chromatographed reaction product was also reduced with sodium borohydride and acetylated. By gas l i q u i d p a r t i t i o n chromatography the r a t i o between 2,3,4,6-tetra-0-acetyl-l,5-anhydro-D-glucitoland 1,3,4,5,7-penta-0-acetyl-2,6 anhydro-D-glycero-D-gulo-heptitol was found to be 1:8. This value can only be considered q u a l i t a t i v e l y . . since no molar response f a c t o r was determined. When the complex mixture was l e f t at room temperature, or e s p e c i a l l y when i t was warmed under vacuum the r a t i o of acetates increased, because of decarbonylation of the acyl complex. ' ' • ' • Judging from the products i t seems safe to assume that inversion at - 66 -C- l of 2,3,4,6-tetra-O-acetyl-a-D-glucosyl bromide has occurred, i f an inversion during the subsequent carbonylation step i s ruled out. CHiPA-c, CH to/J t c ^ o A c The inversion at C - l i n the case of a stable acetylated g l y c o s y l h a l i d e does not n e c e s s a r i l y mean that t h i s i s general, because the p a r t i c i p a t i o n of a 1,2-acetoxonium ion cannot be ruled out at present. The examination of the reaction of 2,3,4,6-tetra-O-acetyl-B-D-glucosyl bromide would show whether the p a r t i c i p a t i o n of an acetoxonium ion i s important or not. The cobalt carbonyl d e r i v a t i v e , 2, 3,4,6-tetra-0_-acetyl-3-D-glucosyl tetracarbonyl cobaltate, underwent i n s e r t i o n of a carbonyl group while absorbing carbon monoxide from the atmosphere, probably analogously to 21 manganese complexes. The product was 3,4,5,7-tetra-O-acetyl-2,6-anhydro-D-glycero-g-gulo-heptosoyl tetracarbonylcobaltate. - 67 -(39) M l ) Since the c a r b o n y l a t i o n step i n v o l v e s a volume r e d u c t i o n , carbon monoxide under pressure should s h i f t the e q u i l i b r i u m towards the carbonylated form;. The phosphine l i g a n d s t a b i l i s e s these compounds s u f f i c i e n t l y so that they can be handled i n a i r f o r short periods of time; under n i t r o g e n or carbon monoxide they are q u i t e s t a b l e . The s t a b i l i t y of the t r i c a r b o n y l t r i p h e n y l -phosphine c o b a l t a t e complexes i s due to the electron-back donations of the c o b a l t atom t o the phosphorus atom by d^-d^ bonding. The carbonylated complex, 3,4,5,7-tetra-0-acetyl-2,6-anhydro-D-glycero-g-gulo-heptosoyl t r i c a r b o n y l .triphenylphosphine'cobaltate (41) r e v e r t e d s l o w l y t o the p e r a c e t y l g l u c o s y l complex (39) at room temperature i n the absence of carbon monoxide (under n i t r o g e n ) , and r e l a t i v e l y r a p i d l y i n vacuo when warmed. Recarbonylation was not p o s s i b l e under the c o n d i t i o n s used. (10 atm, 30 hours, 21°C). - 68 -3,4,5,7-tetra-O-acetyl-2,6-anhydro-D-glycero-D-gulo-heptosoyl t r i -carbonyl triphenylphosphine cobaltate (41) can be de-O-acetylated under very mild conditions without destroying the cobalt complex (IR), however no pure material could be i s o l a t e d . It was believed that treatment with more concentrated sodium methoxide would give r i s e to the 2,6-anhydro-D-glycero-ls- gulo-heptonic acid methyl ester but a complex mixture of methyl esters was obtained. Abstraction of a proton from C-2 to form a carbanion may have caused isomerisation. OH OH Because of the complexity of the products t h i s reaction was abandoned. Sodium borohydride i n methanol or aqueous methanol reduces the cobalt complexes smoothly. '-••69 -The acetate groups are, o f course, removed simultaneously. A non-carbohydrate m a t e r i a l o f brown c o l o u r and amorphous appearance which i s i n s o l u b l e i n water was formed. This substance which r e a c t s with h y d r o c h l o r i c a c i d to g i v e c o b a l t ( I I ) c h l o r i d e w i t h gas e v o l u t i o n was not f u r t h e r i n v e s t i g a t e d . The c o n f i g u r a t i o n about C - l of 2,3,4,6-tetra-O-acetyl-D-glucosyl t r l c a r b o n y l t riphenylphosphine c o b a l t a t e i s u n c e r t a i n , s i n c e r e d u c t i o n to 1,5-anhydro-D-glucitol destroys i t s asymmetry. However si n c e i t i s the probable p r e c u r s o r o f the carbonylated products, and i f i n v e r s i o n during the carbonyl i n s e r t i o n step i s r u l e d out, i t should be the 3-anomer. - 70 -EXPERIMENTAL General Considerations . . ;Hydroformylation Apparatus The high pressure hydroformylation and hydrohydroxymethylation reactions using carbon monoxide and hydrogen were c a r r i e d out i n an Aminco Micro Series autoclave (29/16" outside diameter) made of manganese s t e e l . This reactor i s sold by the American Instrument Company, Inc., S i l v e r Spring, Maryland, U.S.A. Infrared Spectra A l l i n f r a r e d spectra were measured on Perkin Elmer Model 21 and Model 137 (Sodium Chloride) spectrophotometers. Proton Magnetic Resonance Spectra Nuclear magnetic resonance spectra were determined at 60 x 10 6 Hz on a Varian A60 spectrometer and at 100 x 10 6 Hz on a Varian HA-100 Spectro-meter. Gas-Liquid-Partition Chromatography Gas l i q u i d p a r t i t i o n chromatography separations were effected on Aerograph Model A-700 and Model A-1520 instruments s o l d by Varian Associates, Palo A l t o , C a l i f o r n i a , U.S.A. Detectors were of the thermal conductivity type and the c a r r i e r gas was helium. Paper Chromatography A l l paper chromatography was descending. The solvent system was 1-butanol saturated with water at 0°C or water saturated (room temperature) 1-butanol containing 5% ethanol. The addition of ethanol prevents separation of water from the solvent mixture i n case the chromatogram i s run at a temperature lower than that used f o r preparation of the solvent. Reported R^ values are with reference to t h i s solvent system unless otherwise 178 indicated. Polyols were detected with a sodium p e r i o d a t e - S c h i f f reagent. Thin Layer Chromatography Thin layer chromatography was on plates of S i l i c a Gel G and Alumina (according to Stahl) containing 13% calcium sulphate as a binder. Zones were located by spraying with concentrated sulphuric acid, containing 5% concen-trated n i t r i c a c i d followed by heating to 130°C. Elemental Analyses Elemental analyses were performed i n the laboratories of Dr. A. Bernhardt, Mlihlheim (Ruhr), Germany, and i n the M i c r o a n a l y t i c a l Laboratory, Department of Chemistry, The U n i v e r s i t y of B r i t i s h Columbia, Vancouver, Canada. Melting Points A l l melting points are uncorrected and were taken on the Microscope Heating Stage manufactured by L e i t z A.G., Wetzlar, Germany. Catalyst Dicobalt octacarbonyl i s now commercially a v a i l a b l e from Alpha Inorganics Inc., Beverly, Mass., U.S.A. Evaporations of solvents were done under reduced pressure (water aspirator) at 40 to 50°C. Removal of solvents from syrups was done by warming (60°C) under vacuum (mechanical pump). - 72 -180 Dicobalt Octacarbonyl Cobalt (II) carbonate powder (20 g) and petroleum ether (60 ml) were put i n t o the glass l i n e r of the autoclave and shaken under carbon monoxide (160 atmospheres) and hydrogen (160 atm.) at 180°C f o r 2 hours. A f t e r an i n i t i a l increase i n pressure } gas was r a p i d l y absorbed. Upon cooling to room temperature the excess gases ( t o t a l pressure about 130 atm.) were vented. The dark brown s o l u t i o n i n the glass l i n e r was f i l t e r e d to remove unreacted cobalt (II) carbonate and stored i n a t i g h t l y closed container at about -10°C. Dicobalt octacarbonyl c r y s t a l l i s e d as orange c r y s t a l s (21 g). The product was stored,at low temperatures, under i t s mother l i q u o r f o r several months. Dry dicobalt octacarbonyl was stored, under nitrogen or carbon monoxide, for a considerable time m.p. about 50°C. It must be remembered that the gases i s s u i n g from the autoclave are extremely poisonous. They contain, besides carbon monoxide, hydrogen t e t r a -carbonylcobaltate which i s very poisonous, however the l a t t e r compound has a very unpleasant odour and thus indicates i t s presence. 