UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Aza-spirocyclic compounds via oxidative amidation of phenols : application on the studies towards the… Paladino, Marco 2018

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
24-ubc_2018_may_paladino_marco.pdf [ 9.54MB ]
Metadata
JSON: 24-1.0363880.json
JSON-LD: 24-1.0363880-ld.json
RDF/XML (Pretty): 24-1.0363880-rdf.xml
RDF/JSON: 24-1.0363880-rdf.json
Turtle: 24-1.0363880-turtle.txt
N-Triples: 24-1.0363880-rdf-ntriples.txt
Original Record: 24-1.0363880-source.json
Full Text
24-1.0363880-fulltext.txt
Citation
24-1.0363880.ris

Full Text

Aza-spirocyclic compounds via oxidative amidation of phenols Application on the studies towards the synthesis of himandrine and the total synthesis of Erythrina alkaloids  by  Marco Paladino M.Sc., The University of Palermo, 2012  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  in DOCTOR OF PHILOSOPHY  The Faculty of Graduate and Postdoctoral Studies (Chemistry)   THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)   February, 2018 © Marco Paladino, 2018 ii  Abstract This thesis illustrates two application of the oxidative amidation of phenols in the syn-thesis of natural products. The first part focuses on an approach to himandrine via a tandem oxidative cycliza-tion of a phenolic dienylsulfonamide / intramolecular Diels-Alder reaction / epimerization se-quence that produces a substituted trans-fused decalone.  This material exhibits three of the five rings present in the natural product, but it is made in racemic form. Efforts to prepare said trans-decalone in enantioenriched form are also outlined. The strategy that was ex-plored in that respect relies on a Rh(I)-mediated diastereoselective 1,4-addition of an aryl-boronic acid to a conjugated ester derived from L-serine.   The second part of this dissertation describes the total synthesis of two Erythrina alkaloids, (+)-3-demethoxyerythratidinone and (+)-erysotramidine, via the oxidative cyclization of a phenolic oxazoline. A key step of the synthesis involves the desymmetrization of a dienone through a highly diastereoselective, intermolecular 1,4-addition of the alcohol revealed upon unraveling of the oxazoline. This allows the creation of the aza-spirocenter characteristic of this class of alkaloids with the correct configuration. The degree of stereocontrol achieved in the course of such operations is essentially perfect (no diastereomeric side products detectable). This synthesis also introduces improved techniques to effect a crucial eliminative Curtius-Schmidt rearrangement.  iii  Lay Summary In the last twenty years, our laboratory has designed a new reaction for the creation of a specific feature possessed by some molecules (i.e. drugs). In this thesis, the application of this methodology is applied for the studies and synthesis of natural occurring products.   iv  Preface  The thesis is written by, and is based on experiments conducted by M. Paladino. Pro-fessor M. A. Ciufolini provided the overall synthetic strategy and tactics, helpful suggestions, and thorough editing of the thesis. All the experiments and data analyses in the main part i.e. Chapter 3, 5 and 6 were performed by M. Paladino, except for the crystallographic analysis of 5.2.2 which was conducted by Dr. B. Patrick. NMR analyses of compounds 5.2.2 and 3.1.24 were conducted by Dr. M. Ezhova.  The research reported in Chapters 5 and 6 has been published in: Paladino, M.; Zaifmann, J.; Ciufolini, M. A. Org. Lett., 2015, 17, 3422. Compounds 5.2.3-5.3.2 were made by Dr. J. Zaifman. Professor M. A. Ciufolini wrote the manuscript, M. Paladino wrote the supporting information.   v  Table of Contents  Abstract…………………………………………………………………………………………………ii Lay Summary.…………………………………………………………………………………………iii Preface……..………………………………………………………………………………………….iv Table of Contents……………………………………………………………………………………...v List of Tables…………………………………………………………………………………………..x List of Figures…………………………………………………………………………………………xi List of Schemes……………………………………………………………………………………...xiii List of Abbreviations………………………………………………………………………………..xviii Acknowledgements………………………………………………………………………………...xxiii Dedication …………………………………………………………………………………………..xxv Chapter 1 Oxidative amidation of phenols: a method for C-N bond formation……………..…..1  1.1 Introduction…………………………………………………………………………….…1  1.2 The three generations of oxidative amidation……………………………………….4 Chapter 2 Synthetic strategy and exploratory work towards (-)-himandrine…………………..12  2.1 Introduction and previous synthesis………………………………………………….12  2.2 Synthetic studies toward 2.1.1 by Mander and collaborators……………………...13  2.3 Total synthesis of 2.1.1 by Movassaghi and coworkers……………………………16  2.4 Prior work of the Ciufolini group and retrosynthetic considerations……………….19 Chapter 3 A route to an enantioenriched precursor of himandrine and improved avenue to an advanced synthetic intermediate…………………………………………………………………..26  3.1 Studies towards an enantioenriched phenol for the OA-IMDA sequence………..26  3.2 Improvement toward the total synthesis of racemic himandrine…………………..41 Chapter 4 Enantioselective synthesis of Erythrina Alkaloids……………………………………50  4.1 Introduction……………………………………………………………………………...50 vi   4.2 Previous enantioselective syntheses of Erythrina alkaloids……………………….52   4.2.1 Formation of ring A: Tsuda…………………………………………………53   4.2.2 Formation of ring A: Simpkins…………………………………………….55   4.2.3 Formation of ring A: Kaluza………………………………………………...59   4.2.4 Formation of ring B: Reisman………………………………………………60   4.2.5 Formation of ring C: Tsuda…………………………………………………61 Chapter 5 Total synthesis of (+)-3-demethoxyerythratidinone………………………………….63 5.1 Retrosynthetic analysis for oxidative amidation approach…………………………63  5.2 Construction of the appropriate oxazoline…………………………………………...64  5.3 Oxidative amidation and desymmetrization………………………………………….67  5.4 Cleavage of the serine unit……………………………………………………………70  5.5 Construction of B-ring and completion of (+)-3-demethoxyerythratidinone………77 Chapter 6 Total synthesis of (+)-erysotramidine…………………………………………………83  6.1 Amino ketone 5.4.6 as a common intermediate…………………………………….83  6.2 Completion of (+)-erysotramidine……………………………………………………..86 Summary and future work…………………………………………………………………………..88 References……………………………………………………………………………………………92 Appendix…………………………………………………………………………………………….102  A. Experimental protocols………………………………………………………………102  B. Preparation of substrates employed in the present study experimental section..103   Compound 3.1.20…………………………………………………………………103   Compound 3.1.22…………………………………………………………………103   Compound 3.1.23…………………………………………………………………104   Compound 3.1.24…………………………………………………………………105   Compound 3.1.25…………………………………………………………………106   Compound 3.1.26…………………………………………………………………107 vii    Compound 3.1.32…………………………………………………………………107   Compound 3.2.26…………………………………………………………………109   Compound 3.2.20…………………………………………………………………109   Compound 3.2.29…………………………………………………………………110   Compound 3.2.31…………………………………………………………………111   Compound 5.2.3…………………………………………………………………..112   1-(Benzyloxy)-4-iodobenzene…………………………………………………...113   Compound 5.2.7…………………………………………………………………..114   Acid derivative of 5.2.8…………………………………………………………...114   Benzyl-protected oxazoline 5.2.1……………………………………………….115   Compound 5.2.1…………………………………………………………………..116   Compound 5.3.1…………………………………………………………………..117   Compound 5.3.2…………………………………………………………………..118   Compound 5.3.11…………………………………………………………………118   Methyl ester of 5.4.9.……………………………………………………………..119   Compound 5.4.9…………………………………………………………………..120   Compound 5.4.10…………………………………………………………………120   Compound 5.4.16…………………………………………………………………121   Compound 5.4.17…………………………………………………………………122   Compound 5.5.4…………………………………………………………………..123   Compound 5.5.6…………………………………………………………………..123   Compound 5.5.7…………………………………………………………………..124   Compound 5.5.12…………………………………………………………………124   Compound 5.5.13 and 5.5.14……………………………………………………125   (+)-3-Demethoxyerythratidinone 5.5.2………………………………………….126   Compound 6.1.4…………………………………………………………………..127 viii    Compound 6.1.6…………………………………………………………………..128   Compound 6.1.5…………………………………………………………………..129   Compound 6.1.2 (Padwa's intermediate)……………………………………....129   Alcohol derivative of 6.1.2………………………………………………………..130   (+)-Erysotramidine 6.1.1……………………………………………………….131  C. Comparative spectral data………………………………………………………….…132  D. X-Ray crystal structure of lactam 5.3.2………………………………………………136  E. Proton and 13C NMR spectra………………………………………………………….137   1H and 13C spectra of 3.1.20 in CDCl3 …………………………………………137   1H and 13C spectra of 3.1.22 in CDCl3  ………………………………………...138   1H and 13C spectra of 3.1.23 in CDCl3  ………………………………………...139   1H and 13C spectra of 3.1.24 in toluene-d8 at 80 °C ………………………….140   1H and 13C spectra of 3.1.25 in CDCl3 …………………………………………142   HSQC and NOESY spectra of 3.1.25 in CDCl3……………………………….143   1H and 13C spectra of 3.1.26 in CDCl3 …………………………………………144   1H and 13C spectra of 3.1.32 in CDCl3 …………………………………………145   1H and 13C spectra of crude 3.2.26 in CDCl3 ………………………………….146   1H and 13C spectra of 3.2.20 in CDCl3 …………………………………………147   1H and 13C spectra of 3.2.29 in CDCl3 …………………………………………148   1H and 13C spectra of 3.2.31 in CDCl3 …………………………………………149   1H and 13C spectra of 5.2.3 in CDCl3 …………………………………………..150   1H and 13C spectra of 1-(benzyloxy)-4-iodobenzene in CDCl3 .……………..151   1H and 13C spectra of 5.2.7 in CDCl3 …………………………………………..152   1H and 13C spectra acid derivative of 5.2.8 in CDCl3 …………………………153   1H and 13C spectra of benzyl protected oxazoline 5.2.1 in CDCl3 ……….....154   1H and 13C spectra of 5.2.1 in CDCl3 ………………………………….……….155 ix    1H and 13C spectra of 5.3.1 in CDCl3 …………………………………………..156   1H and 13C spectra of 5.3.2 in CDCl3 …………………………………………..157   1H and 13C spectra of 5.3.11 in CDCl3 …………………………………………158   1H and 13C spectra of methyl ester of 5.4.9 in CDCl3 ………………………...159   1H and 13C spectra of 5.4.9 in CDCl3 …………………………………………..160   1H and 13C spectra of 5.4.10 in CDCl3 ………………………………………….161   1H and 13C spectra of 5.4.16 in CDCl3 ………………………………………….163 1H and 13C spectra of 5.4.17 in CDCl3 ………………………………………….164 1H and 13C spectra of 5.5.4 in CDCl3 …………………………………………...165 1H and 13C spectra of 5.5.6 in CDCl3 …………………………………………...166 1H spectra of 5.5.12 in CDCl3 …………………………………………………...167 13C spectra of 5.4.12 in CDCl3 …………………………………………………..168 1H and 13C spectra of 5.5.7 in CDCl3 …………………………………………...169 1H and 13C spectra of 6.1.4 in CDCl3 …………………………………………...170 1H and 13C spectra of 5.5.13 in CDCl3 ………………………………………….171 1H and 13C spectra of 5.5.14 in CDCl3 ………………………………………….172 1H and 13C spectra of (+)-3-demethoxyerythratidinone 5.5.2 in CDCl3 …..173 1H and 13C spectra of 6.1.6 in CDCl3 …………………………………………...174 1H and 13C spectra of 6.1.5 in CDCl3 …………………………………………...175 1H and 13C spectra of 6.1.2 in CDCl3 …………………………………………...176 1H and 13C spectra of allylic alcohol of 6.1.2 in CDCl3 …………………….….177 1H and 13C spectra of (+)-erysotramidine 6.1.1 in CDCl3 ………………….…178 HMBC spectrum of 6.1.1 in CDCl3  ……………………………………….…….179 E. X-Ray data…………………………………………………………………………….…………180   x  List of Tables Table 3.1 Results for the conjugate addition to enone 3.1.13…………………………...29 Table 3.2 Selected substrates and results from Csákÿ’s publication………….…………32 Table 3.3 Results with different bases and temperatures………………………………..39 Table 5.1 Results from VanNieuwenhze and co-workers ………………………………...73 Table 5.2 Conditions for N-Acylation of 5.4.17……………………………………………...78 Table 7.1 Data for natural and synthetic (+)-3-demethoxyerythratidinone………….….132 Table 8.1 Data for natural and synthetic (+)-erysotramidine…………………………….134  xi  List of Figures Figure 1.1 Naturally occurring α-tertiary amines……………………………………………..2 Figure 1.2 Resonance interactions within carboxamide and imidate……………..………..6 Figure 2.1 Representation of (-)-himandrine 2.1.1 from different perspectives……...…12 Figure 2.2 Conformational rational for the desired anti-2.4.8………………………………21 Figure 3.1 Conformers for the nucleophilic attack…………………………………………..27 Figure 3.2  Conformers of γ-N-carbamate-α-β-unsaturated esters………………………...29 Figure 3.3 Possible model for Rh(I)-catalyzed conjugate addition………………………...33 Figure 3.4 Section of 1H NMR spectrum of 3.1.23…………………………………………..34 Figure 3.5 NOESY correlations for 3.1.25…………………………………………………..36 Figure 3.6 Plausible coordination for the anti-approach of the nucleophile………………38 Figure 3.7 Comparison between advanced intermediate 3.2.1 and himandrine…………41 Figure 3.8 Steric interaction during IMDA reaction………………………………………….46 Figure 4.1 Erythrina alkaloids framework…………………………………………………….50 Figure 4.2 Examples of Erythrina alkaloids…………………………………………………..51 Figure 4.3 Last ring formation of aromatic Erythrina alkaloids……………………………..53 Figure 5.1 ORTEP diagram of 5.3.2…………………………………………………………..69 Figure 5.2 Monitoring the formation of 5.4.13 and conversion into 5.4.10 by 1H NMR….75 xii  Figure 5.3 Highly oxygenated erythrinanes and cogenerates……………………………...77  xiii  List of Schemes Scheme 1.1 General mechanism for oxidation of phenols……………………………………..3 Scheme 1.2 General scheme for first-generation of oxidative amidation…………………….4 Scheme 1.3  Retrosynthetic analysis of FR-901483……………………………………………5 Scheme 1.4 Kita’s attempts of oxidation of phenols with amides……………………………..5 Scheme 1.5 Knapp’s attempts of iodolactonization……………………………………………..6 Scheme 1.6 Second generation of oxidative amidation………………………………………..7 Scheme 1.7 An example of para-oxidative amidation reaction: synthesis of (-)-cylindricine C………………………………………………………………………………………………………...8 Scheme 1.8 Third generation of oxidative amidation: bimolecular mode…………………….8 Scheme 1.9 Formal total synthesis of rac-TTX: preparation of intermediate 1.2.37………...9 Scheme 1.10 Stereoselective assembly of the DuBois TTX precursor……………………….10 Scheme 2.1 Initial steps of Mader’s synthesis of carbamate 2.2.12………………..............14 Scheme 2.2 Final transformation for himandrine carbon framework 2.2.16………………..15 Scheme 2.3  Movassaghi’s retrosynthetic analysis of (-)-2.1.1……………………………….16 Scheme 2.4 Preparation of the tetraene 2.3.5…………………………………………………17 Scheme 2.5 Synthesis of tricycle 2.3.15………………………………………………………..18 Scheme 2.6 Completion of Movassaghi’s synthesis of (-)-2.1.1……………………………..19 Scheme 2.7 Retrosynthetic analysis of rac-2.1.1..…………………………………………….20 xiv  Scheme 2.8 Initial steps for the synthesis of Kasahara’s protected phenol 2.4.14………...22 Scheme 2.9 Kasahara’s final phenol 2.4.21……………………………………………………23 Scheme 2.10 OA-IMDA sequence: formation of the desired 2.4.23  and undesired 2.4.24 .24 Scheme 2.11 Formation of C ring and D ring……………………………………………………25 Scheme 3.1 Retrosynthetic analysis for enantioselective synthesis of phenol 3.1.1………26 Scheme 3.2 Reetz’s and Hanessian’s results………………………………………………….28 Scheme 3.3 1,4-addition on δ-N-α-β-unsaturated ketone 3.1.13…………………………….29 Scheme 3.4 Synthesis of acrylate 3.1.5 from Garner’s ester………………………………...30 Scheme 3.5 Conjugate addition with Grignard reagent and organo-cuprate……..………30 Scheme 3.6 Generic reaction scheme for Pd-catalyzed conjugate addition………………..31 Scheme 3.7 Preparation of 3.1.20 for conjugate addition…………………………………….33 Scheme 3.8 Initial attempt of diastereoselective 1,4-conjugate addition of aryl boronic acid…………………………………………………………………………………………………….34 Scheme 3.9 Conjugate addition with acrylate 3.1.5…………………………………………...35 Scheme 3.10 Outcome using Z-3.1.26…………………………………………………………...37 Scheme 3.11 Trials at variable temperatures and different basis……………………………..38 Scheme 3.12 Conjugate addition with alcohol 3.1.27…………………………………………..40 Scheme 3.13 Unsuccessful Boc deprotection of 3.1.5…………………………………………40 Scheme 3.14 Conjugate addition with free amine 3.1.32………………………………………41 xv  Scheme 3.15 Tozer reaction mechanism with methoxyacrolein……………………………....42 Scheme 3.16 Oxidative amidation with phenol 3.2.7…………………………………………...43 Scheme 3.17 Tamao-Fleming oxidation mechanism…………………………………………...44 Scheme 3.18 Plan for Tamao-Fleming oxidation followed by methylation …………………45 Scheme 3.19 Tozer reaction of 3.2.25 and subsequent oxidative amidation …………...47 Scheme 3.20 IMDA reaction with 3.2.18 and preparation for the Stetter reaction ………..48 Scheme 3.21 Undesired lactone 3.2.31 formation………………………………………………48 Scheme 4.1 Biosynthetic pathway for erythrinane alkaloids………………………………….52 Scheme 4.2 Synthesis of dioxopyrroline 4.2.4…………………………………………………54 Scheme 4.3 Diels-Alder reaction at low pressure and high pressure……………………….55 Scheme 4.4 Final steps for the synthesis of (+)-erysotramidine……………………………..55 Scheme 4.5 Chiral base desymmetrization approach………………………………………...56 Scheme 4.6 Completion of the synthesis of 4.2.11 by Simpkins…………………………….57 Scheme 4.7 Speckamp cyclization of 4.2.21…………………………………………………..58 Scheme 4.8 Speckamp cyclization of TIPS-ether 4.2.24…………..…………………………58 Scheme 4.9 Completion of the synthesis of 4.2.28……………………………………………59 Scheme 4.10 Kaluza’s synthesis of ent-4.2.11………………………………………………….60 Scheme 4.11 Reisman’s total synthesis of ent-4.2.28……………………...…………………61 xvi  Scheme 4.12 Tsuda synthesis of (+)-3-demethoxyerythratidinone ……..……………………62 Scheme 5.1 Desymmetrization of dienone 5.1.2………………………………………………63 Scheme 5.2 Retrosynthetic analysis for 4.2.11 and 4.2.28…………………………………..64 Scheme 5.3 Retrosynthetic analysis of oxazoline 5.2.1………………………………………65 Scheme 5.4 Synthesis of oxazoline 5.2.1………………………………………………………66 Scheme 5.5 Oxidative amidation and desymmetrization via 1,4-addition…………………..67 Scheme 5.6 Spiropyrrolidines and spiropiperidines examples……………………………….68 Scheme 5.7 Catalytic reduction of 5.3.2………………………………………………………..70 Scheme 5.8 Strategy for conversion of 5.3.11 into 5.4.3 via retro-Michael……..………….70 Scheme 5.9 Proposed pathway through Curtius rearrangement…………………………….71 Scheme 5.10 Attempted Curtius rearrangement of acid 5.4.9…………………………………72 Scheme 5.11 Oxidative decarboxylation by VanNieuwenhze’s group………………………..72 Scheme 5.12 Possible mechanism for the formation of 5.4.10………………………………..73 Scheme 5.13 Optimization studies for formation of 5.4.10…………………………………….74 Scheme 5.14 Final procedure for the conversion of 5.4.9 into 5.4.10…...……………………76 Scheme 5.15 Preparation of aminoalcohol 5.4.17………………………………………………76 Scheme 5.16 Envisioned completion of (+)-5.5.2……………………………………………….77 Scheme 5.17 Results from the acetylation reactions.………………………………………….78 xvii  Scheme 5.18 Attempts at formal N-acylation of 5.4.17…………………………………………79 Scheme 5.19 Initial attempt of Swern oxidation of aminoalcohol 5.4.17…………...………...79 Scheme 5.20 Proposed mechanism for the formation of 5.5.7………………………………..80 Scheme 5.21 Isomerization of 5.5.6 into enone 5.5.12…………………………………………81 Scheme 5.22 Completion of the synthesis (+)-5.5.2……………………………………………82 Scheme 6.1 Isomerization of 5.5.6 enone 5.5.12…………………………..………………….83 Scheme 6.2 Retrosynthetic analysis for (+)-6.1.1……………………………………………..84 Scheme 6.3 First attempts of reduction of enone 6.1.3……………………………………….84 Scheme 6.4 Metal in ammonia reduction for the synthesis of 6.1.6 and 6.1.5.…………….85 Scheme 6.5 Retro-Michael reaction of 6.1.6……………………………………….…………86 Scheme 6.6  Final steps for the synthesis of (+)-6.1.1………………………………………...87 Scheme 7.1 Summary of the total synthesis of (+)-3-demethoyxyerythratidinone…………89 Scheme 8.1 Summary of the total synthesis of (+)-erysotramidine………………………….90   xviii  List of Abbreviations 9-BBN  9-borabicyclo[3.3.1]nonane Ac AIBN  acetyl  azobis(isobutyronitrile) aq.   aqueous  Ar  generic aryl group  BHT  butylated hydroxytoluene Bn  benzyl  Boc  t-butyloxycarbonyl  BOM  benzyloxymethyl  Br  broad  BRSM   based on recovered starting material  Bu   butyl  Bz   benzoyl  calcd.   calculated  cat.   catalytic  Cbz  benzyloxycarbonyl cHex  cyclohexane  COD  1,5-cyclooctadiene  COSY   correlation spectroscopy  d. b.  DABCO  double bond  1,4-diazabicyclo[2.2.2]octane  DBU   1,8-diazabicycloundec-7-ene  DCC   N,N'-dicyclohexylcarbodiimide  DCE  dichloroethane  xix  DCM   dichloromethane  DDQ   2,3-dichloro-5,6-dicyano-1,4-benzoquinone  DEAD   diethyl azodicarboxylate  DI  deionized  DIAD  Diisopropyl azodicarboxylate DIB   (diacetoxyiodo)benzene  DIBAL   diisobutylaluminum hydride  DIPA   diisopropylamine  DIPEA   N,N-diisopropylethylamine DPPA  diphenylphosphoryl azide dis   disrotatory  DMAP   4-dimethylaminopyridine  DMF   N,N-dimethylformamide  DMP   Dess-Martin periodinane  DMSO   dimethyl sulfoxide dr  diastereomeric ratio  E1cB   elimination, unimolecular, conjugate base  elim.   elimination  epi   epimeric  equiv  fod FPh  equivalent  6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedinato 9-phenyl-9-fluorenyl GB  Galbulimima Et   ethyl  HDA  hetero Diels-Alder xx  Hex   hexanes  HFIP   1,1,1,3,3,3-hexafluoro-2-propanol  HMBC   heteronuclear multiple bond correlation  HMDS  hexamethyldisilazide  HRMS   high resolution mass spectrometry  HSQC   heteronuclear single quantum coherence  imid.   imidazole  iPr  isopropyl IR   infrared spectroscopy  IMDA  intramolecular Diels-Alder L  Leaving group LAH   lithium aluminum hydride  LDA  lithium diisopropylamide  mCPBA   meta-chloroperoxybenzoic acid Me   methyl  Mes  mesitylene MOM   methoxymethyl  mp   melting point  MS  mass spectrometry  Ms   methanesulfonyl  Mt  metal NBS  N-bromo succinamide NCS  N-chloro succinamide NMO  N-methylmorpholine N-oxide  NMR   nuclear magnetic resonance  xxi  NOE   nuclear Overhauser effect  NOESY  N.R.  nuclear Overhauser effect spectroscopy no reaction OA  ORTEP  oxidative amidation  Oak Ridge Thermal Ellipse Program P   generic protecting group  PAN  para-anisyl PCC   pyridinium chlorochromate  Ph   phenyl  PIFA   phenyliodine bis(trifluoroacetate)  Pin  pinacol PMB  para-methoxybenzyl PMP PNB  para-methoxyphenyl para-nitrobenzoate ppm  part per million  PPTS   pyridinium p-toluenesulfonate  Pr   propyl  Pyr  pyridine  quant.   quantitative  Rf   retardation factor  Ref.  reference rsm   recovered starting material  rt   room temperature  sat.   saturated  SM   starting material  xxii  TBAF   tetra-n-butylammonium fluoride  TBDPS   t-butyldiphenylsilyl TBS   t-butyldimethylsilyl  TEA  triethylamine TES   triethylsilyl  Tf   trifluoromethanesulfonyl  TFA   trifluoroacetic acid  TFE   2,2,2-trifluoroethanol  THF   tetrahydrofuran  TIPS  triiso-propylsilyl TLC   thin-layer chromatography  TMS TPAP  trimethylsilyl  tetra-n-propylammonium perruthenate Tr  triphenylmethyl  Ts   p-toluenesulfonyl  TTX UBC  tetrodotoxin  University of British Columbia UV   ultraviolet  XRD   X-ray diffraction  xxiii  Acknowledgments First and foremost, I would like to express my immense gratitude to my supervisor, Professor Marco A. Ciufolini for providing the opportunity to work in his group. The vast knowledge, the passion for his work and research have been a model for me. With his end-less help, I have forged the chemist I am today; I have tempered my spirit not only for the chemistry that he has taught me, but also for the life lessons that he has given. I express my appreciation for members of my comprehensive exam committee, Pro-fessor Glen Sammis, Professor Jennifer Love and Professor Parisa Mehrkhodavandi. Their suggestions helped me to pave the way towards completion of this degree. I am also grateful to Dr. David Perrin for his valuable suggestions while proofreading my thesis even given extremely short deadline.  I would like to thank Dr. Josh Zaifmann for his suggestions and “tricks in the fume-food”, for his dedication in helping his colleagues and friends, for his comforting words when time was hard.  