SYNTHETIC STUDIES TOWARDS TOTAL SYNTHESIS OF BIELSCHOWSKYSIN SUBRAMANIAN GOVINDAN (M.Sc., IIT MADRAS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2010 ACKNOWLEDGEMENTS First, I wish to thank my supervisor Prof. Martin Lear, for giving me the opportunity to join his group. He was always nice, generous and polite; and he encouraged me to read and improve my presentation skills. I am so grateful to him for the time he spent with me, like project discussions, how to present the work in the written proposal, publications and oral presentation. Apart from lab work, he took personal care about my family, how to take a decision, how to take that extra step to achieve a target. It was wonderful to work with him and I have to thank Madam Hilda for the extra care with my family. I would like to thank all my lab mates and friends from the department during my Ph.D work. I would like to mention my thanks to Karthik for his support and all those endless discussions we had. I would like to thank Prof. Ravi (Presidency College, Madras) who taught me chemistry in my school days. With his support and blessings I joined Bachelors in Guru Nanak College. Next, I would like to thank Prof. Bagavathi Sundari (Guru Nanak College); she was the one who advised me to prepare for IISc and IIT’s entrance examination and to specialise in Organic Chemistry. In IIT Madras, I got a chance to meet Prof. K.K.Balasubramanian who lent me books and taught me Chemistry and the research to the next level. I thank him sincerely for his kind help to me and my family. I am grateful to Prof. M.S.Ananth (Director IIT Madras), who helped financially to start my school education. I need to thank Prof. Sriramula (IIT Madras), Dr.Panchalan (Registrar, IIT Madras), Dr.Pattnaik (IIT Madras), Prof. Pramod Mehta   ii   (IIT Madras), Prof. Subramanian (NIH, USA) and Prof. Frank Starmer (Associate Dean, Duke-NUS) for their help to me and my family. Personally, I would like to thank my parents Govindan and Muniammal for their support, love and encouragement to go for higher studies and for emphasising the value of education. Then my brothers, Saravanan and Palani, have always been there to offer support. Thanks to them for being there. I would like to thank my best friends: Suseela and her family, Kalidoss, Rajmohan, Raji, Senthil, Priya, Ravi, Rajesh, Swetansu and Rajan. When I came to Singapore, Rajavel has always been there to help and I will never forget his help. He was always interested in chemistry & research and we have had numerous discussions which seem to never end. Lastly, I thank Thamarai Chelvi for being a beloved wife, always supportive at difficult times. Her love, care and understanding during my long working hours in the lab does need a mention here. Singapore, 15th August 2010   Subramanian iii   TABLE OF CONTENTS ACKNOWLEDGEMENTS i TABLE OF CONTENTS iii SUMMARY vii LIST OF FIGURES AND SCHEMES ix LIST OF ABBREVIATIONS xv PUBLICATIONS AND POSTER PRESENTATIONS xviii EXPERIMENTAL SECTION 82 REFERENCES 148 APPENDICES Chapter 1: Bielschowskysin: A Structurally and Biologically Interesting Class of Diterpene Natural Product. 1.1 Introduction and Background to Bielschowskysin. 1.1.1 Isolation and Structural Characterisation. 1.1.2 Biological Activity 1.1.2.1 Antimalarial Agents and Continuing Needs. 