179 3,4.6-Tri-O-acetyl-^-glucal Commercial a-D-glucose (55 g) was added slowly to col d a c e t i c anhydride (200 ml) containing 1.2 ml concentrated p e r c h l o r i c acid, the temperature was not allowed to exceed 45°C, while the mixture was vigorously s t i r r e d . S t i r r i n g was continued for 30 minutes a f t e r a l l glucose had dissolved. Dried red phosphorus (15 g) was added and the mixture cooled i n an i c e - s a l t mixture. The reaction mixture was s t i r r e d vigorously while bromine was added, very slowly at such a rate that the temperature did not exceed 20-25°C. No dry phosphorus must adhere to the side of the f l a s k since i t w i l l inflame i n contact with bromine. Then water (15 ml)was added slowly and the mixture kept' overnight at 0°C, then i t was f i l t e r e d . The s o l u t i o n contained 2,3,4,6-tetra-0-acetyl-a-g-glucosyl bromide. This s o l u t i o n wasadded gradually - 73 -over 1 hour to a vigorously s t i r r e d mixture previously prepared as follows while the temperature was kept at about -10°C by immersing i n an acetone-dry i c e bath. Hydrated sodium acetate (200 g)was dissolved i n a s o l u t i o n of g l a c i a l a c e t i c acid (200 ml) i n water (190 ml). To t h i s cooled mixture (0°C) zinc dust (110 g) and a s o l u t i o n of hydrated copper (II) sulphate (10 g) i n water (40 ml) was added. When the cupric ion had been reduced the addition of the above 2,3,4,6-tri-O-acetyl-a-D-glucosyl bromide splutionwas begun. During the addition the reaction mixture was s t i r r e d as vigorously as possible with a Hirschberg-type s t i r r e r . The s t i r r i n g was continued f o r about 3 hours a f t e r a l l of the 2,3,4,6-tri-O-acetyl-a-D-glucosyl bromide s o l u t i o n had been added. The reaction mixture was f i l t e r e d . Since the f i l t r a t i o n was very tedious, the top of the f i l t e r was cooled by adding small pieces of dry i c e . A f t e r f i l t r a t i o n the f i l t e r contentwas washed several times with 50% a c e t i c a c i d . Ice-water (500 ml) was added to the combined f i l t r a t e s and the s o l u t i o n exhaustively extracted with chloroform. The combined chloroform extracts were washed thoroughly with water and sodium carbonate s o l u t i o n u n t i l a l l a c i d had been removed. The chloroform layerwasthen dried thoroughly over anhydrous magnesium sulphate. The chloroform s o l u t i o n which could be c l a r i f i e d with charcoal,was evaporated to dryness, the r e s u l t i n g syrup was then r e c r y s t a l l i s e d by seeding, from ethyl ether-petroleum ether. Y i e l d 50 g. One more r e c r y s t a l l i s a t i o n y i e l d e d a product s u f f i c i e n t l y pure f o r future reactions; m.p. 53-54°C, [ a ] Q = -14° (C, 3; chloroform). 181 Hydrohydroxylmethylation of 3,4,6-Tri-O-acetyl-D-glucal 3,4,6-Tri-O-acetyl-D-glucal (12 g) was diss o l v e d i n anhydrous benzene (50 ml) and the s o l u t i o n was put i n t o the l i n e r of the high pressure v e s s e l . The autoclave was flushed with carbon monoxide by f i l l i n g i t with about 20 atm. of carbon monoxide and venting i t four times i n succession. Carbon monoxide - 74 -was then added to a pressure of 55 atmospheres followed by hydrogen to a t o t a l pressure of 200 atmospheres. The reactants were heated to about 130°C for 2 hours. A f t e r cooling to room temperature, usually overnight, the unreacted gases were released and the brown s o l u t i o n i n the autoclave was transferred to a short column (10 x 10 cm) of F l o r i s i l under petroleum ether. E l u t i o n with petroleum ether (b.p. 30-60°C)was continued u n t i l a l l dicobalt octacarbonyl had been washed from the column as ind i c a t e d by a colourless eluate. The reaction product was then eluted from the column with benzene or acetone. Evaporation of the solvent gave a syrup (13 g) c o n s i s t i n g p r i m a r i l y of a mixture of 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-heptitols. Thin layer chromatography proved unsuccessful i n separating the products. Attempts to run square plates i n two directions using the same or d i f f e r e n t solvents also f a i l e d to give a useful separation. .Column chromatography using s i l i c a gel and alumina as absorbent also did not give a ready separation. A c e t y l a t i o n of the Hydrohydroxymethylation Product of 3,4,6-Tri-O-acetyl-D-glucal The hydrohydroxymethylation product was acetylated with a c e t i c anhydride and pyridine and also with a c e t i c anhydride and anhydrous zinc c h l o r i d e by the standard procedure. In both cases p a r t l y c r y s t a l l i n e products were obtained, but they also r e s i s t e d separation. De-O-acetylation of the Hydrohydroxymethylation Product The hydrohydroxymethylation product (2 g) was dissolved i n anhydrous methanol (50 ml) and then a 0.01N s o l u t i o n of sodium methoxide i n anhydrous methanol (50 ml) was added, and the mixture l e f t at room temperature overnight. Then the s o l u t i o n was n e u t r a l i s e d by saturation with carbon dioxide, followed by evaporation to dryness. The c r y s t a l l i n e mass was dissolve - 75 -i n water (50 ml) and passed slowly through an Amerlite-IR-120-H ion exchange column (25 cm x 3cm <(>) to remove sodium bicarbonate. The combined eluate and column washings were evaporated to an almost colourless p a r t l y c r y s t a l l i n e syrup (1.1 g). Exploratory paper chromatography using water-saturated 1-butanol as a developer indicated that f i v e zones were present, two of which were major and the other ones very minor. Preparative Separation by Paper Chromatography of the Anhydrodeoxyhepti'tols (4,5) * The anhydrodeoxyheptitol mixture c o n s i s t i n g p r i m a r i l y of 2,6-anhydro-3-deoxy-D-manno-heptitol and 2,6-anhydro-3-deoxy-D-gluco-heptitol (1 g) was applied from methanol s o l u t i o n (20 ml) to 10 large (48 x 64 cm) Whatman No. 1 paper chromatography sheets. Small amounts were also applied to three narrow (5 x 64 cm) cont r o l s t r i p s . A l l papers were suspended i n a chromatography cabi-net and saturated with the eluant vapour f o r 10 hours. Then water-saturated 1-butanol containing 5% ethanol was allowed to descend the papers. The control s t r i p s were removed i n 10 hour i n t e r v a l s and the zones located by spraying with the per i o d a t e - S c h i f f reagents. A f t e r about 40 hours the zones were s u f f i c i e n t l y f a r apart to allow e f f i c i e n t separation. The sheets were removed from the cabinet and allowed to dry. Three narrow (1-1 1/2 cm) s t r i p s were cut from each large sheet, one i n the centre and one about 5 cm from e i t h e r side. A l l s t r i p s and sheets were marked to avoid confusion. The s t r i p s were sprayed with the pe r i o d a t e - S c h i f f reagents to locate the zones. Rejoining the s t r i p s so t h e i r respective chromatograms allowed marking of the zones. Those areas of the chromatograms containing the two major zones were cut out and shredded i n t o small pieces. Exhaustive extraction with b o i l i n g methanol followed by evaporation to dryness afforded c r y s t a l l i n e 2,6-anhydro-3-deoxy-D-manno-heptitol (400 mg) and 2,6-anhydro-3-deoxy-D-gluco-heptitol ( 410 mg). Chromatography on a c e l l u l o s e column made by packing the c e l l u l o s e as -'''•76. -a s l u r r y i n 1-butanol and then changing the solvent to water-saturated-b u t a n o l , gave s i m i l a r r e s u l t s . However se p a r a t i o n on a column was not advantageous, s i n c e the e l u t i o n took considerable time and the l o c a t i o n o f the zones i n the large number of f r a c t i o n s was q u i t e t e d i o u s . Both p o l y o l s were r e c r y s t a l l i s e d from methanol-isopropyl ether or from methanol--e t h y l ether. 2,6-Anhydro-3-deoxy-D-manno-heptitol (4): M.p. 152-153°C, [ a ] g° .= +60° (c, 1.4; water), R f = 0.21. Anal. c a l c . f o r C 7 H ^ 0 5 : C, 47.18%; H, 7.92%. Found: C, 47.30%; H, 7.82%. 2,6-Anhydro-3-deoxy-Q-gluco-hepitol (5): M.p. 137-138°C [a]2° = -1° ( c, 3.5; water) R f = 0.30. Anal. c a l c . f o r C 7H 1 £ f0 5: C, 47.18%; H, 7.92%. Found: C, 47.19%; H, 7.63%. 