I was lucky to have as a group member Dr. Takahito Kasahara, who provided support and help for the himandrine project. A special thank for all the lab members, Dr. Sanjia Xu, Dimitrios Panagopoulos, Dr. Mara Tomassetti, Dr. Léanne Racicot, Jason Hwang for the un-forgettable moments and their friendship. My acknowledgements would remain incomplete if I do not mention the support of our fantastic technical staff. I would like to acknowledge Dr. Brian Patrick for obtaining X-ray data, David, Benny and Milan of electronic engineering services, Yun, Marshall and Derek, in the mass spectrometry lab, Paul and Maria, in the NMR facility, Emily, Yurou and Ben in the SIF, Brian Ditchburn in the glass shop, John Ellis and Pat Olsthoorn for the chemical acquisition and reception. xxiv  I am thankful to my friends Gabriele, Pierluca and Veronica for all the moments spent together and mutual support. I would like to spend few words for a special man, Mike Wilson. I thank him for teaching to appreciate everything you are given during your life, to always find the good in it  and transform it into your most powerful tool. I would like to thank UBC and Department of Chemistry for the financial support pro-vided throughout my studies. My deepest gratitude is dedicated to my parents for believing in me, their infinite love, moral support and encouragement throughout these years. A unique thought goes to my sister, Letizia, for that feeling of being as at home with her words and comfort. My infinite gratitude is dedicated to my fiancé Xueqing for all the joy, the strength and support she has brought in my life. Thank you for your everyday help and faith in a future to-gether.   xxv  Ai miei nonni    "O frati," dissi, "che per cento milia perigli siete giunti a l'occidente, a questa tanto picciola vigilia  d'i nostri sensi ch'è del rimanente non vogliate negar l'esperienza, di retro al sol, del mondo sanza gente.  Considerate la vostra semenza: fatti non foste a viver come bruti, ma per seguir virtute e canoscenza    Vv 112-120, Dante, Inferno1  Chapter 1 Oxidative amidation of phenols: a method for C-N bond formation  1.1 Introduction The creation of nitrogen-carbon bonds is a key objective in synthetic organic and me-dicinal chemistry because the molecular structures of countless substances of academic and practical interest, including pharmaceutical drugs, contain nitrogen atoms. Yet, much of the technology for the formation of N–C bonds relies on traditional reactions, such as nucleo-philic substitution, reductive amination or on more modern refinements of these classical methods. Sometimes, these techniques prove to be unsuitable for the creation of particular nitrogenous assemblies. An example is the enantiocontrolled synthesis of amines in which the nitrogen atom is bound to a tertiary carbon (Figure 1.1). A limited number of methods have been described to date to access such “α-tertiary amines.” As a consequence, convo-luted methods are often necessary for the synthesis of such features.1 This stands in contrast to the case of amines bound to secondary carbons.2  2   Figure 1.1. Naturally occurring products with α-tertiary amines.  In response to the above problems, our group has researched new techniques for the construction of N–C bonds. A transformation that has emanated from these efforts is the oxi-dative amidation (OA) of phenols (Scheme 1.1): an oxidative dearomatization process that converts a phenol, typically 4-substituted such as 1.1.1, into a nitrogen-substituted dienone, 1.1.6.3 The process involves exposure of the phenol to a hypervalent iodine(III) oxidant, often (diacetoxyiodo)benzene (DIB) or phenyliodine bis(trifluoroacetate) (PIFA). Interestingly, such iodine(III) species are the sole reagents yet identified that perform adequately in this context.  3   Scheme 1.1. General mechanism for oxidation of phenols.  Mechanistically, the reaction is thought to proceed via an initial ligand exchange at the iodine center, leading to formation of complex 1.1.4. Fragmentation of the latter (1.1.4) yields an electrophilic species, perhaps 1.1.5, which is then intercepted by a suitable nucleophile "N" to form 1.1.6. The dashed line in 1.1.1-1.1.6 indicates that the nucleophile may be tethered to the phenolic nucleus (intramolecular reaction) or it may be independent (bimolecular reaction). In all cases, the N atom in 1.1.6 emerges as part of an amide group; hence the terminology "oxidative amidation" of phenols. It should be noted that both the ligand-exchange and the fragmentation steps are strongly proton-catalyzed. Therefore, the reaction is best carried out in a Brønsted acidic medium. The acidic strength of the latter must be adjusted to provide effective catalysis of the above steps without inducing protonation of the nitrogen nucleophile to such an extent that the rate of capture of electrophilic species 1.1.5 becomes excessively slow.  4  1.2 The three generations of oxidative amidation  Three modes – or generations – of oxidative amidation have been developed to date,4 which differ for the nature of the nitrogen nucleophile. Especially relevant to the present study is the first-generation reaction, which employs an oxazoline as the nitrogen nucleophile (Scheme 1.2).  The transformation is best carried out in moderately acidic fluoroalcohol solvents5 such as 2,2,2-trifluoroethanol (TFE, pKa = 12.4)6 or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP, pKa = 9.3)7. These solvents are effective promoters of the mechanistic steps shown in Scheme 1.1, but they are insufficiently acidic to protonate oxazolines (pKa of protonated form = 5-6)8 to a significant extent.   Scheme 1.2. General scheme for first-generation of oxidative amidation.  Oxazoline methodology was initially developed in connection with the synthesis of FR-901483, 1.2.3.9 As seen in Scheme 1.3, a direct route would rely on oxidative cyclization of tyrosine amide 1.2.6 to dienone 1.2.5, which could be advanced to the target compound with ease. Unfortunately, no methods were available at that time to induce the conversion of 1.2.6 into 1.2.5.  5   Scheme 1.3. Retrosynthetic analysis of FR-901483.  Kita and collaborators reported in 1987,10 that oxidative activation of a phenolic amide such as 1.2.7 affords not lactam 1.2.8, but lactone 1.2.10. Arguably lactone 1.2.10 is the result of hydrolysis of iminolactone 1.2.9 during aqueous workup (Scheme 1.4). The carboxamide function thus expresses nucleophilic character at the oxygen atom, not at the nitrogen center.     Scheme 1.4. Kita’s attempts of oxidation of phenols with amides.  6  Knapp and coworkers experienced similar difficulties during their study of alkene io-dolactamization.11 Indeed, treatment of 1.2.11 with I2 afforded lactone 1.2.12 instead of the desired lactam 1.2.14 (Scheme 1.5).    Scheme 1.5. Knapp’s attempts of iodolactonization.  The problem was corrected by converting the amide into silyl imidate 1.2.13, which upon exposure to molecular iodine successfully cyclized to 1.2.14. These results suggest that resonance interactions within the carboxamide unit render this functional group nucleo-philic at oxygen. On the other hand resonance interaction within an imidate promote N-nucleophilicity (Figure 1.2). Imidates proved to be poor substrates for oxidative amidation chemistry, but their cyclic analogs, i.e. oxazolines, were satisfactory.12   Figure 1.2. Resonance interactions within carboxamide and imidate   Efforts towards the synthesis of cylindricine13 revealed limitations of the oxazoline technology that induced us to develop a “second generation” solution. The most direct way to circumvent the foregoing limitations would have been to effect the oxidative cyclization of phenolic free amines. However, ordinary amines are protonated to a significant extent under 7  the conditions of the reaction, rendering the overall process quite problematic. Still today, examples of oxidative cyclization of amines are very rare.14 The use of sulfonamides, in lieu of amines, provided an valuable alternative (Scheme 1.6).15   Scheme 1.6. Second generation of oxidative amidation.  The nonbasic character of sulfonamides permits the conduct of the reaction in neat trifluoroacetic acid (TFA),16 a reaction medium that affords the desired products in generally excellent yield. Phosphoramides may be employed in lieu of sulfonamides.17 This chemistry enabled a straightforward synthesis of cylindricine (1.2.28; Scheme 1.7) and it keys to ongo-ing studies on himandrine, which will be discussed later in this thesis.  8   Scheme 1.7. An example of para-oxidative amidation reaction: synthesis of (-)-cylindricine C.  First- and second-generation reactions are intramolecular processes. A bimolecular mode of oxidative amidation when a 4-substituted phenol (1.2.29) is treated with DIB in ace-tonitrile is referred as the third generation (Scheme 1.8). This chemistry embodies a key step of a recently disclosed formal synthesis of rac-tetrodotoxin (TTX 1.2.41; Scheme 1.9 and Scheme 1.10).18   Scheme 1.8. Third generation of oxidative amidation: bimolecular mode.   Phenol 1.2.31 was oxidized with DIB in acetonitrile into amido-dienone 1.2.32. The resultant 1.2.32 was elaborated to advanced intermediate 1.2.37 by a sequence that involved two key transformations. First,  dienone 1.2.32 was elaborated to nitroketone 1.2.33, which then underwent a Cu(II)-mediated cyclization to isoxazoline 1.2.34 (Machetti-De Sarlo reac-9  tion).19 This step induced the desymmetrization of diene 1.2.33, and as a consequence, the NHBOC-bearing carbon became stereogenic. In its present form, the reaction could not dif-ferentiate between the two enantiotopic double bonds of the diene. Therefore, isoxazoline 1.2.34 and all derived compounds were obtained as racemates. Exposure to methanolic K2CO3 induced nucleophilic fragmentation of 1.2.34 to cyanoester 1.2.35.  The latter was converted into 1.2.36 in preparation for a second crucial transformation: a highly diastereose-lective dihydroxylation of the double bond followed by protection of the diol to afford ace-tonide 1.2.37.   Scheme 1.9. Formal total synthesis of rac-TTX: preparation of intermediate 1.2.37  10  This advanced intermediate 1.2.37 was finally elaborated in a highly stereoselective manner to the Dubois TTX precursor,20 1.2.40 (Scheme 1.10), which could be converted into TTX (1.2.41) in 4 steps.   Scheme 1.10. Stereoselective assembly of the DuBois TTX precursor.20   In this dissertation the scope of first and second generation will be expanded. In Chapters 2 and 3 attention will be focused on an innovative strategy for the synthesis of (-)-himandrine (see structure in Figure 2.1 in the next chapter) using a specific sulfonamide as nucleophile for the oxidative amidation chemistry. Only one total synthesis has been reported to date, signifying that there is a need of new methods for construction of such intricate mol-ecules. We have planned to achieve such goal, relying on a tandem oxidative amidation- in-tramolecular Diels-Alder sequence for the formation of the main framework.  In Chapters 5 and 6, the enantioselective total synthesis of two Erythrina alkaloids will be described. Their synthesis relies on a highly diastereoselective desymmetrization of enone, emerged from an intramolecular oxidative dearomatization of phenol and oxazoline 11  as intercepting nucleophile. This approach aims to illustrate how this methodology can be employed for the construction of moieties exhibiting chiral α-chiral amines, and how the tech-nology facilitates the charting of new enantioselective avenues to aza-spirocyclic compounds.   12  Chapter 2 Synthetic strategy and exploratory work towards (-) – himandrine  2.1 Introduction and previous synthesis  In 1965, Ritchie and Taylor reported the isolation of numerous alkaloids from the bark of Galbulimima belgraveana, a rainforest tree native to Papua New Guinea and northern Australia.21 To date, 30 alkaloids have been isolated and identified from the tree and these compounds are known as the galbulimima alkaloids (GB alkaloids). Himandrine (2.1.1) is one of them and displays a fascinating molecular architecture, which was determined by X-ray structure analysis in 2006.22 As shown in Figure 2.1, the compound consists of a hexacyclic framework containing a trans-decalin system that is attached to a highly substituted spirocy-clic pyrrolidine ring.   Figure 2.1. Representation of (-)-himandrine 2.1.1 from different perspectives.   Biological studies on the GB alkaloids have shown that some of these compounds possess antimuscarinic and antiplatelet activity.23 However, 2.1.1 seems not to possess any significant biological activity, and for this reason it was not subjected to further studies.24 That notwithstanding, himandrine has been an interesting synthetic target on account of its intriguing and challenging structure. However only two publications were reported (prior our 13  contribution) and only one of them describes a completed synthesis of this alkaloid. The absence of further studies and syntheses appears to point a lack of alternative synthetic methods. Later in this dissertation a valuable alternative to this issue will be identified in the methodology developed in the Ciufolini laboratories.  2.2 Synthetic studies toward 2.1.1 by Mander and collaborators In 2004 Mander25 disclosed an approach to the carbon framework of himandrine that rests on a key Diels-Alder reaction of siloxydiene 2.2.9 (Scheme 2.1) with dienophile 2.2.8. The latter was prepared in several steps from 2,5-dimethoxybenzoic acid 2.2.1, starting with Birch reduction-alkylation with 2.2.2, followed by cyclization of 2.2.3 to alcohol 2.2.4. Decar-boxylation, protection of the tertiary alcohol, and diazo transfer reaction converted 2.2.4 into diazoketone 2.2.6, which was immediately subjected to Wolff rearrangement to 2.2.7. Sub-sequent introduction of a double bond by α-selenenylation-elimination afforded dienophile 2.2.8. 14   Scheme 2.1. Initial steps of Mander’s synthesis of carbamate 2.2.12.  15   The key-step of this synthesis, a Diels-Alder reaction between diene 2.2.9 and dieno-phile 2.2.8, afforded pentacyclic intermediate 2.2.10, which was advanced to 2.2.11 by a se-quence of reactions that included a Curtius rearrangement for the installation of the carba-mate segment. Birch reduction of this material (2.2.11) caused the reduction of aryl moiety and the ketone to a secondary alcohol, which was protected prior to a final acidic hydrolysis leading to 2.2.12.   Scheme 2.2. Final transformation for himandrine carbon framework 2.2.16.   Finally, compound 2.2.12 was advanced to 2.2.13 in two steps. The latter was oxida-tively cleaved and the emerging aldehyde was homologated to the corresponding alkene 2.2.14 through an Ohira-Bestmann-metal-reduction sequence. The pyrrolidine and piperidine rings of the final 2.2.16 were the created, respectively, by SN2 displacement of the mesylate derivative of the alcohol, and by intramolecular reductive amination of a ketone arising upon Wacker oxidation of the alkene.   16  2.3 Total synthesis of 2.1.1 by Movassaghi and coworkers  In 2009 Movassaghi and co-workers published the first asymmetric synthesis of (-)-himandrine 2.1.1.26 Their strategy rested on the logic outlined in Scheme 2.3.  Scheme 2.3. Movassaghi’s retrosynthetic analysis of (-)-2.1.1.  The enantioenriched dibromo compound 2.3.9 was obtained from 7-octene- 1,2 diol 2.3.6, in preparation for a sequence of two coupling reaction (Scheme 2.4). The more exposed trans-bromide reacted selectively in a Suzuki reaction with boronic acid 2.3.10 leading to bromodiene 2.3.11, which upon Cu-catalyzed coupling with azetidinone gave triene 2.3.12.  This material was advanced to tetraene 2.3.5 by a sequence that included a selective metathesis reaction of the terminal vinyl group with acrolein in the presence of Grubbs 2nd generation catalyst.  17   Scheme 2.4. Preparation of the tetraene 2.3.5.   Thermally induced intramolecular Diels-Alder reaction (IMDA) of 2.3.5 produced a mixture of two diastereomeric cycloadducts, 2.3.13 and 2.3.14, in a 5:1 ratio (Scheme 2.5). The desired major diastereomer 2.3.13 was isolated through column chromatography and treated with TiCl4 to induce an intramolecular Mukayama aldol reaction.  18   Scheme 2.5. Synthesis of tricycle 2.3.15.  Dehydration of the product resulted in formation of 2.3.15. This tricyclic intermediate underwent a noteworthy [3+3] condensation with imine 2.3.4, leading 2.3.16 after reduction and protection of the N of the pyrrolidine ring (Scheme 2.6). Compound 2.3.16 was formylated under Vilsmeier conditions, followed by oxidative (DDQ, then Pinnick reaction) elaboration to ketoester 2.3.17. Deprotection of the amine and treatment with NCS triggered cyclization to 2.3.18, which exhibits the complete hexacyclic framework of himandrine. Reduction of the ketone and protection led to the final target 2.1.1. 19   Scheme 2.6. Completion of Movassaghi’s synthesis of (-)-2.1.1.  2.4 Prior work of the Ciufolini group and retrosynthetic considerations  Our group has been interested in an approach that showcases a tandem intramolecu-lar oxidative amidation / Diels-Alder / epimerization sequence as a key phase of a synthesis of himandrine. The central idea (Scheme 2.7) is to create the piperidine unit (E ring) of 2.1.1 at a late stage of the synthesis, e.g., by an intramolecular SN2 reaction (Scheme 2.7), while the tertiary alcohol might arise upon cyclization of organometallic agent 2.4.1. The cyclopen-tanone unit (C ring) would result via intramolecular Stetter reaction of 2.4.2, enabling the as-sembly of himandrine from precursor 2.4.3.  20   Scheme 2.7. Retrosynthetic analysis of rac-2.1.1.   Our group demonstrated that compound 2.4.3 can be prepared via a highly facially and diastereoselective IMDA reaction of dienone 2.4.4, which is recognized as a product of oxidative cyclization of phenolic sulfonamide 2.4.5, and that the initially formed cis-decalone 2.4.3 is easily epimerized to the more favorable trans-isomer.27     The elevated degree of selectivity observed in the IMDA reaction of 2.4.4 is attributa-ble to the tendency of the substrate to undergo reaction in an endo mode, through a confor-mation such as 2.4.6, in which steric compression between the SO2 group and the alkyl sub-stituents on the pyrrolidine ring is minimal (Figure 2.2). We describe this as an anti-endo to-pology, in that the sulfonyl group is anti to the R1 and R2 substituents. In contrast, significant 21  steric compression would develop between the SO2 and the pyrrolidine substituents if the cycloaddition proceeded with syn-endo topology; i.e. through conformer 2.4.7.  Figure 2.2. Conformational rational for the desired anti-2.4.8.  A former group member, Dr. T. Kasahara, devised a reliable avenue to the himan-drine framework (rings ABCD)28 that starts with an Yb(III)-catalyzed hetero-Diels-Alder (HDA) reaction of unsaturated α-keto ester 2.4.1029 with ethyl vinyl ether (Scheme 2.8).30 The HDA step occurred in a highly diastereoselective manner to afford the endo-adduct, which was hydrogenated to give tri-substituted tetrahydropyran 2.4.11. 22  Scheme 2.8. Initial steps for the synthesis of Kasahara’s protected phenol 2.4.14.  Reduction of the ester followed by benzylation of the resultant alcohol furnished sub-stance 2.4.12, which was hydrolyzed to the lactol and further reduced to diol 2.4.13. Selec-tive deprotection of the aryl ether was achieved at this stage by heating 2.4.13 with sodium sulfide, and the emerging phenol was converted into bis-TBS intermediate 2.4.14. During his studies, Dr. Kasahara showed the need to homologate the western branch of 2.4.14 into an alkyne at this stage of the synthesis. Therefore 2.4.14 was deprotected and the diol 2.4.15 transformed into acetal 2.4.16 (Scheme 2.9). A subsequent DIBAL reduction of 2.4.16 occurred regioselectively to afford a primary alcohol, which was oxidized to alde-hyde (2.4.17) with the Dess-Martin periodinane in preparation for homologation to alkyne 2.4.18 with the Ohira-Bestmann reagent. Release of the PMB group with DDQ revealed the secondary alcohol, Mitsunobu reaction of which with 2.4.19 afforded 2.4.20 in good yield. A Tozer reaction31 of the latter produced dienic sulfonamide 2.4.21. An expedient modification of the original procedure entailed the use of excess t-BuOK, resulting in simultaneous depro-tection of the phenolic TBS ether, leading to compound 2.4.21 directly and setting the stage for a tandem oxidative cyclization-IMDA sequence.  23   Scheme 2.9. Kasahara’s final phenol 2.4.21.   The oxidative cyclization of 2.4.21 occurred uneventfully, and dienone 2.4.22 was ad-vanced to the IMDA-epimerization sequence to produce trans-decalone 2.4.23 (Scheme 2.10). Yields in this series were lower compared to those observed in previous studies with substrates lacking the ethynyl group. This was attributable to the formation of byproduct 2.4.24, which accounted for almost 50% of the overall yield, and that clearly arose upon Diels-Alder reaction of the dienic sulfonamide with the ethynyl unit, instead of the dienone, followed by double bond isomerization upon DBU treatment. This result pointed to the need to revise the synthetic plan in order to suppress formation of 2.4.24. Such a problem will be addressed in Chapter 3 of this dissertation. 24    Scheme 2.10. OA-IMDA sequence: formation of the desired 2.4.23 and undesired 2.4.24.   Compound 2.4.23 was isolated by column chromatography and elaborated to alde-hyde 2.4.27 in preparation for the closure of rings C and D of the target molecule (Scheme 2.11). A crucial intramolecular Stetter reaction proceeded satisfactorily in the presence of Glorious catalyst 2.4.28,32 affording the 1,4 diketone 2.4.29 in 71% yield. An X-ray analysis highlighted the proximity between the cyclopentanone carbonyl and the alkynyl group, augur-ing well for the success of ring D closure. Indeed, treatment of 2.4.29 with SmI2 converted 2.4.29 into compound 2.4.30. 25   Scheme 2.11. Formation of C ring and D ring.  This work defined a possible route to himandrine. However, it also highlighted the need to improve the yield of the OA-IMDA sequence and the necessity to install an appropriate functional group on the diene that may be turned into an –OMe substituent (“Z” group as depicted in the previous Scheme 2.7) at a suitable stage. A possible strategy for the installation of a suitable functional group (to be converted into –OMe), the suppression of byproducts during the OA-IMDA sequence and an enantioselective route are discussed in the next Chapter as a part of my research in the Ciufolini group. 26  Chapter 3. A route to an enantioenriched precursor of himandrine and improved avenue to an advanced synthetic intermediate  3.1 Studies towards an enantioenriched phenol for the OA-IMDA sequence  The preliminary results, detailed in the previous chapter, indicate that an enantiocon-trolled route to (–)-himandrine requires enantioenriched phenol 3.1.1. Therefore, a first goal was to design a synthesis of 3.1.1 from simple and affordable starting materials.   The retrosynthetic analysis shown in Scheme 3.1 suggests that the desired com-pound could be made from ester 3.1.5, starting with a stereoselective conjugate addition of an appropriate aryl nucleophile. In turn, 3.1.5 should be available by homologation of serine-derived Garner’s ester, 3.1.6.33 Scheme 3.1. Retrosynthetic analysis for enantioselective synthesis of phenol 3.1.1. 27   Our investigation started with finding the conditions to convert acrylate 3.1.5 (Scheme 3.1 above) into 3.1.4 through 1,4 conjugate addition with an appropriate nucleophile. Organo-copper reagents are widely employed for such transformation.34 In the last forty years, many diastereoselectivity studies have been conducted on γ-O/N-α-β-unsaturated carbonyl com-pounds.35 The stereochemical results are difficult to rationalize based on a unified mecha-nism. For example, there are conflicting reports about the dependence or non-dependence of the geometry of the double bond on the stereochemical outcome of the conjugate addition.36 In the majority of the published works it is reported that organocopper reagents attack γ-O-α-β-unsaturated carbonyl compounds in an anti-mode.35 In Figure 3.1, six possible confor-mations are described. D, E and F (syn-pathway) display 1,2-allylic strain, while B and C do not possess such strain. In addition, the electron-withdrawing O in B is better aligned with the π bond, for a better mixing of the HOMO of the nucleophile and the σ*COR orbital the alkoxy group in C is allowed to establish a favorable interaction with the π-system through a two-electrons (p) and a four-electrons (π) interaction in the ground state.37    Figure 3.1. Conformers for the nucleophilic attack.  