1.1.3 Proposed Biosynthesis 1.1.4 Related Diterpene Natural Products 1.1.5 Relevant Synthetic Efforts 1.1.5.1 Butenolide Construction   iv   1.1.5.2 Furan Construction 10 1.1.5.3 Macrocycle Construction 12 1.1.6 Sulikowski’s Synthetic Study 14 1.2 Approaches toward Related Diterpenes 1.2.1 Leo Paquette Approach 15 1.2.2 Marshall Approach 18 1.2.3 Wipf Approach 21 1.2.4 Pattenden Approach 23 1.2.4 Trauner Approach 25 1.2.5 Rawal Approach 27 1.2.6 Summary and Conclusion 28 1.3 Retrosynthetic Analysis 1.3.1 Introduction: First Generation 29 1.3.2 Structural Assessment: Cyclobutane Ring 30 1.3.3 Structural Assessment: Furan Ring 30 1.3.4 Structural Assessment:Macrocyclisation and Allene Formation 31 1.3.5 Structural Assessment: Butenolide and Methylene Lactol 32 1.4 Conclusion 33 Chapter 2: Bielschowskysin: A Biomimetic Model Study   v   2.1 Introduction 34 2.2 Model Study: [2+2] Cycloaddition of Allene-Butenolide 34 2.3 Synthesis of Left Fragment: First Generation 38 2.4 Synthesis of Right Fragment : First Generation 40 2.5 Synthesis of Right Fragment: First Generation Modification 42 2.6 Conclusion 44 Chapter 3: Synthetic Studies toward Left Fragment 3.1 Introduction 45 3.2 Wittig Reagent 45 3.3 Sharpless Asymmetric Epoxidation 48 3.5 Stannyl Butenolide 53 3.6 Conclusion 54 Chapter 4: Synthetic Studies toward Right Fragment   4.1 Introduction 56 4.2 Conjugate Michael Addition of Diethylmalonate 57 4.3 Deethoxycarbonylation 58 4.4 Eschenmoser Reaction 61 4.5 Elaboration of Tartrate Fragment 61 4.6 Homologation of Lactone 64 vi   4.7 Glucose: Synthesis of Right Fragment 67 4.8 Conclusion 68 Chapter 5: Assembly of Bielschowskysin Carbon framework   5.1 Introduction 70 5.2 Baylis-Hillman Reaction 71 5.3 LHMDS Coupling Method 74 5.4 Stannyl butenolide Coupling 78 5.5 CeCl3 Mediated Acetylide Coupling 78 5.6 Conclusion and Future Plans 81 5.7 Experimental Section 82 vii   SUMMARY This thesis presents the synthetic studies towards the natural product bielschowskysin. Bielschowskysin, a new diterpene isolated from the Caribbean gorgonian octocoral Pseudopterogorgia kallos, possesses a fascinating tricyclic [5-4-9] ring architecture, unprecedented in the realms of natural products. This diterpene exhibits antiplasmodial activity against several drug-resistant strains of the malaria-causing protozoan parasite, Plasmodium falciparum, at IC50 of 10 µg/mL. Our initial studies based on the biomimetic inspired model study to fuse the tricyclic core of bielschowskysin. From malic acid, the allene appended butenolide was prepared in 13 steps and [2+2] cycloaddition was carried out under the UV lamps to form the tricyclic core of bielschowskysin. After making the tricyclic core, retrosynthetic analysis of key intermediate leads to left and right fragment. Left fragment, seleno-lactone was prepared in 15 steps from R-glyceraldehyde. SAE and LAH reduction was employed to fix the quartenary chiral centre. In order to form the lactone, Wittig homologation with methyl (triphenylphosphoranylidene) acetate followed by hydrogenation and TBAF mediated cyclisation was performed. Regarding right fragment, our initial approaches were unsuccessful due to scalability and decomposition. Thus tartaric acid was converted into 5-membered