Nature’s expertise in creating breathtaking structural wonders which are vital for sustenance of life on this planet has astonished and inspired many synthetic chemists. We too have been attracted towards understanding, exploring and mimicking a few of these magnificent molecular entities. Our efforts are directed towards the synthesis of two types of molecular assembles of contemporary interest; first of them are medium ring carbohydrate mimetics which are unnatural compounds inspired by Nature and other class consisted of the terpenoid natural products which are conceived and assembled by Nature in ever increasing numbers. The spectacular development of carbohydrate mimetics, prompted primarily by their properties as glycosidase inhibitors, has led to the conception and synthesis of a wide variety of novel structures, the most significant ones belonging to the families of imino sugars and carbasugars. Major advances in diverse subjects such as chemical synthesis, analytical chemistry, structural biology, cell-surface recognition, molecular modeling and spectroscopy have made carbohydrate mimetics embraced by scientific community with increasing vigor. A major area of interest of organic chemistry is the total synthesis of complex natural products conceived and created by Nature. As a result of refinements in isolation and purification techniques and recent advances in spectroscopy and crystallography, unravelling of natural products from exotic species such as wild plants to microorganisms and from geographic locations ranging from mountain tops to the ocean floors, has made identification and structural elucidation of complex natural products a fairly routine exercise. Among natural products, terpenoids are considered as masterpieces of structural diversity with their bewildering carbocyclic arrangements and diverse functionalities embedded in them. The present thesis entitled “Synthesis of medium ring carbasugar analogues and terpenoid natural products” is an effort to design and synthesise natural and unnatural molecular entities either conceived by human mind or inspired by Nature. The research described in this thesis has been organized under three chapters. Chapter I: Design and synthesis of cyclooctanoid and cyclononanoid carbasugar analogues. Chapter II: A total synthesis of putative structure of sesquiterpenoid natural product dichomitol. Chapter III: A total synthesis of diterpenoid natural product guanacastepene C. A brief overview of each of these three chapters is presented below.(For Equations and Figures Refer PDF File) Chapter I: Design and synthesis of cyclooctanoid and cyclononanoid carbasugar analogues In recent years, the search for new therapeutically useful glycosidase inhibitors, mimicking carbohydrates 1, has extended beyond the realm of five and six membered cyclitols 2 (carbasugars), and targeted towards the medium-sized carbocyclic cores. In this context, we have conceptulised a new family of novel cyclooctanoid 3 and cyclononanoid 4 carbasugar analogues in order to study the effect of the enhanced flexibility and of new spatial distribution displayed by these structures on their adaptability in the active site of the enzymes. We have developed a versatile synthesis of cyclooctane based polyols 3 from commercially available hydrocarbon cyclooctatetraene 5. It was visualised that a bicyclo[4.2.1]nona-2,4,7-trien-9-one 6 is a functionally locked cyclooctatetraene with dispensed and differentiated double bonds and a masked C9 cycloocta-carbasugar from which the eight membered ring can be extracted through oxidative C1-C9 bond scission, Scheme 1. Several transformations in 6, leading to a range of polyhydroxylated cyclooctanoids was envisaged. Bayer-villiger oxidation in ketone 6 was smooth and led to a δ-lactone which on catalytic OsO4 dihydroxylation furnished diol 7. Further acetylation on 7 delivered a rearranged γ-lactone 8. LAH reduction in 8 and peracetylation furnished