28  In 1991 Hanessian and co-workers38 reported that E-amino-acid derivative 3.1.10 reacts with organo-cupratres in a syn-mode. This work is a further elaboration of previous studies by Reetz’s group,39 where it is shown that E-isomers (3.1.7) give syn-products with good selectivity using TMSCl as additive (Scheme 3.2).   Scheme 3.2. Reetz’s and Hanessian’s results.   The syn-selectivity can be explained by analyzing the possible relative conformations (Figure 3.2). A can be excluded based on steric ground. Conformer B has a favorable orientation of the electronegative group with the regard of the double bond and the incoming nucleophile. Conformer C stabilizes the TS through the electron-donating character of alkyl group R, and the parallel orientation of the σC-R with the regard to the incipient σ*C-Cu orbital. Moreover, the carbamate and ester carbonyl may develop chelating interactions, which would override the 1,2 allylic strain.  29     Figure 3.2. Conformers of γ-N-carbamate-α-β-unsaturated esters.   Less studied substrates are δ-O/N-α-β-unsaturated carbonyl derivatives. In 2004 Lubell40 described copper reagents attack in a 1,4-mode (see Scheme 3.3 and entries 4-6 table 3.1 below) with poor substrate control (usually slightly in favor of the anti-diastereomer).   Scheme 3.3. 1,4-addition on δ-N-α-β-unsaturated ketone 3.1.13. Entry Nucleophile % yield and dr (syn/anti) 1 MeO2CCH2CO2Me/NaH 77, 1:1 2 KCN/18-crown-6 68, 1:1 3 CH3NO2/DBU 94, 2:1 4 Ph2CuCN(MgBr2) 98, 1:2 5 PhCu.S(CH3)2 74, 1:3 6 PMP2CuCN(MgBr2) 98, 1:2 7 i-Pr2CuCN(MgBr2) 80, 5:1 8 i-PrMgBr/CuI(cat.) 83, 5:1 9 PhMgBr 86, 9:1 10 PhMgBr/MgBr2 100a, 15:1 11 PMPMgBr 82, 10:1 12 i-PrMgBr 71, 3:1 13 i-PrMgBr/MgBr2 80, 6:1 a %conversion  Table 3.1. Results for conjugate addition to enone 3.1.13. 30    On the other hand, Grignard reagents displayed a satisfying selectivity (entries 8-13) and also they showed a preferential reversal syn-attack. On the light of these results, we de-cided to investigate the addition of Grignard reagents to acrylate 3.1.5. Starting from the known Garner’s ester 3.1.6, acrylate 3.1.5 was easily prepared ac-cording to a known procedure (Scheme 3.4).41    Scheme 3.4. Synthesis of acrylate 3.1.5 from Garner’s ester.   Unfortunately, PMPMgBr reacted with 3.1.5 in THF at -78 °C to furnish a complex mixture of products (Scheme 3.5). This strategy was not fully explored because of two main reasons: a) literature precedent indicated that the reaction would proceed with unsatisfactory selectivity;40 b) a publication inspired us to investigate a different approach.   Scheme 3.5. Conjugate addition with Grignard reagent and organo-cuprate. 31    In 2015 Csákÿ and co-workers42 described the selectivity of the conjugate addition of boronic acids, using Bedford’s catalyst (3.1.19) (Scheme 3.6 and Table 3.2). Their attention is focused on the induction of γ-O/N-α-β-unsaturated esters and ketones. Still few examples of δ-O/N- α-β-unsaturated esters were reported. This publication led us question whether Rh(I) would be a better candidate for our transformation. To the best of our knowledge there have not been studies that describe 1,2- and 1,3-stereochemical-substrate induction in the Rh(I)-catalyzed conjugated addition of boronic acids. Scheme 3.6. Generic reaction scheme for Pd-catalyzed conjugate addition.             32  Entry Starting material Product anti/syn ratio (%yield) 1    90:10 (88) 2    90:10 (86) 3    60:40 (70) 4    15:85 (98) 5    20:80 (40) Table 3.2. Selected substrates and results from Csákÿ’s publication.42  We decided to investigate Rh(I)-catalyzed conjugate addition on the basis that the nucleophile would have been delivered in the same mode as described in previous publica-tions with different organometallic reagents. Figure 3.3 depicts the anticipated model for con-jugate addition to our system.       33   Figure 3.3. Possible model for Rh(I)-catalyzed conjugate addition.   Our investigation started with the conversion of 3.1.5 into a secondary carbamate 3.1.20 as shown in Scheme 3.7. Acetonide was removed using Amberlyst 15-(H) and the emerging primary alcohol was protected as silyl ether.   Scheme 3.7. Preparation of 3.1.20 for conjugate addition.  At this point we had in hand the desired unsaturated carbamate, which was employed as described (Scheme 3.8): carbamate 3.1.20 and [RhCl(COD)2]2 were dissolved at room temperature. Then boronic acid 3.1.21 and an aqueous solution of Cs2CO3 were added, and the solution was heated at reflux until the starting material was completely consumed (moni-tored by TLC). After work up, 1H NMR analysis of the crude product thus obtained did not provide clear information regarding the diastereoselectivity of the reaction. Confirmation was provided by conversion of 3.1.22 into lactams 3.1.23 with TFA (Scheme 3.8). In Figure 3.4 two sections of 1H NMR spectrum of 3.1.23 are shown where the presence of the two dia-stereomers in equal amounts is clearly shown. 34   Scheme 3.8. Initial attempt of diastereoselective 1,4-conjugate addition of aryl boronic acid.   Figure 3.4. Section of 1H NMR spectrum of 3.1.23.   To give more rigidity to the system, we attempted the same reaction with acrylate 3.1.5. (Scheme 3.9), which reacted to afford a single product (within the limits of 300 MHz 1H NMR spectroscopy). NOESY analysis of the derived lactam 3.1.25 disclosed that we had on-ly the undesired diastereomer, wherein the aryl group had entered anti to the nitrogen func-tionality.   Ha Hc Hb Hd 35   Scheme 3.9. Conjugate addition with acrylate 3.1.5.   The benzylic proton (Ha) does not have any correlations with the O-methylene pro-tons (Hc and Hd) at about 3.70 and 3.52 ppm. On the other hand, Ha displays a correlation with the methine Hb (approximately at 3.75 ppm), corroborating the anti-addition of the aryl-boronic acid (Figure 3.5). 36   Figure 3.5. NOESY  correlations for 3.1.25: correlations Ha/Hb (in red), no correlations Ha/Hcd (in black).  The good anti-selectivity is an unprecedented outcome for such reaction. Moreover the selectivity is much greater than previous reported with Pd-catalyzed on δ-O-α-β-unsaturated esters (see page 31, Table 3.2, entry 3).  As mentioned before (Scheme 3.6 and Table 3.2, entries 4 and 5) γ-N-α-β-unsaturated carbonyl compounds lead to the syn adduct, while in this case we observed in-version of selectivity.  Ha Hd Hb+Hc Hb 37   In previous publications, it was stated that the geometry of the double bond does not affect the selectivity of the addition (see page 31, Table 3.2, entries 1 and 2). However, we decided to synthetize the Z-isomer (3.1.26) to determine whether, in our case, there was any relationship between syn/anti attack and double bond geometry. Previously shown aldehyde 3.1.15 (Scheme 3.4) was thus subjected to Still-Gennari reaction to afford 3.1.26 (Scheme 3.10). However, this material underwent conjugate addition to produce the same diastere-omer 3.1.24 obtained from the E-isomer.   Scheme 3.10. Outcome using Z-3.1.26.   A plausible transition state is described in Figure 3.6, where the Rh(I) is coordinated to the acetonide O, producing the anti-adduct. It is worth noticing that, without the oxazolidine 38  ring, a significant formation of the desired diastereomer was obtained (see page 33, Scheme 3.8). Arguably the degree of coordination by heteroatoms is responsible for the selectivity.    Figure 3.6. Plausible coordination for the anti-approach of the nucleophile.  Compound 3.1.20 afforded some of the desired diastereomer, therefore we decided to start tuning some of the reactions condition with the aim of finding a possible trend that would lead only to the syn adduct. Firstly, different bases were tried, but no significant changes were observed (Table 3.3, entries 1-3). Then, the reaction was repeated at 3 different temperatures (Table 3.3, en-tries 3-5). In all these experiments the anti-product is favored: at room temperature a 3:1 (an-ti/syn) mixture was obtained (entry 5, Table 3.3). However, most of the starting material re-mained unreacted, while most of the PMP-boronic acid underwent proton-deboronation or homocoupling. When the temperature was raised to 50 °C, all the acrylate 3.1.20 was con-sumed, but the ratio between the two diastereomers was decreased to 2:1.    Scheme 3.11. Trials at variable temperatures and different basis. 39     Entry Conditionsa syn/anti; yield (over two steps) 1 Na2CO3, reflux, 2h 1:1; 49% 2 K2CO3, reflux, 2h 1:1; 50% 3 Cs2CO3, reflux, 2h 1:1; 50% 4 Cs2CO3, rt, 24h 3:1; 24%b 5 Cs2CO3, 50 °C, 16h 2:1; 33%c a) 2.0 equiv of 3.1.21, 3.0 equiv of base, 0.03% equiv. [ClRh(COD)2]2, 1,4-dioxane/water (9:1, 0.3 M); after the conjugate addition, the crude was subjected to TFA/DCM (2:1, 0.3 M) to confirm the ratio, without further purifica-tion (except entry 4-5)  b) During the conjugate addition, 64% rsm c) During the conjugate addition, 44% rsm Table 3.3. Results with different bases and temperatures.  To increase a potential chelating ability of our substrate, we focused our attention to the role of unprotected heteroatoms in our substrate. Primary alcohol 3.1.27, readily pre-pared by deprotection of 3.1.5, was not a substrate for the Rh-catalyzed reaction, being re-covered unchanged upon reaction conditions, together with a small amount of tetrahydrofu-ran 3.1.29 (Scheme 3.12).  40   Scheme 3.12. Conjugate addition with alcohol 3.1.27.   Reasoning that the Boc carbamate was a poor ligand for rhodium, we turned to a substrate containing a free amine, investigating the potential ligating effect of the N for the promotion of  the desired facial selectivity. Selective removal of the Boc group from 3.1.5 in the presence of the acetonide was problematic (Scheme 3.13), but treatment of TBDPS ether 3.1.31 with TFA gave the desired primary amine 3.1.31 in good yield (Scheme 3.14).   Scheme 3.13. Unsuccessful Boc deprotection of 3.1.5.   Unfortunately, the reaction of 3.1.32 with aryl boronic acid 3.1.21 in the presence of Rh(I)COD produced a complex mixture, from which none of the desired product was isolated. 41    Scheme 3.14. Conjugate addition with free amine 3.1.32.   At this point of our studies, we decide to set this problem aside and refocus our ef-forts on an improved route to racemic himandrine. This will be discussed in the next section of this section of this chapter.  3.2 Improvements toward the total synthesis of racemic himandrine   Dr. Kasahara's studies had defined a sound approach to advanced intermediate 3.2.1, (L/R = H). Such an intermediate does not lend itself easily to the introduction of an -OMe group, as required for himandrine (Figure 3.6) — unless L were a substituent other than H.   Figure 3.7. Comparison between advanced intermediate 3.2.1 and himandrine. 42   An obvious solution would be to have L = OMe, in which case the appropriate variant of 3.2.1 could be prepared starting with a Tozer condensation of 3.2.3 with 3-methoxy acrole-in. Such an approach had to be abandoned on account of three difficulties.43 First, the prepa-ration of quantities of methoxyacrolein proved to be troublesome. Second, the Tozer reaction was low yielding (Scheme 3.15). Third, the methoxydiene portion of compound 3.2.7 proved to be quite sensitive to the acidic conditions required for the oxidative cyclization step leading to 3.2.8 (Scheme 3.16), resulting in an intractable mixture of products.  Scheme 3.15. Tozer reaction mechanism with methoxyacrolein and 3.2.2. 43   Scheme 3.16. Oxidative amidation with phenol 3.2.7.   Alternatively, group L could be a silicon-centered substituent amenable to Tamao-Fleming oxidation;44 e.g. a dimethylphenylsilyl group. The Tamao-Fleming reaction is known to occur with retention of configuration, as shown in the mechanistic outline of Scheme 3.17. Thus, an initial treatment of compound 3.2.9 with an appropriate electrophile (for instance Br2) would induce ipso-electrophilic aromatic substitution via intermediate 3.2.10, leading to silyl bromide 3.2.11 and bromobenzene. This step would be followed by addition of a peroxy acid, which displaces the bromide from 3.2.11 to form 3.2.12. The latter then undergoes a 1,2-alkyl shift towards the proximal oxygen atom of the peroxy functionality. This migratory step is a sigmatropic process which occurs suprafacially, resulting in retention of configuration at the migrating carbon atom. Therefore, alcohol 3.2.14 that is generated by basic hydrolysis of intermediate 3.2.13 has the same configuration as the starting material (3.2.9).  44   Scheme 3.17. Tamao-Fleming oxidation mechanism.  In accord with the foregoing, the beta-configuration of substituent L would be required in 3.2.17. This configuration is anticipated to result from the anti-endo product of the DA re-action (see Figure 2.2, page 20). After Tamao-oxidation, the resulting alcohol 3.2.16 may then be methylated to furnish 3.2.17 (Scheme 3.18). 45   Scheme 3.18. Plan for Tamao-Fleming oxidation followed by methylation.  The new approach was also anticipated to disfavor – perhaps suppress – the intra-molecular Diels-Alder reaction of the diene with the alkynyl segment of 3.2.18, previously discussed in Chapter 2, and leading to undesired product 3.2.19. As shown in Figure 3.8, such a reaction would now suffer from a severe steric interaction between the bulky dime-thylphenylsilyl group and the siloxyethyl substituent in 3.2.18. This might cause the diene to react preferentially / exclusively with the dienone, producing largely / only the desired 3.2.20.  46   Figure 3.8. Steric interaction during the IMDA reaction.  Our attention thus refocused on β-silylacrolein 3.2.23, which was synthesized by a method described by Panek45 (Scheme 3.19), starting with Pt-catalyzed syn-hydrosilylation of propargyl alcohol (3.2.21). This afforded trans-silyl allylic alcohol 3.2.22, which was oxidized with PCC to furnish 3.2.23 in good yield. The Tozer condensation with 3.2.2546 afforded silyldiene 3.2.26, which had to be quickly purified through a plug of silica gel due to its sensitivity to column chromatography. Gratifyingly, addition of 3.2.26 to a solution of DIB and TFA formed dienone 3.2.18.  47   Scheme 3.19. Tozer reaction of 3.2.25 and subsequent oxidative amidation.   The IMDA reaction of dienone 3.2.18 produced the desired cis-decalone 3.2.20 in good yield (51% after three steps) and with no trace of the side product encountered in the preliminary studies. In previous studies (see Chapter 2, page 23) epimerization to trans-isomer was performed at this stage. However, the Diels-Alder product was not epimerized at this point because its sensitivity to basic conditions: even a catalytic amount of DBU causes decomposition of the enone 3.2.20. Fortunately, it was found that the epimerization was not necessary at this point, in that further chemical manipulations result in epimerization to the most stable trans-system (Scheme 3.20). Deprotection of the TBS group in 3.2.20 was carried out with catalytic HI in acetoni-trile47 providing alcohol 3.2.28. It was best to avoid basic conditions in this step, because of the tendency of the liberated OH group to undergo Michael addition to the enone. Further-more, the reactions required careful temperature control (-15 °C). Michael cyclization of 3.2.20 was also observed during chromatographic purification on silica gel, causing severe loss of the desired product. Therefore, crude 3.2.28 was directly oxidized to aldehyde 3.2.29 with Dess-Martin reagent. 48   Scheme 3.20. IMDA reaction with 3.2.18 and preparation for the Stetter reaction.   Attempts to induce Stetter cyclization of aldehyde 3.2.29, as seen earlier for 2.4.27 (Chapter 2, page 23, Scheme 2.11) afforded only lactone 3.2.31 instead of the desired 3.2.30. This must have been the result of oxidation of the aldehyde to a carboxylic acid, followed by intramolecular cyclization. Thiazolium ylides are known to promote oxidation of aldehydes to carboxylic acids in the presence of molecular oxygen.48 Unfortunately, both degassing of the solution and addition of BHT as an antioxidant failed to suppress the formation of lactone 3.2.31.  Scheme 3.21. Undesired lactone 3.2.31 formation. 49   Time and material limitations forced us to suspend the effort toward himandrine at this stage. Future studies will seek the appropriate conditions for the creation of the needed cy-clopentanone ring.  50  Chapter 4 Enantioselective synthesis of Erythrina Alkaloids  4.1 Introduction The history of Erythrina alkaloids starts in 1877 when their pharmacological activity was described for the first time. All the natural products have shown a remarkable curare-like neuromuscular blocking activities. Because of their interesting biological chemical properties, occurrence, structure, analytic and spectral properties, Erythrina alkaloids have been regular-ly reviewed.49 Furthermore, their characteristic framework has made them popular targets in synthetic chemistry.50   Figure 4.1. Erythrina alkaloids framework.  Erythrina alkaloids possess an unusual tetracyclic spiroamine framework (Figure 4.1) and they are generally classified into two main groups: compounds possessing a 6-5-6-6-membered indoloisoquinoline core and compounds exhibiting a 6-5-7-6-membered indolobenzazepine skeleton (Figure 4.2). The D ring is most commonly a substituted (mono- or di-methoxy) phenyl unit, but compounds containing heteroaromatic segments, such as pyridyl and furanyl, are also known (Figure 4.2). Finally there are members of the family incorporating a non-aromatic D ring, e.g. (+)-cocculolidine. These alkaloids are generally dextrorotatory and the absolute configuration of their spirocenter is (S). 51   Figure 4.2. Examples of Erythrina alkaloids.  Detailed investigations by Zenk and collaborators revealed that Erythrina alkaloids are biogenetically derived from (S)-norreticuline (4.1.1), by the pathway outlined in Scheme 4.1.51 Thus, para-para oxidative cyclization of 4.1.1 leads to the morphinandienone derivative, norisosalutaridine 4.1.2. The initial steps of the biosynthesis thus retrace the events involved in the biogenesis of other important isoquinoline alkaloids (e.g. protoberberines, aporphines, bisbenzylisoquinolines, morphinanes, pavines, and benzophenanthridines), which are derived from (S)-reticuline: the N-methyl analogue of 4.1.1. Subsequently, norisosalutaridine 4.1.2 undergoes benzo[1,3]dioxole formation to give noramurine 4.1.3, which rearranges to the unsymmetrical dibenzazonine 4.1.5 via cation 4.1.4. Reduction of 4.1.5 to 4.1.6 and 52  oxidative activation of the phenol produces cation 4.1.7, which is intercepted by the nitrogen atom to generate Δ3-erythratinone 4.1.8.   Scheme 4.1. Biosynthetic pathway for erythrinane alkaloids.  4.2 Previous enantioselective syntheses of Erythrina alkaloids The unique structure and interesting biological properties of Erythrina alkaloids have engendered considerable interest in the synthetic arena, and indeed, many total syntheses of, and synthetic studies on, these compounds have been reported in literature to date.50 A common way to classify synthetic approaches to these alkaloids focuses on which of the 53  three alicyclic rings, A, B or C, is completed at the final steps of the synthesis (Figure 4.3). For the purpose of this dissertation, only enantioselective total syntheses of 3-demethoxyerythratidinone and erysotramidine are discussed.   Figure 4.3. Last ring formation of aromatic Erythrina alkaloids.  4.2.1 Formation of ring A: Tsuda The first enantioselective synthesis of (+)-erysotramidine was achieved in 1993 by Tsuda52 by a strategy that demonstrates a late-stage assembly of ring A. As seen below, subsequent enantioselective routes have also relied on a similar approach. The synthesis started with reaction of dimethoxyphenylalanine methyl ester (4.2.1) with methyl malonyl chloride that furnished 4.2.2, followed by Bischler-Napieralski cyclization using polyphos-phate ester to furnish 4.2.3. Subsequent reaction of 4.2.3 with oxalyl chloride produced the desired dioxopyrroline 4.2.4 (Scheme 4.2). 54   Scheme 4.2. Synthesis of dioxopyrroline 4.2.4.  The creation of ring A of the erythrinane core was envisioned to involve Diels-Alder reaction of 4.2.4 with Danishefsky's diene (1-methoxy-3-trimethylsilyloxybutadiene, 4.2.5).53 However, the combination of 4.2.4 and 4.2.5 furnished only products arising from reaction of the diene at the keto-carbonyl group (Scheme 4.3). This can be attributed to unfavorable steric interactions disfavoring the approach of the diene to the tetrasubstituted C=C bond. Interestingly, conduct of the reaction at high pressure (10 kbar, rt) afforded the desired cycloadduct 4.2.8 as a mixture of endo- and exo products (Scheme 4.3). In either case, the diene reacted from the α-face of the molecule, presumably to minimize steric interactions with the COOMe group. The noteworthy pressure-dependent regioselectivity observed in this step may be rationalized based on the principle that high pressures promote reaction through the smallest possible molecular volume of activation,54 which in this case is that corresponding to the desired mode of reactivity. 55  Scheme 4.3. Diels-Alder reaction at low pressure and high pressure.  The mixture of Diels-Alder products was advanced to 4.2.9, which was subjected to a series of decarboxylation and redox reactions, leading to the formation of compound 4.2.10. Reduction of the ketone (5:1 ratio between α:β) and methylation of the resulting alcohol pro-duced (+)-erysotramidine (4.2.11; Scheme 4.4)  Scheme 4.4. Final steps for the synthesis of (+)-erysotramidine.  4.2.2 Formation of A ring: Simpkins  A strategy relying on late formation of the A ring is also described in the work of Simpkins,55 whose approach to Erythrina alkaloids rests on an interesting desymmetrization of a meso-intermediate with a chiral base. Thus, deprotonation of imide 4.2.12 with lithium amide 4.2.13 and reaction of the anion with TMS-Cl returned C-silylated imide 4.2.14 in 94% ee (Scheme 4.5). This material reacted regioselectively with 4-pentenylmagnesium bromide 56  at the less sterically encumbered carbonyl group, and the resulting product was advanced to as a single diastereomer of 4.2.15 through a sequence involving desilylation and intramo-lecular Speckamp-type amidoalkylation reaction.56 Retro Diels-Alder reaction of 4.2.15 and oxidative cleavage of the C=C bond gave aldehyde 4.2.16 in good yield.    Scheme 4.5. Chiral base desymmetrization approach.   Ring A of the alkaloid was formed via a 6-exo-trig radical cyclization of 4.2.16 mediated by Bu3SnH. This step presumably involved ketyl radical formation as intermediate. The emerging alcohol 4.2.17 was advanced in 2 steps to Padwa’s intermediate (4.2.18),57 which can be converted into (+)-erysotramidine (4.2.11) by a highly diastereoselective SeO2 hydroxylation, followed by O-methylation (Scheme 4.6).  57   Scheme 4.6. Completion of the synthesis of 4.2.11 by Simpkins.  A similar strategy was used for the synthesis of (+)-3-demethoxyerythratidinone (4.2.28, for the structure see page 58, Scheme 4.9), which started with a regioselective addi-tion of 4-pentenylmagnesium bromide to the more electrophilic carbonyl group of (L)-malic imide 4.2.19. Release of the acetyl group was also incurred during this step. In contrast to the previous case, the subsequent Speckamp cyclization of 4.2.21 now favored the unde-sired diastereomer, 4.2.22. Reprotection of the secondary alcohol as an acetate was of no avail: the cyclization of the resulting 4.2.21 led only to an unsatisfying diastereoselectivity (3:1) in favor of the desired product 4.2.22 (Scheme 4.7).  58   Scheme 4.7. Speckamp cyclization of 4.2.21.  