Towards Schizozygine Type Alkaloids: Total Synthesis of (+)-Vallesamidine and (+)-Strempeliopine by Xiangyu Zhang A thesis submitted in partial fulfilment of the requirement for the degree of Doctor of Philosophy Department of Chemistry University College London Declaration I, Xiangyu Zhang, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signed: Date: i Abstract As a classic and powerful tool for carbon-carbon bond formation, the nitro-Mannich reaction has shown its versatility in drugs and natural products syntheses. The 1,2- diamine structure, a reduced moiety from nitro-Mannich adduct, is widely present in naturally occurring alkaloids and this feature suggested the potential application of nitro- mannich reaction in such alkaloids synthesis. This thesis showcases the nitro-Mannich reaction as a key strategic reaction through studies towards the total synthesis of 1,2- diamine contained alkaloids, schizozygine, vallesamidine and strempeliopine (Chapter 1 and 2). Initial studies on the schizozygine molecule (Chapter 3) generated a diastereoselective nitro-Mannich reaction on -branched nitroalkanes to synthesise complex -nitroamines with three contigurous chiral centres and syn,anti stereochemistry. This reaction was followed by a reductive cyclisation to achieve the functionalised piperidine ring C. Although the subsequent manipulation towards advanced shcizozygine intermediate was unsuccessful, the nitro-Mannich/reductive cyclisation sequence provided methodology for highly functionalised piperidine ring synthesis. A second generation route using nitro-Mannich reaction was accompanied by other nitro group chemistry, Michael addition, Tsuji-Trost allylation and nitro group reduction/C-N coupling reaction, to realise the quick and concise preparation of an A/B/C ring intermediate. An unusual and novel [1,4]-hydride tansfer/Mannich type cyclisation was carried out to build the ring E. The resulting A/B/C/E ring intermediate was used divergently to complete the total synthesis of (+)-vallesamidine (Chapter 4) and (+)- 14,15-dehydrostrempeliopine (Chapter 5) as well as three other unnatural analogues. These natural and unnatural products could be candidates for drug discovery research and the route would be applicale for the synthesis of schizozygine and related molecules. ii Statement of impact Natural products are chemical compounds or substances produced by living organisms and many of them possess impressive biological activities. Of the approved pharmaceuticals joining the market between 1981 and 2010, 64% were related to natural products. The chemical synthesis of natural products can save the use of precious and sometimes scarce natural resources, provide more material than nature can produce and can facilitate drug discovery. This thesis developed a new route to a late stage synthetic divergent intermediate from which vallesamidine, strempeliopine and schizozygine type alkaloids could be prepared. To exemplify this the total syntheses of alkaloids (+)- vallesamidine and (+)-14,15-dehydrostrempeliopine were completed. This route highlighted nitro group chemistry and intramolecular C-H functionalization and showcased their diversity in multi-target synthesis. The route contributes a notable strategy to the chemical community that will potentially be used for other alkaloid syntheses. This enabling synthetic route will enable the evaluation of rare structures for biological studies and have impact and inspire drug discovery to tackle disease. iii Acknowledgment I would like to thank my supervisor, Prof. Jim Anderson, for his guidance in my research during the last four years. The PhD research journey was full of challenges and no achievement could be made without his mentorship and inspiration. I also want to thank the support from NMR (Dr. Abil Aliev), mass spectroscopy (Dr. Kersti Karu) services and Dr Merina Corpinot for the single crystal X-ray structure determination. My PhD study was funded by UCL-Chinese Scholarship Council (CSC) joint scholarship and I appreciate this funding scheme for providing me a chance to carry out my PhD research at UCL. Finally, I would like to thank the strong backing and support from my Family, especially my mom and my girlfriend Minshan. iv List of abbreviations Ac = Acetyl Aq. = Aqueous Ac2O = Acetic anhydride All = Allyl Alloc = Allyloxycarbonyl Ar = Aryl 9-BBN = 9-Borabicyclo[3.3.1]nonane BMS = Borane-dimethylsulfide complex Bn = Benzyl Boc = tert-Butoxycarbonyl n-Bu = n-Butyl s-Bu = sec-Butyl t-Bu = tert-Butyl Bz = Benzoyl brsm = % yield based on recovered starting material CAN = Ceric ammonium nitrate Cbz = Benzyloxycarbonyl Cod = Cyclooctadiene Cp = Cyclopentadienyl 18-crown-6 = 1,4,7,10,13,16-Hexaoxacyclooctadecane CSA = Camphorsulphonic acid DAST = Diethylaminosulphur trifluoride dba = Dibenzylideneacetone DBAD = Di-tert-butyl azodicarboxylate DBN = 1,5-Diazabyciclo[4.3.0]non-5-ene DBU = 1,8-Diazabyciclo[5.4.0]undec-7-ene DCC = 1,3-Dicyclohexylcarbodiimide DCE = 1,2-Dichloroethane DCM = Dichloromethane v DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DEAD = Diethyl azodicarboxylate DIBAL = Diisobutylaluminium hydride DIBAL-H = Diisobutylaluminium hydride DIPEA = Diisopropylethylamine DMAP = 4-Dimethylaminopyridine DME = 1,2-Dimethoxyethane DMF = N,N-Dimethylformamide DMP = Dess-Martin periodinane DMPU = 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)- pirimidone DMS = Dimethylslfide DMSO = Dimethylsulfoxide DPA = Diisopropylamine DPPA = Diphenylphosphoryl azide dr = Diastereomeric ratio EDCI = 1-Ethyl-3-(3- dimethylaminopropy)carbodiimide hydrochloride EDTA = Ethylenediaminetetraacetic acid EE = Ethoxyethyl EOM = Ethoxymethyl e.e. = Enantiomeric excess e.r. = Enantiomeric ratio EDG = Electron donating group EWG = Electron withdrawing group HMDS = Hexamethyldisilazane HMPA = Hexamethylphosphoramide HOBt = 1-Hydroxybenzotriazole Hoveyda-Grubbs 2nd Gen catalyst (1,3-Bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(o- isopropoxyphenylmethylene)ruthenium vi IPA = Isopropyl alcohol Im = Imidazole IBX = 2-Iodoxybenoic acid KHMDS = Potassium bis(trimethylsilyl)amide LAH = Lithium aluminium hydride LDA = Lithium diisopropylamide LHMDS = Lithium bis(trimethylsilyl)amide mCPBA = meta-Chloroperoxybenzoic acid M.S. = Molecular sieves Ms = Methanesulphonyl NaHMDS = Sodium bis(trimethylsilyl)amide NBS = N-Bromosuccinimide NIS = N-Iodosuccinimide NMM = N-Methylmorpholine NMO = N-Methylmorpholine-N-oxide Ns = p-Nitrophenylsulphonyl Para/ortho/meta (p-, o-, m-) = (1,4)/(1,2)/(1,3)-Substitution on benzene PDC = Pyridinium dichlorochromate PCC = Pyridinium chlorochromate Pg = Protective group Ph = Phenyl PMB = p-Methoxybenzyl PMP = p-Methoxyphenyl PPTS = Pyridinium p-toluensulphonate n-Pr = n-Propyl Pr = Propyl iPr = iso-propyl PTSA = p-Toluenesulphonic acid Py = Pyridine quant. = Quantitative rac = Racemic vii rt = Room temperature TBAF = Tetra-n-butylammonium fluoride TBDMS/TBS = tert-Butyldimethylsilyl TBDPS = tert-Butyldiphenylsilyl TEA = Triethylamine TEBAC = Triethylbenzylammonium chloride TEMPO = (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl radical TES = Triethylsilyl Tf = Trifluoromethanesulfonyl TfO = Trifluoromethanesulfonate Tf2O = Trifluoromethanesulfonyl anhydride TfOH = Trifluoromethanesulfonic acid TFA = Trifluoroacetic acid TFAA = Trifluoroacetic anhydride Thexyl = 2,3-Dimethyl-2-butyl THF = Tetrahydrofurane TIPS = Triisopropylsilyl TMEDA = N,N,N',N'-Tetramethylethylendiamine TMG = Tetramethylguanidine TMS = Trimethylsilyl p-Tol = p-Toluyl or 4-methylbenzyl o-Tol = o-Toluyl or 2-methylbenzyl TPAP = Tetra-n-propylammonium perruthenate Tr = Trityl, triphenylmethyl Troc = 2,2,2-Trichloroethoxycarbonyl p-Ts = p-Toluenesulphonyl p-TsOH = p-Toluenesulphonic acid viii Table of Contents Declaration ..................................................................................................................... i Abstract ......................................................................................................................... ii Acknowledgment ......................................................................................................... iii List of abbreviations ..................................................................................................... v Introduction ....................................................................................................................... 1 Chapter 1. Applications of the nitro-Mannich reaction in organic synthesis ........... 2 1.1 Synthesis of molecules containing the 1,2-diamine moiety ........................... 4 1.2 Nitro-Mannich/reductive denitration sequences in drugs and natural product synthesis .................................................................................................................. 12 1.3 Nitro-Mannich/Nef reaction sequences in organic synthesis ....................... 15 1.4 Research aim ................................................................................................ 18 Chapter 2. Targets background and synthetic studies ............................................. 20 2.1 Monoterpene indole alkaloids ...................................................................... 20 2.2 Schizozygine, vallesamidine and strempeliopine: isolation and potential activities .................................................................................................................. 22 2.3 Schizozygine, vallesamidine and strempeliopine: absolute