diene 9. Controlled catalytic hydrogenation in 8 furnished 1:1 mixture of 10 and 11, which on hydride reduction gave tetrols 12 and 13, respectively, Scheme 2. Protection of vic diol in 12 led to 14. Hydroboration-oxidation of 14 and peracetylation furnished three diastereomeric mixture of acetonide triacetates in 9:4:1 ratio and they were hydrolysed to give 15-17, Scheme 3. Interestingly, pentahydroxy 16 is an eight membered analogue of α-talose. Reagents and conditions: i) m-CPBA, DCM, 60% ii) OsO4, NMMO, acetone-H2O, 75% iii) Ac2O, Py, 90% iv) LAH, THF v) Ac2O, Py, 36% (2 steps) vii) H2, Pd/C, EtOAc, 95% viii) LAH, THF, 40%. Reagents and conditions: i) acetone, amberlyst-15, 80% ii) BH3-THF, NaOH, H2O2 iii) Ac2O, Py, 54% (2 steps) iv) 2N, HCl, 76%. Acetylation of 12 led to tertraacetate 18 which on OsO4-dihydroxylation and acetylation furnished two diastereomeric hexaacetates in 1:1 ratio. Hydrolysis of these hexaacetates with base furnished 19-20, Scheme 4. Reagents and conditions: i) Ac2O, Py, 90% ii) OsO4, NMMO, acetone-H2O iii) Ac2O, Py, 72% (2 steps) iv) NaOMe, MeOH, 75%. Diene 9 on exhaustive stereoselective double dihydroxylation and base hydrolysis led to octahydroxycyclooctane 21, Scheme 5. A cyclooctane derivative bearing eight oxygen atoms has been prepared for the first time. Reagents and conditions: i) OsO4, NMMO, acetone-H2O ii) NaOMe, MeOH, 56% (2 steps). In an unconventional but interesting enterprise, commercially available hydrocarbon cyclooctatetraene 5 has been elaborated to a rare hexose sugar (DL)-β-allose and its 2C branched analogue. The main theme in this approach was to generate a cyclic acetal moiety, a structural characteristic of sugars through ozonolytic cleavage of an appropriately crafted olefin and in situ intramolecular acetalisation, Scheme 6. Acetonide protection in 7 led to 22. LAH reduction in 22 liberated the diol and selective primary alcohol protection as TBS derivative furnished 23. Ozonolysis of 23 and PCC oxidation of the resulting lactal 24 led to lactone 25. Methoxide mediated lactone opening in 25 and protection of anomeric hydroxyl group as methyl ether led to 26. LAH reduction of ester led to 27 and further deprotections furnished (DL)-methyl-2-deoxy-2C-hydroxymethyl-β-allose 28. Protected hexose homologue 27 was converted via a mesylate to the terminal olefin 29 through a series of functional group transformations. Ozonolysis of 29 furnished hemiacetal 30, which on sodium borohydride reduction and acetonide deprotection delivered (DL)-methyl-β-allopyranoside 31, Scheme 7. Motivated and encouraged by the synthesis of cyclooctane carbasugar analogues, it was decided to venture into the synthesis of cyclononane carbasugar analogues. It was visualized that appropriately functionalized bicyclo[4.3.1]decane system 32, can serve as a masked C10 cyclononane carbasugar from which the nine membered ring can be extracted through the C1-C10 bond scission, Scheme 8. Reagents and conditions: i) 2,2-DMP, CSA, 65% ii) LAH, THF, 80% iii) TBSCl, imidazole, 54% iv) O3, DCM-MeOH, DMS v) PCC, DCM, 40% (2 steps) vi) NaOMe, MeOH vii) MeI, Ag2O, 73% (2 steps) viii) LAH, THF, 85% ix) TBAF, THF, 70% x) amberlyst-15, MeOH, 65% xi) Ac2O, DMAP, 92% xii) TBAF, THF, 74% xii) MsCl, DCM, 65% xiv) KOtBu, DMSO, 70% xv) O3, DCM, 75% xvi) NaBH4, MeOH, 80% xvii) amberlyst-15, MeOH, 60%. The bridged dienone 32 was readily prepared from cyclohexanone following a literature protocol. Ketone 32 on Bayer-Villiger oxidation furnished lactone 33 in moderate yield, and further exhaustive double dihydroxylation furnished two unanticipated rearranged products δ-lactone 34 and γ-lactone 35 in 5:3 ratio. Both, the novel lactones 34 and 35 were further elaborated to the corresponding hexahydroxy cyclononane carbasugar analogues 36 and 37, Scheme 9. These novel medium ring carbasugar analogues involving a nine memebered carbocycle have been synthesized for the first time. Reagents and conditions: i) m-CPBA, DCM, 60% ii) OsO4, NMMO, acetone-H2O, 54% of 34 and 32% of 35 iii) acetone, PPTS, 98% iv) LAH, THF, 90% v) 2N HCl, 88% vi) acetone, PPTS, 92% vii) LiBH4, THF, 50% viii) 2N HCl, 88%. All the details of our synthetic efforts towards several novel carbasugar analogues which have been synthesised for the first time, along with the synthesis of some interesting polyoxygenated carbocyclic intermediates, unusual products from rearrangements, incisive NMR studies and X-ray analyses to solve the stereochemical puzzles, along with enzyme inhibition studies will be presented in this chapter of the thesis. Chapter II: A total synthesis of putative structure of sesquiterpenoid natural product Dichomitol This chapter describes the first total synthesis of the putative structure of the sesquiterpenoid natural product dichomitol 55 bearing a novel triquinane framework, and reported in 2004 from the bascidiomycete fungi Dichomitus squalens by a group of Chinese researchers. Dichomitol 55 not only represented a novel skeletal-type among linear triquinanes but was also biogenetically quite intriguing as it was suggested to be related to hirsutanes through an unusual methyl shift. This unusual positioning of methyl group in Reagents and conditions: i) CO(OCH3)2, THF, 82% ii) MeI, THF, 90% iii) ethanedithiol, PTSA, 75%, iv) Raney-Ni, EtOH, 90% v) PCC, DCM, 90% vi) LHMDS, THF, -78 °C; Pd(OAc)2, CH3CN, 86% vii) MeLi, ether viii) PCC, DCM, 84% (2 steps) ix) Mg, 4-bromobutene, CuBr-DMS, THF; AcOH, 95% x) LHMDS, THF, -78 °C; Pd(OAc)2, CH3CN, 80% xi) DBU, KOtBu, PTSA, RhCl3. dichomitol 55 which probably originated through a Wagner-Meerwein rearrangement of a corresponding ceratopicane derivative aroused our interest, curiosity (and suspicion) towards this natural product and it was decided to undertake its total synthesis. Our synthesis commenced from the known bicyclic ketone 39 readily accessible from commercially available 1,5-cyclooctadiene 38 through a sequence previously developed in our laboratory. Successive α- carbomethoxylation and α-methylation correctly installed C-11 centre in 40. Carbonyl group in 40 was protected as its thioketal to furnish 41 which on reductive desulphurization with simultaneous benzyl deprotection and further oxidation led to ketone 42. Following Saegusa protocol, 42 was converted into enone 43. Alkylative transposition in 43 furnished enone 44, which on Cu(I) mediated 1,4-conjugate addition delivered 45 with desired methyl stereochemistry with preferred addition from the exo-face. Kende cyclization in 45 smoothly delivered tricyclic 46, a C5-C6 double bond isomer of the desired tricyclic precursor of the natural product. Several attempts to isomerise the C5-C6 double bond in 46 to the required C6-C7 position failed to deliver 47, Scheme 11. Reagents and conditions: i) ethyleneglycol, PTSA, C6H6, 97% ii) LAH, THF, 96% iii) amberlyst-15, acetone, 95% iv) TBSCl, imidazole, DCM, 98% v) OsO4, NMMO, acetone-H2O, 90% vi) TBSCl, imidazole, DCM, 86% vii) IBX, DMSO-toluene, 78% viii) LHMDS, THF, -78 °C, 40% ix) Martin sulfurane, CHCl3, 40% x) DIBAL-H, DCM, 90% xi) TBAF, THF, 85%. At this stage it was decided to pursue an aldol based approach as it may help to install the tetrasubstituted C6-C7 double bond. Bicyclic ketone 45 was protected as its ethylene ketal, ester group was reduced with LAH and ketal deprotection furnished 48. The primary hydroxyl protection in 48 led to 49. Dihydroxylation on the butenyl arm gave diol 50, wherein the primary hydroxyl was protected as TBS derivative and secondary hydroxyl group was oxidized to furnish 51. Employing LHMDS as a base, key aldol reaction was carried out on 51 to give three aldol products in which the required compound 52 was the major product. The tertiary hydroxyl group in 52 when subjected to dehydration using Martin sulfurane delivered the required 53 with correctly installed C6-C7 double bond, only in trace amounts, along with two other