Curiously, when 4.2.20 was protected as a TIPS ether, the cyclization of 4.2.24 appeared to be more diastereoselective (1 : 9) in favor of the undesired diastereomer 4.2.25. than the 4.2.21 analogue. In spite of it being the minor product, 4.2.26 was chromatographically separated and advanced to the final target.    Scheme 4.8. Speckamp cyclization of TIPS-ether 4.2.24.  59  The synthesis was completed via a Wacker oxidation of the alkene to a methyl ketone and an alane reduction of the lactam to the corresponding amine. In the process, the methyl ketone also underwent reduction. The result was formation of tricyclic amine 4.2.27. Swern oxidation returned a diketone intermediate, which underwent intramolecular aldol condensa-tion to afford (+)-3-demethoxyerythratidinone 4.2.28 (Scheme 4.9).   Scheme 4.9. Completion of the synthesis of 4.2.28.  4.2.3 Formation of A ring: Kaluza In 2015, Kaluza and coworkers58 disclosed a synthesis of the unnatural enantiomer of 4.2.11 by an approach reminiscent of that of Simpkins.55 Their starting point was compound 4.2.29, which differs from the Simpkins malic imide 4.2.20 in that it contains an (L)-tartaric moiety. Addition of the acetylenic Grignard reagent derived from TIPS-protected propargyl alcohol and cyclization of the resultant furnished pyrroloisoquinoline 4.2.30 in three steps and with good diastereoselectivity (Scheme 4.10). Subsequent release of the acetate esters and silver-promoted cyclization of the intermediate homopropargylic alcohol provided dihydrofu-ran 4.2.31, which underwent highly diastereoselective hydrogenation to tetrahydrofuran 4.2.32. In a three-step procedure, this material was deoxygenated to give tetracyclic inter-mediate 4.2.33. At this point, the primary alcohol was deprotected, oxidized to an aldehyde, and homologated to the vinyl iodide 4.2.34. Treatment of the latter with TESOTf and TEA 60  produced 4.2.35 via retro-Michael cleavage of the tetrahydrofuran ring. Finally intramolecular Heck reaction and O-methylation afforded ent-4.2.11.   Scheme 4.10. Kaluza’s synthesis of ent-4.2.11.  4.2.4 Formation B ring: Reisman Reisman's synthesis of ent-demethoxyerythratidinone illustrates a strategy that rests on the late formation of ring B.59 This work also represents the shortest total synthesis of de-methoxyerythrinanone yet described. The key step of the synthesis is the addition of aryllithi-um reagent 4.2.37 to Ellman sulfoximine60 4.2.36 (Scheme 4.11). This reaction occurred with a diastereoselectivity of 98:2. Stille coupling of the resulting spirosulfenamide 4.2.38 with 61  stannane 4.2.39 and acid treatment of the product afforded tetracyclic dienone 4.2.40, through hydrolysis of the sulfenamide, the vinyl ether, and the ketal, followed by enamine formation. Compound 4.2.40 exhibits the complete framework of the target alkaloid, and dif-fers from the latter only for the presence of an additional unsaturation. Hydrogenation of 4.2.40 took place regioselectively to produce ent-4.2.28 over a total of 6 steps from commer-cial available ortho-bromophenol,   Scheme 4.11. Reisman’s total synthesis of ent-4.2.28.  4.2.5 Formation of ring C: Tsuda In 1994, Tsuda described the first enantioselective avenue to (+)-3-demethoxyerythratidinone (4.2.28) by a strategy that centered on late-stage formation of ring C.61 The synthesis (Scheme 4.12) started with the condensation of (S)-dimethoxyphenylalanine methyl ester 4.2.41 with ketoester 4.2.42 (sealed tube, 100 °C- 150 °C). The resulting enamine 4.2.43 was allowed to react with (COCl)2, leading to the crea-tion of bicyclic compound 4.2.44. Reduction of the ketone prepared the molecule for a highly 62  diastereoselective Pictet-Spengler cyclization (BF3-Et2O) to the densely functionalized erythrinane core, 4.2.45. The synthesis of (+)-3-demethoxyerythratidinone (4.2.28) was com-pleted from intermediate 4.2.45 by a sequence involving several decarboxylation reactions and redox steps.  Scheme 4.12. Tsuda synthesis of (+)-3-demethoxyerythratidinone.   The above four publications describe the only enantioselective syntheses reported to date. All of them have been accomplished by adopting previous approaches, refining pre-existing strategies, and employing methodology devised by others. This inspired us to develop a new unified strategy for the synthesis of Erythrina alkaloids, through an extension of oxidative amidation techniques. This will be discussed in the next chapters.  63  Chapter 5 Total synthesis of (+)-3-demethoxyerythratidinone  5.1 Retrosynthetic analysis for oxidative-amidation approach As summarized in the previous chapter, past syntheses of these alkaloids derived key portion of the targets from chiral educts (Tsuda), by desymmetrization of a meso-imide with a chiral base (Simpkins) or nucleophilic addition of organometallic agents to Ellman sulfi-nylimines (Reisman). Our synthesis aims to demonstrate the formation of spiropiperidines via oxidative amidation and desymmetrization of the resultant, “locally symmetrical”, enone through intramolecular Michael addition. The approach detailed herein rests on an observation recorded during the develop-ment of methodology for the oxidative amidation of phenols.62 Oxazolines such as 5.1.1 (Scheme 5.1) are especially good substrates for the oxidative amidation reaction. Interesting-ly, dienone 5.1.2 resulting from oxidative cyclization of 5.1.1 tends to undergo spontaneous Michael cyclisation to 5.1.3 upon standing (structure confirmed by X-ray diffractometry).63 This cyclization is completely diastereoselective within the limits of detection using 600 MHz 1H NMR spectrometry. Noteworthy among the factors that contribute to such a high level of stereoselectivity is the well-documented preference for an axial orientation for substituents adjacent to the N atom in N-acylpiperidines and related 6-membered rings.64    Scheme 5.1. Desymmetrization of dienone 5.1.2.  64  The above cyclization reaction causes the chirotopic spiro carbon in 5.1.2 to become stereogenic65 and to acquire the (R)-configuration in the final 5.1.3. We describe this process as the desymmetrization of "locally symmetrical" dienone 5.1.2.66 Our strategy for the stereocontrolled assembly of Erythrina frameworks rests on such a principle.  Scheme 5.2. Retrosynthetic analysis for 4.2.11 and 4.2.28.  As outlined in Scheme 5.2, the oxidative cyclisation of oxazoline 5.1.4 would produce 5.1.5, which upon stereoselective Michael cyclisation should afford 5.1.6. The spiro carbon in this molecule possesses the correct configuration for the target alkaloids. The product of hy-drogenation of 5.1.6, ketone 5.1.7, would then serve as a common intermediate for the syn-thesis of 4.2.11 and 4.2.28.  5.2 Construction of the appropriate oxazoline As highlighted in the previous section, the first goal is the synthesis of the appropriate enantioenriched oxazoline 5.2.1. Scheme 5.3 outlines the retrosynthetic logic for the con-struction of oxazoline 5.2.1.  65   Scheme 5.3. Retrosynthetic analysis of oxazoline 5.2.1.   Commercial acid 5.2.5 was advanced to 5.2.3 in a conventional fashion, in prepara-tion for Suzuki coupling with aryl boronate 5.2.7 (easily prepared in two steps from 4-iodophenol, Scheme 5.4). The resulting biaryl 5.2.8 underwent saponification and then was condensed with L-serine methyl ester to generate amide 5.2.9. All these steps were per-formed on a one-mole scale without chromatographic purification, but employing sequences of precipitation and recrystallization process. Only amide 5.2.9 was always contaminated (ca. 8-18%) with some DCC byproduct. Despite the small percent of impurities, the following transformation was not affected to an appreciable extent. The emerging 5.2.9 was cyclized into the corresponding oxazoline under Wipf condition.67 Finally hydrogenolysis of the phe-nolic benzyl ether afforded the desired 5.2.1, without affecting the sensitive oxazoline moiety.  66   Scheme 5.4. Synthesis of oxazoline 5.2.1.   A comment is in order at this juncture. The first route to 5.2.1 was devised by Dr. J. Zaifmann, of this group, who employed Deoxofluor67 for oxazoline formation. The scale on which the operations of Scheme 5.4 had to be carried out ruled against the use of such an expensive material. Accordingly, the considerably more economical Burgess reagent was investigated as a replacement for Deoxofluor. The yield of oxazoline was slightly lower com-pared with Deoxofluor,67f but the Burgess reagent clearly established itself as the one of choice in this case, not only because of its inexpensive nature, but also because the reaction was technically easier to set up. Indeed the use of Deoxofluor required cryogenic conditions 67  and careful monitoring of the temperature (always between -40 °C/-25 °C) for several hours (from two to four, depending on the fluctuation of the temperature). In addition to that a very slow addition was mandatory, to obtain good yield.  5.3 Oxidative amidation and desymmetrization  The oxidation of oxazoline 5.2.1 either with DIB or PIFA in HFIP afforded spiro-dienone 5.3.1 (Scheme 5.5). The reaction occurs at a fairly slow rate when DIB is employed as the oxidant, necessitating a rather long contact time (ca. one hour), which tends to be the source of formation of overoxidized byproducts, or even decomposition of the initially formed 5.2.1. The modified conditions developed in our laboratory for the oxidative cyclization of sul-fonamides (DIB/TFA in DCM)62 provided no improvement, likely because of the sensitivity of the oxazoline to Brønsted acids. The use of PIFA as the oxidant resulted in a significantly faster rate and a cleaner reaction. Optimization studies revealed that best results are achieved by syringe-pump addition (0.8 mL/min) of a 0.2M solution of substrate in HFIP to one of PIFA in HFIP (see appendix for details).   Scheme 5.5. Oxidative amidation and desymmetrization via 1,4 addition. 68   It should be noted that while the oxidative cyclization of phenolic oxazoline 5.3.5-5.3.7, leading to spiropyrrolidines 5.3.6-5.3.8, produces satisfactory results, the analogous reaction of 5.3.9 is a generally inefficient method for the preparation of spiropiperidine 5.3.10 (Scheme 5.6).68 In the case of 5.2.1, the presence of the dimethoxy phenyl linker evidently predisposes the oxazoline and the phenolic segment in a favorable relative position for effi-cient capture of the electrophilic species arising through oxidative activation of the phenol.  Scheme 5.6. Spiropyrrolidines and spiropiperidines examples.  Compound 5.3.1 cyclizes upon acid treatment, giving 5.3.2 as single diastereoisomer (Scheme 5.5). The structure of this compound was firmly established by X-ray single-crystal diffractometry (Figure 5.1), whereupon it became apparent that the aza-spiro stereocenter 69  has the (R)-configuration characteristic of many Erythrina alkaloids. Stereorelay from the serine fragment to the spirocenter thus occurred with perfect fidelity. The stereochemical outcome of this step may be understood by recognizing that groups adjacent to the nitrogen atom in the N-acylmorpholine unit of 5.3.2 favor an axial position,64 so as to minimize nonbonding interactions with the N-acyl group. Assuming that cyclization occurs via a chair-like transition state, then 5.3.2 forms via conformer 5.3.4, where the COOMe (depicted in 5.3.4 and 5.3.3 as E, Scheme 5.5) is pseudoaxial in the developing morpholine. The diastereomer of 5.3.2 would result via 5.3.3, wherein the pseudoequatorial COOMe is compressed against the N-acyl group.   Figure 5.1. ORTEP diagram of 5.3.2.        70  Hydrogenation of 5.3.2 afforded ketone 5.3.11 (Scheme 5.7) and denied the molecule any opportunity for loss of configuration at the spiro center. In principle, the five-membered ring of the target alkaloids could be created from two of the serine carbons in 5.3.11. However, numerous difficulties arose during attempts in that sense, leading to the conclusion that it was the best to excise the serine portion altogether.   Scheme 5.7. Catalytic reduction of 5.3.2.  5.4 Cleavage of the Serine unit  Our original plan envisioned the elaboration of 5.3.11 to 5.4.3, a practical precursor of the target alkaloids, through a double retro-Michael reaction followed by acidic hydrolysis of dehydroamino acid ester 5.4.2 (Scheme 5.8). However, it was rapidly evident that such transformation was not possible. Thus, 5.3.11 quickly decomposed upon exposure to basic reagents such as DBU.    Scheme 5.8. Strategy for conversion of 5.3.11 into 5.4.3 via retro-Michael.  71  As an alternative, we refocused on a sequence involving Curtius rearrangement of acid 5.4.4, hydrolysis, and reductive removal of a CH2CHO fragment from 5.4.7 (Scheme 5.9).  Substrate 5.3.11 proved to be sensitive to the action of basic reagents, so long as the ke-tone was present in unprotected form. Mild treatment of 5.3.11 with aqueous LiOH caused decomposition of our material. This necessitated protection of the ketone functionality as a 1,3-dioxolane derivative at this stage of the synthesis.    Scheme 5.9. Proposed pathway through Curtius rearrangement.  Ketalization of 5.3.11 and ester saponification afforded acid 5.4.9. The reaction of the lat-ter with DPPA and Et3N in refluxing toluene, followed by attempted capture of the presumed isocyanate intermediate with t-BuOH, delivered 5.4.10 as the sole isolated product in 7% yield (Scheme 5.10).  72   Scheme 5.10. Attempted Curtius rearrangement of acid 5.4.9.  In light of work by VanNieuwenhze and collaborators,69 such an outcome was not en-tirely surprising. Indeed, these workers reported that N-acetyl amino acid moieties can be oxidatively decarboxylated using DPPA and base (Scheme 5.11 and Table 5.1; for the pre-sumed mechanism see Scheme 5.12, page 71) or excess of Pb(OAc)4 in conjunction with Cu(OAc)2. However, neither of the mentioned condition led to satisfactory yields (Table 5.1).  Scheme 5.11. Oxidative decarboxylation by VanNieuwenhze’s group.69      73  Entry Conditions % yield 1 DPPA, TEA, toluene, 94 °C, overnight 10-12% Z 2 DPPA, DABCO, 1,4-dioxane, 94 °C, overnight 25-30% Z 3 1. Pb(OAc)4 (1.0 equiv.), Cu(OAc)2 (1.0 equiv.) , pyr, THF, 0-25 °C, 3 h 2. TEA in EtOAc N.R. 4 1. Pb(OAc)4 (5.0 equiv.), Cu(OAc)2 (5 equiv.), pyr (excess), THF, 0-25 °C, 3 h 2. TEA in EtOAc 25-30 % Z Table 5.1. Results from VanNieuwenhze and co-workers.69  A plausible mechanism for the formation of 5.4.10 envisions the reversible dissocia-tion of isocyanate 5.4.13 into acyliminium ion 5.4.14 and isocyanate ion, which then is depro-tonated to form 5.4.10 (Scheme 5.12).    Scheme 5.12. Possible mechanism for the formation of 5.4.10.  5.4.10 appeared to be a better candidate than aldehyde 5.3.7 for the synthesis of  amidoalcohol 5.4.8 (or its derivatives); an oxidative cleavage of the double bond would immediately deliver the anticipated amidoalcohol. It should be noted that the DPPA protocol is more attractive than alternative methods that effect the same transformation, in that it delivers the enamide in one step and avoids the use of transition or heavy metals. Indeed, 74  such alternatives require two steps from the acid and involve oxidative decarboxylation by electrochemical means,70 by reaction with Pb(IV)71 or I(III)72 reagents, or by photolysis of N-nitroso derivatives,71 as well as Ni- or Pd-mediated dehydrocarbonylation of thioesters.74,75  For these reasons, our attention was pointed towards the improvement of the yield of 5.4.10. The first modification was the solvent. In accord with VanNieuwenhze,76 operation in dioxane, instead of toluene,77 afforded a slightly greater amount of 5.4.10, although the major product remained 5.4.13 (Scheme 5.13).  Scheme 5.13. Optimization studies for formation of 5.4.10.  The addition of DBU to a mixture of 5.4.13 and 5.4.10 thus obtained, and continued refluxing, induced conversion of 5.4.13 into 5.4.10 (reaction monitored by 1H NMR, Figure 5.2).         75                       starting acid 5.4.9                        crude acylazide 5.4.15  Slowly formation of 5.4.10      Figure 5.2. Monitoring the formation of 5.4.13 and conversion into 5.4.10 by 1H NMR.  It is unlikely that isocyanate ion acts as a leaving group in E2 reactions.78 We pre-sume that the axial N=C=O group can depart with assistance from the lactam N atom by thermal activation of 5.4.13, forming acyliminium ion 5.4.14 (Scheme 5.12), deprotonation of which then gives 5.4.10. Notice that, the use of more polar dioxane in lieu of toluene is likely to favor this dissociative step. On the basis of the foregoing, acid 5.4.9 was elaborated to 5.4.10 in 59% yield by reaction with DDPA and Et3N in dioxane (rt, 1 h), followed by dilution (concentration from 0.2 M to 0.05 M, reflux 2 h), addition of DBU and further refluxing for 2 h (Scheme 5.14).  76   Scheme 5.14. Final procedure for the conversion of 5.4.9 into 5.4.10.  The unsaturated morpholine ring can be cleaved easily with OsO4 and NMO. This Upjohn-type osmylation79 prompted the release of the ethylene bridge, presumably as glyoxal, leading to lactam 5.4.16. Subsequent reduction with BH3•SMe2 afforded the desired aminoalcohol 5.4.17 (Scheme 5.15).   Scheme 5.15. Preparation of aminoalcohol 5.4.17.   It is worthwhile to highlight that amide 5.4.16 should facilitate access to Erythrina alkaloids in which additional oxygen functionalities, or a double bond, are present on the piperidine ring, such as 5.4.18-5.4.22 (Figure 5.3).80 Therefore, lactam 5.4.16 may be regarded as a “universal” precursor of such alkaloids.81 77   Figure 5.3. Highly oxygenated erythrinanes and cogenerates.  For the purpose of the present study, however, the lactam carbonyl was superfluous. Consequently, 5.4.16 was advanced to aminoalcohol 5.4.17 by reduction of with BH3•SMe2 (Scheme 5.15).   5.5 Construction of B-ring and completion of (+)-3-demethoxyerythratidinone  With amino alcohol 5.4.17 in hand, we now focused on the creation of ring B via a sequence encompassing N-acetylation, oxidation of the alcohol to a ketone, and intramolecu-lar aldol condensation to furnish 5.5.1 (Scheme 5.16).   Scheme 5.16. Envisioned completion of (+)-5.5.2.  Surprisingly, the nitrogen atom in 5.4.17 displayed a noteworthy lack of nucleophilic reactivity, arguably due to a combination of steric (the N atom occupies a neopentylic-like 78  position) and electronic (its nucleophilic character is inductively reduced by the neighboring OH group) effects, as well as to a possible presence of an intramolecular H-bond with the OH group. Thus, all attempts to induce N-acylation failed, resulting only is OH group esterifi-cation (Table 5.2).   Scheme 5.17. Results from the acetylation reactions.  Entry Reagent Solvent Temperature (C°) 5.5.3 (% yield) 5.5.4 (% yield) 1 Ac2O (1.20 equiv.), DMAP (0.20 equiv.), Et3N (3.00 equiv.) DCM 20 0 97 2 Ac2O (3.00 equiv.), DMAP (1.10 equiv.), pyr (6.00 equiv.) DCE 70 0 0 3 Ac2O (4.00 equiv.), DMAP (1.10 equiv.) 1:1  THF/pyr 20 0 96 4 AcCl (3.00 equiv.), iPr2NEt (6.00 equiv.) DCM 20 0 98 5 Ac2O (5.00 equiv.), DMAP (0.50 equiv.), iPr2NEt (10.0 equiv.) DCM 20 0 97 6 Ac2O (3.00 equiv.), DMAP (0.20 equiv.), iPr2NEt (6.00 equiv.) DCM 40 0 0 7 DMAP (2.20 equiv.) 1:1 Ac2O/ iPr2NEt 20 0 45 Table 5.2. Conditions for N-Acylation of 5.4.17. 79    In a like vein, attempts to promote acyl group ON migration from esters of 5.5.4 were unfruitful. Moreover, formation of a cyclic carbamate 5.5.5 and subsequent treatment with MeLi,82 led also to the undesired O-acylated product 5.5.4 (Scheme 5.18).   Scheme 5.18. Attempts at formal N-acylation of 5.4.17.  The remarkably poor N-nucleophilicity of 5.4.17 led to the surmise that it may be possible to oxidize the OH group to a ketone without interference from the nitrogen functionality, which could thus be left unprotected. To our delight, this proved to be the case; Swern oxidation of 5.4.17 returned the desired amino ketone 5.5.6. However, the latter was not the only product of the reaction. Indeed, by far, the major product was the rearranged lactam 5.5.7. (Scheme 5.19). It was clearly essential to suppress the formation of 5.5.7, and for that purpose, it was necessary to gain insight on how such a material might arise.   Scheme 5.19. Initial attempt of Swern oxidation of aminoalcohol 5.4.17. 80   The formation of lactam 5.5.7 was envisioned to involve the fragmentation reaction depicted in Scheme 5.20. Cyclization of iminoaldehyde 5.5.9 to 5.5.10 then sets the stage for further oxidation to 5.5.7.    Scheme 5.20. Proposed mechanism for the formation of 5.5.7.  Numerous experiments revealed a direct correlation between the time during which a solution of amino alcohol 5.4.17 and preformed Swern reagent was stirred at –78 °C prior to the final addition of Et3N and the extent of formation of 5.5.7; the longer the time, the more 5.5.7 is produced (however, we never attempted to obtain compound 5.5.7 as a single product). This suggested that the fragmentation of 5.5.8 to 5.5.9 occurs before the addition of the base. We were thus able to suppress the formation of unsaturated lactam 5.5.7 by simultaneous addition of amino alcohol 5.4.17 and Et3N to preformed Swern reagent at –78 °C. This modified Swern protocol afforded the desired amino ketone 5.5.6 in 96% yield. Amino ketone 5.5.6 isomerized rapidly to enone form 5.5.12 via retro-Michael cleavage of the dioxolane ring (see appendix for NMR data, page 165), especially upon exposure to acidic agents. For instance, filtration through silica gel resulted in quantitative 81  conversion to the amino enone 5.5.12 (Scheme 5.21). Because of the tendency of 5.5.6 to isomerize to 5.5.12, it was best to use the crude product of Swern oxidation in subsequent operations.   Scheme 5.21. Isomerization of 5.5.6 into enone 5.5.12.  Unlike 5.4.17, ketone 5.5.6 readily underwent N-acylation, suggesting that H-bond between the lone pair of the N atom and the neighboring OH was the cause of abnormal lack of nucleophilic reactivity of the N atom in the corresponding aminoalcohol.  The final sequence of the synthesis retraced work by Kitagawa, and started with the acylation of 5.5.6 with phosphonate reagent 5.5.13, followed by in situ treatment with aqueous KOH.83 An intramolecular Wadswoth-Emmons reaction ensued, which led to a mixture of readily separable lactams 5.5.14 and 5.5.15 (Scheme 5.22). The mixture of 5.5.14 and 5.5.15 was carried throughout the rest of the synthesis (separation of 5.5.14 and 5.5.15 was performed only for characterization purposes). Thus, selective reduction of the lactam with AlH3·NEtMe2, followed by hydrolysis of the ketal, occurred with concomitant migration of the double bond into conjugation with the keto carbonyl to afford fully synthetic (+)-3-demethoxyerythratidinone, 5.5.2. All the spectroscopic data are consistent with reported literature.84 This work represents the second asymmetric total synthesis of the natural (+)-5.5.2.85 82  Scheme 5.22. Completion of the synthesis of (+)-5.5.2.  This synthesis expands the scope of oxidative amidation chemistry in several respects. First, previous reports from our group68 reported difficulties in the synthesis of spiropiperidines by oxidative cyclization of appropriate phenolic substrates. This work demonstrates that spiropiperidines become accessible if appropriate conformational constraints are imposed upon the substrate. Second, it shows that what was initially as an unwanted side reaction, namely the spontaneous Michael cyclization of compounds of the typo 5.1.2, can actually be harnessed to produce valuable entantiopure building blocks that would be more difficult to prepare otherwise. Third, it provides advanced synthetic intermediates that can be elaborated to diverse Erythrina alkaloids, thus embodying a unified approach to these natural products. This is especially apparent from the next Chapter, which describes the total synthesis of (+)-erysotramidine.   