J., SOUJANYA

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 i   SYNOPSIS Synthesis, Conformation and Glycosidic Bond Stabilities of Septanoside Sugars Supriya Dey Department of Organic Chemistry, Indian Institute of Science, Bangalore-12, India  Seven-membered cyclic sugars, namely, septanoses and septanosides, are less commonly known sugar homologues.  Synthesis of septanoses arise an interest due to their configurational and conformational features and the attendant possibilities to explore their chemical and biological properties.  Septanosides derivatives, mostly, deoxy-septanosides were synthesized, by many synthetic methodologies, such as, Knoevengal condensation, ring-closing metathesis, Bayer-Villeger oxidation and ring-expansion of 1,2-cyclopropanted glycals as key steps.  Apart from septanosyl monosaccharides, septanoside containing di- and tri-saccharides were also performed using glycosylation and ring expansions.   Another area of sustained interest is the studies of the stabilities of glycosidic bonds.  Acid- and enzyme-catalyzed hydrolysis of glycosidic bond were investigated intensely in the case of pyranosides and furanosides.  The explanation of the hydrolysis of such stereomeric sugars were rationalized on the basis of stereoelectronic effects, such as, (i) antiperiplanarity; (ii) synperiplanarity of lone-pair of electrons involed in the hydrolysis process; (iii) steric effects; (iv) field and hyperconjugative effects; (v) conformational effects; (vi) disarming torsional effects and (vii) substituent effects.  Chapter 1 of the thesis describes a survey of (i) synthesis of deoxy-septanosides and septanoside-containing di-and tri-saccharides and (ii) acid-catalyzed hydrolysis of glycopyranosides.    In a programme, it was desired to identify a new methodology for the synthesis of 2-deoxy-2-C-septanosides.  Synthesis of various septanosides from 2-hydroxy glycals, namely, oxyglycals, involves intermediates, such as, vinyl halide (III) and diketone (IV) (Scheme 1).  These intermediates were identified as precursors for the synthesis of desired 2-deoxy-2-C-septanosides.      ii   Scheme 1  In this context, bromo-oxepine III was examined using Pd-catalyzed C-C bond forming reactions, namely, Heck, Suzuki and Sonogashira reaction for the formation of hither-to unknown septanoside, branching out at C-2.  Heck coupling and Suzuki coupling reaction of bromo-oxepine was performed using activated alkenes, acrylates and substituted boronic acid, respectively, in presence of Pd(OAc)2, to furnish 2-deoxy-2-C-alkyl/aryl septanoside derivatives (Scheme 2).  Scheme 2  Sonogashira reaction of bromo-oxepine was performed using acetylenes in presence of Pd(PPh3)2Cl2 as catalyst and CuI as co-catalyst in DMF:THF:Et3N (5:3:2) solvent mixture to furnish 2-deoxy-2-C-alkynyl septanoside derivatives (Scheme 3).  Scheme 3 R = Ph, SiMe3, C6H13OBnOBnOBnO OBnOMeROBnOBnOBnO OBnOMeBrPd(PPh3)2Cl2, CuIDMF:THF:Et3N (3:2:1)98 oC, 72 h   iii   One of the 2-deoxy-2-C-alkyl septanoside derivative was converted to the corresponding protecting-group free 2-deoxy-2-C-alkyl septanoside, using hydrogenolysis (Pd/C, H2) and NaBH4-mediated reduction.  Scheme 4.  Reaction conditions: (i) Pd-C (10 %), H2, MeOH, 24 h; (ii) NaBH4, MeOH, 0 oC-rt, 3 h.  Chapter 2 presents details of the synthesis of 2-deoxy-2-C-alkyl/aryl/alkynyl septanoside derivatives from a bromo-oxepine.   Continuing the efforts to extend the ring-opening of oxyglycal derived gem-dihalo-1,2-cyclopropanted sugar, a Lewis acid-catalyzed ring-opening was considered important.  