1,4,5,7-Tetra-0-acetyl-2,6-anhydro-3-deoxy-g-manno_-heptitol 2,6-Anhydro-3-deoxy-D-manno-heptitol (30 mg) was a c e t y l a t e d w i t h p y r i d i n e (5 ml) and a c e t i c anhydride (4 ml) f o r 14 hours at room temperature, then s a t u r a t e d sodium bicarbonate s o l u t i o n (10 ml) was added and the mixture s t i r r e d f o r a few minutes. The s o l u t i o n was then e x t r a c t e d repeatedly with chloroform; the combined chloroform e x t r a c t s were d r i e d over anhydrous magnesium sulphate, f i l t e r e d and evaporated. The r e s u l t i n g syrup (50 mg) was r e c r y s t a l l i s e d twice from e t h y l ether-petroleum ether. M.p. 123-124°C [ a ] 2 0 = +28° ( c , 0.5, acetone). An a l . c a l c . f o r C 1 5 H 2 2 0 9 : C, 52.02%; H, 6.40%. Found: C, 52.53%; H, 6.55%. - 77 -l,4,5,7-Tetra-0-acetyl-2,6-anhydro-3-deoxy-D-gluco-heptitol 2)6-Anhydro-3-deoxy-D-gluco-heptitol was a c e t y l a t e d as above. R e c r y s t a l l i s a t i o n from e t h y l ether-petroleum ether gave the pure product. M.p. 79-80°C, [ a ] , 2 1 = +2° ( c , 0.5; acetone). A n a l . c a l c . f o r C i 5 H 2 2 0 9 : C, 52.02%; H, 6.40%. Found: C, 52.48%; H, 6.50%. P e r i o d i c A c i d O x i d a t i o n o f 2,6-Anhydro-3-deoxy-p-manno-heptitol (4) to give 2-deoxy-.3-0_-(l, 3 - d i h y d r o x y - 2 - p r o p y l ) - D - g l y c e r o - t e t r i t o l (12) 2,6-Anhydro-3-deoxy-D-manno-heptitol (31 mg) was d i s s o l v e d i n an aqueous s o l u t i o n (13 ml) c o n t a i n i n g p e r i o d i c a c i d (4g/100 ml); the o x i d a t i o n s o l u t i o n was kept i n the dark. A p o r t i o n o f the s o l u t i o n (1.5 ml) was observed i n the po l a r i m e t e r to f o l l o w the course o f the r e a c t i o n (completed a f t e r 2 hours). A f t e r 12 hours the p e r i o d i c and i o d i c acids were n e u t r a l i s e d w i t h barium carbonate and the s o l u t i o n was f i l t e r e d i n t o a s o l u t i o n of sodium borohydride (50 mg) i n water (1 ml). A f t e r two hours a c e t i c a c i d was added u n t i l the e v o l u t i o n o f hydrogen stopped. The s o l u t i o n was dei o n i s e d by passage through a column o f Amberlite I.R.-120-H r e s i n , f i l t e r e d and evaporated t o a s o l i d . About 10 ml of pure methanol were evaporated 5 times from the res i d u e to decompose borate e s t e r s to give a syrup (29 mg); = -25° (c, 0.7 methanol). N.m.r. s i g n a l s (D 20; m u l t i p l e t 3.50-3.85 p.p.m. with a sharp s i g n a l at 3.68 p.p.m.) ; m u l t i p l e t (apparent quartet) 1.47-1.92 p.p.m. This l a e v o r o t a t o r y t e t r i t o L ether was c h a r a c t e r i z e d as the t e t r a - 0 -p_-nitrobenzoyl d e r i v a t i v e . Tetra-0-(p_-nitrobenzoyl)-2-deoxy-3-0-(l,3-dihydroxy-2-propyl)-D-glycero-t e t r i t o l A p o r t i o n of 2-deoxy-3-0-(1,3-dihydroxy-2-propyl)-D-glycero-tetritol - 78 -(20 mg) was heated with p-nitrobenzoyl chloride (0.2 g; previously d i s t i l l e d under vacuum) i n pyridine (1 ml) at 100°C f o r 2 hours. Excess p-nitrobenzoyl . — c h l o r i d e was removed by s t i r r i n g the s o l u t i o n with sodium bicarbonate s o l u t i o n and extraction with chloroform (20 ml). The chloroform extract was thoroughly washed with aqueous sodium hydrogen sulphate, followed by sodium bicarbonate and f i n a l l y by water. Drying over anhydrous magnesium s u l p h a t e , f i l t r a t i o n and evaporation of the solvent y i e l d e d a syrup (75 mg) which was r e c r y s t a l l i s e d from ethyl acetate and a l i t t l e petroleum ether. M.p..149-150 °C [a] 2, 2 = "22° (c, 1.5; chloroform). Anal. c a l c . f o r C s s ^ ^ 7Nk: C, 54.13%; H, 3.63%; N, 7.21%. Found: C, 54.55%; H, 3.71%; N, 7.30%. Periodic Acid Oxidation of 2,6-Anhydro-3-deoxy-D-gluco-heptitol (5) to give 2-Deoxy-3-0-(1,3-dihydroxy-2-propyl)-L-glycero-tetritol (13). • 2,6-Anhydro-3-deoxy-D-gluco-heptitol (50 mg) was dissolved i n a sol u t i o n (20 ml) containing p e r i o d i c a c i d (80 mg) which was kept i n the dark fo r 12 hours. The s o l u t i o n was then n e u t r a l i s e d with barium carbonate and f i l t e r e d into a s o l u t i o n of sodium borohydride (50 mg) i n water (3 ml). A f t e r two hours a c e t i c a c i d was added u n t i l the evolution of hydrogen ceased. The so l u t i o n was deionised by passage through a column of Amberlite IR-120-H r e s i n and evaporated to a s o l i d . Removal of borate esters by successive evaporations of methanol (10 ml portions 5 times) y i e l d e d a syrup (48 mg). [ a]22 = + 2 6 ° (c, 2.9 water). NMR signals i n D 20: mult i p l e t at 3.50-3.85 p.p.m. Sharp signal at 3.7 p.p.m., mult i p l e t at 1.47-1.92 p.p.m. Tetra-0-(p-nitrobenzoyl)-2-deoxy-3-0_- (1,3-dihydro-2-propyl)-L-glycero- t e t r i t o l The 2-deoxy-3-0_- (1, 3-dihydroxy-2-propyl) - L - g l y c e r o - t e t r i t o l was treated with p_-nitrobenzoyl ch l o r i d e and pyr i d i n e as described previously. The product was r e c r y s t a l l i s e d from e t h y l acetate-petroleum ether. M.p. 151-152°C; • [ c j g 1 = +22° (c, 1.2; 'chloroform). Anal. c a l c . f o r C 3 5H 2 8 0 1 7N 1 +: C, 54.13%; H, 3.63%; N, 7.21%. Found: C, 54.46%; H, 3.55%; N, 7.29%. 4,5 ,7 -Tri-O-acety1-2,6-anhydro-3-deoxy-l-O-(p-toluenesulphonyl)-Q-gluco-h e p t i t o l (8). The mixture of 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy h e p t i t o l s (hydrohydroxymethylation product of tri-O-acetyl-Q-glucal) (4.85 g) and p_-toluenesulphonyl chloride (6.00 g) were dissol v e d i n cold anhydrous pyr i d i n e (125 ml). The rea c t i o n mixture was l e f t overnight at room temperature (22°C). The excess p_-toluenesulphonyl chloride was then decomposed with water (10 ml). The mixture was then d i l u t e d with water and extracted thoroughly with chloroform containing a l i t t l e ether. The combined chloroform extracts were washed with saturated sodium bicarbonate s o l u t i o n to n e u t r a l i t y and then washed twice with water. The chloroform s o l u t i o n was dried over anhydrous sodium sulphate and decolorised with activated charcoal. A brown syrup (5.0 g) was obtained upon f i l t r a t i o n followed by evaporation under diminished pressure. R e c r y s t a l l i s a t i o n from ethyl ether-petroleum ether gave a c r y s t a l l i n e s o l i d (2.0 g) . Evaporation of the mother l i q u o r gave a syrup which consisted p r i m a r i l y of untosylated material, predominantly 4,5, 7-Mj-acety 1-2,6-anhydro-3-deoxy-p_-manno-heptitol. . .• 4,5,7-tri-O-acety 1-2,6-anhydro-3-deoxy-l-0_- (p_-toluenesulphonyl) -D-gluco-h e p t i t o l was r e c r y s t a l l i s e d from e t h y l ether-petroleum ether and also from methanol. M.p 117-118°C [a]20 = -5° ( c, 0.5; chloroform). Anal. c a l c . f o r C2 0H 2 6O 1 0S: C, 52.50%; H, 5.52%; Found: C, 52.20%; H, 5.51%; : . .:. - 80 -2.6-Anhydro-3-deoxy-l-0-(p-toluenesulphonyl)-D-gluco-heptitol 4,5,7-Tri-£-acetyl-2,6-anhydro-3-deoxy-l-0- (p_-toluenesulphonyl) -D-g l u c o - h e p t i t o l was treated with 0.01N sodium methoxide i n methanol at room temperature overnight as usual for de-O-acetylations. A f t e r work-up a c y r s t a l l i n e product was obtained. R e c r y s t a l l i s e d from methanol-isopropyl ether. •: • • . • ) • • M.p.- 118°. Anal. c a l c . f o r C i i ^ o O y S : C, 50.60%; H, 6.07%, Found: C, 50.39%, II, 6.06%. Infrared and p.m.r. data showed that de-O-acetylation was complete, but that the p-toluenesulphonyl group had been retained. 