83  Chapter 6 Total synthesis of (+)-erysotramidine  6.1 Amino ketone 5.5.6 as a common intermediate  In the previous chapter, we mentioned the tendency of amino ketone 5.5.6 to undergo isomerization to the corresponding amino enone 5.5.12 upon standing in deuterated chloroform (see NMR spectra in appendix) or upon filtration on silica gel (Scheme 6.1). This isomerization was seized in advantage for the completion of the synthesis of (+)-erysotramidine 6.1.1. The details of this strategy will be discussed in this Chapter.   Scheme 6.1. Isomerization of 5.5.6 into enone 5.5.12.   Compound 5.5.12 appeared to be a good intermediate for a synthesis of (+)-erysotramidine, 6.1.1. Indeed, 5.5.12 should be amenable to elaboration into 6.1.1, which could be processed of as illustrated earlier for 5.5.6 to afford Padwa’s erysotramidine precur-sor, 6.1.2. The latter may be advanced to 6.1.1 in two straightforward steps (Scheme 6.2).  84   Scheme 6.2. Retrosynthetic analysis for (+)-6.1.1.  The free alcohol in 5.5.12 was protected as a TBDPS ether, and the emerging 6.1.3 was subjected to reductive conditions to reach 6.1.4. Hydrogenation of 6.1.3 was unfruitful and only starting material was recovered or decomposition was observed at high pressure (100 psi). Attempts to induce a 1,4 reduction of 6.1.3 with Selectride reagents led a complex mixture which was difficult to analyze.    Scheme 6.3. First attempts of reduction of enone 6.1.3. 85    On the other hand, reduction with lithium in liquid ammonia produced a mixture of readily separable compounds 6.1.6 (43% yield, mixture of diastereomers) and 6.1.5  (29% yield). The latter presumably arises through -elimination of the monoprotected ethylene gly-col segment from the enolate of 6.1.6 generated during the reduction (Scheme 6.4).   Scheme 6.4. Metal in ammonia reduction for the synthesis of 6.1.6 and 6.1.5.   As depicted in 6.1.6, the TBDPS-group underwent Birch reduction in the course of this step. However, this was inconsequential, because for the purpose of our studies the mix-ture of diastereomers of 6.1.6 was treated with t-BuOK, resulting in rapid conversion into 6.1.5. (Scheme 6.5) 86   Scheme 6.5. Retro-Michael of 6.1.6.   6.2 Completion of (+)-erysotramidine  The amino group in 6.1.5 was acylated with phosphonate 6.2.1, this time by employ-ing DCC as a coupling reagent. When the reaction was complete, aqueous KOH was added to induce the final intramolecular Wadsworth-Emmons reaction leading to Padwa’s erysotramidine intermediate, 6.1.2 (Scheme 6.6).86   87   Scheme 6.6. Final steps for the synthesis of (+)-6.1.1.   As demonstrated by Padwa, this lactam underwent diasteoselective allylic oxidation with SeO2. A final O-methylation of the resulting alcohol according to a known procedure86 yielded the target alkaloid 6.1.1. This work represents the fourth enantioselective synthesis of 6.1.1.  In summary, amino ketone 5.5.6 served also as a valuable intermediate for the syn-theses of (+)-erysotramidine. As alluded to earlier, a number of other Erythrina alkaloids could be prepared from the same precursor, reinforcing the notion that the present work con-stitutes a unified approach to that class of alkaloids. Furthermore, the chemistry could be adapted to the synthesis of other interesting natural products possessing a spiropiperidine core.   88  Summary and conclusion  In the first part of this thesis dissertation, efforts towards himandrine have been dis-cussed and several of synthetic solutions have been reported. The approach based on oxi-dative amidation- intramolecular Diels-alder sequence has been validated for complex sub-strates such as 3.2.31 (Scheme 3.21, page 48). An improvement to the forehead mentioned sequence has been accomplished by using β-silyl acrolein 3.2.23 as electrophile for the crea-tion of the diene, needed during the DA reaction. An enantioselective route toward (-)-himandrine has been described. 1,4-Rh(I) cata-lyzed conjugate addition to serine-derived acrylate has been tested. Surprisingly the addition proceeded in an anti-mode (relatively to the N group), representing an exception compared to similar results obtained with Cu- or Pd- catalysis. This work suggests the need of a thor-ough investigation on Rh-catalyzed 1,4-addition to γ/δ-N/O-α-β-unsaturated carbonyl deriva-tives in order to understand reaction pathways and predict stereochemical outcomes.  Future efforts will be dedicated to identify the appropriate pre-catalyst for the intramo-lecular Stetter reaction for the creation of the C ring. Ongoing studies are trying to under-stand the degree of substrate-directed induction during the conjugate addition, with the aim of designing a suitable synthetic plan for the completion of (-)-himandrine. In the second part, oxidative amidation technology has been extended to the domain of Erythrina alkaloids. Scheme 7.1 and Scheme 8.1 summarize the whole synthesis. The fact that the method is employed at a very early stage of the sequence leading to the targets demonstrates its ability to sustain efforts toward the total synthesis of molecules of compara-ble complexity.  We described a unified strategy for these alkaloids, relying on oxidative dearomatiza-tion of phenols- highly diastereoselective intramolecular Michael addition sequence. This strategy devised in our laboratories addresses the need of new tactics for desymmetrization of dienones in modern chemistry. 89   Scheme 7.1. Summary of the total synthesis of (+)-3-demethoxyerythratidinone. 90  We reported an unprecedented high yielding oxidative decarboxylation under Curtius-Schmidt conditions. The observations reported helped us to refine reaction conditions crucial for the ultimate targets, demonstrating that this reaction can be a valuable alternative to ex-pensive and more toxic reagents and also be able to sustain a multistep synthesis.   Scheme 8.1. Summary of the total synthesis of (+)-erysotramidine.  In conclusion, a significant dimension of the work described herein is that oxidative amidation represents a tool for aza-spirocyclic compounds and their analogues using easy reaction procedures and inexpensive reagents.    91  References [1]  Review: Hager, A.; Vrielink, N. ; Hager, D.; Lefranc, J.; Trauner, D. Nat. Prod. Rep., 2016, 33, 491. [2] Review: Nugent, T. C. Chiral Amine Synthesis, 2010, Ed. Wiley-VCH: Weinheim, Germany. [3]   (a) Ciufolini, M. A.; Canesi, S.; Ousmer, M.; Braun, N. A. Tetrahedron, 2006, 62, 5318. (b) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthe-sis, 2007, 3759. (c) Liang, H.; Ciufolini, M. A. Tetrahedron, 2010, 66, 5884. [4]   Reviews: (a) Ciufolini, M. A.; Canesi, S.; Ousmer, M.;. Braun, N. A Tetrahedron,  2006, 62, 5318. (b) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis, 2007, 3759. (c) Liang, H.; Ciufolini, M. A. Tetrahedron,  2010, 66, 5884. [5]  Review: Tohma, H.; Kita, Y. Adv. Synth. Catal., 2004, 346, 111-124. [6]  Shuklov, I. A.; Dubrovinaa, N. V.; Börner, A. Synthesis, 2007, 19, 2925. [7]  Kesavan, V.; Bonnet-Delpon, D.; Bégué, J. P. Tetrahedron Lett., 2000, 41, 2895. [8]  Decken, A.; Eisnor, C. R.; Gossage, R. A.; Jackson, S. M. Inorganica Chimica Acta, 2006, 359, 1743. [9]  Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc,. 2001, 123, 7534. [10] (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem., 1987, 52, 3927. (b) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J. Org. Chem., 1991, 56, 435. [11]  (a) Knapp, S.; Gibson, F. S. Org. Synth., 1992, 70, 101. (b) Knapp, S. In Advances in Heterocyclic Natural Product Synthesis, Vol. 3; Pearson, W. H., Ed.; JAP Press: Greenwich CT, 1996, Chapter 2. [12]  Braun, N. A.; Ousmer, M.; Bray, J. D.; Bouchu, D.; Peters, K.; Peters, E.; Ciufolini, M. A. J. Org. Chem., 2000, 65, 4397. 92  [13]  Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew. Chem. Int. Ed., 2004, 43, 4336. [14]  (a) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem. Int. Ed., 2000, 39, 4593. (b) Mizutani, H.; Takayama, J.; Honda, T. Synlett , 2005, 328. [15]  (a) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M. A. Tetrahedron Lett., 2002, 43, 5193. (b) Liang, H.; Ciufolini, M. A. Chem. Eur. J., 2010, 16, 13262. (c) Jain, N.; Ciufolini, M. A. Synlett, 2015, 26, 631. (d) Wang, X. Msc Dissertation University of British Co-lumbia, 2017. [16]  Liang, H.; Ciufolini, M. A. Chem. Eur. J., 2010, 16, 13262. [17]  Liang, H.; Ciufolini, M. A. Tetrahedron, 2010, 66, 5884. [18]  Xu, S.; Ciufolini, M. A. Org. Lett., 2015, 17, 2424. [19] (a) Cecchi, L.; De Sarlo, F.; Machetti, F. Chem. Eur. J.,  2008, 14, 7903. (b) Guideri, L.; De Sarlo, F.; Machetti, F. Chem. Eur. J., 2013, 19, 665. [20] Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510. [21]  (a) Binns, S. V.; Dustan, P. J.; Guise, G. B.; Holder, G. M.; Hollis, A. F.; McCredie, R. S.; Pinhey, J. T.; Prager, R. H.; Rasmussen, M.; Ritchie, E.; Taylor, W. C. Aust. J. Chem., 1965, 18, 569. (b) Guise, G. B.; Mander. L. N.; Prager, R. H.; Rasmussen, M.; Ritchie, E.; Taylor, W. C. Aust. J. Chem., 1967, 20, 1029. [22]  Willis, A. C.; O’Connor, P. D.; Taylor, W. C.; Mander, L. N. Aust. J. Chem., 2006, 59, 629. [23]  (a) Chackalamannil, S.; Doller, D.; McQuade, R.; Ruperto, V. Bioorg. Med. Chem. Lett., 2004, 14, 3967. (b) Zaks, A.; Tamarez, M.; Li, T. Adv. Synth. Catal., 2009, 351, 2351 (c) Chackalamannil, S. et al. J. Med. Chem. 2008, 51, 3061. [24]  (a) Cobbin, L. B.; Thorp. R. H. Aust. J. Exp. Biol. Med. Sci., 1957, 35, 15. (b) Miller, J. H.; Aagaard, P. J.; Gibson, V. A.; McKinney, M. J. Pharmacol. Exp. Ther., 1992, 263, 663. [25]  O’Connor, P. D.; Mander, L. N.; McLachlan, M. M. W. Org. Lett., 2004, 6, 703. 93  [26]  (a) Movassaghi, M.; Tjandra, M.; Qi, J. J. Am. Chem. Soc., 2009, 131, 9648. (b) Mo-vassaghi, M.; Chen, B. Angew. Chem. Int. Ed., 2007, 46, 565. [27]  Kasahara, T.; Ciufolini, M. A. Can. J. Chem., 2013, 91, 82. [28]  Kasahara, T. Ph.D. Dissertation University of British Columbia, 2015. [29]  From experimental of Kasahara, T. Ph.D. Dissertation University of British Columbia, 2015. [30]  (a) Ciufolini, M. A.; Chan, B. K. Heterocycles, 2007, 74, 101. (b) For a similar process, see: Danishefsky, S.; Bednarski, M. Tetrahedron Lett., 1984, 25, 721. [31]  Tozer, M.; Woolford, A. J. A.; Linney, I. D. Synlett, 1998, 186. [32]  Lebeuf, R.; Hirano, K.; Glorius, F. Org. Lett. 2008, 10, 4243. [33]  Garner, P.; Park, J. M. Org. Synth., 1992, 70, 18. [34]  Review: Krause, N.; Gerold, A. Angew. Chem. Int. Ed., 1997, 36, 186. [35]  Review: Yamamoto, Y. Angew. Chem. Int. Ed., 1986, 25, 947. (a) Lipshutz, B. H.; Ellsworth, E. L.; Siahaan, T. J. J. Am. Chem. Soc., 1989, 111, 1351. (b) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H. J. Am. Chem. Soc., 1990, 112, 5869. (c) Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc., 1984, 106, 3693. (d) Roush, W. R.; Lesur, B. M. Tetrahe-dron Lett., 1983, 24, 2231. (e) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J. Am. Chem. Soc., 1981, 103, 1224. (f) Ziegler, F. E.; Gilligan, P. J. J. Org. Chem., 1981, 46, 3874. (g) Nemoto, H.; Ando, M.; Fukumoto, K. Tetrahedron Lett., 1990,31, 6205. (h) Larcheveque, M.; Tama-gan, G.; Petit, Y. J. Chem. Soc. Chem. Comm., 1989, 31. (i) Reetz, M. T.; Rohrig, D. Angew. Chem. Int. Ed., 1989, 28, 1706. (j) Iako, Uiber, P.; Mann, A.; Taddei, M.; Wermuth, C. G., Tetrahedron Lett., 1990, 31, 1011. (k) Cardani, S.; Poli, G.; Scolastico, C.; Villa, R. Tetrahedron, 1988, 44, 5929. (l) Ibuka, T.; Nakao, T.; Nishii, S.; Yamamoto, Y. J. Am. Chem. Soc., 1986, 108, 7420.  [36]  Yamamoto, Y.; Maruyama, K. J. Am. Chem. Soc., 1978, 100, 3240. 94  [37]  (a) Lessard, J.; Saunders, J. K.; Viet, M. T. P. Tetrahedron Lett., 1982, 23, 2059. (b) Stork, G.; Kahn, M. Tetrahedron Lett., 1983, 24, 3951. [38]  Hanessian, S.; Sumi, K. Synthesis, 1991, 1083. [39]  Reetz, M. T.; Röhrig, D. Angew. Chem. Int. Ed., 1989, 12, 1706. [40]  Cluzeau, J.; Lubell, W. D. J. Org. Chem., 2004, 69, 1504. [41]  (a) Singh, P.; Manna, S. K.; Panda, G. Tetrahedron, 2014, 70, 1363. (b) Karjalainen, O. K.; Koskinen, A. M. P. Org. Biomol. Chem., 2011, 9, 1231. (c) Karjalainen, O. K.; Passiniemy, M.; Koskinen, A. M. P. Org. Lett., 2010, 12, 1145. (d) Guaragna, A.; D’Alonzo, D.; Paolella, C.; Palumbo, G. Tetrahedron Lett., 2009, 50, 2045. (e) Pearson, M. S. M.; Evain, M.; Mathe-Allainmat, M.; Lebreton, J. Eur. J. Org. Chem., 2007, 4888. (f) Guaragna, A.; D’Errico, S.; D’Alonzo, D.; Pedatella, S.; Palumbo, G. Org. Lett., 2007, 9, 3473. (g) Takahata, H.; Banba, Y.; Sasatani, M.; Nemoto, H.; Kato, A.; Adachi, I. Tetrahedron, 2004, 60, 8199. (h) Takahata, H.; Banba, Y.; Ouchi, H.; Nemato, H. Org. Lett., 2003, 5, 2527. (i) Altenbach, H. J.; Himmeldirk, K. Tetrahedron: Asymmetry, 1995, 6, 1077. (j) Dondoni, A.; Merino, P.; Perrone, D. Tetrahedron, 1993, 49, 2939. (k) Bera, S.; Mondal, D.; Singh, M.; Kale, R. K. Tetrahedron, 2013, 3, 969. [42]  Roscales, S.; Sánchez, F., Csákÿ, A. G., Eur. J. Org. Chem., 2005, 1754. [43]  Results with this substrate are described in Kasahara, T. Ph.D. Dissertation Universi-ty of British Columbia, 2015. [44]  (a) Tamao, K.; Akita, M.; Kumada, M. J. Organomet. Chem., 1983, 254, 13. (b) Flem-ing, I.; Henning, R.; Plaut, H. J. Chem. Soc. Chem. Commun., 1984, 29. (c) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett., 1987, 28, 4229.  [45]  (a) Lowe, J. T.; Youngsaye, W.; Panek, J. S. J. Org. Chem., 2006, 71, 3639. (b) Su, Q.; Dakin, L. A.; Panek, J. S. J. Org. Chem., 2007, 72, 2. [46]  Synthesis of this compound is described in Kasahara, T. Ph.D. Dissertation University of British Columbia, 2015. 95  [47]  Grieco, P. A.; Markworth, C. J. Tetrahedron Lett., 1999, 40, 665. [48]  Reviews: (i) Mӧhlmann, L.; Ludwig, S.; Blechert, S. Beilstein J. Org. Chem. 2013, 9, 602. (ii) de Sarkar, S.; Biswas, A.; Samanta, R. C.; Studer, A. Chem. Eur. J. 2013, 19, 4664. (a) Chiang, P.-C.; Bode, J. W. Org. Lett. 2011, 13, 2422. (b) Liu, Y.-K.; Li, R.; Yue, L.; Li, B. J.; Chen, Y. C.; Wu, Y.; Ding, L. S. Org. Lett., 2006, 8, 1521. (c) Maji, B.; Vedachalan, S.; Ge, X.; Cai, S.; Liu, X. W. J. Org. Chem., 2011, 76, 3016. (d) Bortolini, O.; Chiappe, C.; Fogagnolo, M.; Giovannini, P. P.; Massi, A.; Pomelli, C. S.; Ragno, D. Chem. Commun., 2014, 50, 2008. [49]  Reviews: (a) Parsons, A.; Palframan, M. J., in The Alkaloids: chemistry and biology, Cordell, G. A., Ed.; Academic Press: Chennai, 2010; Vol 68, 39. (b) Reimann, E. Prog. Chem. Org. Nat., 2007, 88, 1. (c) Bentley, K. W. Nat. Prod. Rep. 2004, 21, 395. (d) Sano, T.; Tsuda, Y. In The Alkaloids; Cordell, G. A., Ed., Academic Press: New York, NY, 1996; Vol. 48, 249. [50]  Syntheses of racemic 3-demethoxyerythratidinone: (a) Tanaka, H.; Shibata, M.; Ito, K. Chem. Pharm. Bull., 1984, 32, 1578. (b) Tsuda, Y.; Nakai, A.; Ito, K.; Suzuki, F.; Haruna, M. Heterocycles, 1984, 22, 1817. (c) Danishefsky, S. J.; Panek, J. S. J. Am. Chem. Soc., 1987, 109, 917. (d) Ishibashi, H.; Sato, T.; Takahashi, M.; Hayashi, M.; Ikeda, M. Heterocycles, 1988, 27, 2787. (e) Irie, H.; Shibata, K.; Matsuno, K.; Zhang, Y. Heterocycles, 1989, 29, 1033. (f) Wasserman, H. H.; Amici, R. M. J. Org. Chem., 1989, 54, 5843. (g) Ishibashi, H.; Sato, T.; Takahashi, M.; Hayashi, M.; Ishikawa, K.; Ikeda, M. Chem. Pharm. Bull., 1990, 38, 907. (h) Tsuda, Y.; Sakai, Y.; Nakai, A.; Kaneko, M.; Ishiguro, Y.; Isobe, K.; Taga, J.; Sano, T. Chem. Pharm. Bull., 1990, 38, 1462. (i) Cassayre, J.; Quiclet-Sire, B.; Saunier, J. B.; Zard, S. Z. Tet-rahedron Lett., 1998, 39, 8995. (j) Chikaoka, S.; Toyao, A.; Ogasawara, M.; Tamura, O.; Ishibashi, H. J. Org. Chem., 2003, 68, 312. (k) Wang, Q.; Padwa, A. Org. Lett., 2006, 8, 601. (l) Gao, S.; Tu, Y. Q.; Hu, X.; Wang, S.; Hua, R.; Jiang, Y.; Zhao, Y.; Fan, X.; Zhang, S. Org. Lett., 2006, 8, 2373. (m) Padwa, A.; Wang, Q. J. Org. Chem., 2006, 71, 7391. (n) Liang, J.; Chen, J.; Liu, J.; Li, L.; Zhang, H. Chem. Commun., 2010, 46, 3666. (o) Tuan, L. A.; Kim, G. 96  Bull. Korean Chem. Soc., 2010, 31, 1800. (p) Pan, Z. Q.; Liang, J. X.; Chen, J. B.; Yang, X. D.; Zhang, H. B. Nat. Prod. Bioprospect., 2011, 1, 129. (q) Heller, S. T.; Kiho, T.; Narayan, A. R. H.; Sarpong, R. Angew. Chem. Int. Ed,  2013, 52, 11129. (r) Xu, R. Q.; Gu, Q.; Wu, W. T.; Zhao, Z. A.; You, S. L. J. Am. Chem. Soc., 2014, 136, 15469. Syntheses of racemic erysotramidine: (a) Ito, K.; Suzuki, F.; Mitsumasa, H. J. Chem. Soc., Chem. Commun., 1978, 733. (b) Sano, T.; Toda, J.; Kashiwaba, N.; Ohshima, T.; Tsuda, Y. Chem. Pharm. Bull., 1987, 35, 479. (c) Lee, H. I.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A. Org. Lett., 2003, 5, 5067. (d) Padwa, A.; Lee, H. I.; Rashatasakhon, P.; Rose, M. J. Org. Chem., 2004, 69, 8209. (e) Gao, S.; Tu, Y. Q.; Hu, X.; Wang, S.; Hua, R.; Jiang, Y.; Zhao, U.; Fan, X.; Zhang, S. Org. Lett., 2006, 8, 2373. (f) L’Homme, C.; Menard, M. A.; Canesi, S. J. Org. Chem., 2014, 79, 8481. Enantioselective synthesis and synthetic studies of 3-demethoxyerythratidinone and erytrosamidine: (a) Hosoi, S.; Ishida, K.; Sangai, M.; Tsuda, Y. Chem. Pharm. Bull., 1992, 40, 3115. (b) Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko, C.; Sano, T. Chem. Pharm. Bull., 1993, 41, 2087 (c) Tsuda, Y.; Hosoi, S.; Ishida, K.; Sangai, M. Chem. Pharm. Bull., 1994, 42, 204. (d) Zhang, F.; Simpkins, N. S.; Wilson, C. Tetrahedron Lett., 2007, 48, 5, 942. (e) Blake, A. J.; Gill, C.; Greenhalgh, D. A.; Simpkins, N. S.; Zhang, F. Synthesis, 2005, 19, 3287. (f) Zhang, F.; Simpkins, N. S.; Blake, A. J. Org. Biomol. Chem., 2009, 7, 1963. (g) Moon, J. T.; Jung, J. A.; Ha, S. H.; Song, S. H.; Park, S. J.; Kim, J.; Choo, D. J.; Lee, Y. S.; Lee, J. Y. Synth. Commun., 2011, 41, 1282. (h) Allin, S. M.; Streetley, G. B.; M. Slater, M.; James, S. L.; Martin, W. P. Tetrahedron Lett., 2004, 45, 5493. (i) Gaskell, S. N.; Duffy, L. J.; Allin, S. M. Nat. Prod. Commun., 2008, 3, 1825. (j) Tietze, L. F.; Tölle, N.; Kratzert, D.; Stalke, D. Org. Lett., 2009, 11, 5230 (k) Yasui, Y.; Suzuki, K.; Matsumoto, T. Synlett, 2004, 619. (l) Chuang, K. V.; Navarro, R.; Reisman, S. E. Chem. Sci., 2011, 2, 1086. (m) Mostowicz, D.; Dygas, M.; Kaluza, Z. J. Org. Chem., 2015, 80, 1957. [51]  Maier, H. U.; Rödl, W.; Deus-Neumann, B., Zenk, M. H, Phytochemistry, 1999, 52, 373. 97  [52] Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko, C.; Sano, T. Chem. Pharm. Bull., 1993, 41, 2087. [53]   Danishefsky, S. J.; Kitahara, T. J. Am. Chem. Soc., 1974, 96, 7807. [54] Matsuno, K.; Sera, A. Synthesis, 1985, 999. [55]  (a) Blake, A. J.; Gill, C.; Greenhalgh, D. A.; Simpkins, N. S.; Zhang, F. Synthesis, 2005, 19, 3287. (b) Zhang, F.; Simpkins, N. S.; Blake, A. J. Org. Biomol. Chem., 2009, 7, 1963. [56] Reviews: (a) De Koning, H.; Speckamp, W. N. Methods Org. Chem., Houben-Weyl, 1995, vol. E21b Stereoselective Synthesis, 1953. (b) De Koning, H.; Moolenaar, M. J.; Hi-emstra, H.; Speckamp, W. N. Studies in Natural Products Chemistry: Bioactive Natural Prod-ucts, Part A Ed. Atta-ur-Rahman, F. Z. Basha, Elsevier, Amsterdam, 1993, vol. 13, 473. (c) Hiemstra, H. W. N. Speckamp, in Comprehensive Organic Synthesis: Additions to C-C π-Bonds, Part 2 Ed. C. H. Heathcock, Pergamon Press, Oxford, 1991, vol. 2, 1047. [57] Padwa, A.; Lee, H. I.; Rashatasakhon, P.; Rose, M. J. Org. Chem., 2004, 69, 8209. [58] Mostowicz, D.; Dygas, M.; Kaluza, Z. J. Org. Chem., 2015, 80, 1957. [59] Chuang, K. V.; Navarro, R.; Reisman, S. E. Chem. Sci., 2011, 2, 1086. [60] (a) Ellman, J. A.; Cogan, D. A. J. Am. Chem. Soc., 1999, 121, 268. (b) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev., 2010, 110, 3600. [61] Tsuda, Y.; Hosoi, S.; Ishida, K.; Sangai, M. Chem Pharm Bull, 1994 42, 204. [62] Reviews: (a) Ciufolini, M. A.; Canesi, S.; Ousmer, M.;. Braun, N. A Tetrahedron, 2006, 62, 5318. (b) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Syn-thesis, 2007, 3759. (c) Liang, H.; Ciufolini, M. A. Tetrahedron, 2010, 66, 5884. [63] Braun, N. A.; Ousmer, M.; Bray, J. D.; Bouchu, D.; Peters, K.; Peters., E.-M.; Ciufolini, M. A. J. Org. Chem., 2000, 65, 4397. [64] This avoids a severe nonbonding interactions with the amide carbonyl group, even at the cost of a syn-pentane-like interaction with other axial substituents: (a) Chow, Y. L.; Colon, 98  C. J.; Tan, J. N. S. Can. J. Chem., 1968, 46, 2821. (b) Lunazzi, L.; Cerioni, G.; Foresti, E.; Macciantelli, D. J. Chem. Soc., Perkin Trans. 2, 1980, 717. See also: (c) Johnson, F. Chem. Rev., 1968, 68, 375. [65] For this terminology see; Mislow, K, Siegel, J. J. Am. Chem. Soc., 1984, 106, 3319. [66]  Previous examples: (a) Kasahara, T.; Ciufolini, M. A. Can. J. Chem., 2013, 91, 82. (b) Liang, H.; Ciufolini, M. A. Chem. Eur. J., 2010, 16, 13262. (c) Mendelsohn, B. A.; Ciufolini, M. A. Org. Lett., 2009, 11, 4736. (d) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.; Ciufolini, M. A. Org. Lett., 2009, 11, 1539. (e) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew. Chem., Int. Ed.,  2004, 43, 4336; Angew. Chem. 2004, 116, 4436. [67] Wipf, P.; Miller, C. P. Tetrahedron Lett., 1992, 33, 907. (b) Wipf, P.; Miller, C. P. J. Org. Chem., 1993, 58, 1575. (c) Wipf, P.; Miller, C. P. Tetrahedron Lett., 1992, 6267. (d) Wipf, P.; Hayes, G. B. Tetrahedron, 1998, 54, 6987. (e) Wipf, P.; Venkatram, S. Tetrahedron Lett., 1996, 37, 4659. (f) Philips, A. J.; Uto, Y.; Wipf, P.; Reno, M.; Williams D. R. Org. Lett., 2000, 8, 1165-1168. (f) Conditions: either Burgess reagent, THF, reflux ( 54% over 2 steps) or De-oxofluor, CH2Cl2, -20 °C ( 63% over 2 steps). [68]  Braun, N. A.; Ousmer, M.; Bray, J. D.; Bouchu, D.; Peters, K.; Peters, E.; Ciufolini, M. A., J. Org. Chem., 2000, 65, 4397. [69] Carrillo, A. K.; VanNieuwenhze, M. S. Org. Lett., 2012, 14, 1034. [70] Horikawa, H.; Iwasaki, T.; Matsumoto, K.; Miyoshi, M. J. Org. Chem., 1978, 43, 335. [71] (a) Chu, K. S.; Negrete, G. R.; Konopelski, J. P.; Lakner, F. J.; Woo, N. T.; Olmstead, M. M. J. Am. Chem. Soc., 1992, 114, 1800. (b) Wang, X.; Porco, J. A., Jr. J. Org. Chem., 2001, 66, 8215. (c) Ghosez, L.; Yang, G.; Cagnon, J. R.; Le Bideau, F.; Marchand-Brynaert, J. Tetrahedron, 2004, 60, 7591. [72] Simpkins, L. M.; Bolton, S.; Pi, Z.; Sutton, J. C.; Kwon, C.; Zhao, G.; Magnin, D. R.; Augeri, D. J.; Gungor, T.; Rotella, D. P.; Sun, Z.; Liu, Y.; Slusarchyk, W. S.; Marcinkeviciene, 99  J.; Robertson, J. G.; Wang, A.; Robl, J. A.; Atwal, K. S.; Zahler, R. L.; Parker, R. A.; Kirby, M. S.; Hamann, L. G. Bioorg. Med. Chem. Lett., 2007, 17, 7476. [73] Chow, Y. L.; Polo, J. S. J. Chem. Soc., Perkin Trans. 2, 1986, 727. [74]  (a) Goto, T.; Onaka, M.; Mukaiyama, T. Chem. Lett., 1980, 9709. (b) Min, G. K.; Her-nandez, D.; Lindhardt, A. T.; Skrydstrup, T. Org. Lett., 2010, 12, 4716. [75] Reactions related to those of ref. 72: (a) Goossen, L. S.; Rodriguez, N. Chem. Com-mun., 2004, 724. (b) Le Notre, J.; Scott, E.L.; Franssen, M. C. R.; Sanders, J. P. M. Tetrahe-dron Lett., 2010, 51, 3712. (c) Liu, Y.; Kim, K. E.; Herbert, M. B.; Fedorov, A.; Grubbs, R. H.; Stoltz, B. M. Adv. Synth. Catal., 2014, 356, 130. [76] Carrillo, A. K.; VanNieuwenhze, M. S. Org. Lett., 2012, 14, 1034. [77]  (a) Martin-Lopez, M. J.; Bermejo-Gonzalez, F. Tetrahedron Lett., 1994, 35, 4235. (b) Martin-Lopez, M. J.; Bermejo-Gonzalez, F. Tetrahedron Lett., 1994, 35, 8843. [78]  The pKa of H-NCO ≈ 3.5: Perrin, D. D. Ionization Constants of Inorganic Acids and Bases in Aqueous Solution, 2nd Ed., Pergamon Press, Oxford, UK, 1982. [79]  VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett., 1976, 17, 1973. [80]  (a) Juma, B. F.; Majinda, R. R. T. Phytochemistry, 2004, 65, 1397. (b) Tanaka, H.; Hattori, H.; Tanaka, T.; Sakai, E.; Tanaka, N.; Kulkarni, A.; Etoh, H. J. Nat. Med., 2008, 62, 228. [81]  Solid precedent exists for the conversion of a valerolactam into a Δ2,3-piperidine [e.g.: (a) Hwang, Y. C.; Chu, M.; Fowler, F. W. J. Org. Chem., 1985, 50, 3885. (b) Ebner, T.; Meese, C. O.; Lackner, H.; Remberg, G. Liebigs Ann. Chem., 1989, 1989, 197. (c) Achenbach, H.; Dûthorn, B.; Weibel, R. Liebigs Ann. Chem., 1992, 1992, 1159. (d) Suarez del Villar, I.; Gradillas, A.; Perez-Castells, J. Eur. J. Org. Chem., 2010, 2010, 5850. (e) Lancefield, C. S.; Zhou, L.; Lébi, T.; Slawin, A. M. Z.; Westwood, N. J. Org. Lett., 2012, 14, 6166. (f) Gigant, N.; Chausset-Bossaire, L.; Belhomme, M.-C.; Poisson, T.; Pannecoucke, X.; Gillaizeau, I. Org. Lett., 2013, 15, 278. ] or a 3-hydroxypiperidine [e.g.: (g) Burgess, L. E.; 100  Gross, E. K. M.; Jurka, J. Tetrahedron Lett., 1996, 37, 3255. (h) Johnson, T. A.; Jang, D. O.; Slafer, B. W.