unsaturated lactone in steps. Michael addition of diethyl malonate and decarboxylation was key step to generate the C1 chiral centre. Homologation with acetylene unit, protection and aldehyde formation will then complete the synthesis of right fragment. But in our hands, we were able to complete the synthesis at the aldehyde stage and last step, the final protecting group at the lactol needs to be revised. Meanwhile, right fragment was successfully prepared from D-glucose. Thus, C1 chiral centre was constructed via hydrogenation of the trans-unsaturated ester followed by homologation and aldehyde formation with DIBAL-H. Initially, we relied on the Baylis-Hillman reaction to couple the two fragments. But in our hands, we were able to achieve the product in lesser yields. Finally, we were able to couple the two fragments using Pattenden’s alkylation methods. The future plans will be the protection of the alcohol, deprotection of the silyl group followed by   viii   oxidation would afford the precursor for macrocyclisation. At this stage, NHK protocol would be useful to form the macrocyclic propargylic alcohol. The one step procedure of Myer’s stereospecific allene synthesis and the resultant allene butenolide would be subjected for novel [2+2] cycloaddition to form the cyclobutane ring. Remaining steps would be the cationic cyclisation with the Lewis acid and adjustment of the protecting groups to achieve the total synthesis of bielschowskysin.   ix   LIST OF FIGURES AND SCHEMES Chapter 1: Bielschowskysin: A Structurally and Biologically Interesting Class of Diterpene Natural Product. Figure 1.1 Structure of Bielschowskysin Figure 1.2 Structure of Antimalarial Drugs Figure 1.3 Related Diterpene Natural Products from Pseudopterogorgia species. Figure 1.4 : Structural features of bielschowskysin 29 Figure 1.5 : Proposed route to bielschowskyane ring system 30 Figure 1.6 : Proposed Synthetic Route to Bielschowskysin Framework 30 Figure 1.7 : Furan ring formation 31 Figure 1.8 : Macrocyclisation and allene formation 31 Figure 1.9: Retrosynthesis of left and right fragment. 32 Scheme1.1 Proposed biosynthesis of bielschowskyane skeleton and related cembranes Scheme 1.2 Rodríguez’s chemical isomerisation of bipinnatin J to kallolides and pinnatins Scheme 1.3 Biosynthetic conjecture to plumarellide, bielschowskysin and verrillin Scheme 1.4 Trauner’s biomimetic evidence to the biosynthesis of intricarene. Scheme 1.5 Pattenden’s cyclobutanol synthesis of providencin. Scheme 1.6 Stereo-defined syntheses of chiral γ-butenolides 10 Scheme 1.7 Paquette’s synthesis of the furan moiety of acersolide. 10 Scheme 1.8 Wipf’s late-stage construction of a furan moiety in lophotoxin and 11 pukalide.   x   Scheme 1.9 Marshall’s synthesis of the furan moiety of rubifolide. 11 Scheme 1.10 Marshall’s synthesis of furan moiety from an alkynone β-ketoester 11 Scheme 1.11 Paquette’s Cr-mediated Nozaki-Hiyama-Kishi macrocyclisation 12 Scheme 1.12 Marshall’s allenylstannane macrocyclisation to the rubifolide 12 framework Scheme 1.13 Marshall’s macrocyclic etherification of kallolide B 13 Scheme 1.14 Pattenden’s arsenine mediated Stille macrocyclisation to deoxy- 13 lophotoxin Scheme 1.15 Trauner, Rawal and Pattenden’s Cr-mediated macrocyclisation of 13 bipinnatin J Scheme 1.16. Sulikowski’s synthesis of the tetracyclic core of bielschowskysin 15 Scheme 1.17 Paquette’s synthesis of dihydropseudopterolide and gorgiacerone 17 Scheme 1.18 Paquette’s synthesis of acersolide 18 Scheme 1.19 Marshall’s synthesis of kallolide B 20 Scheme 1.20 Wipf’s approach towards the fragment for lophotoxin and pukalide 22 Scheme 1. 