4,5,7-Tri-O-acety1-2,6-anhydro-1-0-(p_-bromobenzenesulphonyl)-3-deoxy-D-glu c o - h e p t i t o l (11) The mixture of' 4,5,7-tri-0_-acetyl-2,6 anhydro-3-deoxy-heptitols (2 g) was d i s s o l v e d i n dry pyridine (15 ml) and the s o l u t i o n cooled to 0°C, then p u r i f i e d p_-bromobenzenesulphonyl bromide (2.6 g) was added. A f t e r 30 hours at room temperature 20 ml of water was added and the mixture was l e f t f o r 24 hours. The s o l u t i o n was then extracted with three portions of chloroform. The combined chloroform extracts were washed with water and dried over anhydrous sodium sulphate. Evaporation of the chloroform layer under reduced pressure y i e l d e d a syrup which was c r y s t a l l i s e d once from ether-petroleum ether. In order to obtain c r y s t a l s s u i t a b l e f o r an X-ray c r y s t a l structure analysis the compound was twice r e c r y s t a l l i s e d from methanol and once from methanol-water. ( Y i e l d 1.01 g). M.p 104°; [ a ] 2 2 = -10° (c, 3; chloroform). Anal. c a l c . f o r C 1 9H 23O 1 0SBr: C, 43.58%; H, 4.43%; S, 6.13; Br, 15.27%. Found:C, 43.57%, H, 4.47%; S, 6.32%; Br, 15.26%. X-ray c r y s t a l structure determination confirmed that t h i s compound was 4,5,7-- 81 -t r i - O - acetyl-2,6-anhydro-l-O-(p-bromobenzenesulphonyl)-3-deoxy-Q-gluco-» .•. ,182 heptitoJ. 4,5,7-Tri-O-acetyi-2,6-anhydro-l,3-dideoxy-l-iodo-g-gluco-heptitol (9) from 4,5,7-Tri-0-acetyl-2,6-anhydro-3-deoxy-l-0-(p-toluenesulphonyl)-Q-gluco-. i . : -h e p t i t o l (8). 4,5,7-Tri-£-acetyl-2,6-anhydro-l-0- (p_-toluenesulphonyl) -3-deoxy-D-gl u c o - h e p t i t o l (128 mg) was dissolved i n p u r i f i e d acetone (10 ml) and mixed with 10 ml of a s o l u t i o n of sodium iodide (130 mg) acetone. This mixture was put i n t o a thick-walled Carius tube (almost 75 ml volume) sealed, and : : > heated to 100°C f o r two hours. Then the tube was cooled and opened and the pre-r c i p i t a t e d sodium p-toluenesulphonate f i l t e r e d o f f . The f i l t e r paper was washed with a l i t t l e acetone and the combined f i l t r a t e and washings evaporated to a c r y s t a l l i n e s o l i d (115 mg). The product was r e c r y s t a l l i s e d from ethyl ether-petroleum ether and methanol-water. M.p. 100°C, [ a ] 2 2 = -13° ( c, 0.1; chloroform). Anal. c a l c . f o r C 1 3 H 1 9 0 7 I : C, 37.69%; H, 4.62%; I, 30.64%. Found: C, 37.58%; H, 4.35%; I, 30.58%. 4,5,7-Tri-O-acety1-2,6- anhydro-1,3-dideoxy-l-iodo-D-gluco-heptitol ( 9 ) from 4,5,7-Tri-0_-acetyl-2 ,6-anhydro-3-deoxy-1-0- (p_-bromobenzenesulphonyl) -D-gl u c o - h e p t i t o l (11). ° ' 4,5,7-Tri-£-acetyl-2,6-anhydro-3-deoxy-l-0_- (p_-bromobenzenesulphonyl) -D-gluco-heptitol was treated vv'ith sodium iodide i n acetone s o l u t i o n at 100°C as described above f o r 4,5,7-tri-0_-acetyl-2,6-anhydro-3-deoxy-l-0_- (^-toluene-sulphonyl)-D-gluco-heptitol. The product obtained was shown to be i d e n t i c a l to 4,5,7-tri-0_-acetyl-2,6-anhydro-l,3-dideoxy-l-iodo-D-heptitol, by i d e n t i c a l chromatographic behaviour, i n f r a r e d and p.m.r. spectra, o p t i c a l r o t a t i o n and melting point. There was no depression f o r the mixture-melting point. . - - 82 -(99.5-100°C) . 4,5,7-Tri-O-acety1-2,6-anhydro-3-deoxy-l-O-nitro-D-gluco-heptito1 (10). 4,5,7-Tri-O-acety1-2,6-anhydro-1,3-dideoxy-l-iodo-D-gluco-heptitol (70 mg) was d i s s o l v e d i n anhydrous a c e t o n i t r i l e (2.5 ml) and a s o l u t i o n o f s i l v e r n i t r a t e (50 mg) i n a c e t o n i t r i l e (2.5 ml) was added. The mixture was heated i n a t h i c k w a l l e d Carius tube (about 15 ml volume) at 100°C f o r 2 hours. During t h i s time y e l l o w s i l v e r i o d i d e p r e c i p i t a t e d . The tube was cooled, opened, and the contents were f i l t e r e d . Chloroform (10 ml) was added to the f i l t r a t e and the mixture was e x h a u s t i v e l y e x t r a c t e d with water. The organic l a y e r was d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d , and evaporated to a c r y s t a l l i n e s o l i d . , (55 mg). The product was r e c r y s t a l l i s e d from e t h y l ether-petroleum ether, to give large c r y s t a l s . M.p. 79°C; [a]j*2 = -8° (c, 0.7; acetone). An a l . c a l c . f o r C 1 3 H 1 9 0 1 0 N j C, 44.71%; H, 5.48%; N, 4.08%. Found: C, 44.48%; H, 5.12%; N, 4.06%. 4,5,7-Tri-O-acety1-2,6-anhydro-3-deoxy-p-gluco-heptitol (3) 4,5,7-Tri-O-acety1-2,6-anhydro-3-deoxy-l-0-nitro-D- glucorheptitol (27 mg) i n 15 ml p u r i f i e d methanol was hydrogenated at atmospheric pressure i n a m i c r o -hydrogenator w i t h p a l l a d i u m black (3 mg)as. c a t a l y s t . The r e d u c t i o n was' completed a f t e r 40 minutes. (hydrogen absorbed: 4.5 ml at 22°C, 759 mm. Hg.). The s o l u t i o n was f i l t e r e d to remove the c a t a l y s t , and evaporated to a c o l o u r l e s s syrup (25 mg). The product gave one zone upon t h i n l a y e r chromatography ( S i l i c a Gel G, benzene, 5% ethanol V/V.). A l l attempts'to c r y s t a l l i s e the compound were u n s u c c e s s f u l . 2,6-Anhydro-3-deoxy-D-gluco-heptitol (3). 1,4,5,7-Tetra-0-acety1-2,6-anhydro-3-deoxy-D-gluco-heptitol (25.mg) •• - 83 -was dissolved i n 10 ml methanol containing sodium methoxide (0.01N). The usual work-up f o r a de-O-acetylation gave a colourless syrup (11 mg) which was r e c r y s t a l l i s e d from methanol-isopropyl ether, m.p. 135-137°C. This product was i d e n t i c a l to the 2,6-anhydro-3-deoxy-D-gluco-heptitol obtained by paper chromatography of the anhydrodeoxy h e p t i t o l mixture as ind i c a t e d by comparative paper chromatography and a mixture melting point, which was not depressed. (136-137°C). l-Acetamido-4,5,7-tri-O-acetyl-2,6-anhydro-1,3-dideoxy-g-gluco-heptitol 4,5, 7-Tri-0_-acetyl-2,6-anhydro-3-deoxy-l-0_- (p_-toluenesulphonyl) -D-gluco-h e p t i t o l (148 mg.) was added to anhydrous methanol (2 ml) saturated with dried ammonia at 0°C. The reactants were heated i n a thick •••walledCarius tube (about 30 ml,vol.) at 100°C f o r 65 hours. Then, a f t e r c o o l i n g , the tube was opened and allowed to warm to room temperature so that most of the ammonia could escape. Evaporation under diminished pressure gave a colourless syrup. This material consisted ofthe amino-polyol, acetamide, and p-toluenesulphon-amide. A c e t y l a t i o n with a c e t i c anhydride (4 ml) and pyridine (4 ml) i n the usual way was followed by p u r i f i c a t i o n on a s i l i c a gel column using benzene-methanol (96:4 V/V) as a developer. The carbohydrate zone (65 mg) was r e c r y s t a l l i z e d from acetone-isopropyl ether-heptane to give the pure product. M.p. 136-137°C [a]22 = . 3 ° ( c , 1 . 8 ; chloroform). Anal. c a l c . f o r C 1 5H 2 30 8N: C, 52.17%; H, 6.71%; N, 4.06%. ..'-Found: C, 51.94%; H, 7.01%; N, 3.94%. Attempted Preparation of l-Acetamido-4,5,7-Tri-0-acetyl-2,6-anhydro-1,3-dideoxy-D-gluco-heptitol v i a the Azide 4,5,7-Tri-0-acetyl-2,6-anhydro-3-deoxy-l-0_-(p_-toluenesulphonyl)-D-gluco- heptitol (240 mg) with sodium azide (500 mg) i n acetone (3 ml) and water (2ml) was heated i n a. sealed tube at 110-120°C f o r 10. hours'. Then the tube was opened and the content washed with e t h y l ether. The ether layer was evaporated to a yellow syrup which was redissolved i n acetone and decolourised by passage through a short column of charcoal. Evaporation y i e l d e d the azide (83 mg). Thin-layer chromatography showed one zone ( S i l i c a Gel G, benzene,5% ethanol). The i n f r a r e d spectrum showed a strong azide absorption at 2120 cm 1 . A f t e r the product was dissolved i n ethanol (20 ml), i t was hydrogenated at atmospheric pressure f o r 6 hours over platinum black (made i n s i t u from 2.2 mg', Adam's c a t a l y s t ) . Since no decrease of gas volume can be observed during the hydrogenation of azides, small amounts of material were removed, and upon evaporation t h e i r i n f r a r e d spectra were measured. The disappearance of the azide absorption served as an i n d i c a t o r f or the progress of the reduction. A f t e r removal of the c a t a l y s t , followed by evaporation of the solvent, the product was acetylated with a c e t i c anhydride (4 ml) and pyridine (4 ml). The product i s o l a t e d was a discoloured syrup which contained only traces of the desired acetamide (T.L.C.). The Reaction of 3,4,6-Tri-O-acetyl-D-glucal with Carbon Monoxide and Deuterium 3,4,6-Tri-O-acetyl-D-glucal was reacted with carbon monoxide and deuterium i n the presence of d i c o b a l t octacarbonyl under the same conditions used for i t s hydrohy droxymethyl at ion/The products , upon de-O-acetylation, were also separated by paper chromatography. The two polyols corresponding to 2,6-anhydro-3-deoxy-D-gluco-heptitol and 2,6-anhydro-3-deoxy-D-manno-heptitol were i s o l a t e d , however they could not be c r y s t a l l i s e d . . 