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc., 2002, 124, 11689. (i) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am. Chem. Soc., 2006, 128, 10596 ]. [82]  Inspired by Nicolau, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Nature, 1994, 367, 630. [83] Zhang, Y.; Takeda, S.; Kitagawa, T.; Irie, H. Heterocycles, 1986, 24, 2151. [84] Amer, M. E.; Shamma, M., Freyer, A. J. Nat. Prod., 1991, 54, 329. [85] The third enantioselective synthesis, considering Reisman’s synthesis of (-)-3-demethoxyerythratidinone. [86] Padwa, A.; Lee, H. I.; Rashatasakhon, P.; Rose, M. J. Org. Chem., 2004, 69, 8209.   101  APPENDIX A. Experimental protocols Melting points are uncorrected. Unless otherwise stated, 1H (300 MHz) and 13C NMR (75 MHz) spectra were recorded at room temperature in CDCl3 solutions. Chemical shifts are re-ported in parts per million (ppm) on the δ scale and coupling constants, J, are in hertz (Hz). Multiplicities are reported as “s” (singlet), “d” (doublet), “dd” (doublet of doublets), “ddd” (dou-blet of doublets of doublets), “t” (triplet), “q” (quartet), “quin” (quintuplet), “sex” (sextet), “m” (multiplet), and further qualified as “app” (apparent) and “br” (broad). Infrared (IR) spectra (cm–1) were recorded from solution in CHCl3. Low– and high-resolution mass spectra (m/z) were obtained in the electrospray (ESI) mode. Optical rotations were measured at the sodi-um D line (589 nm). All reagents and solvents were commercial products and used without further purification except THF, Et2O and 1,4-dioxane (both freshly distilled from Na/benzophenone under Ar) and Et3N and CH2Cl2 (freshly distilled from CaH2 under Ar). Flash chromatography was performed on Silicycle 230-400 mesh silica gel. Analytic and pre-parative TLC was carried out with Merck silica gel 60 plates with fluorescent indicator. Spots were visualized with UV light. X-ray crystal measurements were made on a Bruker APEX DUO diffractometer by Dr. Brian Patrick of UBC.   102  B. Preparation of substrates employed in the present study experimental section  Compound 3.1.20 A round bottom flask was charged with acrylate 3.1.5 (73 mg, 244 µmol), freshly washed Amberlyst-15(H) (100 mg) in MeOH  (2.4 mL, 0.1 M). The reaction was stirred for 6 hours at rt, then filtered through Celite and rinsed with MeOH (2 x 2mL). The filtrate was concentrated under vacuum. The obtained oil was redissolved in DMF (1.2 mL, 0.2 M). Imidazole (65 mg, 960 µmol, 4.0 equiv.) and TIPSCl (100 µL, 480 µmol, 2.0 equiv.) were added and the reaction was allowed to stir for 16h at rt. The reaction was quenched with aq. HCl 0.5 M (3mL) and Et2O (6 mL) was added. The organic layer was separated and the aqueous layer was extracted with Et2O (2 x 5 mL). The combined organic fractions were dried (Na2SO4) and concentrated under re-duced pressure and purified by flash column chromatography on silica gel  (EtOAc/hexanes 5:95) to give 3.1.20 (67 mg, 48% yield over 2 steps) as a colorless oil, Rf= 0.32 (EtOAc/hexanes 1:9), [α]D24= +6.8 (c 5.0, CHCl3). 1H: 6.94 (dd, J= 7.5, 15.7, 1H), 5.87 (d, J= 15.7, 1H), 4.74 (app d, J= 7.1, 1H), 3.79-3.67 (m, 3H), 3.71 (s, 3H), 2.56-2.38 (m, 2H), 1.42 (s, 9H), 1.05 (br s, 21H). 13C: 166.3, 155.1, 145.3, 123.1, 79.0, 64.5, 51.2, 34.4, 28.1, 17.7, 11.7. IR: 2944, 2866, 1713, 1169. MS: 416 [M + H+]. HRMS: calcd for C21H42NO5Si [M + H+]: 416.2815; found 416.2778.  Compound 3.1.22 A solution of 3.1.20 (67 mg, 161 µmol) in 1,4-dioxane (0.90 mL, 0.2M) was purged with an argon balloon. At rt, solid [ClRh(COD)2]2 (1 mg, 2.42 µmol, 0.03 equiv.) was added and the reaction mixture was heated at 100 °C for 10 min. The solution was allowed to cool 103  down, then aryl boronic acid 3.1.211 (59 mg, 320 µmol, 2.0 equiv.) and a solution of Cs2CO3 (150 mg, 480 µmol, 3.0 equiv.) in water (100µL) were added and the solution was heated at reflux for 5 h. After having let the reaction cool down to rt, water (2 mL) and Et2O (2 mL) were added. The organic layer was separated and aqueous layer was extracted with Et2O (3 x 2 mL). The combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure and purified by flash column chromatography on silica gel (EtOAc/hexanes 1:9) to give 3.1.22 (82 mg, 93% yield) as colorless oil as 1:1 mixture of diastereomers, Rf= 0.35 (EtOAc/hexanes 1:9; stains bright red with p-anisaldehyde), [α]D24=+11.1 (c 1.0, CHCl3). 1H (a+b): 7.13-7.08 (m, 2H), 6.96-6.92 (m, 2H), 5.13 (s, 2H), 3.67-3.45 (m, 8H), 3.21-3.13 (m, 1H), 2.7-2.46 (m, 2H), 1.92-1.8 (m, 2H), 1.40 (s, 9H), 1.07-1.00 (m, 21H). 13C  (a+b): 172.7, 172.3, 156.0, 155.9, 155.3, 136.6, 128.5, 128.3, 116.4, 116.3, 94.5, 79.0, 65.7, 64.4, 56.0, 55.9, 51.5, 51.4, 50.0, 41.9, 41.6, 38.3, 38.0, 37.1, 28.4, 24.8, 17.7, 12.3, 11.9, 11.8, 11.5. IR: 2943, 2866, 1738, 1713, 1111. MS: 554 [M + H+]. HRMS: calcd for C29H52NO7Si [M + H+]: 554.3445; found 554.3444.  Compound 3.1.23 Compound 3.1.22 (24 mg, 43 µmol) was dissolved in 1:1 TFA/CH2Cl2 (1 mL, 0.05M) and stirred for 20 min at rt. The reaction was slowly quenched with aq. sat. K2CO3 (5 mL) and diluted with CH2Cl2 (5 mL). The organic layer was separated and aqueous layer was extracted with CH2Cl2 (3 x 2 mL). The combined organic fractions were dried (Na2SO4) and concentrated and purified by flash column chromatography on silica gel (EtOAc/hexanes/MeOH 49:50:1) to give 3.1.23 (12 mg, 75% yield) as a white foam, Rf= 0.51 (EtOAc/hexanes/MeOH 49:50:1) as 1:1 mixture of diastereomers, [α]D25= -14.8 (c 0.76, CHCl3). 1H (a+b): 7.02 (d, J= 7.5, 4H), 6.82 (d, J= 7.5, 4H), 6.40 (s, 1Ha), 6.31 (s 1Hb), 3.80-                                                          1 Selepe, M. A.; Drewes, S. E.; van Heerden, F. R., J. Nat. Prod., 2010, 73, 1680. 104  3.43 (m, 8H a+b), 3.24 (br s, 1Ha), 3.03 (app t, J= 12.0, 1Hb), 2.72-2.34 (m, 4H a+b), 2.01-1.77 (m, 4H a+b) 1.50-1.40 (m, 2H, a+b) 1.08-1.03 (m, 42 H a+b). 13C (a+b): 172.7, 172.3, 154.8, 154.7, 133.8, 128.6, 128.3, 115.7, 115.6, 64.8, 62.9, 51.7, 51.6, 50.0, 42.5, 41.5, 38.5, 37.8, 35.8, 29.7, 17.8, 17.7, 12.3, 11.8. IR: 3200, 2942, 1646, 1516. MS: 376 [M -H]-. HRMS: calcd for C21H34NO3Si [M - H]- : 376.2403; found 376.2410.   Compound 3.1.24 A solution of acrylate 3.1.5 (160 mg, 535 µmol) in 1,4-dioxane (2.4 mL, 0.2 M) was purged with an argon balloon. At rt, solid [ClRh(COD)2]2 (4 mg, 8.02 µmol, 0.03 equiv.) was added and the reaction mixture was heated at 100 °C for 10 min. The solution was allowed to cool down, then aryl boronic acid 3.1.21 (190 mg, 1.1 mmol, 2.0 equiv.) and a so-lution of Cs2CO3 (523 mg, 1.6 mmol, 3.0 equiv.) in water (200 µL) were added and the solu-tion was heated at reflux for 5 h. After having let the reaction cool down to rt, water (3 mL) and Et2O (3 mL) were added. The organic layer was separated and aqueous layer was ex-tracted with Et2O (3 x 3 mL). The combined organic fractions were dried (Na2SO4) and con-centrated and purified by flash column chromatography on silica gel (EtOAc/hexanes 1:4) to give 3.1.24 (150 mg, 67% yield) as colorless oil, Rf= 0.33 (EtOAc/hexanes 1:4), [α]D25= +12.1 (c 0.2, CHCl3). 1H  (at 80 °C toluene-d8, 400MHz): 7.07-6.9 (m, 4H), 4.84 (s, 2H), 3.77-3.48 (m, 2H), 3.30 (s, 3H), 3.18 (s, 3H), 2.61-2.4 (m, 2H), 2.18-2.10 (m, 3H), 1.82-1.75 (m, 1H), 1.47-1.35 (m, 15H). 13C (at 80 °C toluene-d8, 100MHz) 172.4, 172.0, 157.1, 152.1, 137.7, 117.1, 95.0, 79.6, 67.9, 57.4, 55.6, 51.0, 42.8, 41.8, 40.4, 39.6, 28.8, 28.4. IR: 2941, 2856, 1710, 1118. MS: 460 [M + Na+]. HRMS: calcd for C23H35NO7Na [M + Na+]: 460.2701; found 460.2707. And recovered starting material 3.1.5 (16 mg, 10% yield).  105  Compound 3.1.25 Compound 3.1.24 (113 mg, 2.58 µmol) was dissolved in 1:1 TFA/CH2Cl2 (5.2 mL, 0.05M) and stirred for 16 h at rt. The reaction was slowly quenched with aq. sat. K2CO3 (12 mL) and diluted with CH2Cl2 (15 mL). The organic layer was separated and aqueous layer was extracted with CH2Cl2 (3 x 8 mL). The combined organic fractions were dried (Na2SO4) and concentrated to provide a brown crude oil. This oil was redissolved in DMF (1.3 mL, 0.2 M) and solid imidazole (141 mg, 2.06 mmol, 8.0 equiv.) was added. Then TBDPSCl (270 µL, 1.03 mmol, 4.0 equiv.) was added and the reaction was stirred at rt until consumption of starting material (monitored by TLC). Then the reaction was quenched with aq. 1.0 M HCl (5 mL) and diluted with EtOAc (15 mL). The organic layer was separated and aqueous layer was extracted with EtOAc (3 x 6 mL). The combined organic fractions were dried (Na2SO4) and concentrated and purified by flash column chromatog-raphy on silica gel (EtOAc/hexanes 6:4) yielding 3.1.25 as colorless oil (80 mg, 67% over two steps) Rf= 0.43 (EtOAc/hexanes 7:3), [α]D25= -33.4 (c 0.4, EtOH). 1H: 7.68-7.64 (m, 4H), 7.47-7.39 (m, 6H), 7.00 (d, J= 7.2, 1H), 6.80 (d, J= 7.2, 1H), 6.52 (s, 1H) 3.75-3.68 (m, 2H), 3.52 (app t, J= 10.8, 1H), 3.02 (app t, J= 10.8, 1H), 2.68 (dd, J= 3.6, 18.0, 1H), 2.38 (dd, J= 12.2, 17.3, 1H), 1.89 (app d, J= 12.2, 1H), 1.42 (app d, J= 12.2, 1H), 1.09 (s, 9H). 13C: 172.3, 155.1, 135.5, 134.7, 132.7, 132.6, 130.0, 127.9, 127.4, 115.7, 67.6, 54.6, 39.4, 37.0, 32.1, 26.8, 19.2. IR: 3470, 2870, 1698, 1121. MS: 460 [M + H+ ]. HRMS: calcd for C28H33NO3SiNa [M + Na+]: 482.2271; found 482.2269.      106  Compound 3.1.26 A round bottom flask was charged with freshly recrystallized 18-crown-6 (1.70 g, 6.40 mmol, 5.0 equiv.) and Still-Gennari reagent2 (432 mg, 1.35 mmol, 1.2 equiv.) in 1:1 mixture toluene/THF (2.3 mL, 0.5 M). The reaction was cooled down to -78 °C, then a 0.5 M solution of KHMDS in toluene (3.8 mL, 1.90 mmol, 1.5 equiv.) was slowly added dropwise via syringe into the reaction flask. After 30 minutes, a solution of 3.1.15 (275 mg, 1.13 mmol) in THF (1 mL) was added and the reaction was monitored by TLC analysis. When the starting material appeared to be con-sumed, a 1.0 M solution of AcOH in THF (2 mL) was added, followed by EtOAc (3 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 3 mL). The combined organic fractions were dried (Na2SO4), concentrated under vacuum and puri-fied by flash column chromatography on silica gel (EtOAc/hexanes 5:95) affording 3.1.26 (200 mg, 53% yield) Rf: 0.11 (EtOAc/hexanes 5:95); [α]D25= -33.1 (c 0.21, toluene). 1H: 6.21 (app d, J= 10.4, 1H), 5.87 (d, J= 10.4, 1H), 4.11-3.93 (m, 2H), 3.74-3.70 (m, 1H), 3.70 (s, 3H), 3.12-2.98 (m, 2H), 1.60-1.46 (m, 15 H). 13C (toluene-d8): 166.1, 152.1, 144.9, 124.1, 79.7, 67.1, 56.9, 50.8, 28.7, 28.6, 27.4. IR: 2980, 1726, 1694,  1376, 1364. MS: 322 [M + Na+]. HRMS: calcd for C15H25NO5Na [M + Na+]: 322.1630; found 322.1629. Also the E-isomer 3.1.5 (18 mg, 9% yield) was isolated.   Compound 3.1.32 A round bottom flask was charged with acrylate 3.1.5 (73 mg, 240 µmol), freshly washed Amberlyst-15(H) (110 mg) in MeOH (2.4 mL, 0.1 M).  The reaction was stirred for 6 hours at rt, then filtered through Celite and rinsed with MeOH (2 x 2mL). The filtrate was concentrated under vacuum. The                                                           2  Still, W. C.; Gennari, C. Tetrahedron Lett., 1983, 24, 4405. 107  obtained oil was redissolved in DMF (1.2 mL, 0.2 M). Imidazole (65 mg, 960 µmol, 4.0 equiv.) and TBDPSCl (100 µL, 480 µmol, 2.0 equiv.) were added and the reaction was allowed to stir for 16 h at rt. The reaction was quenched with aq. HCl 0.5 M (3 mL) and Et2O (6 mL) was added. The organic layer was separated and the aqueous layer was extracted with Et2O (2 x 5 mL). The combined organic fractions were dried (Na2SO4) and concentrated under vacuum. The obtained colorless oil was dissolved in CH2Cl2 (600 µL, 0.4 M), then TFA (600 µL) was added at 0 °C. The reaction was stirred for 15 min, after which starting material judged to be consumed via TLC analysis. The reaction was quenched with sat. aq. Na2CO3 (3 mL) and then diluted with CH2Cl2 (3 mL). The organic layer was separated and aqueous layer was ex-tracted with CH2Cl2 (3 x 3 mL). The combined organic fractions were dried (Na2SO4) and concentrated and purified by flash column chromatography on silica gel (EtOAc) affording 3.1.32 as an orange oil (39 mg, 54% yield over three steps) Rf= 0.55 (EtOAc). [α]D21= +25.2 (c 0.1, CHCl3). 1H: 7.68-7.66 (m, 4H), 7.46-7.38 (m, 6H), 6.95 (dt, J= 15.4, 7.5, 1H), 5.9 (d, J= 15.4, 1H), 3.74 s, 3H), 3.63-3.50 (m, 2H), 3.09-3.01 (m, 1H), 2.46-2.38 (m, 1H), 2.26-2.16 (m, 1H), 1.09 (s, 9H). 13C: 166.7, 146.1, 135.5, 133.3, 129.8, 127.8, 123.2, 68.4, 52.1, 51.5, 37.0, 26.9, 19.3. IR: 3566, 3491, 1719, 1121. MS: 398 [M + H+]. HRMS: calcd for C23H32NO3Si [M + H+]: 398.4511; found 398.4511.          108   Compound 3.2.26 Compound 3.2.253 (700 mg, 1.08 mmol) was dissolved in THF (1 mL, 1.0 M) under anhydrous condition and inert atmosphere. The solution was cooled down to -78 °C and a solution of t-BuOK in THF (1 mL, 2.00 equiv., 1.1 M) was slowly added dropwise via sy-ringe. The reaction was stirred for 0.5 h at -78 °C, then a solution of aldehyde 3.2.23 (309 mg, 1.62 mmol, 1.5 equiv.) in THF (1 mL) was added. After 1 h at -78 °C, an excess of t-BuOK in THF (2 mL, 4.0 equiv, 1.1 M) was added and the reaction was allowed to warm up to rt and then heated at 45 °C for 16 h. The reaction was quenched with aq. HCl (5 mL, 0.05 M) and diluted with EtOAc (5 mL). The organic layer was separated and aqueous layer was extracted with EtOAc (3 x 6 mL). The combined organic fractions were dried (Na2SO4) and concentrated and rapidly filtered through a pad of silica gel (ca. 1 g) and eluted with EtOAc/hexanes 1:1 (3 x10 mL). The filtrate was concentrated to obtain a crude product (460 mg, 73% crude yield) pure enough for the next step. Rf= 0.2 (EtOAc/hexanes 1:9).   Compound 3.2.20 Phenol 3.2.26 (260 mg, 450 µmol) was dissolved in CH2Cl2 (2 mL, 0.22 M) and slowly added via syringe into a round bottom flask previously loaded with DIB (174 mg, 540 µmol, 1.2 equiv.),                                                           3 Synthesis of this compound is described in Kasahara, T. Ph.D. Dissertation University of British Co-lumbia, 2015.  109  TFA (20 µL, 270 µmol, 0.5 equiv. Vs DIB) and CH2Cl2 (2.5 mL, 0.22 M). When the addition was completed, the reaction was quenched with sat. aq. NaHCO3 (4 mL) and diluted with EtOAc (6 mL). The organic layer was separated and aqueous layer was extracted with EtOAc (3 x 6 mL). The combined organic fractions were dried (Na2SO4) and concentrated to afford a dark oil. This oil was dissolved in toluene (9 mL, 0.05 M) and heated at reflux for 8 h. Then the reaction was cooled down, the solvent was evaporated under reduced pressure and the oil was purified by flash column chromatography on silica gel (EtOAc/hexanes 1:4) affording 3.2.20 as orange oil (132 mg, 51% yield after three steps), Rf= 0.33 (EtOAc/hexanes 1:4). 1H: 7.56-7.51 (m, 2H), 7.42-7.36 (m, 3H), 6.56 (d, J= 11.0, 1H), 6.26 (app d, J= 9.1, 1H), 6.09 (d, J= 11.0, 1H), 5.95 (app d, J= 9.1, 1H), 4.57 (app t, J= 6.5, 1H), 3.82 (app dd, J= 2.7, 12.1, 1H), 3.70 (app q, J= 5.8, 11.6, 2H), 3.35 (dd, J= 8.5, 12.0, 1H), 2.92 (dd, J= 4.4, 8.8, 1H), 2.63-2.53 (m, 3H), 2.44 (d, J= 1.9, 1H), 2.15-2.10 (m, 1H), 1.78 (app q, J= 6.2, 12.3, 2H), 1.60 (m, 1H), 0.90 (s, 9H), 0.56 (s, 3H), 0.44 (s, 3H), 0.10-0.05 (m, 6H). 13C: 196.3, 145.6, 139.6, 133.9, 133.7, 133.6, 133.5, 129.9, 128.9, 128.2, 127.9, 127.8, 118.7, 113.3, 82.3, 72.5, 69.4, 60.6, 57.3, 51.4, 48.9, 48.4, 43.3, 38.3, 32.5, 25.9, 18.2, 1.0, -2.3, -3.6, -5.3. IR: 3377, 3054, 1692, 1121. MS: 604 [M + Na+]. HRMS: calcd for C31H43NO4SSiNa [M + Na+]: 604.3522; found 604.3530.    Compound 3.2.29 Decalone 3.2.20 (100 mg, 170 µmol) was dissolved in MeCN (0.60 mL, 0.3 M). Then NaI (2 mg, 17.1 µmol, 0.1 equiv.), water (3 µL, 170 µmol, 1.0 equiv.) and TMSCl (4 µL, 34.4 µmol, 0.2 equiv.) were add-ed in the respective order. The reaction was stirred for 20 min and 110  then quenched with sat. aq. NaHCO3 (2 mL) and diluted with EtOAc (2 mL). The organic lay-er was separated and aqueous layer was extracted with EtOAc (3 x 2 mL). The combined organic fractions were dried (Na2SO4) and concentrated to afford a brown oil which was used for the next step without further purification. The crude was dissolved in CH2Cl2 (1 mL, 0.2 M) under inert and anhydrous atmosphere. Solid DMP (115 mg, 270 µmol, 1.6 equiv.) was add-ed at 0 °C. The reaction was allowed to stir at rt for 1 h and then quenched with sat. aq. Na-HCO3 (2 mL) and diluted with CH2Cl2 (2 mL). The organic layer was separated and aqueous layer was extracted with CH2Cl2 (3 x 2 mL). The combined organic fractions were dried (Na2SO4) and concentrated and purified by flash column chromatography on silica gel (EtOAc/hexanes 1:4  1:1) yielding 3.2.29 as colorless oil (43 mg, 57 % yield over two steps), Rf= 0.66 (EtOAc/hexanes 1:1) as 3:1 mixture of cis and trans diastereomers (ratio was calculated by integration of the relative H-C=CHCO protons). 1H (α+β): 9.69 (s, 1H), 7.54-7.36 (m, 5H), 6.58 (d, J= 9.8, 1Hα), 6.25 (d, J= 9.0, 1Hβ), 6.07-6.00 (m, 2Hα+β), 5.86 (d, J= 9.8, 1Hα) 5.76 (d, J= 9.0, 1Hβ), 4.57 (br s, 2H), 3.95-3.67 (m, 2H), 2.89 (br s, 1H), 2.79 (br s, 1H), 2.61-2.23 (m, 4H), 1.95-1.93 (m, 1H), 0.49 (s, 3H), 0.45 (s, 3H). 13C (α+β): 198.4, 195.5, 144.5, 135.3, 134.0, 133.8, 133.7, 130.0, 128.4, 128.3, 127.7, 113.0, 82.1, 72.7, 72.3, 71.5, 65.8, 64.0, 57.9, 56.7, 51.4, 45.0, 44.9, 44.0, 43.9, 40.9, 40.6, 39.7, 35.6, 29.7, 24.8, 23.9, -2.5, -3.5, -4.1, -4.6. IR: 3277, 2925, 1721, 1692, 1121. MS: 464 [M - H]-. HRMS: calcd for C25H26NO4SSi [M - H]-: 464.0800; found 464.0794.  Compound 3.2.31 A suspension of 3.2.29 (12 mg, 25.1 µmol), Glorius precatalyst 2.4.28 (2 mg, 5.7 µmol, 0.22 equiv.), BHT (1 mg, 1.5 µmol, 0.06 equiv.) in THF (0.26 mL, 0.1M) was prepared in a round bottom flask and purged with Ar for 10 min while being sonicated. To the suspension 111  was added a 0.1 M solution of DBU in THF (52 µL, 5.2 µmol, 0.20 equiv.) to form a red solu-tion. The reaction was stirred for 15 min at rt. The reaction was quenched with sat. aq. NH4Cl (500 µL) and diluted with EtOAc (2 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2 x 2mL). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (EtOAc/hexanes 1:1) gave compound 3.2.31 as a white foam (10 mg, 84%), Rf= 0.32 (EtOAc/hexanes 1:1) as a 6:1 mixute of epimers (ratio was calculated by integration of H-C=C).1H (α+β): 7.53-7.36 (m, 5H), 6.14 (d, J= 9.2, 1H), 5.72 (d, J= 9.2, 1H), 4.55 (brs, 1H), 4.27 (brs, 1H), 3.95-3.67 (m, 1H) 3.48 (d, J= 11.1, 1H), 3.27-2.92 (m, 3H), 2.79 (s, 1H), 2.65-2.18 (m, 5H), 1.86 (appd, J=16.9, 1H) 0.44 (d, J= 18.0, 6H). 13C (α+β): 205.8, 204.7, 177.5, 136.0, 135.8, 134.6, 134.0, 133.8, 133.7, 129.9, 128.8, 128.3, 127.7, 114.5, 114.3, 81.7, 75.7, 75.2, 65.9, 65.8, 56.7, 51.4, 48.1, 44.01, 43.9, 43.4, 40.9, 39.7, 39.6, 35.6, 34.3, 34.1, 32.3, 25.1, 1.0, -3.5, -3.8, -4.1. IR: 3247, 2931, 1765, 1725, 1147. MS: 480 [M - H]-. HRMS: calcd for C25H26NO5SSi [M - H]-: 480.0800; found 480.0798.  Compound 5.2.3 In a similar manner to Pyne et al.,4 thionyl chloride (7.39 mL, 102 mmol, 2.00 equiv.) was added dropwise over 10 minutes from a dry addition funnel to a stirring ice-cold MeOH (100 mL) solution of 3,4-dimethoxyphenylacetic acid (10.0 g, 51.0 mmol) in a dry round bottom flask under argon. After 16 h, the volatiles were removed on a rotary evaporator, the residue redissolved in EtOAc, washed with water (1 x 100 mL), saturated aq. NaHCO3 (1 x 100 mL), brine (1 x 100 mL), dried over Na2SO4 and concentrated on a rotary evaporator to afford a yellow oil as the intermediate methyl ester (11.0 g, 100% crude yield), Rf= 0.45 (EtOAc/hexanes 1:1), which was used without further purification.                                                            4 Taylor, S. R.; Ung, A. T.; Pyne, S. G.; Skelton, B. W.; White, A. H. Tetrahedron, 2007, 63, 11377. 112  The methyl ester was redissolved in MeCN (40 mL) in a round bottom flask under argon and a MeCN (85 mL) solution of N-bromosuccinimide (10.9 g, 61.2 mmol, 1.20 equiv.) was added to it with stirring, while the temperature was maintained with a room temperature water bath. After 16 h of stirring in the dark, the mixture was concentrated on a rotary evaporator, resus-pended in eluent and filtered through silica gel (125 mL) with EtOAc/hexanes 1:1. The filtrate was concentrated to obtain a golden brown oil, which was crystallized from Et2O/hexanes at –20 ºC to afford aryl bromide 5.2.3 (11.7 g, 85% over two steps) as off-white needles in two crops, Rf= 0.42 (EtOAc/hexanes 1:1); mp 65-66 °C ( hexanes/Et2O). 1H: 7.03 (s, 1H), 6.79 (s, 1H), 3.86 (apps, 6H), 3.72 (apps, 5H). 13C: 171.3, 148.8, 148.4, 125.9, 115.4, 114.9, 113.8, 56.2, 56.0, 52.2, 41.0.  1-(benzyloxy)-4-iodobenzene In a similar manner to Botting et al.,5 benzyl bromide (9.00 mL, 75.8 mmol) was added to an Me2CO (225 mL) suspension of 4-iodophenol (20.0 g, 90.9 mmol, 1.20 equiv.) and K2CO3 (62.8 g, 454 mmol, 6.00 equiv.) in round bottom flask, fitted with a condenser and under argon, and the resulting mixture heat-ed at reflux. After 16 h, the mixture was cooled to room temperature, filtered through Celite and concentrated on a rotary evaporator. The resulting pale yellow oil was redissolved in Et2O, washed with aq. 1M NaOH (2 x 100 mL), water (1 x 100 mL), brine (1 x 100 mL), dried ( Na2SO4) and concentrated on a rotary evaporator, leaving a pale yellow oil that crystallized. This was recrystallized from hexanes at –20 ºC to afford 1-(benzyloxy)-4-iodobenzene (22.4 g, 95% yield) as pale yellow crystals, Rf = 0.55 (hexanes/EtOAc 4:1); mp 61-63 °C (hexanes). 1H: 7.57 (d, J = 9.0, 2H), 7.47-7.30 (m, 5H), 7.77 (d, J = 9.0, 2H), 5.04 (s, 2H). 13C: 158.6, 138.2, 136.4, 128.6, 128.1, 127.4, 117.2, 83.0, 70.0.                                                           5 Oldfield, M. F.; Chen, L.; Botting, N. P. Tetrahedron, 2004, 60, 1887.  113  Compound 5.2.7 1-(Benzyloxy)-4-iodobenzene (12.4 g, 40.0 mmol), bis(pinacolato)diboron (12.2 g, 48.0 mmol, 1.20 equiv.), [Pd(OAc)2]3 (330 mg, 4.90 mmol, 0.04 equiv.) and KOAc (11.8 g, 120 mmol, 3.00 equiv.) were added to a dry round bottom flask under argon, followed by DMF (80 mL) and the resulting dark brown suspension was heated at 80 ºC. After stirring for 16 h, the reaction mixture was cooled to room temperature, diluted with Et2O and filtered through Celite. The filtrate was washed with water (3 x 150 mL), brine (1 x 150 mL), dried (Na2SO4) and concen-trated to obtain the crude boronate ester as a yellow semisolid. The crude was redissolved in eluent, filtered through silica gel (100 mL) with hexanes/EtOAc 4:1 and the eluent concen-trated on a rotary evaporator to obtain a pale yellow oil, which was crystallized from hexanes at –20 ºC to afford boronate ester 5.2.7 (10.1 g, 81% yield) as white crystals in two crops, Rf= 0.36 (hexanes/EtOAc 9:1); mp 87-89 °C (hexanes). A small amount of additional material could be obtained by flash column chromatography of the mother liquor. Spectroscopic data is in agreement with the literature.6 1H: 7.70 (d, J = 6.0, 2H), 7.52-7.26 (m, 5H), 7.00 (d, J = 6.6, 2H), 5.10 (s, 2H), 1.34 (s, 12H). 13C: 161.3, 136.8, 136.5, 128.6, 128.0, 127.5, 114.9, 83.6, 69.7, 24.9.    Acid derivative of 5.2.8  A solution of boronate ester 5.2.7 (10.2 g, 33.0 mmol, 1.1 equiv), aryl bromide 5.2.3 (8.7 g, 30.0 mmol), aqueous 2.0 M Na2CO3 (45 mL, 90 mmol, 3.0 equiv) and solid Pd(PPh3)4 (347 mg, 0.33 mmol, 0.01 equiv.) in 1,4-dioxane (75 mL) was purged with Ar and then heated at 80 ºC under argon. After 16 h, the mixture was cooled to rt, diluted with water and extracted                                                           6 Ebisawa, M.; Ueno, M.; Oshima, Y.; Kondo, Y. Tetrahedron Lett., 2007, 48, 8918 114  with Et2O (3 x 100 mL). The combined extracts were sequentially washed with water (1 x 150 mL) and brine (1 x 150 mL), dried (Na2SO4), and concentrated in vacuo. The crude residue was redissolved in hexanes/EtOAc 9:1 and filtered through silica gel (150 mL) with hex-anes/EtOAc 9:1  6:4. The fraction obtained using hexanes/EtOAc 6:4 was concentrated in vacuo to provide 5.2.8 (9.03 g, 76% crude yield), Rf= 0.26 (hexanes/EtOAc 7:3). A solution of the above ester (5.9 g, 15.0 mmol) and LiOH•H2O (755 mg, 18.0 mmol, 1.2 equiv) in 2:1 THF/H2O (30 mL) was stirred at rt for 14 h, then the mixture was acidified to pH 1 (aq. 6M HCl) and extracted with EtOAc (3 x 50 mL). The combined extracts were sequentially washed with water (2 x 50 mL) and brine (1 x 50 mL), dried (Na2SO4) and concentrated in vacuo. The crude yellowish residue was recrystallized from EtOAc/hexanes to afford acid analogue of 5.2.8 (5.6 g, quantitative) as a powdery white solid, mp 118-120 °C, Rf= 0.23 (Me2CO/hexanes/MeOH 58:40:2). 