The presence of an additional substituent in C-2 of oxyglycal switches reactivity as compared to glycals.  For example, ring-opening of glycal derived gem-dihalo-1,2-cyclopropane generates 2-C-branched pyranoside, whereas corresponding oxyglycal generates oxepines even when both the reactions were performed under a mild basic condition, illustrating a sufficient reactivity difference between a glycal and an oxyglycal.  Thus, ring-opening reaction of gem-dichloro-1,2-cyclopropanted oxyglycal in the presence of a Lewis acid, hither-to unknown, was examined.  In this event, it was found that ring-opening reaction led to chloro-oxepine derivatives in the presence of AgOAc, using alcohol as nucleophiles.  Primary, secondary, unsaturated and aromatic alcohols were used in the ring-opening reaction.  The ring-opening reaction was stereoselective and only α-anomer was obtained in a good yield in each case (Scheme 5).  The counter-anion also reacted in an instance, so as to furnish O-acetyl chloro-oxepine during the ring-opening reaction.    Scheme 5   iv     The course of the reaction in the absence of alcohol led to afford only the O-acetyl chloro-oxepine (Scheme 6).   Scheme 6 OBnOOBnOBnClClBnOAgOAc:NaOAc (1:1)PhCH3, reflux, 48 h, 78 %OBnOBnOBnO OBnClOAc  It became pertinent to compare the result this work with that of AgOAc-catalyzed ring-opening of glycal derived gem-dihalo-1,2-cyclopropanated sugar, which led to C-furanoside derivative, as reported by Harvey and co-workers.  The sequence of reactions involved were protonation of the endo-cyclic oxygen, followed by ring-opening to generate resonance stabilized allylic ion, which rearranged to C-furanoside.  In contrast, oxyglycal derived gem-dihalo-1,2-cyclopropane studied herein led to chloro-oxepine exclusively, without subsequent rearrangement.  Ring-opening of glucal derived gem-dihalo-1,2-cyclopropanated sugars, followed by cyclization to C-furanoside were likely to have occurred, due to isomerisation of less-substituted endo-cyclic double bond at C2-C3 of oxepine to C1-C2 unsaturated vinyl ether. Such a reaction was related closely to the acid-catalyzed rearrangement in less-substituted oxepine systems.  On the other hand, gem-dichloro-1,2-cyclopropanated oxyglycal  derived chloro-oxepine did not undergo such an isomerisation, possibly due to unsaturation being present at highly substituted C2-C3 carbons (Scheme 7).  Thus, the presence of an additional oxy-substituent at C-2 in oxyglycal derived cyclopropane derivative plays a major role to control the reactivity, as compared to glycal derived cyclopropane derivatives.     v   Scheme 7  The observation that D-oxyglycal derived cyclopropanes afforded only halo-oxepines, without undergoing further reactions, was confirmed further by the following reactions: (i) RuCl3-NaIO4 mediated oxidation; (ii) NaBH4 reduction and (iii) Pd/C mediated hydrogenolysis (Scheme 8).  Scheme 8  Chapter 3 describes details of the ring-opening reactions of oxyglycal derived gem-dihalo-1,2-cyclopropane to exclusive formation of chloro-oxepine in the presence of AgOAc. It was planned further to synthesize a 1,7-linked-α-D-diseptanoside, through the oxyglycal route.  Ring-opening of oxyglycal derived gem-dihalo-1,2-cyclopropanated derivative with 6-hydroxy glycal led to 1,7-α-linked disaccharide unit.  The following reactions were performed in order to synthesize 1,7-linked-α-diseptanoside 2: (i) cyclopropanation of the glycal double bond; (ii) ring opening of the gem-dihalo cyclopropane; (iii) RuO4 mediated oxidation; (iv) NaBH4 reduction  vi   and (v) hydrogenolysis using Pd/C, H2 (Scheme 9).  