21 Pattenden’s synthesis of deoxylophotoxin 24 Scheme 1. 22 Trauner’s synthesis of bipinnatin J, rubifolide and isoepilophodione 26 Scheme 1.23 Rawal’s synthesis of bipinnatin J 28 Chapter 2: Bielschowskysin: A Biomimetic Model Study Figure 2.1: Proposed model study of tricyclic core of bielschowskysin 34 Figure 2.2: Retrosynthesis of iodo butenolide from malic acid. 39 Figure 2.3: Retrosynthesis of right fragment from tartaric acid. 40 Scheme 2.1: Chelation controlled addition of ethynylmagnesium bromide. 35 Scheme 2.2: Dioxolane/dioxane exchange with mesitaldehyde acetal. 35   xi   Scheme 2.3: Dioxolane/dioxane exchange with benzaldehyde dimethyl acetal. 35   Scheme 2.4: cis-selective Wittig reaction in methanol. 36 Scheme 2.5: Proposed model study of [2+2] cycloaddition of allene-butenolide. 36 Scheme 2.6: Thermal [2+2] cycloaddition of allene-butenolide. 37 Scheme 2.7: Photochemical [2+2] cycloaddition of allene-butenolide using UV 38 lamps. Scheme 2.8: Synthesis toward left fragment from malic acid. 39 Scheme 2.9: Sharpless Asymmetric Dihydroxylation of methylene acetonide. 40 Scheme 2.10 : Synthesis toward right fragment and Michael addition. 41 Scheme 2.11: Michael addition of vinyl iodide to PMB lactone. 42 Scheme 2.12 : Revised retrosynthesis of right fragment, PMB lactone. 42 Scheme 2.13: Synthesis towards right fragment from tartaric acid. 43 Chapter 3: Synthetic Studies toward Left Fragment Figure 3.1: Retrosynthesis of seleno lactone from glyceraldehyde 45 Figure 3.2: Stereofacial selectivity rule for the Sharpless Asymmetric Epoxidation 47 Scheme 3.1: Synthesis of seleno-lactone (3-1) from D-mannitol 46 Scheme 3.2: Preparation of methyl (triphenylphosphoranylidene) propionate 47 Scheme 3.3: Smith’s synthesis epoxy alcohol in the synthesis of spongistatin 48 Scheme 3.4: Sharpless Asymmetric Epoxidation of allylic alcohol 48 Scheme 3.5: Regioselective hydride ring opening of epoxy alcohols 49 Scheme 3.6: Hydride ring opening of epoxy alcohol with LAH 49 Scheme 3.7: Dioxolane/dioxane exchange with benzaldehyde dimethyl acetal 49 Scheme 3.8: Deprotection of acetonide under various conditions 50 Scheme 3.9: TES and TBS protection and selective Swern oxidation 51   xii   Scheme 3.10: Acid catalysed deprotection of TES and TBS groups 51 Scheme 3.11: Benzylation and acetonide cleavage 51 Scheme 3.12: Selective mono silylation of diol 52 Scheme3.13: Hydride ring opening of epoxy alcohol with LAH 53 Scheme 3.14: Synthesis of PMB protected aldehyde 53 Scheme 3.15: Addition of lithiated ethyl propiolate to PMB protected aldehyde 54 Scheme 3.16: Tributyl tin hydride addition and butenolide formation 54 Chapter 4: Synthetic Studies toward Right Fragment Figure 4.1: Retrosynthetic analysis toward right fragment 56 Scheme 4.1: Synthesis towards the methylene lactol 57 Scheme 4.2: Acetonide deprotection and lactonisation 57 Scheme 4.3: Michael addition of diethyl malonate to TBS protected lactone 58 