2.,6-Anhydro-3-deoxy-D-manno-heptitol-l,1,3- 2 H3(cis) (6) This compound has the same m o b i l i t y on paper chromatography as the corresponding non-deuterated compound. Clear colourless syrup. R^ = 0.21, [a]. = +55° (c,1; water). 2,6-Anhydro-3-deoxy-D-gluco-heptitol-l, 1,3- 2H 3(cis) (7). This compound has the same mo b i l i t y i n paper chromatography as the corresponding non-deuterated compound. Clear, colourless syrup R^ . = 0.30 [ct] D = 0° (c, 1; water). 4,5,7-Tri-O-acety1-2,6-anhydro-3-deoxy-1-0-(p_-toluenesulphonyl)-D-manno- h e p t i t o l (14) The hydrohydroxymethylation product of t r i - O - a c e t y l - D - g l u c a l (41.8 g) was treated with p_-toluenesulphonyl chloride (6.0 g) i n anhydrous pyridine (125 ml) at room temperature (21°C) f o r 12 hours and at 100°C f o r two hours. A f t e r cooling,saturated sodium bicarbonate s o l u t i o n (100 ml) was added and the s o l u t i o n s t i r r e d u n t i l the evolution of carbon dioxide ceased. The s o l u t i o n was then extracted thoroughly with chloroform, and the combined chloroform extracts were i n turn washed with more sodium bicarbonate s o l u t i o n u n t i l a l l evolution of C0 2 had stopped. The chloroform layer was dried over anhydrous sodium sulphate, f i l t e r e d and evaporated to a l i g h t brown syrup. (5.06 g). Thin layer chromatography on s i l i c a gel G plates using toluene-ethyl ether 2:1 V/V as developer showed several zones, when sprayed with the concentrated s u l p h u r i c - n i t r i c a c i d mixture followed by heating to 130°C; but only two major fluorescent zones when, sprayed with .me'thanolic diphenylamine (1%) and viewed under u l t r a v i o l e t l i g h t . Hence these l a t t e r zones represent . the p_-toluenesulphonates. Preparative t h i n layer chromatography of the reaction product (650 mg) on s i l i c a gel G ( a i f i d r i e d ) using toluene-ethyl ether (2:1 V/V), or isopropyl ether as developer afforded a major component (300 mg) and a minor one (80 mg). The tosylates were -detected by spraying several narrow areas with diphenylamine (1%) i n methanol while the rest of the plate was covered. Under u l t r a v i o l e t l i g h t i l l u m i n a t i o n those zones containing p_-toluenesulphonates fluoresce. These 'zones were then removed from the plates (avoiding the sprayed areas) and extracted with ether. - 86 -A f t e r f i l t r a t i o n , and evaporation of the solvent the two compounds were obtained. Slower Zone: 4,5,7-Tri-O-acety1-2,6-anhydro-3-deoxy-1-0-(p_-toluenesulphonyl)-D-gluco-heptitol R =0.57 (toluene-ethyl ether 2:1 V/V). R e c r y s t a l l i s e d from ethyl ether-petroleum ether, m.p. 118-C, no depression i n mixture-melting point with an authentic sample. ! . Faster Zone: 4,5,7-Tri-0-acetyl-2,6-anhydro-3-deoxy-1-0-(p_-toluenesulphonyl)-D-manno-heptitol. Colourless syrup. R f = 0.64 (toluene-ethyl ether 2:1, V/V), J e t ] 2 3 = +30° (c, 1.7; chloroform). Anal. c a l c . f o r C 2 0 H 2 6 O i o S : C, 52.50%; H, 5.52%. Found: C, 52.36%, H, 6.08%. Comparison of the Exchangeability of the p_-toluenesulphonoxy Groups by Iodide f o r 4,5, 7-Tri-0-acetyl-2,6-anhydro-l-0- (p_-'toluensulphonyl) -3-deoxy-Q-gluco-and manno-heptitols (8,14). Preliminary Experiment The unseparated p_-toluenesulphonate mixture above (20 mg) was dissolved together with sodium iodide (10 mg) in•N,N-dimethylformamide (1.5 ml). The sol u t i o n was heated to 100°C i n a small t e s t tube and at ce r t a i n i n t e r v a l s the mixture was spotted on t h i n layer chromatography plates made of s i l i c a gel G, developed i n toluene-ethyl ether (2:1, V/V) and the zones were detected by spraying with the acid reagent. Obviously the D-gluco isomer reacted f a s t e r than the D-manno isomer. / c? 0 o c? 0 / 0 o o O o O o O 0 0 0 0 o o o O CP o O 0 0 0 Q a 6 C H t O / i c 0 4 H 10 /s" 2o 25 3o 3,5 4 0 TiMf iw M I N ore's Figure 8- - Comparison of the Exchangeability of the p_-Toluene-sulphonoxy Groups by Iodide. Quantitative Experiment In each run the p a r t i c u l a r p_-toluene-sulphonyl d e r i v a t i v e (9.1 mg) and sodium iodide (9.1 mg) with acetone (1.4 ml) were put i n t o i d e n t i c a l Carius tubes (3 ml). The tubes were sealed and heated at 100°C f o r varying periods of time. A f t e r cooling and-opening the p r e c i p i t a t e d sodium p_-toluene sulphonate was c o l l e c t e d i n a sintered-glass c r u c i b l e , washed with 2ml cold dry acetone and d r i e d under reduced pressure to constant weight. A c o r r e c t i o n amounting to 0.2 mg per sample was added for the s o l u b i l i t y of sodium p_-toluenesulphonate i n acetone. The r e s u l t s were as follows: - 88 -D-gluco isomer D-manno isomer Time (min.) % Exchange Time (min.) % Exchange 5 .14 30 .20 10 18 60 32 23 41 120 41 41 46 300 47 60 51 420 56 90 59 630 73 162 93 The Hydroformylation of Tri-O-acetyl-D-Glucal (1) ' • Freshly r e c r y s t a l l i s e d t r i - O - a c e t y l - D - g l u c a l (13.5 g, 0.05 mole) was dissolved i n dry benzene (50 ml) and then 3.0 g dry dicobalt octacarbonyl (0.009mole) was added.The s o l u t i o n was hydroformylated i n the high pressure system described previously. The t o t a l void of the autoclave was 200 ml. The autoclave was charged with carbon monoxide (41 atm) and with hydrogen to b r i n g the t o t a l pressure to 205 atmospheres at 10°C. Upon rocking the autoclave the pressure dropped to 203 atm. due to s o l u t i o n of the gases i n the benzene. The autoclave, while being rocked, was then heated to 120°C. Irt order to be able to stop the reaction, the expected pressure drop at v 120°C necessary f o r hydroformylation of t r i - O - a c e t y l - D - g l u c a l was previously calculated, using Boyle's Law. The reaction of 0.05 moles of the g l u c a i would consume 16.1 atmospheres and the reduction of 0.009 moles of dicobalt octacarbonyl would require 1.4 atmospheres, making a t o t a l gas absorption of 1.7.5 atmospheres. A f t e r the pressure had dropped 17 atm. (at 120°C) the auto-clave was cooled by immersing i n ice-water. The work-up was s i m i l a r to that described previously. The reaction s o l u t i o n was poured i n t o a large s i n t e r e d -glass funnel (<j> 20 cm) containing about 8 cm of c e l i t e covered with l i g h t petroleum ether. Dry petroleum ether was passed through the funnel (1 l i t e r ) u n t i l the f i l t r a t e was c o l o u r l e s s . The f i l t e r was then washed with dry - 89 -benzene (0.5 1) u n t i l a l l carbohydrate material was removed. The benzene so l u t i o n was c l a r i f i e d with a l i t t l e activated charcoal and evaporated to a colourless glass (14.6 g) . The product consisted of a mixture of 4,5,7-tri-O-acety 1-2,6-anhydro-3-deoxy-D-gjAicjo-heptose, 4,5,7-tri-0-acetyl-2,6-anhydro-3-deoxy-D-manno-heptose and the corresponding h e p t i t o l s (I.R.), 2,4-Dinitrophenylhydrazones of the Hydroformylation Product The hydroformylation product (7.0 g) and 2,4-dinitrophenyl hydrazine (3.0 g.) were dissolved i n anhydrous methanol (160 ml) and 1 ml of g l a c i a l a c e t i c acid was added. The s o l u t i o n was refluxed f o r 4 hours and then allowed to coo l . The s o l u t i o n was then s t i r r e d vigorously and water (about 100 ml) was added, giving a f l u f f y yellow precipate. When the f i r s t drops of a yellow syrup could be noticed the addition of water was stopped. The mixture was f i l t e r e d and the f i l t e r content washed with water. Drying gave a yellow powder (8.8 g). Separation of 2,4-Dinitrophenylhydrazones The mixture of 2,4-dinitrophenylhydrazones (2.5 g) was applied to eight preparative thin layer chromatography plates (20 x 60 cm - Woelm s i l i c a gel G - 0.8 mm t h i c k ) . M u l t i p l e (4x) development with chloroform y i e l d e d two main yellow zones. These two zones were removed from the plate and were extracted exhaustively with d i e t h y l ether. The ether solutions gave yellow syrups. Faster Zone: 4,5,7-Tri-0-acetyl-2,6-anhydro-3-deoxy-D-gluco-heptose 2,4-dinitrophenylhydrazone. R