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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

Towards The Total Synthesis Of Polycyclic Polyprenylated Acyl Phloroglucin (PPAP) Natural Products : Garsubellin A And Hyperforin

Bera, Mrinal Kanti 05 1900 (has links)
Organic synthesis has a rich history, ever since Friedrich Wohler’s synthesis of urea from ammonium cyanate in 1828 that gave birth to this important discipline of science. While organic synthesis has found many application and witnessed many triumphs in improving the quality of life, it is the creative instinct, reminiscent of art, associated with this discipline that holds special appeal. This creative flair finds its best expression in the domain of natural product synthesis, which has witnessed spectacular advances and attainments, particularly in the second half of the 20th century . Many natural products exhibit wide range of biological activities and thus provide useful leads for drug discovery. But very often, they are available only in minute quantities from natural sources and access to them poses threat to biodiversity conservation. Therefore, it is sometimes necessary to synthesize bioactive natural products to obtain requisite quantities and build diversity around their scaffold to explore their therapeutic potential. Thus, natural product synthesis provides an opportunity to organic chemists not only to demonstrate their creativity and intellectual ability but also render available materials for possible application in human health and wellbeing. It is not surprising that the study of the chemistry, biology and synthesis of natural products has emerged as one of the most flourishing and rewarding frontiers in modern science. The efforts delineated in this thesis are the continuation of our research group’s long standing interest directed towards the total synthesis of structurally complex and biologically promising natural products. The present thesis entitled “Towards the total synthesis of polycyclic polyprenylated acyl phloroglucin (PPAP) natural products : garsubellin A and hyperforin” is organized in two parts. PART A : Towards the total synthesis of garsubellin A and PART B : Towards the total synthesis of hyperforin. PART A : TOWARDS THE TOTAL SYNTHESIS OF GARSUBELLIN A Part A deals with the studies towards the total synthesis of garsubellin A 1, a polycyclic polyprenylated acyl phloroglucin (PPAP) natural product. In the year 1997, garsubellin A was isolated from the wood of garcinia subelliptica by Fukuyama and coworkers. Structurally, garsubellin A belongs to a small but rapidly growing class of natural products characterized by the presence of a highly oxygenated and densely functionalized bicyclo[3.3.1]nonan-2,4,9-trione core embellished with more than one hydrophobic prenyl side chain. Apart from its enchanting structural architecture, garsubellin A 1 also exhibits promising biological activity. Neurodegenerative diseases like Alzheimer’s have been attributed to the deficiencies in the level of neurotransmitter acetylcholine (ACh). Any inducer of the enzyme choline acetyltransferase (ChAT), which is responsible for the biosynthesis of acetylcholine has therapeutic potential in the area of neuro degeneration. Preliminary investigations have indicated that 1 enhances in vitro choline acetyltranferase (ChAT) activity in P10 rat septal neuron cultures by 154% at 10 μM concentration. In view of this unique bioactivity and complex structural architecture garsubellin A 1 attracted immediate attention from the synthetic organic chemistry community. We too, entered this arena being inspired by the complexity and the biological activity of 1. It is relevant to mention that garsubellin A 1 is a typical example of PPAP class of natural products like nemorosone 2, clusianone 3, hyperpapuanone 4, enervosanone 5 and garcinol 6, to name a few, Chart 1 Chart 1 (Fig) Garsubellin A 1 Nemorosone 2 Clusianone 3 Our first generation synthetic strategy towards garsubellin A 1 is depicted in Scheme 1. Retrosynthetically, it was envisaged that the functionalization pattern in the bicyclic core of garsubellin A 1 could be accessed from an appropriately functionalized bicyclo[3.3.1]nonene-9-one 7. Bicyclic nonane(-)-7, in turn could be obtained from di-prenylated cyclohexanone derivative (+)-8 through regio-selective allylation followed by Kende cyclization. Chiral cyclohexanone derivative (+)-8 was to be prepared through a series of chemical transformation from campholenic aldehyde (+)-9, readily available from monoterpene chiron (-)-(α)-pinene 10, Scheme1. Scheme 1 (Fig) Retrosynthetic analysis for garsubellin A The choice of α-pinene, available in both the enantiomeric forms, as the starting material provided the opportunity to devise the first enantiospecific approach toward garsubellin A 1 and offered opportunity to address the issue of absolute configuration of the natural product and its siblings (-)-α-pinene 10 was reconstructed into (+)-campholenic aldehyde 9 through epoxidation and Lewis acid mediated fragmentation as described in literature. OsO4 mediated dihydroxylation of (+)-9 followed by Wittig olefination furnished (+)-11 as a a single diastereomer. Compound (+)-11 was subjected to oxidative cleavage in the presence of NaIO4 to furnish a keto-aldehyde which upon base mediated aldol cyclization furnished cyclohexenone (+)-12. Luche