Similar methodology was used for the synthesis of monoseptanoside, namely, n-pentyl-D-glycero-D-galacto-septanoside.  Scheme 9 OBnOOBnOBnClClBnO OHOHOHO OHOHO1   Oxyglycal route was also used for the synthesis of 2-chloro-2-deoxy septanoside 3, using hydrogenolysis (Pd/C, H2) and NaBH4 mediated reduction of chloro-oxepine (Scheme 10). Scheme 10  A kinetic study of the hydrolytic stabilities of mono-and diseptanoside was undertaken using an acid-catalysis, in a subsequent investigation.  In the course of studies, it was observed that glycosidic bond in the reducing-end hydrolyzed twice faster than that at the non-reducing end, whereas glycosidic bond in monosaccharide 1 hydrolyzed 1.5 times faster than of reducing-end glycosidic bond in diseptanoside 2.  Further, it was found that the replacement of the C-2 hydroxyl group by a chloride group reduced the rate of hydrolysis (Table 1).    vii   Table 1. First order rate constants and thermodynamic parameters for the acid-catalyzed hydrolysis of glycosidic bond in septanosides 1, 2 and 3.           a non-reducing end of 2.  A computational study was conducted, in order to gain further insight into the hydrolysis, using B3LYP/6-311G* level theory in the Gaussian 09 program packages.  Calculations using the PCM solvent model with water as the solvent showed that the orientation of hydroxylmethyl group plays an important role.  In the case of 1, the gg conformer was calculated stable by 2.12 kcal/mol, as compared, to tg-conformer.  In the gg conformation, the optimal positioning of the dipole C7-O7 stabilized the oxo-carbonium ion in the transition state (Figure 1).  Also, hydroxyl group at C4 stabilized the transition state, through non-covalent interaction (Figure 1).  The transition state for the hydrolysis of 1 was found to present activation barrier (∆G#) of 19.9 kcal/mol, which was in good agreement with value for 1 (∆G# = 23.26 kcal/mol), as calculated from Erying plot (Table 1).  On the other hand, inductive effect of the chloride group, as well as, the tg-orientation of the hydroxymethyl group appeared to contribute to the slower rate of the hydrolysis.   Figure 1. gg- and tg-conformations in the ground state of 1.   Compound  Rate of hydrolysis (kobs) (104 s-1)    ΔH# (kcal/mol) ΔS# (cal/mol K)  ΔG# (kcal/mol) 35 oC 45 oC 85 oC 90 oC    1 2.34 5.61 - - 12.95 −32.88 23.26 2 1.54 - 3.31 1.36a - - 13.18 −33.17 23.56 3 - - 0.418 2.12 72.44 −123.60 27.90 OHOHOHO OHOHOMe1 gg tg viii   Chapter 4 describes synthesis of 1,7-linked-α-D-diseptanoside, 2-chloro-2-deoxy septanoside and their acid-catalyzed hydrolysis studies.  Solid-state and solution phase conformation of septanosides are rare at present even when solid-state structures of pyranoside and furanosides are known commonly, that provide rich information of covalent and non-covalent interactions.  In this context, single crystal X-ray structural analysis of septanosides, namely, n-pentyl-2-chloro-2-deoxy-α-D-manno-sept-3-uloside 4 and p-bromo phenyl 4,5,7-tri-O-benzyl-β-D-glycero-D-talo-septanoside 5 were analyzed.  It was observed that the solid-state structure of 4 adopted twist-chair conformation, namely, 5,6TC3,4, whereas 5 adopted O,1TC2,3 conformation (Figure 2).  