e c r y s t a l l i z e d twice from ethyl ether-petroleum ether. R^ (chloroform, s i l i c a gel) = 0.57 . M.p. 120-121°C,[a ] 2 6 ° = +6.6 (c, 7; chloroform). Anal. c a l c . f o r C 1 9 H 2 2 0 1 1 N 2 : C, 47.28%; H, 4.59%; N, 11.63%.' Found: C, 47.54%; H, 4.77%; N, 11.43%. - 90 -Slower Zone: 4,5,7-Tri-O-acety1-2,6-anhydro-3-deoxy-D-manno-heptose 2,4-dinitrophenylhydrazone, r e c r y s t a l l i z e d twice from ethyl ether-petroleum ethe (chloroform, s i l i c a gel) = 5.3. M.p. 78-79°C, [ a ] 2 6 " = + 18.8 (c, 1.5; chloroform). Anal. c a l c . f o r C 1 9H220 1 1N 2: C, 47.28%; H, 4.59%; N, 11.63%. Found: C, 47.64%; H, 4.99%; N, 11.32%. Conversion of 4,5,7-Tri-O-acety1-2,6-anhydro-3-deoxy-D-gluco-heptose 2,4-,Dinitrophenylhydrazone (16) to 2,6-anhydro-3-deoxy-D-gluco-heptitol (5) The 2,4-dinitrophenylhydrazone (70 mg) was dissolved i n p u r i f i e d chloroform (0.5 ml) i n a Carius tube. Pyruvic acid (0.1 ml) and a 10% s o l u t i o n of anhydrous hydrogen bromide in g l a c i a l a c e t i c acid (0.9 ml) was added,the sealed tube was heated to 45°C for 1 hour. A f t e r opening the tube, chloroform (5 ml) was added and the s o l u t i o n washed with saturated aqueous sodium bicarbonate s o l u t i o n u n t i l most of the yellow colour was removed. The chloroform layer was dried over anhydrous sodium sulphate and evaporated to a l i g h t brown syrup. This syrup was reduced with sodium borohydride (200 mg) i n aqueous methanol (5 ml, 50% v o l ) . i n the usual way. The r e s u l t i n g l i g h t yellow syrup (10 mg) could be c r y s t a l l i z e d from methanol iso-prqpyl ether. M.p. 130-135°C, mixture m.p. with authentic 2,6-anhydro-3rde o x y - D T g l u c o - h e p t i t o l 132-136°c. Paper chromatography shows one zone of the same R^ as the authentic material. Conversion of 4,5,7-Tri-0-acety1- 2 ,6-anhydro-3-deoxy-D-manno-heptose-2,4-dinitro-phenylhydrazone :(17) to. 2,6-anhydro-3-deoxy-D-manno-heptitol (4) The 2,4-dinitrophenylhydrazone (70 mg) was treated as described above. The product was shown to be i d e n t i c a l to authentic 2,6-anhydro-3-deoxy-D-mannq-heptitol by paper chromatography and mix-ture melting point. 3.4- Di-O-acetyl-D-arabinal (18) The preparation of 3,4-di-O-acetyl-D-arabinal was s i m i l a r to that described f o r 3,4,6-tri-O-acetyl-D-glucal. P u r i f i c a t i o n was by d i s t i l l a t i o n under vacuum c o l l e c t i n g the main f r a c t i o n d i s t i l l i n g at about 80°C at 0 . 4 ™ Hg. 3,4-di-O-acetyl-D-arabinal i s a t h i n colourless syrup and i s rather .unstable, i t i s not know i n a c r y s t a l l i n e s t a t e . 183 The Hydrohydroxymethylation of 3,4-Di-O-acetyl-D-arabinal (18) 3,4-Di-O-acetyl-D-arabinal (12 g) was allowed to react with carbon monoxide (34 atm) and hydrogen (170 atm) i n the presence of dicobaltocta-carbonyl (2 g) f o r 1.5 hours at 125°C. The product (13 g), f i r s t freed of c a t a l y s t by f i l t r a t i o n through F l o r i s i l , contained traces of reducing sugars. The product was de-O-acetylated with 0.1N sodium methoxide i n methanol followed by reduction with sodium borohydride to convert any sugars to the correspond-ing sugar alcohols . Separation of the isomers into two major zones was achieved by paper chromatography as described e a r l i e r or on a c e l l u l o s e powder column (410 x 17 mm diameter) using water-saturated 1-butanol contain-ing 5% ethanol as developer. Two main zones were i s o l a t e d , one being 1,5-anhydro-4-deoxy-Q-lyxo-hexitol, and the other 1,5-anhydro-4-deoxy-L-ribo-h e x i t o l . 1.5- Anhydro-4-deoxy-D-lyxo-hexitol (22): the compound c r y s t a l l i s e d slowly when kept i n a desiccator f o r several months over phosphorus pentoxide. M.p. 85-87°C, [ a ] 2 0 = -50° (c, 1.7; water), Rf'= 0.26. The compound could not b e ' r e c r y s t a l l i s e d from methanol-isopropyl ether. Anal. c a l c . f o r -C 6H 1 2 C v C, 48.64%; H, 8.17%. Found: C, 48.38%; H, 8,22%. The n.m.r. spectrum was i d e n t i c a l to a compound of the same structure • - 92 - . . reported by G o r i n . 1 8 ^ l,5-Anhydro-4-deoxy-L-ribo-hexitol (21) This f r a c t i o n i s very hygroscopic, attempts to c r y s t a l l i s e i t from various s o l v e n t s were u n s u c c e s s f u l , although i t does s o l i d i f y i f kept over phosphorus pentoxide f o r s e v e r a l months. A m e l t i n g p o i n t would have to.be taken i n a dry-box. [ c t ] 2 0 = +29° (c, 2.5 water); R f = 0.36 Anal c a l c . f o r C 6H 1 2Cv C, 48.64%; H, 8.17%. Found: C, 48.49%; H, 8.22%. 1,5-Anhydro-2,3,6-Tri-0-benzoy1-4-deoxy-D-lyxo-hexitol 1,5-Anhydro-4-deoxy-D-lyxo-hexitol was O-benzoylated by the procedure • 229 of Smith and van Cleve ; . t o y i e l d syrupy l,5-anhydroT-2,3,6-tri-0_-benzoyl-4-\deoxy-D-lyxo-hexitol. The product r e s i s t e d a l l attempts to c r y s t a l l i s e i t ; [ a ] 2 1 = -^63° (c, 3; et h a n o l ) . Anal. c a l c . f o r C 2 7H 2 l t0 7: C, 70.41%; H, 5.25%. Found: C, 70.60%; H, 5.42%. 1,5-Anhydro-2,3-Tri-0-benzoyl-4-deoxy-L-ribo-hexitol l , 5 - A n h y d r o - 4 - d e o x y - L — r i b o - h e x i t o l was benzoylated as above t o give l,5-anhydro-2,3,6-tri-0_-benzoyl-4-deoxy-L-ribo-hexitol, which was r e c r y s t a l l i z e d from e t h y l a c e t a t e - l i g h t p e t r o l e u m ether and methanol-water. M.p. 132-133°C [ c t ] 2 1 = +79° (c, 1.6; chloroform). Anal', c a l c . f o r C 2 7H 2 1 +0 7: C, 70.41%; H, 5.25%-Found: C, 70.75; H, 5.31%. P e r i o d i c A c i d O x i d a t i o n of l,5-Anhydro-4-deoxy-D-lyxo-hexitol (22) to give 2-Deoxy-3-0-(2-hydroxyethyl)-D-glycero t e t r i t o l (24) 1,5-Anhydro-4-deoxy-D-lyxo-hexitol v;as o x i d i s e d according to the - 93 -procedure previously described with 0.1M p e r i o d i c acid. The dialdehyde was immediately reduced with sodium borohydride to y i e l d the t r i o l ' ether. [ a ] j 2 4 = -17° (c, 1; water). The product was characterised as the p_-nitro benzoate. M.p. '102-102.5°C; [a]*2 = -23° (c, 2; chloroform). Anal. c a l c . f o r C 27H 23N30 1 3: C, 54.27%; H, 3.88%; N, 7.03. Found: C, 54.55%; H, 3.96%; N, 7.36%. Per i o d i c Acid Oxidation of 1,5-Anhydro-4-deoxy-L-ribo-hexitol (21) to give - 2-Deoxy-3-0-(2-hydroxyethyl)-L-glycero-tetritol (23) 1,5-Anhydro-4-deoxy-D-ribo-hexitol was oxidised as previously described with 0.IM p e r i o d i c acid. The r e s u l t i n g dialdehyde was immediately reduced to give the t r i o l ether. [C'JQ4 = +17° (c, 1; water) . Reaction with p_-nitrobenzoyl chloride i n pyridine y i e l d e d the tris-p-nitrobenzoate: M.p. 102-102.5°C; [ a ] ^ 2 = +22.3 (c, 3.6; chloroform). Anal. c a l c . f or C 27H 2 3N 3Oi3: C, 54.27%; H, 3.88%; N, 7.03%. Found: C, 54.39%; H, 3.98%;'N, 7.29. The i n f r a r e d and p.m.r. spectra of 2-deoxy-3-0-(2-hydroxyethyl)-D-g l y c e r o - t e t r i t o l and i t s enantiomer were i d e n t i c a l ; a mixture melting point of the p_-nitrobenzoate showeddepression. 2-deoxy-3-0_-(2-hydroxyethyl)-L-glycero-t e t r i t o l tris-p_-nitrobenzoate was compared and shown to be i d e n t i c a l to a genuine sample of the compound obtained by periodate oxidation, followed by sodium borohydride reduction, of authentic 1,4-anhydro-5-deoxy-D-arabino-185 h e x i t o l . The mixture melting point was 101-103° . 2,3,4,6-Tetra-O-acetyl-a-D-glucosyl Bromide (26) The preparation i s i d e n t i c a l to that used f o r the synthesis of 3,4,6-tri - O - a c e t y l - D - g l u c a l (1) (page 72). However,the reduction step was omitted - 94 -and the s o l u t i o n of 2, 3 , 4 , 6-tetra-O-acetyl-ct-D-glucosyl bromide was washed with 400 ml of ice-water, the water l a y e r being washed twice w i t h chloroform (50 ml) each time. The combined chloroform l a y e r s were then s t i r r e d f o r 30 minutes with s a t u r a t e d sodium bicarbonate s o l u t i o n . The aqueous l a y e r was washed with a l i t t l e chloroform and the combined chloroform l a y e r s were s t i r r e d f o r 10 minutes w i t h s i l i c i c a c i d (10 g). F i l t r a t i o n f o l l o w e d by evaporation o f the f i l t r a t e , gave a t h i c k y e l l o w syrup (130 g). R e c r y s t a l l i s e d from dry ether m.p. 87-88°C. The l i t e r a t u r e m e l t i n g p o i n t i s 88-89°C.