reduction in (+)-12 was stereoselective and the resulting allylic alcohol was subjected to a stereospecific orthoester Claisen rearrangement (Johnson modification) to deliver (+)-13. Base promoted hydrolysis of ester (+)-13 furnished the carboxylic acid which under standard iodolactonization protocol afforded iodolactone (+)-14. Reductive deiodination in (+)-14 in presence of TBTH led to a lactone which upon stereoselective DIBAL-H reduction delivered lactol (_)-15. Lactol (-)-15 was bearing the masked aldehyde functionality which was required to install the second prenyl side chainIsopropylidlene Wittig olefination of the lactol (-)-15 proceeded as planned to give cyclohexanol (+)-16 with two prenyl sub units at the desired positions, Scheme 2. Oxidation in (+)-16 with PCC led to cyclohexanone (+)-8 and further allylation employing NaH was stereoselective and furnished a single diastereomer (+)-17 to set the stage for Kende cyclization. To execute the Kende cyclization, cyclohexanone derivative (+)-17 was transformed to its TMS enol ether and subjected to Pd+2 mediated Kende cyclization protocol to furnish(-)-7 in moderate yield, Scheme 3. Scheme 3 (Fig) (+)-8 (+)-17 (-)-(-)-7 Reagents and conditions : i) PCC, DCM, 0 oC, 1 h, 98 % ; ii) NaH, allyl bromide, THF, 60 oC, 4 h, 70 % ; iii) LDA, TMSCl, THF, -78 oC, 1 h ; iv) Pd(OAc)2, CH3CN-DCM, rt, 12 h, 30 % (over two steps) . Having demonstrated an enantiospecific route to the bicyclo[3.3.1]nonan-9-one core (-)-7 present in garsubellin A 1 from(-)-α-pinene, efforts were directed to build the oxyfunctionalization pattern present in the natural product. But various oxidative maneuvers on (-)-7 were not successful and we did not succeed in introducing the key enone functionality by employing allylic oxidation. As a result, we had to explore an alternative synthetic approach that could provide a short access to the core structure present in polyprenylated acyl phloroglucin natural products with appropriate functionalization. Our second generation approach depicted in scheme 4, emanated from commercially available dimedone. Retrosynthetically, it was envisaged that garsubellin A 1 could be elaborated from an appropriately functionalized bicyclo[3.3.1]nonan-9-one derivative 20 which in turn could be accessible from enol lactone 19. The enol lactone 19 could be made from dimedone 18 in only three carefully crafted steps, Scheme 4. Scheme 4 (Fig) Retrosynthetic analysis for garsubellin A Sequential addition of methyl acrylate and prenyl bromide to dimedone 18 in the presence of DBU led to the formation of 21 in a single-pot operation. Acid catalyzed hydrolysis of 21 delivered carboxylic acid 22 and was transformed into enol lactone 23 following standard enol lactonisation protocol. Quenching the kinetic enolate derived from 23 with prenyl bromide introduced the second prenyl group to deliver 24 in a stereoselective manner. Enol lactone 24 was subjected to DIBAL-H reduction to trigger the retro-aldol/re-aldol cyclization cascade. In the event, the anticipated bicyclo[3.3.1]nonane diol 25 was realized and its structure was secured through regioselective derivatization to a crystalline monoacetate 26 and X-ray crystalstructuredetermination,Scheme 5. Scheme 5 (Fig) 18 21 22 23 26 25 24 Reagents and conditions : i) a) DBU, methyl acrylate, THF, rt, 3 h ; b) DBU, prenyl bromide, THF, rt, 3 h, 70 % (over two steps) ; ii) conc.HCl, acetone-H2O, 50 oC, 12 h, 87% ; iii) NaOAc, Ac2O, 140 oC, 1 h, 92 % ; iv) LHMDS, prenyl bromide, THF, 78 oC,1h,62% ; v) DIBAL-H, DCM, 0 oC, 2 h, 52 % ; v) Ac2O, Et3N, DMAP, DCM, 0 oC, 3 h, 92 % . At this stage, attention was turned to address the issue of installation of the C-7 prenyl group on the bicyclic skeleton by employing a similar strategy. Towards this end, the methyl enol ether derivative of dimedone was subjected to prenylation under kinetically controlled condition to furnish 27 in excellent yield and was converted to xiv28 in a four steps sequence. Apart from acid catalysed hydrolysis of 27 to afford the cyclohexa-1,3-dione derivative, the other three steps were exactly similar to those depicted in Scheme 5. DIBAL-H reduction of 28 led to the desired structural reconstitution along with the concomitant reduction of the bystander carbonyl group to afford a mixture of bicyclic diols 29. The diol mixture was regioselectively protected as acetate and diastereomeric hydroxy group was oxidized by PCC to deliver bicyclic diketo acetate 30, Scheme 6. Scheme 6 (fig) Reagents and conditions : i) TiCl4, MeOH, 0 oC-rt, 1 h, 85 % ; ii) LDA, prenyl bromide, THF, 78 oC-rt, 12 h, 90 % ; iii) conc.HCl, acetone-H2O, 12 h, 86 % ; iv) a) DBU, methyl acrylate, THF, rt, 3 h b) DBU, prenyl bromide, THF, rt, 3 h, 49 % (over two steps) ; v) conc.HCL, acetone-H2O, 60 oC, 12 h, 85 % ; vi) NaOAc, Ac2O, 140 oC, 1 h, 69 % ; vii) DIBAL-H. DCM, 0 oC, 2 h, 46 % ; viii) Ac2O, Et3N, DMAP, DCM, 0 oC, 1 h, 76 % ; ix) PCC, DCM, rt, 2 h, 82 % . In this model study, we installed the C-7 prenyl group but the stereochemistry at this center was found to be epimeric as compared to the natural product garsubellin A 1. Thus, our strategy needed further rectification. Moreover, in the approach depicted in Scheme 6, an additional unwanted oxy functionality at C-6 was also generated. A refined second generation approach was thus devised. Accordingly, dimedone 18 was elaborated to a phenyl thio