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(+)-Belactosin A Total Synthesis of (+)-Belactosin A A thesis submitted by James Nicholas Scutt in partial fulfilment of the requirements for the degree of Doctor of Philosophy TT MU r u * 1630444 Heilbron Laboratory Department of Chemistry Imperial College London London SW7 2AY January 2005 Contents Contents 2 Abstract 4 Acknowledgements 5 Abbreviations 6 Stereochemical notation 9 Chapter 1 - Introduction 10 1.1 Isolation and structure of (+)-belactosin A 11 1.2 Proteasome inhibition 12 1.2.1 Biological activity of (+)-belactosin A 12 1.3 Review of previous work 14 1.3.1 De Meijere's synthesis of(2S/R*, I'R, 2'5)-AcpAla 14 1.3.2 Synthesis of a related (isomeric) p-lactone 20 1.4 Recent synthetic work 22 1.4.1 De Meijere's synthesis of AcpAla (all isomers) 23 1.4.2 Vedaras' synthesis of (2S, 1 'R, 2'S)-AcpAla 25 1.4.3 De Meijere's total synthesis of (+)-belactosin A 26 Chapter 2 - Results and discussion 30 2.1 Project aims 31 2.1.1 Synthesis of trans-AcpAla isomers - overview of synthetic strategy 32 2.2 Boronic ester route 34 2.2.1 Introduction 34 2.2.2 Synthesis of cyclopropyl boronic esters 36 2.2.3 Amination of cyclopropyl boronic esters 39 2.3 Epoxide cyclopropanation route 43 2.3.1 Introduction 43 2.3.2. Stereoselectivity and stereospecificity 47 2.3.3 Wadsworth-Emmons aminocyclopropanation 49 2.3.4 Optimisation of Wadsworth-Emmons cyclopropanation 53 2.3.5 Increasing reactivity 59 2.3.6 Room temperature Wadsworth-Emmons cyclopropanation 62 2.3.7 Horner cyclopropanation 64 2.3.8 Asymmetric Wadsworth-Emmons cyclopropanation 65 2.4 Conversion of cyclopropyl ester to aminocyclopropyl electrophile 69 2.4.1 Deprotection of cyclopropyl ester 69 2.4.2 Curtius rearrangement 71 2.4.3 Phase-transfer mesylation 73 2.4.4 Synthesis of aminocyclopropyl iodide 76 2.4.5 Further work towards total synthesis and analogue synthesis 79 2.5 Organocatalytic amino acid synthesis 80 2.5.1 Introduction 80 2.5.2 Non-selective glycine alkylation 86 2.5.3 Asymmetric glycine alkylation 88 2.6 Alternative route to (25, 1 'S, 2'R)-AcpA\a and (2R, 1'/?, 2'S)-AcpAla 94 2.7 Coupling of (2S, 1 'R, 2'5)-AcpAla to L-alanine 97 2.8 Synthesis of p-lactone - overview of synthetic strategy 101 2.8.1 Organocatalytic P-lactonisation 103 2.8.2 Introduction 103 2.8.3 Glyoxylate-based Organocatalytic P-lactonisation 109 2.9 Diastereoselective synthesis of p-lactone 121 2.9.1 Synthesis of P-lactone via Evans alkylation route 123 2.9.2 Synthesis of succinate via malonate substitution 126 2.10 Final coupling - synthesis of TV-CBz-belactosin A 130 2.11 Deprotection of CBz - first total synthesis of (+)-belactosin A 135 Chapter 3 - Conclusion 140 3.1 Synopsis of results 141 Chapter 4 - Experimental 149 Appendix 1 : Chiral shift experiment 201 Appendix 2 : X-ray crystallographic data 202 References 213 Abstract (+)-Belactosin A is a novel peptide, first isolated in Japan in 1997, that has recently been shown to be a potent proteasome inhibitor. It contains a novel aminocyclopropyl alanine amino acid core, and a novel carboxamido (3-lactone. Chapter 1 presents the isolation, structure and biological properties of (+)-belactosin A, then proceeds to review all relevant synthetic work prior to the start of our research programme, and also work published since we began investigations into this area. Chapter 2 begins with our synthetic plan aimed towards the total synthesis of (+)-belactosin A and analogues, then discusses execution of this strategy. All four stereosiomers of the central amino acid were successfully synthesised using an unusual epoxide cyclopropanation, and an organocatalytic amino acid synthesis as the two key steps. Efforts were also made to synthesise the [3-lactone moiety using organocatalysis, but this was eventually accessed by a one-pot diastereoselective chlorination/lactonisation strategy. Finally, the first total synthesis of (+)-belactosin A was achieved using a new amino acid coupling procedure. Chapter 3 summarises the findings discussed in Chapter 2, and Chapter 4 gives full experimental details and spectroscopic and physical data for all new compounds prepared. d/astereqse/ecf/Ve Curtius rearrangement chlorination/lactonisation (+)-belactosin A - 2 PTC catalysed • | malonate substitution asymmetric alkylation Wadsworth.Emmons cyclopropanation Acknowledgements I would like to thank Prof. Alan Armstrong for giving me the opportunity to work in his research group, and for his encouragement, patience and support over the past three years. I would also like to acknowledge the financial support given by both Prof. Alan Armstrong and the EPSRC. Thanks must also go to all the members of the Armstrong group who have contributed to the excellent time I have had during my studies, and with whom I have had the pleasure of sharing a lab over the past three years. From my first year, to final year, I would like to thank Nick C, Huw, Nick