* 8 6 2: ,3 ,4 ,6-Tetra -0-acetyl -2-hydroxy-D-glucal (27) 2 , 3 , 4 , 6-Tetra-O-acetyl-a-D-glucosyl bromide (120 g) was warmed i n dry benzene (60 m l ) , to which diethylamine (36 g) had been added, u n t i l i t had d i s s o l v e d . A f t e r about 32 hours the r e a c t i o n mixture was d i l u t e d w i t h e t h y l ether (600 ml). F i l t r a t i o n removed diethylammonium bromide. The f i l t r a t e was washed with d i l u t e s u l p h u r i c a c i d (2%) u n t i l n e u t r a l and then twice w i t h water. The organic l a y e r was d r i e d over anhydrous sodium sulphate, f i l t e r e d and evaporated t o dryness. Y i e l d 74 g . The m a t e r i a l was r e c r y s t a l l i s e d from ethanol-petroleum ether. M.p. 66°C [a]20 = _3o° ( c, 2; c h l o r o f o r m ) , r e p o r t e d m.p. 65-66°C, [ a ] * 8 -32° ( c h l o r o f o r m ) * 8 ' 7 1,2,,4,6-Tetra-0_-acetyl-3-deoxy-D-erythro-hex-2-enopyranose (29) * 4 * 2 ,3 ,4 ,6-Tetra -0_-acetyl -2-hydroxy-D-glucal (50 g) was d i s s o l v e d i n a c e t i c anhydride (200 ml) c o n t a i n i n g 10 g f r e s h l y fused z i n c c h l o r i d e . A f t e r 10 minutes the mixture was poured i n t o 2 l i t e r s of v i g o r o u s l y s t i r r e d ice-water. The c r y s t a l l i n e p r e c i p i t a t e was f i l t e r e d o f f and washed thoroughly w i t h water, y i e l d 36 g. The product was r e c r y s t a l l i s e d from ethanol. M.p. 69-71°C [ct]p 2 = +48° (c,4; c h l o r o f o r m ) . Reported v a l u e s . * 4 * m.p. 70-- 9 5 -71°C, [ a ] 2 2 = +50° ( c, 3; chloroform). The Hydrohydroxymethylation of 1,2,4,6-Tetra-O-acetyl-3-deoxy-ct-D-erythro-hex-2-enopyranose (29). -1,2,4,6-Tetra-0-acetyl-3-deoxy-g-D-erythro-hex-2-enopyranose (8 g) was dissolved i n dry benzene (35 ml) and dicobalt octacarbonyl (3 g) was added; the mixture, contained i n a glass l i n e r , was put i n t o the autoclave. The vessel was charged with carbon monoxide (54 atm) and hydrogen to a t o t a l pressure of 146 atm at room temperature. It was then heated to 160°C and rocked f o r 2 hours a f t e r which time the gas absorption has stopped. A f t e r the gases were vented, the autoclave was opened and the contents which had the odour of a c e t i c ac i d was d i l u t e d with 100 ml l i g h t petroleum ether. The brown syrup which p r e c i p i t a t e d was separated, from the s o l u t i o n and dissolved i n benzene. The benzene s o l u t i o n was decolourised with activated charcoal f i l t e r e d and evaporated to an amber syrup (7.7 g). The syrup was acetylated with pyridine (50 ml) and a c e t i c anhydride (50 ml) overnight. Then the ac e t y l a t i o n mixture was evaporated to dryness and dissolved i n chloroform. The chloroform s o l u t i o n was extracted with water. The dried organic layer was evaporated to a l i g h t brown syrup (8.8 g). This syrup was dissolved i n toluene (200 ml) and separated by gas l i q u i d phase chromatography, (Figure 4 ). Each i n j e c t i o n consisted of about 1 ml of s o l u t i o n . The column which was made up of copper tube (12* x 3/8") was packed with chromosorb W (manu-factured by F and M ) carrying 10% (wt) s i l i c o n gum rubber SE-52 (manufactured by iF and M S c i e n t i f i c , Avondale, Penn., U.S.A.) and operated at 280°C. The c a r r i e r gas was helium (200 ml/min. detector temperature: 310°C, i n j e c t o r temperature: 280°C, filament current 150 mA). The gas chromatograph was an Aerograph 1520 instrument using thermal conductivity detectors. Two zones were i s o l a t e d (Figure 4 ). In both cases the loss due to aerosol formation was considerable. - 96 -Zone A (Figure 4) ~ Retention time: 11 min. Amount: 1.6 g. This zone was c o l l e c t e d as a l i g h t yellow syrup which could not be c r y s t a l l i s e d . The i n f r a r e d spectrum showed i t to be completely acetylated. The proton magnetic resonance spectrum (Figure 7) i n d i c a t e d that i t contained branched-chain products which are 1,5-anhydro d e r i v a t i v e s . Gas phase chromatography on the same column at 180°C resolved t h i s zone into two very close major zones and one smaller one (Figure 4 ). Separation was not attempted at t h i s time. For p.m.r. spectrum see Figure 7. Zone B (Figure 4) 1,2,3 *,4,6-Penta-O-acetyl-3-deoxy-3-C_- (hydroxymethyl) -a-D-gluco-pyranose (31) . Retention time: 15.4 min. Amount 530 mg. . This zone was c o l l e c t e d as a colourless syrup which c r y s t a l l i s e d r e a d i l y from et h y l e t h e r - l i g h t petroleum ether. For the p.m.r. spectrum see Figure 5. . M.p. 100°C, [ a ] 2 2 = 58.4° (c, 3.6; benzene). Anal. c a l c . - f o r ' C 1 7 H 2 4 0 1 x : C, 50.47%; H, 5.98%. . Found: C, 50.41%; H, 5.98%. The Hydrohydroxylmethylation of 1,2,4,6-Tetra-Q-acetyl-3-deoxy-a-D-erythro-hex-2-enopyranose (29) with Carbon Monoxide and Deuterium The hydrohydroxymethylation was performed i n a s i m i l a r manner as described above. The o l e f i n (2.6 g) was reacted with deuterium (54 atm) and carbon monoxide (67 atm) at 160°C f o r 3 hours. The a c e t y l a t i o n and chromato-graphic separation were i d e n t i c a l to the procedure described above, (page 9 5 ) . Zone A Retention time 11 min. This zone was a mixture. - 97 -Zone B 1,2,3*,4,6- Penta-0-acetyl-3-deoxy-3-£- (hydroxymethyl) -a-D-gluco-pyranose Retention time 15.4 min. This zone-was c o l l e c t e d as a colourless syrup which was r e c r y s t a l l i s e d from ethyl e t h e r - l i g h t petroleum ether. For p.m.r. spectrum see Figure 6. M.p. 100°C, [ a ] 2 2 = 52° (c, 3; benzene). _Anal. c a l c . f o r C 1 7 H 2 1 D 3 0 1 1 : C,." 50.10%; H and D, 6.68%. Found: C, 50.26%; H and D, 6.56%. 188 Preparation of Sodium Tetracarbonylcobaltate Dicobalt octacarbonyl (5 g) i n dry ethyl ether (100 ml) was added to sodium amalgam (1.1 g sodium, 120 g mercury) i n a three-necked round-bottom f l a s k f i t t e d with a gas-tight s t i r r e r ; a condenser with a calcium chloride drying tube and a rubber septum (serum cap). The apparatus was f i l l e d with dry nitrogen or preferably with dry carbon, monoxide. The amalgam was s t i r r e d u n t i l the colour of the ether s o l u t i o n had changed from brown to b r i g h t yellow. A f t e r a l l s o l i d material had s e t t l e d the s o l u t i o n could be withdrawn with a syringe.. . The Reaction of 2,3,4,6-Tetra-C^-acetyl-a-D-glucosyl Bromide (26) with Sodium Tetracarbonylcobaltate Apparatus The Aminco autoclave was used, however an injector-septum of the type used i n gas chromatographs capable of withstanding a pressure of at least 12 atm. was f i t t e d to the i n l e t so that l i q u i d could be i n j e c t e d without opening the v e s s e l . The f i r s t part of the experiment r e q u i r i n g the handling of non-phosphine-substituted carbonyls was c a r r i e d out under nitrogen i n a dry box. 2,3,4,6-tetra-O-acetyl-ct-D-glucosyl bromide (5 g) i n ethyl ether (40 ml) was - 98 -placed i n the glass l i n e r of the autoclave (void 270ml ) which was then sealed and flushed with dry carbon monoxide. A l l of the sodium tetracarbonylcobaltate s o l u t i o n prepared above was then i n j e c t e d through a rubber septum into the autoclave. The autoclave was then f i l l e d with 10 atm. of carbon monoxide and rocked at room temperature f o r 2 days; about 2.7 atm. of gas was absorbed by then and no more gas was taken up.. The gas was then vented to atmospheric pressure. A s o l u t i o n of triphenylphosphine (4 g) i n ethyl ether (50 ml) was in j e c t e d and the mixture l e f t at room temperature f o r 9 hours (2.8 atm. pressure increase). The gas was vented and the autoclave opened. The pre-c i p i t a t e d sodium bromide (1.0 g) was removed by f i l t r a t i o n and the f i l t r a t e was mixed with 10 ml p u r i f i e d methyl iodide. A f t e r about 24 hours a l l excess triphenylphosphine had p r e c i p i t a t e d as triphenylmethylphosphonium iodide. The p r e c i p i t a t e was f i l t e r e d o f f and the f i l t r a t e was evaporated to a yellow syrup (5.6 g) which was extracted with b o i l i n g l i g h t petroleum ether (600 ml.). Upon cooling (0°C) the petroleum ether s o l u t i o n y i e l d e d a yellow s o l i d (4 g). An amount (3 g) of t h i s s o l i d was chromatographed under nitrogen on a column (50 x 45 cm) of a i r - d r i e d s i l i c a gel G using a 1:1 (V/V) mixture of ethyl ether-petroleum ether (30-60°) as developer. Two yellow zones developed which however, were not completely separable since the slower material changed slowly i n -to the f a s t e r moving one. The f a s t e r moving zone on the column was eluted and upon evaporation of the solvent gave syrupy 2,3,4,6-tetra-0_-acetyl-Q-glucosyl t r i c a r b o n y l triphenylphosphine cobaltate (39) ( l g ) . The slower moving zone gave syrupy yellow 3,4,5,7-tetra-0-acety1-2,6-anhydro-D-glycero-D-gulo-heptosoyl t r i c a r b o n y l triphenylphosphine cobaltate (41) (1.4 g). 