An analysis of non-covalent interactions revealed that a dense network of O−H···O and C−H···O stabilized the crystal lattice of 4, whereas O−H···O and C−H···π stabilized the crystal lattice of 5. Chapter 5 describes the detailed analysis of X-ray crystal structure of two septanoside derivatives including non-covalent interactions responsible for the stabilization of crystal lattice.       4           5 Figure 2. ORTEP of 4 and 5 with displacement ellipsoids, at a 10 % and 50 % probability level.  In summary, the thesis established the following major results: (i) synthesis of 2-deoxy-2-C-alkyl/aryl septanoside from a bromo-oxepine, using organometallic C-C bond forming reactions; (ii) the ring-opening reaction of oxyglycal derived gem-dihalo-1,2-cyclopropane in the presence of AgOAc and the effect of additional C-2 oxy-substituent in the reactivity, in comparison to glycal; (iii) an oxyglycal route for the synthesis of 1,7-linked-α-D-diseptanoside, 2-chloro-2-deoxy septanoside and their acid-catalyzed hydrolysis studies and (iv) solid-state X-ray crystal structural analysis and computational analysis of the conformation and non-covalent interactions associated with the stabilization of crystal lattice. Overall, the studies presented in the thesis provide a new insight into the synthesis, acid-catalyzed hydrolysis and solid-state structural analysis of septanoside derivatives.  O6C1C2C3 C4 C5 C6C7 C8 C9 C10  C11 C12O1O3O4O5O7ClO1 ix   The following publications and presentations were based on the Thesis work:  1. Dey, S.; Jayaraman, N. “Branching out at C-2 of Septanosides. Synthesis of 2-deoxy-2-C-alkyl/aryl septanosides from a bromo-oxepine”, Beilstein J. Org. Chem. 2012, 8, 522-527.  2. Dey, S.; Jayaraman, N. “Exclusive Ring Opening of gem-dihalo-1,2-Cyclopropanated Oxyglycal to Oxepines in AgOAc”, Carbohydr. Res. 2014, 389, 66-71.  3. Dey, S.; Jayaraman, N. “Dense Network of O−H···O and C−H···O Interactions in the Solid-state Structure of n-Pentyl-2-Chloro-2-Deoxy-α-D-manno-Sept-3-Uloside”, Carbohydr. Res. 2014, Revised manuscript submitted.  4. Dey, S.; Jayaraman, N. “Glycosidic Bond Hydrolysis in Septanosides: A Comparison of Mono-, Di- and 2-Chloro-2-Deoxy-Septanosides”, Manuscript submitted.   5. Dey, S.; Jayaraman, N. “Solid-state Structure of p-Bromo Phenyl 4,5,7-Tri-O-benzyl-β-D-glycero-D-talo-septanoside: Stabilization of the crystal lattice by a network of O−H···O, C−H···O and C−H··· π interactions”, Manuscript to be submitted.  6. Dey, S.; Jayaraman, N. “Studies of 1,2-Unsaturated Sugars Through Expansion, Shifts and Rearrangements”, Oral presentation in 26th International Carbohydrate Symposium, July 2012, Madrid, Spain.   7. Dey, S.; Jayaraman, N. “Studies of 1,2-unsaturated sugars through expansions and rearrangements”, Poster presentation in International Meeting on Chemical Biology, May 2013, IISER-Pune, India.  8. Dey, S.; Jayaraman, N. “Branching out at C-2 of septanosides. Synthesis of 2-deoxy-2-C-alkyl/aryl septanosides from a bromo-oxepine”, Oral presentation in 27th International Carbohydrate Symposium, Jan 2014, IISc, Bangalore, India.    x   9. Dey, S.; Jayaraman, N. “Ring Opening of Cyclopropanated Oxyglycals: (i) Branching out at C-2 of Septanosides and (ii) Studies of Ring Opening Reactions”, Oral presentation on Pfizer Symposium on Organic Chemistry, Prof. D.K. Banerjee and Prof. A. Srikrishna Memorial Award Lectures, Jan 2012, IISc-Bangalore, India.    

VAPOUR-LIQUID EQUILIBRIUM (VLE) MEASUREMENT AND PREDICTION FOR PROCESS EQUIPMENT DESIGN

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VAPOUR-LIQUID EQUILIBRIUM (VLE) MEASUREMENT AND PREDICTION FOR PROCESS EQUIPMENT DESIGN

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