D, Rich, Chris, Tim, Dick, Jenna, Fred, lan, Graham, Nat, Tom, Nicky, Steve, Nigel, Jamie, Lizzie, Rich, Dave and Hans. Special thanks also go to Dave, Steve, Jamie and Lizzie for careful proof-reading of this thesis, and very helpful suggestions. I would also like to acknowledge the technical support I have received, in particular Mr. Pete Haycock from the Imperial College NMR support service, and all staff from the Imperial College Mass Spectrometry Service. Finally, I would like to thank my parents for their continued support throughout many years as a student. Abbreviations 'H Proton 13C Carbon-13 A Angstrom(s) Ac Acetyl aq. Aqueous Ar Aryl substituent BEMP 2-te^Butylimino-2-diethylamino-l ,3- dimethylperhydro-1,3,2-diazaphosphorine Boc tert-Butoxycarbonyl t-Bu tert-Butyl Bn Benzyl br Broad cat Catalyst/Catalytic CBz Benzyl carbamate CI Chemical ionisation d Doublet DCC N, N -Dicyclohexy Icarbodiimide dd Doublet of doublets (etc.) DMAP 4-(Ar-dimethylamino)pyridine DMF A^A^-Dimethylformamide DMSO Dimethyl sulfoxide d.e. Diastereomeric excess DPPA Diphenyl phosphoryl azide d.r. Diastereoisomeric ratio dt Doublet of triplets EDCI 1 -[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide e.e. Enantiomeric excess Eq Equivalent(s) Et Ethyl FAB Fast Atom Bombardment g Gram(s) GC Gas chromatography h Hour(s) HOAt 1 -Hydroxy-7-azabenzotriazole HOBt 1 -Hydroxybenzotriazole HOSA Hydroxylamine-0-sulfonic acid Hunig's base jV^/V-Diisopropylethylamine Hz Hertz IR Infrared J Coupling constant (in Hz) L Ligand LiHMDS Lithium hexamethyldisilazide LiTMP Lithium 2,2,6,6-tetramethylpiperidide LDA Lithium di-/^o-propylamide m Multiplet M Molar Me Methyl mg Milligram(s) MHz Megahertz min Minute(s) ml Millilitre(s) mmol Millimole(s) m.p. Melting point MS Molecular sieves m/z Mass/charge ratio (in mass spectrometry) NaHMDS Sodium hexamethyldisilazide NMR Nuclear magnetic resonance Nu Nucleophile petrol Petroleum ether (b.p. 40-60°C) Ph Phenyl ppm Part(s) per million Proton sponge N, N, N', W-Tetramethy 1-1,8-naphthalenediamine Quartet r.t. Room temperature s Singlet sat. Saturated t Triplet TBAB Tetrabutylammonium bromide THAI Tetrabutylammonium iodide TEMPO 2,2,6,6-Tetramethyl-l -piperidinyloxyl radical TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography Ts p-Toluenesulfonyl 8 Stereochemical notation Throughout this thesis, the pictorial representation of stereochemistry is consistent with the conventions proposed by Maehr. Thus, solid/broken wedges represent absolute configuration, in which case, greater narrowing of the wedges indicates distance from the viewer. In contrast, structures drawn with solid/broken lines represent racemates. single enantiomer racemate * Maehr, J. J. Chem. Ed. 1985, 62, 114. CHAPTER 1 Introduction 10 Chapter 1: Introduction 1.1 Isolation and structure of (+)-belactosin A The natural product (+)-belactosin A (UCK14AO (+)-! (Figure 1) was first reported in the patent literature in 1997 by scientists at Kyowa Hakko Kogyo Co. Ltd.. 1 It is a novel Streptomyces metabolite isolated using a yeast-based assay from the culture broth of KY11780. In addition, belactosin B 2 and belactosin C 3 (Figure 2) were also isolated in smaller quantities.2 The structure and relative stereochemistry of (+)-belactosin A was elucidated after MS and NMR investigations, and reported in the Japanese literature in 1999.3 Spectral analysis showed that (+)-! possessed a unique central amino acid - 3-(2- aminocyclopropyl)-alanine (AcpAla) - and a unique carboxamido p-lactone. The absolute stereochemistry was assigned as shown for (+)-!, revealing an L-alanine component, a (2S, \'R, 2'S)-AcpAla component 4 and a (2R, 3S, l'S> p-lactone component 5 (Figure 1). I H2N^x , // r > NH2 ^ 21 L-alanine (2S, 1'R, 2'S)-AcpAla 4 O CO2H v O (+)-belactosin A (+)-1 HO2C'2 ^^r (2R, 3S, 1'S)-5 Figure 1 Belactosin B 2 contains a p-hydroxy methyl ester which is thought to be the result of f\ methanol-induced ring opening of (+)-! during isolation, whereas (-)-belactosin C 3 contains an ornithine, rather than AcpAla central fragment (Figure 2). 11 H,N' O CO2H v O CO2Me O CO2H belactosin B 2 (-)-belactosin C 3 Figure 2 1.2 Proteasome inhibition The 26S proteasome is a large, multiprotein enzyme complex present in the cytoplasm and nucleus of all eukaryotic cells.4 It consists of a 20S catalytic core, capped at either end by 19S regulatory subunits (Figure 3).4 Evidence suggests that the 26S proteasome plays a critical role in the regulation of cell-cycle growth and survival, through both the degradation of short-lived regulatory proteins that govern cellular functions, and also the degradation of damaged or obsolete cellular proteins.4 Blockade of proteasome function halts cell division, and since malignant cells are particularly sensitive to the loss of proteasome activity,4 proteasome inhibition has therefore become a logical target for therapeutic intervention.
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