ether derivative 31 following the literature procedure. Compound 31 was transformed to 33 via kinetic prenylation product 32 followed by 1,3-transposition of the carbonyl functionality. Enone double bond of 33 was reduced and the resulting cyclohexanone derivative was prenylated under kinetically controlled conditions to afford 34. Michael addition of methyl acrylate to 34 completed the sequential geminal alkylation and generation of the key quaternary centre. Since, the stereochemistry of alkylation in 34 was determined by the pre-existing prenyl group, the sequence of prenylation and Michael addition in 34 can be harnessed for the installation of requisite stereochemistry. Ester hydrolysis followed by enol lactonisation gave 19 which was subjected to DIBAL-H reduction to deliver the bicyclo[3.3.1]nonane derivative 35 as an epimeric mixture through retro-aldol/re-aldol reaction cascade. Oxidation in 35 with PCC furnished the diketo compound 20 which was no longer bearing any excess oxy functionality. Enone functionality was introduced in 20 to furnish 36 by employing Saegusa’s protocol, Scheme 7. Scheme 7 (Fig) Reagents and conditions : i) LDA, prenyl bromide, THF78 oCrt, 12 h, 95 % ; ii) LAH, THF, rt, 1 h ; iii) HgCl2, CH3CN-H2O (5:1), 60 oC, 1 h, 64 % (over two steps) ; iv) NiCl2, NaBH4, MeOH, 0 oCrt, 1 h, 94 % ; v) LDA, prenyl bromide, THF, -78 oC, 72 % ; vi) methyl acrylate, KOtBu, C6H6, 30 min, 71 % ; vii) KOH, MeOH, H2O, 60 oC, 1 h, 93 % ; viii) NaOAc, Ac2O, 140 oC,1h,79%;ix)DIBAL-H,DCM,0 oC,2h,67%;x)PCC,DCM,rt,1h,95%;xi)Et3N, DMAP, TMSOTf, DCM, 0 oC, 1 h ; xii) Pd(OAc)2, CH3CN, 6 h, 60 oC, 59 % (over two steps). Nucleophilic epoxidation in 36 led to a single epoxide and the α-epoxy ketone was converted to β-hydroxy ketone 37 through reductive cleavage in the presence of NaSeH. The intent was to oxidize 37 to a 1,3-diketo compound and to use the highly enolizable 1,3-diketo functionality for selective functionalization of the bridgehead prenyl group to generate the tetrahydrofuran ring present in garsubellin A 1. Scheme 8 (Fig) Reagents and conditions : i) H2O2, NaOH, MeOH, 0 oC, 1 h, 85 % ; ii) PhSePhSe, NaBH4, EtOH, 0 oC, 1 h, 71 % ; iii) PCC, DCM, rt, 1 h, 76 % ; iv) Et3N, DMAP, TMSOTf, DCM, 0 oC, 1 h ; v) Pd(OAc)2, CH3CN, 60 oC, 6 h, 55 % (over two steps) ; vi) PPTS, MeOH, 0 oC, 30 min, 88 % . Oxidation of 37 in the presence of PCC directly and quite unexpectedly furnished 38 having a tetrahydrofuran ring. Compound 38 was converted to 39 in a three steps xvi sequence involving Saegusa’s protocol followed by deprotection of tertiary OTMS group, Scheme 8. This was a welcome outcome as prenylation in 39 at C-3 position could lead us to the advanced intermediate of Danishefsky and a formal total synthesis of garsubellin A 1. However, the crystal structure of compound 38 revealed that the stereochemistry at C-18 was epimeric compared to that of the natural product. At this stage, we decided to revert back to our original proposition to install 1,3-dicarbonyl functionality by oxidation of 37. Many additional efforts in this direction did not bear fruit. Repeated failure to generate the requisite 1,3-dicarbonyl functionality forced us to look at alternatives and it was decided to explore Effenberger cyclization to achieve our desired 1,3-diketo functionality in direct way and in a much shorter sequence. To adopt this shorter sequence, we went back to compound 34 which was transformed to its TBS enol ether 40 and was exposed to malonyl dichloride under carefully controlled conditions to afford a non separable mixture of regioisomers 41 and 42. This mixture of regioisomers was converted to their methyl enol ethers 43 and 44 and could be readily separated to furnish the two regioisomers in equal amounts, Scheme 9. Scheme 9 (Fig) Reagents and conditions : i) Et3N, DMAP, TBSOTf, DCM, 0 oC, 98 % ; ii) malonyl dichloride, DCM, 10 oC, 24 h ; iii) TMS-CHN2, Et2O, 0 oC, 1 h, 31 % (over two step, 43:44=1:1) ; iv) PTSA, HC(OMe)3, MeOH, 50 oC, 48 h, 67 % . The structures of two isomers 43 and 44 could be assigned by comparing with the spectra reported recently in the literature. Among these two diastereomers, 44 was useful for selective functionalization of the bridgehead prenyl group but the formation of 43 was not fully unwelcome as it could be isomerized to 44 under thermodynamic conditions, Scheme 9. Further efforts are on to achieve the selective functionalization of the bridgehead prenyl side arm in 44 which will lead to the formation of tetrahydro-furan ring with correct stereochemistry at C-18 centre. In summary, we have demonstrated the first enentiospecific approach towards garsubellin A 1 starting from ()--pinene. We have also delineated a protocol for the construction of the bicyclo[3.3.1]nonan-9-one framework present in garsubellin A 1 in 5 steps with overall yield of 17 % starting from dimedone. By using the same strategy We have synthesized the 18-epi-tricyclic core present in garsubellin A 1. PART B : TOWARDS THE TOTAL SYNTHESIS OF HYPERFORIN The use of St. John’s Wort in the treatment of mild to moderate depression has been known for long time. The prominent constituent of the St. John’s Wort is hyperforin 45, a polycyclic polyprenylated acyl phloroglucin natural product (PPAP), which is also responsible for the biological activity. Structurally, Hyperforin is characterized by a highly oxygenated and densely