Scheme 4.4: De-ethoxycarbonylation of the Michael adduct 58 Scheme 4.5: TBDPS protection of lactone 59 Scheme 4.6: Synthesis of bis-TBS protected lactone 59 Scheme 4.7: Reduction of acetic ester under different conditions 60 Scheme 4.8: Selective hydrolysis and reduction of acid to alcohol 60 Scheme 4.9: Eschenmoser reaction of acetic ester 61 Scheme 4.10: Elaboration of the other arm of threitol via SAD 62 Scheme 4.11: Elaboration of threitol via vinyl magnesium bromide to ketone 62 Scheme 4.12: Wittig homologation to aldehyde 280 63 Scheme 4.13: Wittig homologation to the aldehyde 284 64 Scheme 4.14: Wittig homologation to the aldehyde 65 Scheme 4.15: Extension of the acetic ester to propargylic alcohol 65   xiii   Scheme 4.16: Protection of terminal alkyne and completion of right fragment 66 Scheme 4.17: One pot DIBAL-H reduction of lactone and ethyl ester to lactol 66 and aldehyde Scheme 4.18: Synthesis of Right fragment from glucose 67 Scheme 4.19: Conversion of primary silyl ether to aldehyde 68 Scheme 4.20: Completion of right fragment-aldehyde 68 Chapter 5: Assembly of Bielschowskysin Carbon framework Figure 5.1: Retrosynthetic analysis macrocyclic allene 70 Figure 5.2: Pattenden’s Baylis-Hillman adducts 76 Scheme 5.1: Baylis-Hillman reaction 71 Scheme 5.2: Baylis-Hillman reaction of methyl acrylate to aldehyde 71 Scheme 5.3: Baylis-Hillman reaction of butenolide to aldehyde 72 Scheme 5.4: Baylis-Hillman reaction of 2(5H)-furanone to aldehyde 72 Scheme 5.5: Baylis-Hillman reaction of allenyl-2(5H)-furanone to aldehyde 73 Scheme 5.6: Mechanism of Baylis-Hillman reaction of furanone to aldehyde 73 Scheme 5.7: Alkylation of lactone 74 Scheme 5.8: Alkylation and One pot oxidation 75 Scheme 5.9: Alkylation of lactone 341 under various anionic methods 75 Scheme 5.10: Alkylation of lactone 76 Scheme 5.11: Silyl protection of coupled product 77 Scheme 5.12: Alkylation of lactone 343 77 Scheme 5.13: Hydrogenolysis of coupled product 77 Scheme 5.14: Stannyl butenolide coupling with aldehyde 78 Scheme 5.15: n-BuLi coupling of alkyne and aldehyde 79   xiv   Scheme 5.16: CeCl3-mediated coupling study of alkyne 355 and aldehyde 356 79 Scheme 5.17: Alkylation of lactone and selenoxide elimination 80 Scheme 5.18: Sonogashira Coupling of Lactone and Vinyl Iodide 80 Scheme 5.19: Suggested macrocyclisation approach to bielschowskysin (1) 81   xv   LIST OF ABBREVIATIONS AcOH acetic acid AcN acetonitrile AIBN 2,2’-azobisisobutyronitrile Bn benzyl n-Bu butyl t-Bu tert-Butyl °C degrees Celsius calc’d calculated CCDC Cambridge Crystallographic Data Centre CDCl3 chloroform-d conc. concentrated CSA camphorsulfonic acid CuH Copper(I)hydride m-CPBA meta-chloroperoxybenzoic acid d doublet DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIBAL-H diisobutylaluminium hydride DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide Eq. equivalent Et ethyl   xvi   g gram(s) hr hour(s) [H] reduction HMDS 1,1,1,3,3,3-hexamethyldisilazane HMPA hexamethylphosphoramide HRMS high resolution mass spectroscopy IR infrared (spectroscopy) IBX 2-iodoxybenzoic acid J coupling constant L liter LiOH lithium hydroxide m multiplet m/z mass to charge ratio Me methyl MeOH methanol MHz megahertz minute(s) mol mole(s) Ms methanesulfonyl (mesyl) MS molecular sieves NMR nuclear