2,3,4,6-Tetra-O-acetyl-D-glucosyl t r i c a r b o n y l triphenylphosphine cobaltate (39) was r e c r y s t a l l i s e d from ether-petroleum-ether (30-60°C). M.p. 79-80°C, [a]20 = -19° (c, 3; benzene). Anal. Calc. f o r C3 5H 3 L f0 1 2CoP: C, 57.02%; H, 4.65%. - 99 -Found: C, 57.30%; H, 4.90%. The p.m.r. spectrum i n deuterochloroform was i n agreement with the structure, m u l t i p l e t at 2 p.p.m. (12 H) , mu l t i p l e t s at 5.7 to 3.5 p.p.m. (7'H), signal at 7.5 p.p.m. (15 H). 3,4,5,7-Tetra-O-acety1-2,6-anhydro-D-glycero-D-gulo-heptosoyl t r i c a r b o n y l triphenylphosphine cobaltate (41)'. This compound could not be obtained free of 2,3,4,6-tetra-0_-acetyl-D-glucosyl t r i c a r b o n y l triphenylphosphine cobaltate since i t slowly decomposed to that substance. Anal. Calc. f o r C 3 6H 3 1 +0 1 3CoP: C, 56.53%; H, 4.48%. Found: C, 57.11%; H, 4.34%. Gas Li q u i d P a r t i t i o n Chromatographic Separation of the Acetylated Polyols derived from the Cobalt Complexes (39, 41). The reaction product c o n s i s t i n g of the mixture of sugar cobalt complexes (200 mg) was reduced with sodium borohydride (200 mg) i n methanol (20 ml). A f t e r two hours the reaction mixture was f i l t e r e d , d i l u t e d with water (20 ml) and deionized with Amberlite IR-120H ion exchange r e s i n . Evaporation of the solvent y i e l d e d a c r y s t a l l i n e mass from which methanol (20 ml) was evaporated f i v e times to remove borate esters. Removal of the solvent gave a l i g h t brown syrup (40 mg) which was acetylated with a c e t i c anhydride (1 ml) and pyridine (1 ml) as usual. The syrupy acetate mixture (70 mg) was in j e c t e d into the G.L.P. apparatus as an ethyl ether s o l u t i o n . The column temperature was 240°C and the helium flow rate 150 ml per minute (other values as before, page 95 ). Two large peaks of retention times 4.6 min. and 8.8 minutes, and three very small peaks of retention times of 2,2, 3.8, and 7.6 minutes were observed. Injecting solutions of 2,3,4,6-tetra-0-acetyl-l,5-anhydro-D-glucitol (39) and 1,3,4,5,7-penta-0-acety1-2,6-anhydro-D-glycero-D-gjjlo-heptitol (42) under the same conditions i t was found that these compounds also have retention times - 100 -of 4.6 and 8.8 minutes r e s p e c t i v e l y . The major peaks were condensed i n a c r y s t a l l i n e s t a t e i n s t r a i g h t g l a s s tubes ( i . e . 1 x 200 mm) and weighed. Peak of r e t e n t i o n time 4.6 min:6 mg, peak of r e t e n t i o n time:8.8 min:13 mg. 2,3,4,6-Tetra-0-acetyl-l,5-Anhydro-Q-glucitol (38) I t was compared w i t h an a u t h e n t i c sample and shown to have i d e n t i c a l i n f r a r e d and p.m.r. s p e c t r a and.no mixture-melting p o i n t depression (73-75°) 1,3,4,5, 7-Penta-0-acetyl-2,6-anhydro-D-glycero-D,-gulo-heptitol (42). Retention time 8.8 minutes. M.p. 92°C. The compound was compared with an a u t h e n t i c sample, 1 8^ 5^® and was shown t o have i d e n t i c a l p.m.r. and i n f r a r e d s p e c t r a and no mixture m e l t i n g p o i n t depression (92-93.5°). Reduction of 2,3,4,6-Tetra-O-acetyl-D-glucosyl t r i c a r b o n y l triphenylphosphine c o b a l t a t e (39) This compound was reduced and deacetylated w i t h sodium borohydride i n methanol as described above. The product was a c e t y l a t e d and i n j e c t e d i n t o the gas chromatograph and gave one zone which was i d e n t i c a l to t e t r a - 0 _ - a c e t y l -1,5-anhydro-D-glucitol. Reduction of Impure 3,4,5,7-Tetra-0-acety1-2,6-anhydro-Q-glycero-D-gulo-heptosoyl t r i c a r b o n y l triphenylphosphine c o b a l t a t e (41) This cobalt complex (200 mg) was a l s o reduced and de-O-acetylated with sodium borohydride (200 mg) i n methanol (20 ml). The composition was determined by s e p a r a t i o n of the peracetates by gas l i q u i d phase chromatography as described p r e v i o u s l y . Both 2 , 3 , 4 , 6 - t e t r a - 0 - a c e t y l - D - p o l y g a l i t o l (6 mg) 1,3,4,5,7-penta-0-acetyl-2,6-anhydro-D-glycero-Q-gulo-heptitol (47 mg) were obtained. I d e n t i f i c a t i o n was by r e t e n t i o n time, m e l t i n g p o i n t , and mixture m e l t i n g p o i n t . - 101 -Decarbonylation of 3,4,5, 7-Tetra-0_-ace.tyl-2 16-anhydro-D-'gIycero-D-gulo-heptosoyl t r i c a r b o n y l triphenylphosphine cobaltate (41) 3,4,5,7-Tetra-0-acetyl-2,6-anhydro-p-glycero-D-gulo-heptosoyl t r i -carbonyl triphenylphosphine cobaltate (180 mg) was deposited from ethyl ether s o l u t i o n as a t h i n f i l m on the walls of a f l a s k (100 ml) and kept under vacuum (about 1 mm. Hg) at 60°C for 8 hours. No v i s i b l e change occurred. Reduction and deacetylation by sodium borohydride (170 mg) i n methanol (20 ml) followed by a c e t y l a t i o n i n pyridine (15 ml) and a c e t i c anhydride (1.5 ml) gave a syrup (56 mg) which, when analyzed by gas l i q u i d phase chromatography consisted almost e n t i r e l y of tetra-0_-acetyl-l,5-anhydro-D-glucitol which was i d e n t i c a l by i t s melting point (71°) and mixture melting point with an authentic sample. Attempted Carbonylation of 2,3,4,6-Tetra-0_-acety.l-D-glucosyl t r i c a r b o n y l t r i -phenylphosphine cobaltate (39). Impure 2,3,4,6-tetra-O-acetyl-D-glycosyl t r i c a r b o n y l triphenylphosphine cobaltate (210 mg) was divided i n t o two equal parts, and one h a l f of i t was reduced with sodium borohydride and acetylated as usual. The composition was obtained by separating the acetate mixture on the gas l i q u i d phase chromatograph and measuring the r e l a t i v e peak areas, not taking any molar response f a c t o r i n t o account. The r a t i o of 2,3,4,6-tetra-0_-acetyl-l,5-anhydro-D - g l u c i t o l (40) to 1,3,4,5,7-penta-0-acetyl-2,6-anhydro-D-glycero-D-gulo-h e p t i t o l was 1:8. The other h a l f of the material was diss o l v e d i n ethyl ether (10 ml) and put into the reaction v e s s e l described above. The vessel was charged with 10 atm. carbon monoxide gas and rocked; 1 atm. of gas was absorbed within 10 minutes, probably due to d i s s o l u t i o n i n the solvent, but no further absorption was observed. A f t e r 24 hours the reactor was opened. The - 102 -solvent was evaporated, and the r e s u l t i n g syrup (102 mg) was reduced by sodium borohydride and then acetylated with p y r i d i n e and a c e t i c anhydride. Gas l i q u i d p a r t i t i o n chromatography showed that both 2,3,4,6-tetra-O-acetyl-D - p o l y g a l i t o l (2,3,4,6-tetra-0-acetyl-l,5-anhydro-D-glucitol) and 1,3,4,5,7-penta-0-acetyl-2,6-anhydro-D-glycero-D-gulo-heptitol were present i n an unchanged r a t i o . , 2,3,4,6-Tetra-O-acetyl-D-polygalitol (2,3,4,6'-Tetra-0-acetyl-l ,5-anhydro-D-g l u c i t o l ) . 2,3,4,6-Tetra-0-acetyl-a-D-glucosyl bromide (2.5 g) i n dry ethyl ether (50 ml) was slowly added, over a period of 30 minutes, to a s o l u t i o n of l i t h i u m aluminum hydride (3.8 g) i n dry ethyl ether (50 ml) while the mixture was s t i r r e d vigorously. S t i r r i n g was continued f o r 30 minutes a f t e r a l l of the g l y c o s y l h a l i d e had been added. Methanol was added cautiously u n t i l most l i t h i u m aluminum hydride was decomposed, followed by water. 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