substituted bicyclo [3.3.1]nonan -2,4,9-trione core embellished with several prenyl and one homoprenyl subunit. Chart 2 (Fig) The major structural difference between garsubellin A 1 and hyperforin 45 is with respect to the C-8 quaternary centre. Garsubellin A 1 is embodied with a gem-dimethyl group at C-8 centre whereas in hyperforin 45 bears a stereogenic C-8 centre with a methyl and a homoprenyl substituents. Probably because of this stereogenic C-xviii 8 centre, hyperforin and its analogues (Chart 2) constitute thorny synthetic challenges and remains to this day defiant to chemical synthesis. But, the remarkable biological as well as structural features associated with this molecule make hyperforin 45 as a tempting target for total synthesis. So far, very little attention has been paid towards it’s total synthesis and no one has yet addressed the crucial issue of setting up the C-8 stereogenic centre. For our synthetic approach towards hyperforin 45, it was crucial to identify a starting material in which the key C-8 quaternary centre was pre-installed. Towards this end, the cyclohexane 1,3-dione derivative 53 was identified as the synthon and our synthetic strategy towards hyperforin was designed in a manner that could give expression to an experiences in the quest for garsubellin A. Hyperforin 45 synthesis was sought to be accomplished from fully embellished bicyclic ketone 51. Its precursor enol lactone 52 could readily be transformed to bicyclic ketone 51 via DIBAL-H promoted retro-aldol/re-aldol cascade cyclization pathway. It has already been demonstrated that the type of enol lactone like 52 could be accessed from cyclohexane-1,3-dione derivative 53 through appropriate stereocontrolled chemical steps, Scheme 10. Scheme 10 (Fig) Retrosynthetic strategy for hyperforin Since the cyclohexane-1,3-dione derivative 53 has not been reported in the literature, a straight forward multi-gram access to it from commercially available citral 54 was devised. Citral 54 was transformed to -unsaturated ketone 55 viaMeLi addition and MnO2 oxidation. Tandem Michael addition-Claisen condensation in 55 with diethyl malonate delivered a cyclic intermediate 56 which upon further decarboxylation furnished the requisite 1,3-dicarbonyl compound 53 in moderate yield, Scheme 11. One-pot tandem Michael addition with methyl acrylate and prenylation in 1,3-diketone 53 in the presence of DBU led to a readily separable mixture of diastereomers 57 and 58 in a ratio of 1.2 :1, Scheme 11. Scheme 11 (Fig) Reagents and conditions : i) MeLi, 0 oC, Et2O, 82 %, ii) MnO2, rt, 12 h, 72 % ; iii) CH2(CO2Et)2, NaOEt, EtOH, 60 oC, 12 h; iv) KOH, MeOH, 60 oC, 72 h, 58 % (2 steps), v) a) DBU, methyl acrylate, THF ; b) prenyl bromide, rt, 6 h, 48% (over two steps); (57 : 58 = 1.2 :1) It was decided to first proceed with the diastetreomer 58. The diastereomer 58 washydrolyzed to the carboxylic acid and the acid was further elaborated to enol lactone 59. At this stage, it was felt useful to introduce an additional prenyl sub-unit that would eventuate at the C-3 position in hyperforin 45. This was readily realized through kinetic deprotonation of 59 and a prenyl bromide quench to furnish 60 through 1,3-stereoinduction attributable to the pre-existing bridgehead prenyl group. Chemoselective DIBAL-H reduction of the lactone moiety in 60 initiated the thermodynamically controlled retro aldol/re-aldonization cascade to furnish the desired bicyclo[3.3.1]nonan-9-one scaffold 61 in a moderate yield, Scheme 12. Scheme 12 (Fig) Reagents and conditions : i) conc.HCl, acetone-H2O, 60 oC, 88 % ; NaOAc, Ac2O, 140 oC, 1 h, 75 % ; iii) LDA, prenyl bromide, THF, 78 oC,1h,51%;iv)DIBAL-H,DCM,0 oC,2, 54 % . This was a very satisfying outcome as in 61 we not only had correctly installed the C-8 stereogenic centre but also adequate functionality in the two bridges for further elaboration to the target structure. However, oxidation of 61 to the triketone and introduction of the C-7 prenyl group through α-prenylation proved unproductive. Recourse was further taken to a modified strategy to install the C-7 prenyl group. According to this plan, the 1,3-dicarbonyl moiety in 53 was readily elaborated to the methyl enol ether and the prenylation of this compound under kinetically controlled conditions led to a diastereomeric mixture of enol ethers 62 and 63 (1.2:1). As anticipated, there was only marginal diastereoselection during this alkylation, but the two stereogenic centres corresponding to C-7 and C-8 of the target structure were now duly installed. Among two diastereomers, the right one was picked up and elaborated towards the target structure. Compound 63 was converted to enol lactone 64 in a four steps sequence as described previously. Enol lactone 64 was reduced with DIBAL-H to trigger the desired structural rearrangement and furnish a mixture of diastereomers. PCC oxidation of the diol readily afforded the tricarbonyl compound 65, Scheme 13. Scheme 13 (Fig) Reagents and conditions : i) TiCl4, MeOH, 0 oC -rt, 90%, ii) LDA, prenyl bromide, THF, -78 oC -0 oC, 12 h, 90%; iii) conc.HCl, acetone, rt, 12 h, 83%; iv) a) DBU, methyl acrylate, THF; b) prenyl bromide, rt, 6 h, 45%; v) conc.HCl, acetone-H2O, 50 oC, 12 h, 87%; vi) NaOAc, Ac2O, 140 oC, 1 h, 70%; vii) DIBAL-H, DCM, 0 oC, 2 h, 41%; viii) PCC, DCM,0 oC-rt,1h,70%. From structural perspective, the C-7 prenyl (exo-) and C-8 homoprenyl (endo-) are trans-in hyperforin 45 but quite interestingly in guttiferone A 48 and hypersampsone F 49, the C-7 prenyl is endo-and the C-8 homoprenyl is exo-, although their trans relationship is retained. Therefore, the stereochemical disposition of prenyl and homoprenyl groups at C-7 and C-8 centre respectively in 65 matched with the basic skeleton of guttiferone A 48 and hypersampsone F 49 instead of hyperforin 45. In order to realize the requisite C-7, C-8 stereochemistry of the target molecule hyperforin 45, it was considered essential to manipulate the sequence of single pot tandem dialkylation and once again we ventured to build upon our experience in context of the synthesis of garsubellin A 1. Accordingly, 53 was elaborated to the ethyl enol ether derivative 66 and its prenylation under kinetically controlled conditions afforded a readily separable mixture of diastereomers 67 and 68 (1.2:1). Following Prenylation, one of the diastereomers 68 was subjected to DIBAL-H reduction to furnish a mixture of allylic alcohol and this mixture on acid catalysis furnished the enone 69. Enone double bond of 69 was stereoselectively and regioselectively reduced to afford tri-alkylated cyclohexanone 70. LDA mediated prenylation on 70 went in a straightforward manner to deliver a mixture of diastereomers which underwent Michael addition to methyl acrylate in presence of KOtBu to furnish 71 as a single diastereomer. To realize the requisite stereochemistry at C-7 and C-8 stereogenic centre of the natural product hyperforin 45, it was inevitable to carry out prenylation first on 70 followed by Michael addition of acrylate in a stepwise manner to afford 71, Scheme 14. Scheme 14 (Fig) Reagents and conditions : i) TiCl4, EtOH, 0 oC-rt, 1 h, 83 % ; ii) LDA, prenyl bromide, THF, 78 oC-0 oC, 10 h, 92 % ; iii) DIBAL-H, DCM, 0 oC, 30 min ; iv) conc.HCl, acetone, 0 prenyl bromide, THF, 78 oC,4h,73%;vii)KOtBu, methyl acrylate, C6H6, rt, 15 min, 65 % It was very satisfying to see that through this maneuver it was possible to install the quaternary centre in a requisite manner to secure the correct stereochemistry at C-7, C-8 present in hyperforin 45. Ester 71 was hydrolysed to carboxylic acid which was routinely transformed to enol lactone 72 under standard enol lactonisation condition. Enol lactone 72 was xxii exposed to DIBAL-H to trigger the retro-aldol/re-aldol reaction cascade and led to a diastereomeric mixture of bicyclic alcohols. This mixture of bicyclio[3.3.1]nonane based alcohols was routinely oxidized to bicyclic diketo compound 73 in good yield and further alkylated with prenyl bromide under kinetically controlled condition to afford 51 stereoselectively, Scheme 15. Scheme 15 (Fig) Reagents and conditions : i) KOH, MeOH, 60 oC, 78 %; ii) NaOAc, Ac2O, 140 oC, 1h, 69 %; iii) DIBAL-H, DCM, 0 oC, 2 h, 64%; iv) PCC, DCM, rt, 1 h, 87 %; v) LDA, prenyl bromide, THF, -78 oC, 2 h, 73 %. Overall, this was very pleasing outcome as we could construct the bicyclo[3.3.1]nonan-9-one framework 51 present in hyperforin 45 in which all the prenyl sub-units and the homoprenyl unit are duly installed. Our efforts to introduce the enone functionality in 51 through Saegusa and other related protocols was not successful. Therefore, it was mandatory to ponder over our strategy once again and tactically modify it. Once again, it was decided to employ the Effenberger methodology. It was greatly advantageous to utilize Effenberger protocol because it was not only expected to shorten the synthetic sequence, but would also directly introduce the 1,3-dicarbonyl functionality in the substrate. Thus, we turned back to the diprenylated cyclohexanone derivative 70 and converted it to the TBS enol ether, which in turn, was exposed to malonyl dichloride under carefully controlled condition to afford an inseparable mixture of two regioisomers. This mixture of regioisomers was converted to the corresponding methyl enol ether derivatives 74 and 75 and these could be readily separable. Even though 74 and 75 were separated, it was difficult to identify them individually through spectroscopic techniques. Therefore, the mixture of isomers was thermodynamically equilibrated to a single isomer which was recognized as 75. This isomer which was serviceable for further elaboration to the natural product. Thermodynamically more stable isomer 75 was subjected to kinetically controlled, LDA ediated prenylation to furnish 76 in fairly good yield, Scheme 16.In 76, we had arrived at very advanced precursor of the natural product hyperforin 45 and it was time to pass the baton to another colleague in the group to reach the summit. Scheme 16 (Fig) Reagents and conditions : i) Et3N, DMAP, TBSOTf, DCM, 0 oC, 1 h, 95 % ; ii) malonyl dichloride, DCM, 10 oC, 12 h ; iii) TMS-CHN2, Et2O, 0 oC, 1 h, 30 % (over two steps, 74:75=1:1) ; iv) PTSA, CH(OMe)3, MeOH, 50 oC, 48 h, 67 % ; v) LDA, prenyl bromide, _78 oC,1h,61%. In short, construction of basic bicyclo[3.3.1]nonan-9-one framework present in hyperforin 45 has been outlined in which the crucial issue of setting up the C-8 stereogenic centre has been addressed for the first time. Installation of all prenyl and omoprenyl side chains present in the natural product was also achieved. Effenberger cyclization has been successfully employed to access an advance precursor in a shorter sequence but with the higher level of oxy functionalization.