magnetic resonance NaHCO3 sodium bicarbonate Na2SO4 sodium sulfate NH4Cl sodium chloride [O] oxidation   xvii   PCC pyridinium chloro chromate PDC pyridinium dichromate Ph phenyl Pr propyl i-Pr iso-propyl py pyridine q quartet rt room temperature RCM Ring Closing Metathesis s singlet SAE Sharpless Asymmetric Epoxidation SAD Sharpless Asymmetric Dihydroxylation t triplet TBAF tetrabutylammonium fluoride TBS tert-butyldimethylsilyl TBSOTf tert-butyldimethylsilyl trifluoromethane sulfonate TBDPS tert-butyldiphenylsilyl TES triethyl silyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl Ts p-toluenesulfonyl (tosyl) p-TsOH p-toluenesulfonic acid   xviii   PUBLICATIONS AND POSTER PRESENTATIONS Publications: 1. Ru Miao, Subramanian G. Gramani and Martin J. Lear., “Stereocontrolled entry to the tricyclo [3.3.0] oxoheptane core of bielschowskysin by a [2+2] cycloaddition of an allene-butenolide” Tetrahedron Letters, 2009, 50, 17311733. 2. Manuscripts Under Preparation : Subramanian G. Gramani and Martin J. Lear Poster Presentations: 1. Poster presentation at the Singapore International Chemical Conference, December 2005; Title of Presentation: “First Steps towards Bielschowskysin” 2. International Symposium by Chinese Inorganic Chemists & International Symposium by Chinese Organic Chemists, Singapore, 2006 Title of Presentation: “First Steps Towards the Total Synthesis of Bielschowskysin” 3. Poster presentation at the Gordon Research Conference Tilton School, USA, July 2007. Title of Presentation: “Towards the Total Synthesis of Bielschowskysin – Recent Progress to the Cembranoid Framework” 4. Poster presentation at the Gordon Research Conference Tilton School, USA, July 2010. Title of Presentation: “One Small Step for Synthesis; One Giant Leap for Total Synthesis”   xix   [...]... deoxy- 13 lophotoxin Scheme 1. 15 Trauner, Rawal and Pattenden’s Cr-mediated macrocyclisation of 13 bipinnatin J Scheme 1. 16 Sulikowski’s synthesis of the tetracyclic core of bielschowskysin 15 Scheme 1. 17 Paquette’s synthesis of dihydropseudopterolide and gorgiacerone 17 Scheme 1. 18 Paquette’s synthesis of acersolide 18 Scheme 1. 19 Marshall’s synthesis of kallolide B 20 Scheme 1. 20 Wipf’s approach towards. ..Scheme 1. 9 Marshall’s synthesis of the furan moiety of rubifolide 11 Scheme 1. 10 Marshall’s synthesis of furan moiety from an alkynone β-ketoester 11 Scheme 1. 11 Paquette’s Cr-mediated Nozaki-Hiyama-Kishi macrocyclisation 12 Scheme 1. 12 Marshall’s allenylstannane macrocyclisation to the rubifolide 12 framework Scheme 1. 13 Marshall’s macrocyclic etherification of kallolide B 13 Scheme 1. 14 Pattenden’s... 1 21 Pattenden’s synthesis of deoxylophotoxin 24 Scheme 1 22 Trauner’s synthesis of bipinnatin J, rubifolide and isoepilophodione 26 Scheme 1. 23 Rawal’s synthesis of bipinnatin J 28 Chapter 2: Bielschowskysin: A Biomimetic Model Study Figure 2 .1: Proposed model study of tricyclic core of bielschowskysin 34 Figure 2.2: Retrosynthesis of iodo butenolide from malic acid 39 Figure 2.3: Retrosynthesis of. .. oxidation 51   xii   Scheme 3 .10 : Acid catalysed deprotection of TES and TBS groups 51 Scheme 3 .11 : Benzylation and acetonide cleavage 51 Scheme 3 .12 : Selective mono silylation of diol 52 Scheme3 .13 : Hydride ring opening of epoxy alcohol with LAH 53 Scheme 3 .14 : Synthesis of PMB protected aldehyde 53 Scheme 3 .15 : Addition of lithiated ethyl propiolate to PMB protected aldehyde 54 Scheme 3 .16 : Tributyl... 