1H: 7.49-7.30 (m, 5H), 7.24 (d, J = 9.3, 2H), 7.01 (d, J = 8.7, 2H), 6.85 (s, 1H), 6.70 (s, 1H), 5.10 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.58 (s, 2H). 13C: 177.6, 158.0, 148.1, 147.9, 136.9, 134.8, 133.5, 130.5, 128.6, 128.0, 127.5, 123.0, 114.6, 113.3, 112.9, 70.1, 56.0, 55.9, 38.0. IR: 3042, 1705, 1503, 1236. MS: 401 [M+Na+]. HRMS: calcd for C23H22O5Na [M+Na+]: 401.1365; found 401.1371.   Benzyl-protected oxazoline 5.2.1  A solution of the acid analogue of 5.2.8 (6.5 g, 16.7 mmol), DCC (3.45 g, 16.7 mmol, 1.0 equiv), and Et3N (3.0 mL, 21.7 mmol, 1.3 equiv) in CH2Cl2 (35 mL, 0.5 M) was stirred at rt, under Ar, for 30 min, then serine methyl ester•HCl (3.1 g, 20.0 mmol, 1.2 equiv) and DMAP (2.65 g, 21.7 mmol, 1.3 equiv) were added. The resulting mixture was stirred at rt for 14 h, then it filtered through Celite. The filtrate was washed with aq. 1M HCl (2 x 50 mL) and water (1 x 50 mL), dried (Na2SO4) and concentrated in vacuo. The yellow semisolid residue was precipitated twice from an EtOAc 115  solution by addition of hexanes. Amide 5.2.9 thus obtained (6.2 g, off-white amorphous solid) was contaminated with dicyclohexylurea (8-18%, 1H NMR). Further purification by chroma-tography caused loss of material. Therefore, compound 5.2.9 was used in the next step with-out further purification. Freshly prepared Burgess reagent7 (4.37 g, 18.3 mmol, 1.1 equiv) was added portion wise over 10 min to a refluxing THF (65 mL, 0.2 M, Ar atmosphere) solu-tion of amide 5.2.9 (6.2 g, 1.0 equiv). Heating was continued for 40 min, then the solution was cooled and evaporated to dryness in vacuo. The yellow-brown oily residue was purified by flash column chromatography (EtOAc/hexanes 60:40  75:25) to afford benzyl-protected oxazoline 5.2.1 (4.3 g, 54% yield over two steps) as a pale yellow oil, Rf= 0.27 (EtOAc/hexanes 7:3), [α]D22= + 68.1° ( c 1.55, CHCl3). 1H: 7.53-7.30 (m, 5H), 7.28 (d, J = 8.4, 2H), 7.02 (d, J = 8.7, 2H), 6.92 (s, 1H), 6.75 (s, 1H), 5.11 (s, 2H), 4.71 (dd, J = 10.8, 7.8, 1H), 4.44 (dd, J = 10.8, 8.6, 1H), 4.36 (dd, J = 10.5, 8.7, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.78, (s, 3H), 3.59 (s, 2H). 13C: 171.7, 169.8, 157.9, 148.1, 147.7, 137.0, 134.3, 133.5, 130.6, 128.6, 128.0, 127.5, 124.1, 114.5, 113.2, 112.2, 70.0, 69.7, 68.0, 56.0, 55.9, 52.6, 31.7. IR: 2960, 1740, 1502, 1235. MS: 462 [M + H+]. HRMS: calcd for C27H28NO6 [M + H+]: 462.1917; found 462.1920.  Compound 5.2.1  A solution of protected oxazoline 5.2.1 (8.3 g, 18.0 mmol) in EtOAc (90 mL, 0.2 M) containing suspended Pd(OH)2/C 10% (2.5 g, 0.18 mmol, 0.1 equiv) was carefully saturated with H2 (caution: flammable; balloon, bubbling) and stirred under H2 at rt for 18 h. The solution was filtered through Celite and the solvent was re-moved in vacuo, affording a bright yellow, oily residue. This material was taken up in EtOAc and filtered through silica gel (250 mL) with more EtOAc. Concentration of the eluate afford-                                                          7 Burgess, E. M.; Penton, H. R.; Taylor, E. A.; Williams, W. M. Org. Synth., 1977, 56, 40. 116  ed 5.2.1 as a bright yellow oil (5.8 g, 86% yield), Rf= 0.19 (EtOAc/hexanes 7:3), [α]D22= + 49.2° (c 0.5, CHCl3). 1H: 7.16 (d, J = 8.4, 2H), 6.91 (s, 1H), 6.82 (d, J = 8.4, 2H), 6.74 (s, 1H), 4.73 (dd, J = 10.5, 7.5, 1H), 4.39 (dd, J = 10.2, 8.7, 1H), 4.36 (dd, J = 10.8, 9.0, 1H), 3.90 ( s, 3H), 3.84 (s, 3H), 3.75, (s, 3H), 3.63 (s, 2H). 13C: 171.4, 170.5, 155.6, 148.0, 147.8, 134.7, 132.5, 130.6, 123.8, 115.2, 113.4, 112.6, 69.9, 67.4, 56.0, 55.9, 52.6, 31.8. IR: 3411, 1742, 1505, 1238, 1210. MS: 372 [M + H+]. HRMS: calcd for C20H22NO6 [M + H+]: 372.1447; found 372.1446.   Compound 5.3.1  A solution of phenol 5.2.1 (2.8 g, 7.5 mmol) in HFIP (38 mL, 0.2 M) was added over 48 min (syringe pump, flow rate = 0.8 mL/min), at rt and under Ar, to a stirred solution of PIFA (3.6 g, 8.3 mmol, 1.1 equiv) in HFIP (38 mL, 0.2 M). After the ad-dition, solid NaHCO3 (1.89 g, 22.5 mmol, 3.0 equiv) was added and the reaction was stirred for another 2 min. Silica gel (ca. 10 g) was added, the solvent was removed in vacuo, and the residual material was loaded on a silica gel (ca. 200 g) column. Elution with EtOAc re-turned dienone 5.3.1 (1.8 g, 62% yield) as a dark orange solid, Rf= 0.32 (EtOAc), mp 165-168 °C (EtOAc/hexane), [α]D22= + 22.6° (c 0.3, CHCl3). 1H: 6.95 (dd, J=8.7, 3.0, 1H), 6.92 (dd, J= 8.7, 3.0, 1H), 6.61 (s, 1H), 6.49 (s, 1H), 6.49 (dd, J= 3.9, 1.9, 1H), 6.32 (dd, J= 3.9, 1.9, 1H), 4.34 (dd, J=6.0, 2.9, 1H), 3.88 (s, 3H), 3.82 (m, 4H) 3.77 (s, 3H), 3.76 (s, 3H). 13C: 184.2, 170.0, 168.8, 150.0, 149.5, 148.9, 148.6, 129.6, 127.8, 123.2, 118.7, 110.2, 108.9, 65.1, 62.1, 60.7, 56.0, 56.0, 52.7, 34.8. IR: 3470, 1739, 1667, 1522. MS: 410 [M + Na+]. HRMS: calcd for C20H21NO7Na [M + Na+]: 410.1216, found 410.1219.     117  Compound 5.3.2  A solution of dienone 5.3.1 (1.8 g, 4.7 mmol) and p-TsOH•H2O (444 mg, 2.3 mmol, 0.5 equiv) in CH2Cl2 (23 mL, 0.2 M) was stirred at rt for 16 h, then it was quenched by the addition of aq. sat. NaHCO3 solution (15 mL; caution: foaming). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2 x 20 mL). The combined organic fractions were dried (Na2SO4) and concentrated in vacuo, and the residue was purified by crystallization from EtOAc/Hex to afford 5.3.2 (1.6 g, 90% yield) as light orange flakes, Rf= 0.41 (EtOAc/hexanes 7:3), mp 121-124 °C (EtOAc/hexanes), [α]D22= – 89.7° (c 0.25, CHCl3). 1H: (600 MHz, CDCl3): 6.90 (dd, J= 10.7, 2.7, 1H), 6.83 (s, 1H), 6.68 (s, 1H), 6.03 (d, J= 10.3, 1H), 5.29 (d, J= 3.7, 1H), 4.53 (d, J= 12.3, 1H), 4.34 (d, J= 2.7, 1H), 3.92 and 3.75 (ABq, JAB= 20.4, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 3.78 (d, J= 3.7, 1H), 3.76 (s, 3H) 3.22 (dd, J= 17.8, 3.2, 1H), 2.90 (dd, J= 17.8, 2.0, 1H). 13C: (150 MHz, CDCl3): 193.9, 170.4, 169.8, 149.8, 148.0, 146.3, 127.0, 124.8, 124.0, 111.1, 108.6, 77.7, 66.3, 60.6, 56.3, 56.0, 52.6, 52.5, 43.1, 36.9. IR: 1743, 1668, 1515. MS: 410 [M + Na+]. HRMS: calcd for C20H21NO7Na [M + Na+] 410.1216, found 410.1214.   Compound 5.3.11 A solution of ketone 5.3.2 (3.6 g, 9.3 mmol) and dried Pd/C 10% (2.6 g, 0.93 mmol, 0.1 equiv) in EtOAc was stirred for 18 h at rt under H2 atmosphere (balloon), then it was filtered through a pad of Celite. The filtrate was evaporated in vacuo and the residue was purified by crystallization from EtOAc/hexanes to afford (3.22 g, 89% yield) of 5.3.11 as bright yellow flakes, Rf= 0.40 (EtOAc), mp 81-84 °C (EtOAc/hexanes), [α]D21= – 78.8° (c 0.65, CHCl3). 1H: 6.72 (s, 1H), 6.59 (s, 1H), 4.80 (d, J= 4.47, 1H), 4.54 (d, J= 12.7, 1H), 4.31 (dd, J= 4.0, 2.3, 1H), 3.92 and 3.62 (ABq, J= 19.3, 2H), 3.88 (s, 3H), 3.83 118  (s, 3H), 3.82 (s, 3H), 3.77 (d, J= 4.5, 1H), 3.29 (dd, J= 17.6, 6.7, 1H), 3.02-2.86 (m, 2H), 3.41 (dt, J= 17.9, 4.0, 1H), 2.20-2.15 (m, 1H), 1.93 (ddd, J= 18.2, 12.6, 5.4, 1H). 13C: 207.4, 171.5, 170.7, 148.8, 147.4, 128.5, 125.0, 111.6, 108.0, 77.2, 67.2, 59.1, 56.3, 56.0,  52.7, 52.6, 47.3, 37.8, 37.3, 28.6. IR: 3015, 1750, 1721, 1654. MS: 390 [M + H+]. HRMS: calcd for C20H23NO7Na [M + Na+]: 412.1372, found 412.1378.     Methyl ester of 5.4.9  A solution of ketone 5.3.11 (1.0 g, 2.6 mmol) and PPTS (132 mg, 0.5 mmol, 0.2 equiv) in 3:1 benzene/ethylene glycol (10 mL, 0.30 M) was stirred at 90 °C for 4 hours, then it was cooled to room temperature, quenched with aq. sat. NaHCO3 solution (10 mL), and partitioned between EtOAc (5 mL) and water (5 mL). The organic layer was separated and washed with water (3 x 10 mL) and brine (1 x 10mL). The aqueous layer was extracted with more EtOAc (2 x 10mL). The combined extracts were dried (Na2SO4) and concentrated under vacuum to afford the corresponding ketal as a white solid, which was recrystallized from EtOH/water to furnish 1.1 g (≈100% yield) of product as an amorphous white solid. Rf= 0.14 (EtOAc/hexanes 7:3), mp 154°-156°C (EtOH/water); [α]D22= –28.7° (c 1.75, CHCl3). 1H: 6.83 (s, 1H), 6.61 (s, 1H), 4.55 (d, J= 4.7, 1H), 4.49 (d, J= 12.2, 1H), 3.95 (m, 2H), 3.85-3.64 (m, 4H) 3.76 (s, 3H), 3.75 (s, 3H),  3.66 (s, 3H), 3.58 and 3.44 (ABq, J = 19.6, 2H), 2.76 (dt J= 14.1, 2.4, 1H), 2.6 (dd, J= 15.7, 4.9, 1H), 2.27(app d, J= 15.7, 1H), 1.84 (app d, J= 13.8, 1H), 1.50 (dd, J= 13.8, 2.7, 1H), 1.09 (dt, J= 14.1, 2.4, 1H). 13C: 171.7, 170.6, 148.6, 147.1, 129.4, 125.7, 111.7, 109.2, 106.4, 77.8, 68.0, 65.0, 60.5, 56.5, 55.9, 53.1, 52.5, 41.6, 38.1, 31.2, 28.3. IR: 1760, 1653, 1514. MS: 434.3 [M + H+]. HRMS: calcd for C22H28NO8 [M + H+] 434.1815, found 434.1812. 119    Compound 5.4.9  A solution of the above ketal (1.1 g, 2.6 mmol) and LiOH·H2O (220 mg, 5.2 mmol, 2.0 equiv) in 1:1 THF/water (10 mL, 0.30 M) was stirred at 50 °C for 3 h, then was cooled to rt and diluted with Et2O (10 mL). The aqueous layer was separated, acidified to pH < 3 with aq. 1.0 M HCl solution, and extracted with EtOAc (3 x 10 mL). The combined extracts were dried (Na2SO4) and concentrated under vacuum to afford acid 5.4.9 (1.0g, 93% yield) as a white solid. This material was of sufficient purity and was used without further purification. An analytical sample was obtained by recrystallization from EtOAc/hexanes to give 5.3.9 as white needles. Rf= 0.19 (EtOAc/MeOH 4:1); mp 131-133 °C (EtOAc/hexanes); [α]D22= – 33.1° (c 4.3, CHCl3). 1H: 6.91 (s, 1H), 6.70 (s, 1H), 4.72 (d, J= 4.5, 1H), 4.66 (d, J= 12.2, 1H), 4.06-4.00 (m, 2H), 3.97-3.56 (m, 6H), 3.58 (s, 3H), 3.84 (s, 3H), 2.87 (app t, J= 12.3, 1H), 2.68 (dd, J= 15.4, 4.4, 1H), 2.2 (app d, J= 15.4, 1H), 1.94 (app d, J= 14.0, 1H), 1.61 (app d, J= 11.5, 1H), 1.2 (app t, J= 11.5, 1H). 13C: 172.4, 171.8, 148.5, 147.0, 129.1, 125.5, 111.8, 109.1, 106.5, 77.6, 67.9, 64.8, 63.8, 60.7, 56.5, 55.9, 52.9, 41.4, 37.9, 31.1, 28.3. IR: 3017, 1755, 1652, 1614. MS: 442.3 [M + Na+]. HRMS: calcd for C21H25NO8Na [M + Na+] 442.1478; found 442.1473.   Compound 5.4.10 A solution of acid 5.4.9 (500 mg, 1.2 mmol), Et3N (0.78 mL, 5.4 mmol, 4.5 equiv) and DPPA (0.77 mL, 3.6 mmol, 3.0 equiv) in dry dioxane (6 mL, 0.2 M) was stirred for 1 h at rt, under Ar, then it was diluted with more dioxane (18 mL, 0.05 M final concentration) and heated to reflux 120°C for 2 hours. Neat DBU (0.54 mL, 3.6 mmol, 3.0 equiv) was added, and refluxing was continued for another 2 h. The cooled solution was concentrated under 120  vacuum and the residue was purified by flash column chromatography on silica gel (EtOAc/hexanes 7:3) to give 5.4.10 (261 g, 59% yield) as a pale yellow oil. Rf= 0.19 (EtOAc/hexanes 7:3), [α]D20= + 7.6° (c 1.0, CHCl3). 1H: 7.03 (s, 1H), 6.83 (d, J= 4.8, 1H), 6.69 (s, 1H), 6.21 (d, J= 4.8, 1H), 4.35 (app s, 1H), 4.14-3.95 (m, 4H), 3.84 and 3.59 (ABq, J= 19.1, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.79 (dd, J= 15.7, 3.6, 1H), 2.53 (app d, J= 15.7, 1H), 2.27 (dt, J= 14.0, 2.5, 1H), 1.90 (dd, J= 13.3, 2.4, 1H), 1.66 (dd, J= 13.3, 2.4, 1H), 1.35 (dt, J= 14.0, 2.5, 1H). 13C: 165.7, 148.6, 147.0, 129.9, 127.0, 125.0, 111.9, 109.3, 106.4, 104.1, 73.7, 64.9, 63.8, 60.5, 56.5, 55.9, 40.5, 38.1, 31.6, 27.8. IR: 2962, 1656, 1519, 1391. MS: 374 [M + H+]. HRMS: calcd for C20H24NO6 [M + H+] 374.1604; found 374.1600.   Compound 5.4.16  A solution of 5.4.10 (208 mg, 0.5 mmol), 4% aq. OsO4 solution (14 µL, 55 µmol, 0.1 equiv) and NMO (135 mg, 1.1 mmol, 2.1 equiv) in 2:1 acetone/water (6 mL, 0.1 M) was stirred overnight at rt. Solid Na2SO3 was added, the reaction mixture was stirred for 30 min, then it was treated with aq. 1.0 M HCl solution (0.1 mL) and diluted with EtOAc (10 mL) and H2O (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (4 x 10 mL). The combined extracts were dried (Na2SO4) and concentrated under vacuum to afford a yellow oil, which was purified by flash chromatography on silica gel (EtOAc/Acetone 50:50→100 acetone) to give 5.4.16 (151 mg, 79%) as a colorless oil. Rf= 0.51 (acetone); [α]D20= + 5.0° (c 0.85, CHCl3). 1H: 7.12 (s, 1H, NH), 6.78 (s, 1H), 6.56 (s, 1H), 4.04 (dd, J= 12.0, 4.9, 1H), 3.98 (app s, 4H), 3.88 (s, 3H), 3.84 (s, 3H), 3.68 and 3.51 (ABq, J= 20.6, 2H), 2.26-1.72 (m, 6H). 13C: 172.5, 148.5, 148.0, 127.7, 124.7, 110.2, 108.2, 107.1, 74.0, 64.44, 64.41, 61.98, 56.2, 55.8, 38.58, 35.42, 33.8, 29.7. IR: 3333, 2939, 1651, 1518. MS: 372 [M + Na+]. HRMS: calculated for C18H23NO6Na [M + Na+] 372.1423; found 372.1420.  121   Compound 5.4.17 Commercial BH3•SMe2 complex (1.0 M in THF, 0.05 mL, 0.53 mmol, 2.5 equiv) was carefully added dropwise via syringe into a cold (0 °C) solution of lactam 5.4.16 (75 g, 0.2 mmol) in dry THF (2.1 mL, 0.1 M), under Ar. The cooling ice bath was removed, the mixture was stirred at rt for 15 min, then it was warmed to 45 °C and stirred at that temperature for 2 h. The mixture was cooled to 0 °C and carefully quenched with aq. 1 M NaOH solution (≈ 2 mL, caution: flammable H2 gas evolved). The solution was diluted with EtOAc (5 mL) and water (5 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (4 x 8 mL) and the combined extracts were dried (Na2SO4) and concentrated under vacuum to afford a colorless oil, which was purified by flash chromatography on silica gel (aq. conc. NH4OH/EtOAc 5:95) to give amino alcohol 5.4.17 (59 mg, 84% yield) as white flakes, mp 174-177 °C (EtOAc/hexanes), Rf= 0.54 (EtOAc/Et3N 9:1), [α]D22 = – 57.2° (c 0.25, CHCl3). 1H: 6.73 (s, 1H), 6.55 (s, 1H), 4.18 (dd, J= 11.4, 5.0, 1H), 4.02-3.96 (m, 4H), 3.87 (s, 3H), 3.84 (s, 3H), 3.20 (dd, J= 12.0, 3.1, 1H). 2.98 (dt, J= 11.7, 3.4, 1H), 2.85 (dt, J= 11.7, 5.2, 1H), 2.56 (app d, J= 14.9, 1H), 2.05-1.78 (m, 5H), 1.61-1.56 (m, 1H). 13C: 147.7, 147.6, 131.3, 129.4, 111.7, 108.6, 108.3, 73.3, 64.4, 64.3, 58.6, 56.2, 55.7, 38.5, 38.4, 32.0, 30.1, 29.6. IR: 3495, 2935, 1514. MS: 336 [M + H+]. HRMS: calcd for C18H26NO5 [M + H+] 336.1811; found 336.1815.        122  Compound 5.5.4 Acetic anhydride (30 µL, 320 µmol, 4.0 equiv.) was added into a solu-tion of amino alcohol 5.4.17 (27 mg, 80 µmol) and DMAP (10 mg, 88 µmol, 1.1 equiv.) in THF/pyr (800 µL, 1:1, 0.1M). The reaction was stirred at rt for 16h. Then sat. aq. K2CO3 (2 mL) was added and the reaction was diluted with EtOAc (3 mL) and water (1 mL). The organic layer was separated the aqueous layer was extracted with more EtOAc (2 x 3 mL). The combined extracts were dried (Na2SO4) and concentrated under vacuum. The colorless crude was redissolved in DCM and filter through a pod of SiO2 (≈ 2mL) and eluted with EtOAc/acetone (1:1, 3mL). the solvent was evapored under vacuum to afford 5.5.4 as a colorless oil (29 mg, 96% yield), Rf= 0.41 (EtOAc/acetone 1:1), [α]D25 = – 41.4° (c 0.37, CHCl3). 1H: 6.72 (s, 1H), 6.53 (s, 1H), 5.7 (dd, J= 5.3, 12.5 Hz, 1H) , 4.09-3.95 (m, 4H), 3.87 (s, 3H), 3.85 (s, 3H), 3.21 (appd, J= 13.1, 1H), 3.00 (dt, J= 4.4, 10.4, 1H) 2.79-2.68 (m, 1H), 1.95 (appt, J= 13.1, 2H), 1.82-1.76 (m, 1H), 1.79 (s, 3H), 1.52 (d, J= 12.4, 1H). 13C: 169.4, 147.2, 147.1, 131.9, 128.5, 111.6, 208.8, 108.3, 75.1, 64.5, 64.4, 57.1, 56.1, 55.7, 38.6, 35.7, 32.2, 30.2, 29.9, 20.9. IR: 3482, 2929, 1689, 1501. MS: 378 [M + H+]. HRMS: calcd for C20H28NO6 [M + H+] 378.1807; found 336.1813.   Compound 5.5.6 Neat (COCl)2 (23 µL, 280 µmol, 1.5 equiv) was slowly (caution: vigorous exothermic reaction and evolution of toxic CO) syringed into a cold (–78 °C) solution of DMSO (40 µL, 560 µmol, 3.0 equiv) in dry CH2Cl2 (0.9 mL), under Ar. The reaction was stirred for 15 min at –78°C, then a solution of aminoalcohol 5.4.17 (63 mg, 180 µmol, 1.0 equiv) and Et3N (235 µL, 1.7 mmol, 9.0 equiv) in dry CH2Cl2 (1.0 mL, 0.1 M) was syringed into the reaction mixture, and stirring was continued for 1 h at –78 °C. The mixture was quenched with aq. sat. NaHCO3 123  solution (≈ 2 mL) and warmed to rt, then it was diluted with EtOAc (10 mL) and water (6 mL). The organic layer was separated and washed with water (3 x 2 mL), and the aqueous layer was extracted with more EtOAc (2 x 5 mL). The combined extracts were dried (Na2SO4) and concentrated under vacuum to afford a yellow oil (60 mg, 95% crude), Rf= 0.6 (CHCl3/MeOH/Et3N 95:5:5), which was used for the following step without further purification, since it rearranges to 5.5.12 upon chromatography.  If aminoalcohol 5.4.17 is not added in solution with Et3N, byproduct 5.5.7 can be form, Rf= 0.27 (EtOAc/hex 1:4). 1H: 7.09 (s, 1H), 6.60 (s, 1H), 6.19 (t, J=7.3, 1H), 4.01-3.95 (m, 6H), 3.90 ( s, 3H), 3.88 (s, 3H), 2.86-2.82 (m, 4H) 2.60 (d, J= 7.3, 2H). 13C: 168.1, 149.5, 147.9, 139.3, 127.21, 122.58, 117.0, 111.2, 109.1, 105.8, 64.7, 56.0, 55.9, 46.3, 40.1, 36.1, 28.8. IR: 2955, 1649, 1534.. MS: 354 [M + Na+]. HRMS: calcd for C18H21NO5Na [M + Na+]: 354.1317; found 354.1321.    Compound 5.5.12 Neat (COCl)2 (23 µL, 280 µmol, 1.5 equiv) was slowly (caution: vigorous exothermic reaction and evolution of toxic CO) syringed into a cold (–78 °C) solution of DMSO (40 µL, 560 µmol, 3.0 equiv) in dry CH2Cl2 (0.9 mL), under Ar. The reaction was stirred for 15 min at –78°C, then a solution of aminoalcohol 5.4.17 (63 mg, 180 µmol) and Et3N (0.024 mL, 1.7 mmol, 9.0 equiv) in dry CH2Cl2 (1.0 mL, 0.1 M) was syringed into the reaction mixture, and stirring was continued for 1 h at –78 °C. The mixture was quenched with aq. sat. NaHCO3 solution (≈ 2 mL) and warmed to rt, then it was diluted with EtOAc (10 mL) and water (6 mL). The organic layer was separated and washed with water (3 x 2 mL), and the aqueous layer 124  was extracted with more EtOAc (2 x 5 mL). The combined extracts were dried  (Na2SO4) and concentrated under vacuum to afford a yellow oil which was purified by silica gel flash chromatography (CHCl3/MeOH/Et3N 95:5:5) to give aminoketone 5.5.12 (53 mg, 88% yield) as a colorless oil, Rf= 0.48 (CHCl3/MeOH/Et3N 95:5:5), [α]D22= – 325° (c 0.25, CHCl3). 1H: 6.58 (s, 1H), 6.45 (s, 1H), 5.48 (s, 1H), 4.00 (m, 2H), 3.93 (m, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 3.11 ( m, 2H), 2.85 (m, 1H), 2.72 (m, 2H), 2.44 (m, 2H), 2.16 (m, 1H). MS 356 [M + Na+]. HRMS calcd for C18H24NO5 [M + H+] 334.1654; found 334.1651. It was not possible to obtain a 13C NMR spectrum of pure 5.5.12, due its equilibration with ketal 5.5.6 in CDCl3 solution.   Compound 5.5.13 and 5.5.14 Neat (COCl)2 (49 µL, 540 µmol, 1.5 equiv vs. diethylphosphonoacetic acid) was slowly added via syringe into a cold (0 °C) solution of diethylphosphonoacetic acid (57 µL, 360 µmol, 2.1 equiv vs. 5.5.6) and DMF (one drop) in dry benzene (1.2 mL, 0.3 M), under Ar. The cooling ice bath was removed, stirring was continued for 1 h at rt, then the mixture was concentrated under vacuum. The residue was dissolved in dry THF (1.2 mL, 0.3 M) and syringed into a cold (0 °C) solution of crude 5.5.6 (60 mg, 180 µmol) and Et3N (150 µL, 1.1 mmol, 6.0 equiv) in dry THF (0.6 mL, 0.3 M), under Ar. The cooling ice bath was re-moved, stirring at rt was continued for 18 h, then 10% aq. KOH solution (1 mL) was added and stirring at rt was continued for another 4 hours. The reaction mixture was diluted with EtOAc (3 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 3 mL) and the combined extracts were washed with brine (10 mL), dried (Na2SO4), and evaporated under vacuum. The residual dark orange oil was purified by silica gel flash chromatography (CH2Cl2/iPrOH 97:3→90:10) to give 5.5.13 (22 mg, 34% yield over three steps), Rf= 0.26 (EtOAc), mp 133-135 °C (Et2O), [α]D26= + 13.0° (c 0.8, CHCl3) and 125  5.5.14 (0.014 g, 21% yield over three steps), Rf= 0.14 (EtOAc), mp 201-203 °C (benzene) [α]D21= + 22.9° (c 1.25, CHCl3). Data for 5.5.13: 1H: 7.00 (s, 1H), 6.71 (s, 1H), 5.79 (s, 1H), 4.13-3.95 (m, 5H), 3.87 (s, 3H), 3.86 (s, 3H), 3.42 (dt, J= 13.3, 6.7, 1H), 3.11 (dd, J= 23.4, 14.4, 2H), 3.00-2.84 (m, 2H), 2.34-2.25 (m, 1H), 2.11-1.99 (m, 1H) 1.86-1.77 (m, 2H). 13C: 169.9, 160.0, 148.2, 146.8, 129.3, 127.0, 123.7, 112.5, 109.7, 109.0, 65.6, 64.9, 64.6, 56.3, 55.8, 40.0, 36.2, 36.0, 31.0, 28.2. IR: 2935.1, 1668.1, 1512.8. MS: 380 [M + Na+]. HRMS: calcd for C20H24NO5Na [M + Na+]: 358.1654; found 358.1663. Data for 5.5.14: 1H: 6.98 (s, 1H), 6.68 (s, 1H), 5.93 (s, 1H), 5.69 (s, 1H), 4.11-3.90 (m, 5H), 3.83 (s, 3H), 3.72(s, 3H), 3.53 (dt, J= 12.4, 6.1, 1H), 2.99-2.93 (m, 2H), 2.83 (brs, 1H, OH), 2.41-2.18 (m, 3H), 1.85 (dt, J= 11.3, 4.9, 1H). 13C: 172.5, 164.0, 159.8, 148.2, 146.7, 128.8, 126.5, 114.7, 112.1, 108.4, 95.4, 69.7, 64.6, 60.6, 55.9, 55.8, 37.2, 33.3, 27.0, 26.9. IR: 3345, 2935, 1656, 1610. MS 358 [M + H+]. HRMS: calcd for C20H24NO5Na [M + H+]: 358.1646; found 358.4654.   (+)-3-demethoxyerythratidinone 5.5.2 Commercial AlH3•NMe2Et (0.5 M in toluene, 670 µL, 335 µmol, 6.0 equiv) was added to a cold (0 °C) solution of a mixture of 5.5.13 and 5.5.14 (20 mg, 56 µmol) in dry THF (0.3 mL, 0.2 M), under Ar, and the solution was stirred for 1 h, during which time it was allowed to warm to rt. The mixture was quenched with conc. aq. NH4OH (1 mL) and diluted with EtOAc (3mL) and water (1mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 3 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4), and concentrated under vacuum to yield a colorless oil, which was dissolved in acetone (1 mL) and treated with aq. 1.5 M HCl solution (0.5 mL). The solution was heated at 70 °C for 2 h, then it was cooled to rt, basified with aq. 15% NaOH solution (2 mL), and diluted with CHCl3 (3 mL) and water (1 mL). The organic layer separated and the aqueous layer was extracted with CHCl3 (2 x 3 mL). The combined extracts were washed with brine (2 126  mL), dried (Na2SO4) and concentrated under vacuum to give a colorless oil, which was purified by silica gel flash chromatography (EtOAc/acetone 1:1) to afford totally synthetic 5.5.2 (11 mg, 63% yield), Rf= 0.34 (acetone) as a colorless oil. This material was dissolved in warm benzene. Petroleum ether was added dropwise until the solution became cloudy. Upon standing at rt for several hours, the solution deposited crystals of 5.5.2 (needles), mp 110-111 °C (lit8 111-112 °C), [α]D21 = + 322° (c 0.25 CHCl3) [ lit6 [α]D21 = + 325° (c 0.249 CHCl3)]. 1H: 6.64 (s, 1H), 6.55 (s, 1H), 6.10 (s, 1H), 3.85 (s, 3H), 3.74 (s, 3H), 3.54-3.43 (m, 1H), 3.28-3.21 (m, 1H), 3.12-3.03 (m, 2H), 2.90-2.68 (m, 2H), 2.63-2.46 (m, 4H), 2.34-2.20 (m, 2H). 13C: 199.3, 168.8, 148.3, 146.8, 125.5, 124.5, 123.7, 112.7, 110.1, 63.6, 55.9, 55.8, 45.7, 40.1, 36.0, 32.7, 28.6, 21.4. IR: 2934, 1668, 1510. MS: 300 [M + H+]. HRMS: calcd for C18H22NO3 [M + H+]: 300.1600; found 300.1596.   Compound 6.1.4 A solution of 5.5.12 (353 mg, 1.1 mmol), imidazole (225 mg, 3.2 mmol, 3.0 equiv), and TBDPSCl (0.40 mL, 1.6 mmol, 1.5 equiv) in DMF (2 mL, 0.5 M) was stirred at rt for 18 h, then it was dilut-ed with EtOAc (5 mL) and washed with water (3 x 8 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo to yield an orange oil, which was purified by silica gel flash chromatography (EtOAc/hexanes/Et3N 63:27:10) to afford 6.1.4 as a colorless oil (563 mg, 93% yield), Rf= 0.40 (EtOAc/hexanes/Et3N 63:27:10), [α]D21= + 45.8° (c 0.6, CHCl3). 1H: 7.69 (dd, J= 7.31, 1.54, 4H), 7.41 (m, 6H), 6.59 (s, 1H), 6.46 (s, 1H), 5.44 (s, 1H), 3.98 (apps, 4H), 3.84 (s, 3H), 3.77 (s, 3H), 3.10 (m, 2H), 2.77 (m, 3H), 2.40 (m, 2H), 2.10 (m, 1H), 1.07 (s, 9H). 13C: 199.17, 176.68, 147.8, 147.1, 135.6, 133.27, 133.25, 129.8, 128.2, 127.7, 111.9, 109.5, 101.6, 69.8,                                                           8 Amer, M. E.; Shamma, M.; Freyer, A. J. J. Nat. Prod., 1991, 2, 329. 127  61.9, 61.0, 55.9, 55.7, 38.9, 35.1, 29.4, 26.7, 25.8, 19.2. IR: 2933, 1652, 1608. MS 572 [M + H+]. HRMS calcd for C34H41NO5NaSi [M + Na+]: 594.2652; found 594.2658.    