Radical Cyclisation Based Approaches To 9-Pupukeanone And Lignan Precursors

Danialdoss, S 08 1900 (has links) (PDF)
No description available.

Synthesis Of Bioactive Marine Meroterpenoids : Frondosins And Liphagal

Shripad, Likhite Nachiket 10 1900 (has links) (PDF)
The sea conceals a mermaid’s grotto of useful chemicals-marine natural products of therapeutic potential. Marine sponges in particular are a rich source of natural products with structural diversity and novel biological activity. In recent times, there has been a growing interest in the synthesis of marine natural products. The present thesis entitled, “Synthesis of bioactive marine meroterpenoids: frondosins and liphagal” is an endeavor along the same lines and is organized under two parts –Part A and Part B. Part A: Studies towards the total synthesis of (±) frondosins A and B Frondosins A-E are IL-8 inhibiting marine meroterpenoids, with novel bicyclo[5.4.0]undecane framework, exhibiting anti-inflammatory and anti HIV-1 activities. A relatively simple and inherently flexible ring-closing metathesis (RCM) based strategy was employed to achieve the total synthesis of frondosins A (formal) and B in only 17 linear steps (total 13 operations) and 5% overall yield. A concise route, based on RCM, to the core structure of bioactive frondosins is amenable to ready appendage diversification and enables implementation of functionalization manoeuvres on all positions in the seven-membered ring of the bicyclic framework was also developed. A Diels-Alder strategy that led to the synthesis of 8-des-methyl norfrondosin A dimethyl ether is also delineated in Part A of the thesis. Part B: A concise synthesis of (±) liphagal Liphagal is a marine meroterpenoid displaying an unprecedented “liphagane” skeleton. It is a selective inhibitor of PI3K  and significantly toxic against a small panel of human tumor cell lines (LoVo, CaCo-human colon and MDA-468-human breast). A concise and straightforward biomimetic strategy towards liphagal and its 14-des-formyl analogue that awarded liphagal dimethyl ether in only eight steps from commercially available building blocks is described in Part B of the thesis.

Using molecular oxygen in synthesis : applications in lignin valorisation and natural product synthesis

Lancefield, Christopher Stuart January 2015 (has links)
The first part of this thesis describes my research towards the valorisation of lignin. Due to environmental and political pressures, there has been a drive to start the transition from a fossil fuel based economy to a renewable based one. This will require the development of novel routes to renewable chemicals, one source of which may be the biopolymer lignin. Through the synthesis of advanced lignin model compounds, the chemistry of real lignin is explored. This work culminates in the development of a novel method for the depolymerisation of real lignin to simple mixtures of aromatic chemicals that could be useful building blocks for the chemical industry. One of the key steps in this process is the oxidation of the β-O-4 linkages in lignin using catalytic amounts of DDQ and molecular oxygen as the terminal oxidant. The second part of this thesis details the first synthesis of melohenine B and O-ethyl-14-epimelohenine B, two medium sized ring containing natural products. The key step in the synthesis of these natural products was the photo-sensitised oxidative cleavage of an indolic substrate by molecular oxygen. Additionally, the use of residual dipolar coupling (RDC) analysis for the conformational analysis of these molecules in solution has been explored. Finally, the absolute configurational assignment of the natural products was established and their biological activities investigated.

The total synthesis of chamuvarinin

Morris, Joanne Charleen January 2013 (has links)
In 2004, the polyketide natural product, chamuvarinin (72) was isolated by Laurens et al. from the roots of Uvaria chamae, a member of the Annonaceae plant family. This unique tetrahydropyran containing acetogenin displayed potent levels of cytotoxic activity against the KB 3-1 cell line with an ED50 value of 0.8 nM. Upon initial isolation the relative and absolute stereochemical assignment of chamuvarinin (72) was unable to be readily achieved through ¹H and ¹³C NMR analysis. The initial synthetic route described herein has enabled the relative and absolute stereochemical determination of chamuvarinin (72) through the first total synthesis completed in 20 longest linear steps in 1.5% overall yield. A revised synthetic strategy towards chamuvarinin (72) was completed in 17 longest linear steps in 2.2% overall yield. The revised route facilitated the assembly of non-natural chamuvarinin-like analogues and their trypanocidal and cytotoxic activities have been assessed. The synthesis of these analogues has formed the basis of a more focussed study through the design and synthesis of simplified triazole (295), isoxazole (325) and butenolide triazole (305) analogues as potential Trypanosoma brucei (causative agent in African Sleeping sickness) inhibitors.