5 .10 : Alkylation of lactone 76 Scheme 5 .11 : Silyl protection of coupled product 77 Scheme 5 .12 : Alkylation of lactone 343 77 Scheme 5 .13 : Hydrogenolysis of coupled product 77 Scheme 5 .14 : Stannyl butenolide coupling with aldehyde 78 Scheme 5 .15 : n-BuLi coupling of alkyne and aldehyde 79   xiv   Scheme 5 .16 : CeCl3-mediated coupling study of alkyne 355 and aldehyde 356 79 Scheme 5 .17 : Alkylation of. .. cycloaddition of allene-butenolide using UV 38 lamps Scheme 2.8: Synthesis toward left fragment from malic acid 39 Scheme 2.9: Sharpless Asymmetric Dihydroxylation of methylene acetonide 40 Scheme 2 .10 : Synthesis toward right fragment and Michael addition 41 Scheme 2 .11 : Michael addition of vinyl iodide to PMB lactone 42 Scheme 2 .12 : Revised retrosynthesis of right fragment, PMB lactone 42 Scheme 2 .13 : Synthesis. .. Scheme 4.6: Synthesis of bis-TBS protected lactone 59 Scheme 4.7: Reduction of acetic ester under different conditions 60 Scheme 4.8: Selective hydrolysis and reduction of acid to alcohol 60 Scheme 4.9: Eschenmoser reaction of acetic ester 61 Scheme 4 .10 : Elaboration of the other arm of threitol via SAD 62 Scheme 4 .11 : Elaboration of threitol via vinyl magnesium bromide to ketone 62 Scheme 4 .12 : Wittig... 280 63 Scheme 4 .13 : Wittig homologation to the aldehyde 284 64 Scheme 4 .14 : Wittig homologation to the aldehyde 65 Scheme 4 .15 : Extension of the acetic ester to propargylic alcohol 65   xiii   Scheme 4 .16 : Protection of terminal alkyne and completion of right fragment 66 Scheme 4 .17 : One pot DIBAL-H reduction of lactone and ethyl ester to lactol 66 and aldehyde Scheme 4 .18 : Synthesis of Right fragment... lactone 42 Scheme 2 .13 : Synthesis towards right fragment from tartaric acid 43 Chapter 3: Synthetic Studies toward Left Fragment Figure 3 .1: Retrosynthesis of seleno lactone from glyceraldehyde 45 Figure 3.2: Stereofacial selectivity rule for the Sharpless Asymmetric Epoxidation 47 Scheme 3 .1: Synthesis of seleno-lactone (3 -1) from D-mannitol 46 Scheme 3.2: Preparation of methyl (triphenylphosphoranylidene)... 67 Scheme 4 .19 : Conversion of primary silyl ether to aldehyde 68 Scheme 4.20: Completion of right fragment-aldehyde 68 Chapter 5: Assembly of Bielschowskysin Carbon framework Figure 5 .1: Retrosynthetic analysis macrocyclic allene 70 Figure 5.2: Pattenden’s Baylis-Hillman adducts 76 Scheme 5 .1: Baylis-Hillman reaction 71 Scheme 5.2: Baylis-Hillman reaction of methyl acrylate to aldehyde 71 Scheme 5.3: . 1. 1.5 .1 Butenolide Construction 9 ! v! 1. 1.5.2 Furan Construction 10 1. 1.5.3 Macrocycle Construction 12 1. 1.6 Sulikowski’s Synthetic Study 14 1. 2 Approaches toward Related Diterpenes 1. 2 .1. Characterisation. 1 1. 1.2 Biological Activity 2 1. 1.2 .1 Antimalarial Agents and Continuing Needs. 1. 1.3 Proposed Biosynthesis 4 1. 1.4 Related Diterpene Natural Products 5 1. 1.5 Relevant Synthetic. macrocyclisation of 13 bipinnatin J Scheme 1. 16. Sulikowski’s synthesis of the tetracyclic core of bielschowskysin 15 Scheme 1. 17 Paquette’s synthesis of dihydropseudopterolide and gorgiacerone 17 Scheme