regioisomeric dehydration products. DIBAL-H reduction on 53 stereoselectively delivered 54 and TBS deprotection furnished a product 55 bearing the structure assigned for the natural product ‘dichomitol’, Scheme 12. Significant variation in the spectral characteristics of our synthetic product 55 and those reported for ‘dichomitol’ necessitates a reinvestigation of the structure of natural product. All the details of our synthetic efforts, problems and challenges encountered enroute and the synthetic insights used to address them will be presented in this chapter of the thesis. Chapter III: A total synthesis of diterpenoid natural product Guanacastepene C This chapter describes the first total synthesis of a novel 5,7,6 fused tricyclic diterpenoid natural product guanacastepene C 71 isolated from an unidentified fungus growing on the tree Daphnopsis americana by Clardy in 2001. Besides guanacastepene C 71, fourteen other guanacastepenes A-O have also been isolated and these compounds have evoked unprecedented attention from the synthetic community. In particular, several Reagents and conditions: i) LAH, THF, 55% ii) a. PMBCl, THF, 67% b. TBSOTf, DCM, 68% c. DDQ, DCM-H2O, 95% iii) IBX, toluene-DMSO, 92% iv) Ph2POCH2COCH2COOEt, THF, 86% v) H2, Pd/C, EtOAc, 99% vi) a. 6N H2SO4, THF-H2O, 80% b. 2,2-DMP, PPTS, 91% vii) PCC, DCM, 80% viii) DBU, C6H6, 82% guanacastepenes exhibit antibacterial activity against MRSA and VREF. Several total syntheses of guanacastepenes have been reported in the last two years due to their enticing architecture and promising biological activity profile. Our group has also been in the fray and following the early leads, we embarked on an ambitious journey towards the total synthesis of guanacastepene C 71. The synthetic approach towards guanacastepene C 71, envisaged in this study, was revealed through a retrosynthetic analysis which identified hydroazulene core 57, bearing AB rings of the natural product as an advanced precursor on which ring ‘C’ could be annulated, Scheme 13. Earlier efforts from our group have demonstrated that AB ring precursor 57 can be elaborated from readily available tri-cylcopentadienone 56. Keto-ester in 57 on LAH reduction led to diol 58 and following a three step protocol of protection-deprotection led to 59 wherein the free primary hydroxyl was oxidized to furnish the required aldehyde 60. It was condensed with appropriate four carbon Horner-Wittig partner to furnish a mixture of keto-enol tautomers 61. Hydrogenation of trans double bond led to 62 and TBS deprotection and concomitant acetonide deprotection followed by acetonide protection furnished the hemiketal 63. PCC oxidation in 63 furnished tricyclic precursor 64 for the key Knoevenagel cyclization. Exposing 64 to DBU delivered 65 embodying complete tricarbocyclic framework of guanacastepene C, Scheme 14. LAH reduction on 65, was stereoselective and led predominantly to the unrequired α- isomer 66. Reagents and conditions: i) LAH, THF, -78 °C, 65% ii) PPh3, C6H5COOH, DIAD, THF, 78% iii) LAH, THF, 84% iv) Ac2O, DCM, 90% v) 4N H2SO4, THF-H2O, 44% vi) DDQ, THF, 85% vii) K2CO3, MeOH, 70%. Diol 66 was subjected to standard Mitsunobu protocol to furnish dibenzoate 67 which was hydrolysed and reprotected as diacetate 68 with the desired 5β stereochemistry. Deprotection of acetonide in 68 led to the diol 69. Chemoselective allylic oxidation of vicinal diol employing DDQ furnished guanacastepene C diacetate 70. Finally, careful base hydrolysis of 70 delivered guanacastepene C 71, Scheme 15. Synthesis of guanacastepene C was a difficult and often frustrating journey. Many trials and tribulations to overcome the synthetic challenges and our persistant and sincere efforts to overcome the hurdles confronted by us during the synthesis and finally attainment of the first total synthesis of guanacastepene C 71 will be the subject matter of the last chapter of this thesis.(For structural formula pl refer pdf file)