Synthetic studies towards total synthesis of bielschowskysin 1

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

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

(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

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

1.1.2 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 Efforts 9

1.1.5.1 Butenolide Construction 9

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

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

4.7 Glucose: Synthesis of Right Fragment 67

Chapter 5: Assembly of Bielschowskysin Carbon framework

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 7 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

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

LIST OF FIGURES AND SCHEMES

Chapter 1: Bielschowskysin: A Structurally and Biologically Interesting Class of Diterpene Natural Product

Figure 1.1 Structure of Bielschowskysin 1

Figure 1.2 Structure of Antimalarial Drugs 3

Figure 1.3 Related Diterpene Natural Products from Pseudopterogorgia species 6

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 5

cembranes

Scheme 1.2 Rodríguez’s chemical isomerisation of bipinnatin J to kallolides and 7

pinnatins

Scheme 1.3 Biosynthetic conjecture to plumarellide, bielschowskysin and 8 verrillin

Scheme 1.4 Trauner’s biomimetic evidence to the biosynthesis of intricarene 8

Scheme 1.5 Pattenden’s cyclobutanol synthesis of providencin 9

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

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

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

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

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