Enantioselective Synthesis Of Bio-Active Bicyclic Acetals, Cyclic Ethers And Lactones

Anbarasan, P 07 1900 (has links)
The thesis entitled “Enantioselective synthesis of bio-active bicyclic acetals, cyclic ethers and lactones” demonstrates the utility of chiral pool tartaric acid as the source in the synthesis of natural products. The results are discussed in three chapters; 1) Enantioselective synthesis of bio-active bicyclic acetals, 2) Enantioselective synthesis of bio-active cyclic ethers and 3) Enantioselective synthesis of bio-active lactones. A brief introduction is provided in each chapter to keep the present work in proper perspective. Compounds (in bold) and references (in superscripts) are sequentially numbered differently for each chapter and references are given as foot notes. Experimental procedures are given differently for each chapter and placed at the end of chapter. Scanned 1H and 13C NMR spectras are given with description of signals. Chapter 1 describes the enantioselective synthesis of bicyclic acetal containing insect pheromones. First part of this chapter deals with the enantiodivergent synthesis of both enantiomers of hydroxy-exo-brevicomin and 2-hydroxy-exo-brevicomin starting from a single chiral compound, bis-Weinreb amide derived from L-(+)-tartaric acid. Controlled addition of Grignard reagent to bis-Weinreb amide followed by diastereoselective reduction of the resultant ketone was employed as the key step for the enantiodivergent synthesis of hydroxy-exo-brevicomin and 2-hydroxy-exo-brevicomin. In the second part, enantioselective synthesis of exo-brevicomin, iso-exo-brevicomin and formal synthesis of frontalin comprising similar framework is demonstrated, utilizing á -benzyloxy aldehydes derived from L-(+)-tartaric acid as chiral building block. Second Chapter describes the enantioselective synthesis of bio-active cyclic ethers, disparlure, centrolobine and isolaurepan. Employing á-benzyloxy aldehydes derived from L-(+)-tartaric acid as the chiral building block, synthesis of both enantiomers of insect pheromone disparlure is achieved involving the diastereoselective addition of allyltributyl tin to the á-benzyloxy aldehyde and cross metathesis of the resultant homoallylic alcohol with 4-methyl-1-pentene. Formal synthesis of centrolobine and isolaurepan are accomplished. Pivotal step involved in the synthesis of centrolobine is iron(III) mediated cyclization of 1,5-diol derived from L-(+)-tartaric acid, while Lewis acid mediated reductive cyclization of the hydroxy ketone derived from á-benzyloxy aldehyde is the key step in the synthesis of isolaurepan. Third chapter in the thesis deals with the enantioselective synthesis of bio-active lactones muricatacin, 6-acetoxy-5-hexadecanolide and boronolide. Utilizing á-benzyloxy aldehyde as the building block, synthesis of five and six membered lactones, muricatacin and 6-acetoxy-5-hexadecanolide were accomplished via the diastereoselective addition of 3-butenylmagnesium bromide and allyltributyl tin to á-benzyloxy aldehyde, respectively. Stereoselective formal synthesis of boronolide was described, starting from D-(–)-tartaric acid. Key reaction sequence includes the elaboration of ã-hydroxy amide obtained by a combination of controlled Grignard addition and diastereoselective reduction from bis- Weinreb amide derived from D-(–)-tartaric acid.

Synthesis Of Medium Ring Carbasugar Analogues And Terpenoid Natural Products

Pallavi, Kotapalli 01 1900 (has links)
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)

Enantioselective Total Synthesis Of Bioactive Epoxyquinoid Natural Products

Roy, Subhrangsu 01 1900 (has links)
Total synthesis of natural products with diverse architecture and varying degree of complexity is an area that has not only inspired and attracted several generations of organic chemists but also continues to enrich and refresh the foundations of organic chemistry itself, by offering new ideas and directions. Synthetic organic chemistry is perhaps the most formative and expressive enterprise of science in terms of its creative power and unlimited scope. Its impact on present day life and prosperity gets manifested when we see this science as the bedrock behind the production of pharmaceuticals, pesticides, fertilizers, nutritional products, high tech materials, polymers, cosmetics, plastics and clothing. Science of synthesis is also going to play an important role in the evolution of future societies based on the principles of the sustainable development. Being a precise science and a fine art, the endeavor of total synthesis is in a constant state of effervescence. Most significantly, the discipline is being continually challenged by new structures unraveled from the Nature’s bosom. The practice of total synthesis is being enriched constantly by new tools such as new reagents and catalysts as well as by analytical techniques. In fact, there has been a dramatic advancement in the recent past in the development of new synthetic protocols with high regio-, streo-, and enantiocontrol, which makes it possible to target natural product of any complexity. The demand for enantiomerically pure drugs, agrochemicals and food additives is growing, since pure enantiomers are often more target-specific and have fewer side effects than the recemic mixtures. As a result, synthesis of natural products in an enantioselective manner has been receiving increasing attention from synthetic chemists in recent years. Nature synthesizes a vast array of novel molecular structures in enantioselective fashion through several well-established biosynthetic pathways utilizing a few key building blocks. Among them mevalonate pathway to terpenes, shikimate pathway to aromatics, alkaloids and the polyketide pathway to aromatics, macrolides and related compounds are the most noteworthy. Polyketides, constitutes a large family of natural products built from acyl coenzyme A monomers and exhibit remarkable diversity both in terms of their structure and function. These natural products display a wide range of medicinally important activities such as antibiotic, anticancer, antifungal, hypolipidemic and immunosuppressive properties. In recent years, polyketide derived natural products embodying an epoxyquinone core, have been surfacing with increasing frequency from diverse natural sources. Both on account of their structural diversity and promising biological activity, polyketide derived epoxyquinoid natural products have evoked considerable attention from the synthetic community during the past few years. We too got enticed towards these natural products as an offshoot of ongoing research activity in the group. The present thesis entitled “Enantioselective Total Synthesis of Bioactive Epoxyquinoid Natural Products” is described in four chapters. Chapter 1: Enantioselective total synthesis of (+)-eupenoxide, (+)-6-epi-eupenoxide and (+)-phomoxide; Chapter 2: Enantioselective total synthesis of (−)-EI-1941-2; Chapter 3: Enantioselective total synthesis of (+)-integrasone. Chapter 4: Enantioselective total synthesis of (+)-hexacyclinol. It’s quite tempting to highlight the fact that while Nature might have used entirely different biochemical machinery to build up all these diverse natural products; but in the chemical laboratory all the syntheses have emanated from a single starting material, symbolizing the intrinsic power and versatility of chemical synthesis.

Some synthetic carbohydrate chemistry : natural product synthesis, rational inhibitor design and the development of a new reagent

Goddard-Borger, Ethan D January 2008 (has links)
Earnest carbohydrate research was initiated in the nineteenth century by several talented organic chemists. Carbohydrates, now known to play essential roles in a range of fundamental biological processes, are presently studied by a throng of scientists from many fields, including: biochemistry, molecular biology, immunology, structural biology, medicine, agriculture, pharmacology and, of course, chemistry. Organic chemistry remains as relevant to carbohydrate research as it has ever been; its practitioners, with their skills in synthesis and fundamental understanding of molecules, are truly indispensable. This thesis details various synthetic endeavours within the field of carbohydrate chemistry. It describes four projects with goals as diverse as natural product synthesis, rational inhibitor design and the development of new reagents in organic synthesis. The first chapter provides an account of the synthesis of compound 1, a potent germination stimulant present in smoke, from D-xylose. Many analogues of 1 were prepared from carbohydrates and evaluated as germination stimulants, which permitted the dissemination of several structure-activity relationships. Subsequent chapters describe the design and preparation of inhibitors for various carbohydrate-processing enzymes. Compounds 55 and 56 were sought after as putative synergistic inhibitors of a Vitis vinifera (grape) uridine diphospho-glucose:flavonoid 3-O-glucosyltransferase (VvGT1). It was hoped that crystallographic investigations of VvGT1-UDP-2/3 complexes by a collaborator, structural biologist Professor Gideon Davies, would aid in clarifying mechanistic aspects of this enzyme.Compounds 114, 115 and 118 were prepared as putative arabinanase inhibitors. Once again, this work was undertaken to assist in crystallographic studies that might provide a better understanding of how these enzymes operate. The thesis concludes by describing the development of compound 152.HCl, a novel reagent for the diazotransfer reaction. Previously, this reaction utilised trifluoromethanesulfonyl azide (TfN3), an expensive and explosive liquid with a poor shelf-life, to convert a primary amine directly into an azide. Reagent 152.HCl was developed to replace TfN3 in this useful synthetic transformation. A one-pot procedure enabled the simple and inexpensive preparation of 152.HCl, which was demonstrated to be shelf-stable, crystalline and, crucially, effective in the diazotransfer reaction.

Tandem intramolecular photocycloaddition-retro-Mannich fragmentation as a route to indole and oxindole

Li, Yang 22 February 2012 (has links)
Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue results in an intramolecular [2 + 2] cycloaddition to the indole 2,3-double bond. The resultant cyclobutane undergoes spontaneous retro-Mannich fission to produce a spiro[indoline-3,3-pyrrolenine] with relative configuration defined by the orientation of substituents in the transient cyclobutane. The novel tandem intramolecular photocycloaddition- retro-Mannich (TIPCARM) sequence leads to a spiropyrrolidine which is poised to undergo a second retro-Mannich fragmentation [TIPCA(RM)₂] that expels the malonate unit present in the photo substrate and generates transiently an indolenine. The indolenine undergoes rearrangement to a β-carboline which can undergo further rearrangement under oxidizing conditions to an oxindole. Three oxindole natural products, coerulescine, horsfiline and elacomine, were synthesized using this strategy. The TIPCARM strategy was extended to an approach that would encompass the Vinca alkaloids vindorosine and minovine. In this case, the TIPCARM sequence was followed by an intramolecular cyclization that provided tetracyclic ketone 5.86 containing rings A, B, C and D of vindorosine. A tetracyclic intermediate was synthesized which could also provided access to the Vinca alkaloid minovine. / Graduation date: 2012

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