Compound 6.1.6 Metallic lithium (6 mg, 850 µmol, 7.0 equiv) was added to a cold (–78 °C) solution of enone 6.1.4 (70 mg, 120 µmol) and t-BuOH (250 µL, 2.5 mmol, 21.0 equiv) in a mixture of liquid NH3 (≈ 3 mL) and dry THF (0.6 mL, 0.5 M), and stirring at –78 °C was continued for a further 30 minutes. The reaction was quenched at –78 °C with solid NH4Cl (≈ 20 mg), then it was removed from the cooling bath and warmed to rt to allow the NH3 to evaporate. The residual slurry was dissolved in CHCl3 (3 mL) and treated with aq. sat. Na2CO3 solution (2 mL). The organic layer separated and the aqueous layer was extracted with CHCl3 (2 x 2 mL). The combined extracts were washed with brine (6 mL), dried (Na2SO4) and concentrated under vacuum to a yield pale yellow oil, which was a ca.1.5:1 mixture of saturated aminoketone 6.1.6 (major) and enone 6.1.5 (minor). Silica gel flash chromatography (EtOAc) readily separated 6.1.6 (30 mg, 43%, mixture of diastereomers, colorless oil) and 6.1.5 (10 mg, 29%, colorless oil). Data for 6.1.6: Rf= 0.27 (EtOAc/hexanes 1:1). 1H: 6.55 (s, 1H), 6.52 (s, 1H), 5.84-5.80 (m, 3H), 5.56-5.52 (m, 3H), 4.10 (apps, 1H), 3.95 (t, J= 5.4, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.66-3.51 (m, 2H), 3.28 (dd, J= 14.4, 3.3, 1H), 3.13 (dd, J= 8.3, 2.3, 1H), 2.81-2.55 (m, 10H), 2.30-2.21 (m, 1H), 1.97 (appd, J= 11.6, 1H), 1.73 (appd, J= 14.1, 1H), 1.04-0.95 (m, 9H). 13C: 209.7, 147.8, 146.9, 129.2, 128.0, 125.9, 125.87, 125.81, 121.9, 121.8, 111.4, 110.8, 69.7, 65.3, 63.8, 56.0, 55.6, 42.1, 39.9, 35.7, 29.8, 28.98, 28.95, 27.5, 26.0, 25.0, 21.7. IR: 2930, 2856, 1716, 1511. MS 578 [M + H+]. HRMS calcd for C34H47NO5NaSi [M + Na+]: 600.3121; found 600.3134. Data for 6.1.5 are reported below.  128  Compound 6.1.5 A 0.25 M THF solution of t-BuOK (260 µL, 65 µmol, 0.5 equiv) was added to a cold (0 °C) solution of 6.1.6 (75 mg, 130 µmol, 1.0 equiv) in dry THF (2.6 mL, 0.05 M) under Ar, and the mixture was stirred for 30 min at 0 °C, after which time no starting material was visible by TLC (EtOAc). Aqueous sat. NH4Cl solution was added (1.5 mL) and then the pH of the solu-tion was adjusted to ca. 8 (pH paper) with aq. sat. Na2CO3 solution. The aqueous layer was extracted with CHCl3 (3 x 5 mL), and the combined extracts were washed with brine (10 mL), dried (Na2SO4) and concentrated under vacuum. The dark orange oily residue was purified by silica gel flash chromatography (MeCN/Et2O 4:6 → 7:3) to furnish 6.1.5 (29 mg, 82% yield) as a pale yellow oil, Rf= 0.15 (EtOAc/NH4OH 98:2), [α]D22= + 33.5° (c 0.6, CHCl3). 1H: 7.07-7.01 (m, 1H), 6.60 (s, 1H), 6.50 (s, 1H), 6.14 (d, J = 10.0, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.08 (dt, J= 11.9, 7.3, 2H), 2.76-2.70 (m, 2H), 2.59-2.37 (m, 2H), 2.26-2.14 (m, 2H). 13C: 198.0, 149.6, 148.0, 147.2, 128.7, 128.4, 127.9, 11.9, 109.3, 61.8, 56.0, 55.7, 38.7, 36.3, 29.1, 23.2. IR: 3319, 2932, 1669, 1512. MS 274 [M + H+]. HRMS calcd for C16H20NO3 [M + H+]: 274.1443; found 274.1443.  Compound 6.1.2 (Padwa’s intermediate) Solid DCC (83 g, 402 µmol, 2.2 equiv) was added to a solution of enone 6.1.5 (50 mg, 183 µmol), diethylphosphonoacetic acid (60 µL, 366 µmol, 2.0 equiv), DMAP (24 mg, 201 µmol, 1.1 equiv) and Et3N (122 µL, 915 µmol, 5.0 equiv) in CH2Cl2 (0.9 mL, 0.2M), at rt and under Ar. After stirring at rt for 18 h, the mixture was filtered through Celite, the filtrate was washed with aq. 1.0 M HCl (2 x 5 mL), dried (Na2SO4) and concentrated in vacuo. The residual orange oil was dissolved in THF (1 mL) and treated with 10% aq. KOH solution (1 mL). The resulting mixture was stirred for 2 h at rt, then it was diluted with EtOAc (3mL) and 129  water (2 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 3 mL) and the combined organic phases were washed with brine (10 mL), dried (Na2SO4), and concentrated under vacuum. The dark orange oil thus obtained was purified by silica gel flash chromatography (MeCN/Et2O 3:7 → 1:1) to provide 6.1.2 as a pale yellow oil (35 mg, 66% yield after two steps), Rf= 0.23 (EtOAc/benzene 7:3), [α]D21= + 90.5° (c 0.82, CHCl3) [ lit.9 [α]D25= + 43.7° c 0.44, CHCl3)]. 1H: 6.98 (s, 1H), 6.80 (dd, J= 9.5, 2.8, 1H), 6.68 (s, 1H), 6.30-6.24 (m, 1H), 5.86 (s, 1H), 4.02 (dt, J= 12.8, 6.5, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 3.54 (dt, J= 12.8, 6.5, 1H), 2.96 (t, J= 6.8, 2H), 2.44-2.14 (m, 3H), 1.83 (dt, J= 11.4, 5.7, 1H). 13C: 171.2, 157.8, 148.1, 146.8, 135.9, 128.6, 126.3, 124.0, 118.9, 112.0, 108.6, 64.5, 56.0, 55.8, 36.9, 35.0, 27.1, 24.5. IR: 2934, 1673. MS 298 [M + H+]. HRMS calcd for C18H19NO3Na [M + Na+]: 320.1263; found 320.1269.   Alcohol derivative of 6.1.2  A solution of lactam 6.1.2 (35 mg, 110 µmol), SeO2 (130 mg, 1.1 mmol, 10.0 equiv), and glacial AcOH (67 µL, 1.1 mmol, 10.0 equiv) in dry dioxane (1.1 mL, 0.1 M) in a reaction tube sealed with a Tef-lon cap was heated in an oil bath set at 110 °C. After 48 h, the mix-ture was cooled to rt and 10% aq. KOH solution (1 mL) was added. After stirring at rt for 1h, the organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 2 mL). The combined organic phases were washed with brine (4 mL), dried (Na2SO4), and evapo-rated in vacuo to afford a dark red oily residue, which was purified by silica gel column chro-matography (CH2Cl2/MeOH 95:5) to afford unreacted 6.1.2 (8 mg, 24% yield) and the desired allylic alcohol (15 mg, 43% yield) as a pale yellow oil, Rf= 0.2 (CH2Cl2/MeOH 7:3), [α]D21= +                                                           9 Blake, A. G.; Gill, C.; Greenhalgh, D. A.; Simpkins, N. S.; Zhang F. Synthesis, 2005, 3287. 130  193° (c 0.5, CHCl3) [ lit.10 [α]D23= + 182°, c 0.25, CHCl3)]. 1H: 6.86 (dd, J= 10.0, 2.4, 1H), 6.79 (s, 1H), 6.71 (s, 1H), 6.31 (d, J= 10.0, 1H), 6.01 (s, 1H), 4.33-4.28 (m, 1H), 3.97 (dt, J= 12.7, 6.0, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.60 (dt, J= 12.7, 6.0, 1H), 3.13-2.95 (m, 2H), 2.81 (dd, J= 11.4, 5.2, 1H), 1.69 (appt, J= 10.5, 1H). 13C: 171.0, 157.1, 148.5, 147.0, 139.1, 128.4, 126.4, 123.6, 120.2, 112.1, 108.0, 66.6, 66.5, 56.0, 55.9, 45.0, 37.4, 27.0. IR: 3358, 2935, 1654.  (+)-erysotramidine 6.1.1 A solution of alcohol, described above, (3.2 mg, 10 µmol), n-Bu4NBr (9.6 mg, 31 µmol, 3.0 equiv), and MeI (128 µL, 2.0 mmol, 200 equiv) in dry THF (0.2 mL, 0.05 M) containing solid KOH (6.4 mg, 120 µmol, 12.0 equiv) was stirred for 24 h at rt under Ar, then it was diluted with EtOAc (1 mL), washed with water (3 x 1 mL) and brine (1 mL), dried (Na2SO4) and evapo-rated in vacuo. The residual pale yellow oil was purified by preparative TLC (MeCN/Et2O 1:4) to provide (+)-erysotramidine 6.1.1 as a colorless oil (3.0 g, 95% yield), Rf= 0.16 (MeCN/Et2O 4:1), [α]D21 = + 94.6° (c 0.64 CHCl3) [lit.7 [α]D25 = + 65°, c 0.15, CHCl3; lit.8 [α]D23 = + 148.5°, c 1.2, CHCl3; lit.11 [α]D21 = + 121°, c 0.10, CHCl3]. 1H: 6.92 (dd, J= 10.0, 2.4, 1H), 6.81 (s, 1H), 6.73 (s, 1H), 6.35 (d, J= 10.0, 1H), 6.04 (s, 1H), 4.01 (appdt, J= 12.8, 8.0, 1H), 3.87 (s, 4H), 3.78 (s, 3H), 3.63 (appdt, J= 12.8, 8.0, 1H), 3.36 (s, 3H), 3.17-2.95 (m, 2H), 2.83 (dd, J= 11.2, 4.7, 1H), 1.72(dd, J= 11.2, 10.3, 1H). 13C 170.9, 157.0, 148.5, 146.9, 136.2, 128.6, 126.5, 124.1, 120.3, 112.2, 108.1, 74.9, 66.3, 56.4, 56.1, 55.9, 41.4, 37.3, 27.0. IR: 2933, 1681, 1462.                                                             10 Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko, C.; Sano, T. Chem. Pharm. Bull., 1993, 41, 2087.  Simp-kins (footnote 9) reports [a]D25 = + 65° (c 0.25, CHCl3) for material of 93% ee. 11 Ito, K.; Furukawa, H.; Haruna, M. Yakugaku Zasshi, 1973, 93, 1617. 131  C. COMPARATIVE SPECTRAL DATA     1H-NMR (CDCl3) Natural6 Simpkins synthetic (+)-5.5.212 Reisman synthetic (–)-5.5.213 This Work synthet-ic (+)-5.5.2  6.59 (s, 1H) 6.51 (s, 1H) 6.04 (s, 1H) 3.79 (s, 3H) 3.68 (s, 3H) 3.52-1.85 (m, 12H) 6.66 (s, 1H) 6.56 (s, 1H) 6.12 (s, 1H) 3.88 (s, 3H) 3.76 (s, 3H), 3.52-3.45 (m, 1H) 3.26 (dd, J=14.4, 7.6, 1H) 3.12-3.03 (m, 2H) 2.92-2.68 (m, 2H) 2.68-2.43 (m, 4H) 2.33-2.24 (m, 2H) 6.65 (s, 1H) 6.56 (s, 1H) 6.11 (app s, 1H) 3.86 (s, 3H) 3.77 (s, 3H), 3.49 (m, 1H) 3.24 (dd, J=14.4, 7.6, 1H) 3.12-3.00 (m, 2H) 2.86 (q, J=7.7, 1H) 2.68-2.43 (m, 4H) 2.33-2.24 (m, 2H) 6.64 (s, 1H) 6.55 (s, 1H) 6.10 (s, 1H) 3.85 (s,3H) 3.74 (s, 3H) 3.54-3.43 (m, 1H) 3.28-3.21 (m, 1H) 3.12-3.03 (m, 2H) 2.90-2.68 (m, 2H) 2.63-2.46 (m, 4H) 2.34-2.20 (m, 2H)      13C-NMR (CDCl3)   No 13C data reported    199.3 168.5 148.4 146.9 125.4 199.5 162.2 148.3 146.8 125.7 199.3  168.8  148.3 146.8 125.5                                                            12 Zhang, F.; Simpkins, N. S.; Wilson, C. Tetrahedron Lett., 2007, 48, 5942. 13 Chuang, K. V.; Navarro, R.; Reisman S. E. Chem. Sci., 2011, 2, 1086. 132  13C-NMR (CDCl3) Natural6 Simpkins synthetic (+)-5.5.214 Reisman synthetic (–)-5.5.215 This Work synthet-ic (+)-5.5.2   124.4 123.9 112.8 110.2 63.7 56.0 55.9 45.7 40.1 35.9 32.8 28.6 21.5 124.8 123.4 112.8 110.3 63.5 56.0 55.9 45.7 40.1 36.1 32.8 28.7 21.4 124.5 123.7 112.7 110.1 63.6 55.9 55.8 45.7 40.1 36.0 32.7 28.6 21.4      IR C=O  1667 cm-1 1666 cm-1 1667 cm-1 1668 cm-1      Optical Rotation [α]D22 = + 325° (c= 0.249, CHCl3) [α]D26 = + 316° (c= 0.4, CHCl3) [α]D25 = – 296.5° (c= 0.57, CHCl3) [α]D21 = + 322° (c= 0.25, CHCl3) Table 7. Data for natural and synthetic (+)- 3-demethoxyerythratidinone.                                                              14 Zhang, F.; Simpkins, N. S.; Wilson, C. Tetrahedron Lett., 2007, 48, 5942. 15 Chuang, K. V.; Navarro, R.; Reisman S. E. Chem. Sci., 2011, 2, 1086. 133    1H-NMR (CDCl3) Natural6 Tsuda8 synth. (+)-6.1.1 Simpkins 16 synth. (+)-6.1.1 Kaluza 17 synth. (–)-6.1.1 This Work synth. (+)-6.1.1  6.90 (dd, 1H) 6.80 (s, 1H) 6.72 (s, 1H) 6.32 (d, 1H) 6.02 (s, 1H) 3.95 (dd, 1H) 3.88 (m, 1H) 3.86 (s, 3H) 3.76 (s, 3H) 3.57 (dd, 1H) 3.34 (s, 3H) 3.02 (dd, 2 H) 2.77 (dd, 1H) 1.70 (dd, 1H) 6.91 (dd, 1H) 6.81 (s, 1H) 6.73 (s, 1H) 6.34 (d, 1H) 6.03 (s, 1H) 4.00 (ddd, 1H) 3.86 (m, 1H) 3.86 (s, 3H) 3.77 (s, 3H) 3.35 (s, 3H) 3.62 (ddd, 1H) 3.09 (ddd, 1H) 3.00 (ddd, 1H) 2.81 (dd, 1H) 1.71 (dd, 1H) 6.92 (dd, 1H) 6.81 (s, 1H) 6.73 (s, 1H) 6.35 (d, 1H) 6.04 (s, 1H) 4.01 (ddd, 1H) 3.90-3.85 (m, 1H) 3.86 (s, 3H) 3.78 (s, 3H) 3.63 (ddd, 1H) 3.36 (s, 3H) 2.97-3.14 (m, 2H) 2.82 (dd, 1H) 1.72 (dd, 1H) 6.90 (dd, 1H) 6.80 (s, 1H) 6.72 (s, 1H) 6.33 (d, 1H) 6.05 (s, 1H) 4.01 (dt,1H) 3.86 (s, 4H) 3.76 (s, 3H) 3.66-3.58 (m, 1H) 3.34 (s, 3H) 3.13-2.95 (m, 2H) 2.81 (dd, 1H) 1.71 (t, 1H) 6.92 (dd, 1H) 6.81 (s, 1H) 6.73 (s, 1H) 6.35 (d, 1H) 6.04 (s, 1H) 4.01 (dt, 1H) 3.87 (s, 3H) 3.87 (m, 1H) 3.63 (dt, 1H) 3.36 (s, 3H) 3.17-2.95 (m, 2H) 2.83 (dd, 1H) 1.72 (dd, 1H)       13C-NMR (CDCl3) 13C-170.0 157.0 148.5 Natural6    Tsuda8 synth. 171.0 157.0 148.5 Simpkins 18 170.9 157.2 148.6 Kaluza 19 170.9 157.0 148.5 This Work                                                           16 Footnote 9 as well as: Zhang, F.; Simpkins, N. S.; Blake, A. J. Org. Biomol. Chem., 2009, 7, 1963. 17 Mostowicz, D.; Dygas, M.; Kaluza, Z. J. Org. Chem., 2015, 80, 1957.  134  NMR (CDCl3)  (+)-6.1.1 synth. (+)-6.1.1  synth. (–)-6.1.1  synth. (+)-6.1.1  147.1 136.3 128.6 126.5 124.1 120.2 112.5 108.8 74.9 66.3 56.2 56.2 56.2 41.4 37.2 27.0  147.0 136.3 128.6 126.5 124.2 120.3 112.2 108.1 74.8 66.4 56.5 56.1 55.9 41.4 37.4 27.1 147.1 136.4 128.6 126.5 124.1 120.2 112.3 108.3 74.9 66.5 56.4 56.2 55.9 41.4 37.3 27.1 146.9 136.2 128.6 126.5 124.1 120.3 112.2 108.1 74.9 66.3 56.4 56.1 55.9 41.4 37.3 27.0        IR C=O  1665 cm-1 1670 cm-1 1672 cm-1 not reported 1681 cm-1       Optical Rotation [α]D23= +121° (c= 1.0, CHCl3)5 [α]D23= +148.5° (c= 1.2, CHCl3) [α]D26= +65° (c= 0.25, CHCl3) [α]D22= –145.2°  (c= 1.57, CHCl3) [α]D21 = + 94.6  (c= 0.64, CHCl3) Table 8. Data for natural and synthetic (+)-erysotramidine.                                                                                                                                                                                       18 Footnote 9 as well as: Zhang, F.; Simpkins, N. S.; Blake, A. J. Org. Biomol. Chem., 2009, 7, 1963. 19 Mostowicz, D.; Dygas, M.; Kaluza, Z. J. Org. Chem., 2015, 80, 1957.  135  D. X-RAY crystal structure lactam 5.3.2            136  E. Proton and 13C NMR spectra 1H NMR Spectrum of 3.1.20 in CDCl3 13C NMR Spectrum of 3.1.20 in CDCl3    137  1H NMR Spectrum of 3.1.22 in CDCl3 13C NMR Spectrum of 3.1.22 in CDCl3   138   1H NMR Spectrum of 3.1.23 in CDCl3  13C NMR Spectrum of 3.1.23 in CDCl3   syn anti anti syn 139   1H NMR Spectrum of 3.1.24 in toluene-d8 at 80 °C 13C NMR Spectrum of 3.1.24 in toluene-d8 at 80 °C   140   Comparison 1H spectra of 3.1.24 at rt and at 80 °C in toluene d8    141  1H NMR Spectrum of 3.1.25 in CDCl3  13C NMR Spectrum of 3.1.25 in CDCl3  142   HSQC NMR Spectrum of 3.1.25 in CDCl3 NOESY NMR Spectrum of 3.1.25 in CDCl3   143   1H NMR Spectrum of 3.1.26 in CDCl3 13C NMR Spectrum of 3.1.26 in CDCl3 144  1H NMR Spectrum of 3.1.32 in CDCl3  13C NMR Spectrum of 3.1.32 in CDCl3   145  1H NMR Spectrum of crude 3.2.26 in CDCl3  13C NMR Spectrum of crude 3.2.26 in CDCl3  146  1H NMR Spectrum of 3.2.20 in CDCl3 13C NMR Spectrum of 3.2.20 in CDCl3    147  1H NMR Spectrum of 3.2.29 in CDCl3  13C NMR Spectrum of 3.2.29 in CDCl3 148   1H NMR Spectrum of 3.2.31 in CDCl3  13C NMR Spectrum of 3.2.31 in CDCl3 149  H NMR Spectrum of 5.2.3 in CDCl3  13C NMR Spectrum of 5.2.3 in CDCl3      150   1H NMR Spectrum of 1-(benzyloxy)-4-iodobenzene in CDCl3  13C NMR Spectrum of 1-(benzyloxy)-4-iodobenzene in CDCl3 151   1H NMR Spectrum of benzyl protected 5.2.7 in CDCl3  13C NMR Spectrum of benzyl protected 5.2.7 in CDCl3 152              1H NMR Spectrum of acid derivative of 5.2.8 in CDCl3            13C NMR Spectrum acid derivative of 5.2.8 in CDCl3  153              1H NMR Spectrum of benzyl protected oxazoline 5.2.1 in CDCl3             13C NMR Spectrum of benzyl protected oxazoline 5.2.1 in CDCl3 154              1H NMR Spectrum of compound 5.2.1 in CDCl3             13C NMR Spectrum of compound 5.2.1 in CDCl3 155              1H NMR Spectrum of compound 5.3.1 in CDCl3             13C NMR Spectrum of compound 5.3.1 in CDCl3 156              1H NMR Spectrum of compound 5.3.2 in CDCl3 (600 MHz)             13C NMR Spectrum of compound 5.3.2 in CDCl3 (150 MHz) 157              1H NMR Spectrum of compound 5.3.11 in CDCl3             13C NMR Spectrum of compound 5.3.11 in CDCl3 158              1H NMR Spectrum of methyl ester of 5.4.9 in CDCl3             13C NMR Spectrum of methyl ester of 5.4.9 in CDCl3 159               1H NMR Spectrum of compound 5.4.9 in CDCl3            13C NMR Spectrum of compound 5.4.9 in CDCl3 160              1H NMR Spectrum of compound 5.4.10 in CDCl3             13C NMR Spectrum of compound 5.4.10 in CDCl3 161  Monitoring the reaction leading to the formation of 5.4.10 by 1H NMR spectrometry (CDCl3): the unsaturated morpholine forms from isocyanate 5.4.13                      starting acid 5.4.9                        crude acylazide 5.4.15  Slowly formation of 5.4.10                              162              1H NMR Spectrum of compound 5.4.16 in CDCl3             13C NMR Spectrum of compound 5.4.16 in CDCl3 163              1H NMR Spectrum of compound 5.4.17 in CDCl3             13C NMR Spectrum of compound 5.4.17 in CDCl3 164             1H NMR Spectrum of compound 5.5.4 in CDCl3    13C NMR Spectrum of compound 5.5.4 in CDCl3  165              1H NMR Spectrum of crude compound 5.5.6 in CDCl3            13C NMR Spectrum of crude compound 5.5.6 in CDCl3: some 5.5.12 is also present (see next page) 166              1H NMR Spectrum of compound 5.5.12 in CDCl3              167                  13C NMR Spectrum of compound 5.5.12 in CDCl3 (lower spectrum, blue): more than one-third of this material has cyclized back to 5.5.6 (upper spectrum, red) after 10 min.       5.5.6 5.4.12 5.5.6 5.5.6 5.5.6 5.5.6 5.5.6 5.5.12 5.5.12 5.5.12 5.5.12 168   1H NMR Spectrum of compound 5.5.7 in CDCl3  13C NMR Spectrum of compound 5.5.7 in CDCl3  169              1H NMR Spectrum of compound 6.1.4 in CDCl3             13C NMR Spectrum of compound 6.1.4 in CDCl3 170             1H NMR Spectrum of compound 5.5.13 in CDCl3             13C NMR Spectrum of compound 5.5.13 in CDCl3  171              1H NMR Spectrum of compound 5.5.14 in CDCl3             13C NMR Spectrum of compound 5.5.14 in CDCl3 172              1H NMR Spectrum of (+)-3-demethoxyerythratidinone 5.5.2 in CDCl3             13C NMR Spectrum of (+)-3-Demethoxyerythratidinone 5.5.2 in CDCl3 173              1H NMR Spectrum of compound 6.1.6 (mixture of diastereomers) in CDCl3             13C NMR Spectrum of compound 6.1.6 (mixture of diastereomers) in CDCl3 174              1H NMR Spectrum of compound 6.1.5 in CDCl3            13C NMR Spectrum of compound 6.1.5 in CDCl3  175              1H NMR Spectrum of compound 6.1.2 in CDCl3            13C NMR Spectrum of compound 6.1.2 in CDCl3  176              1H NMR Spectrum of allylic alcohol from 6.1.2 in CDCl3            13C NMR Spectrum of allylic alcohol from 6.1.2 in CDCl3  177              1H NMR Spectrum of (+)-Erysotramidine 6.1.1 in CDCl3            13C NMR Spectrum of (+)-Erysotramidine 6.1.1 in CDCl3  178              Expanded portion of the HBMC Spectrum of (+)-erysotramidine 6.1.1 in CDCl3, showing the correlation between aromatic and olefinic protons with the corresponding carbons.     179  E. X-RAy data  Data Collection   A colourless, blade-like crystal of C20H23NO8, having approximate dimensions of 0.09 x 0.19 x 0.32 mm was mounted on a glass fiber. All measurements were made on a Bruker APEX DUO diffractometer with cross-coupled multilayer optics Cu-Kα radiation.  The data were collected at a temperature of -183.0 + 0.1oC to a maximum 2 value of 135.64o. Data were collected in a series of  and  scans in 2o oscillations using 8.0-second exposures. The crystal-to-detector distance was 59.76 mm.    Data Reduction   Of the 17984 reflections that were collected, 3374 were unique (Rint = 0.031); equiva-lent reflections, excluding Friedel pairs, were merged.  Data were collected and integrated using the Bruker SAINT1 software package. The linear absorption coefficient, µ, for Cu-Kα radiation is 9.31 cm-1. Data were corrected for absorption effects using the multi-scan tech-nique (SADABS2), with minimum and maximum transmission coefficients of 0.795 and 0.920, respectively.  The data were corrected for Lorentz and polarization effects.   Structure Solution and Refinement   The structure was solved by direct methods3.   The material crystallizes with one molecule of water in the asymmetric unit.  All non-hydrogen atoms were refined anisotropi-cally.  All O—H hydrogen atoms were located in difference maps.  All other hydrogen atoms were placed in calculated positions.  The absolute configuration was assigned on the basis of the refined Flack12 x-parameter [0.02(5)]  The final cycle of full-matrix least-squares refine-ment4 on F2 was based on 3374 reflections and 273 variable parameters and converged (largest parameter shift was 0.00 times its esd) with unweighted and weighted agreement factors of:  180   R1 =  ||Fo| - |Fc|| /  |Fo| = 0.028   wR2 = [  ( w (Fo2 - Fc2)2 )/  w(Fo2)2]1/2 = 0.068    The standard deviation of an observation of unit weight5 was 1.07. The weighting scheme was based on counting statistics.  The maximum and minimum peaks on the final difference Fourier map corresponded to 0.12 and –0.19 e-/Å3, respectively.    Neutral atom scattering factors were taken from Cromer and Waber6. Anomalous dis-persion effects were included in Fcalc7; the values for Δf' and Δf" were those of Creagh and McAuley8. The values for the mass attenuation coefficients are those of Creagh and Hubbell9. All refinements were performed using the SHELXL-9710 via the WinGX11 interface.   References     (1) SAINT. Version 7.68A. Bruker AXS Inc., Madison, Wisconsin, USA. (1997-2010).   (2) SADABS. Bruker Nonius area detector scaling and absorption correction - V2008/1, Bruker AXS Inc., Madison, Wisconsin, USA (2008).  (3) SIR97 - Altomare A., Burla M.C., Camalli M., Cascarano G.L., Giacovazzo C. , Guagliardi A., Moliterni A.G.G., Polidori G.,Spagna R. (1999) J. Appl. Cryst. 32, 115-119.   181  (4) Least Squares function minimized:    w(Fo2-Fc2)2  (5) Standard deviation of an observation of unit weight:        [w(Fo2-Fc2)2/(No-Nv)]1/2      where:  No  = number of observations         Nv  = number of variables    (6) Cromer, D. T. & Waber, J. T.; "International Tables for X-ray Crystallography", Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974).   (7) Ibers, J. A. & Hamilton, W. C.; Acta Crystallogr., 17, 781 (1964).   (8) Creagh, D. C. & McAuley, W.J .; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992).   (9) Creagh, D. C. & Hubbell, J.H..; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992).   (10) SHELXTL Version 2008/4. Bruker AXS Inc., Madison, Wisconsin, USA. (2008).   (11) WinGX – V1.80.05 – Farrugia, L.J.; J. Appl. Cryst., 32, 837 (1999).  182  (12)  FLACK X-PARAMETER - (a) Flack, H.D. Acta Crystallogr., Sect A 1983, 39, 876-881. (b) Bernardinelli, G.; Flack, H. D. Acta Crystallogr., Sect A 1985, 41, 500-511.   183                                                EXPERIMENTAL DETAILS     A. Crystal Data     Empirical Formula C20H23NO8  Formula Weight 405.39  Crystal Colour, Habit colourless, blade  Crystal Dimensions 0.09 x 0.19 x 0.32 mm  Crystal System orthorhombic  Lattice Type primitive  Lattice Parameters  a = 8.7215(6) Å  b = 11.3257(8) Å  c = 19.217(1) Å  α = 90o  β = 90o 184   γ = 90o  V = 1898.2(3) Å3  Space Group P 212121  (#19)  Z value 4  Dcalc 1.419 g/cm3  F000 856.00  µ(Cu-Kα) 9.31 cm-1 185  B. Intensity Measurements     Diffractometer Bruker APEX DUO   Radiation Cu-Kα (λ = 1.54178 Å)       Data Images 2585 exposures @ 8.0 seconds  Detector Position 59.76 mm  2max 135.64o   No. of Reflections Measured Total: 17984    Unique: 3374 (Rint = 0.031; Friedels not merged) Corrections Absorption (Tmin = 0.795, Tmax= 0.920)   Lorentz-polarization 186  C. Structure Solution and Refinement     Structure Solution Direct Methods (SIR97)  Refinement Full-matrix least-squares on F2  Function Minimized  w (Fo2 - Fc2)2   Least Squares Weights w=1/(σ2(Fo2)+(0.0377P) 2+ 0.4031P)  Anomalous Dispersion All non-hydrogen atoms  No. Observations (I>0.00σ(I)) 3374  No. Variables 273  Reflection/Parameter Ratio 12.36  Residuals (refined on F2, all data): R1; wR2 0.028; 0.068  Goodness of Fit Indicator 1.07  No. Observations (I>2.00σ(I)) 3286   187  Residuals (refined on F2): R1; wR2 0.027; 0.067  Max Shift/Error in Final Cycle 0.00  Maximum peak in Final Diff. Map 0.12 e-/Å3  Minimum peak in Final Diff. Map -0.19 e-/Å3 188           Table 2.  Atomic coordinates ( x 10^4) and equivalent isotropic          displacement parameters (A^2 x 10^3) for mc049.          U(eq) is defined as one third of the trace of the orthogonalized          Uij tensor.            ________________________________________________________________                            x             y             z           U(eq)          ________________________________________________________________             C(1)         1614(2)       4478(1)       7713(1)       21(1)           C(2)         1798(2)       5363(1)       7136(1)       21(1)           C(3)         3357(2)       5476(1)       6853(1)       20(1)           C(4)         4442(2)       4683(1)       6982(1)       18(1)           C(5)         4221(2)       3564(1)       7410(1)       18(1)           C(6)         2490(2)       3344(1)       7557(1)       20(1)           C(7)         2292(2)       1740(1)       6801(1)       24(1)           C(8)         3927(2)       1837(1)       6538(1)       21(1)           C(9)         6411(2)       2422(1)       6919(1)       19(1)           C(10)        7436(2)       3235(1)       7331(1)       19(1)           C(11)        6747(2)       3536(1)       8028(1)       18(1)           C(12)        5166(2)       3658(1)       8084(1)       17(1)           C(13)        4520(2)       3833(1)       8745(1)       19(1)           C(14)        5439(2)       3917(1)       9330(1)       19(1)           C(15)        7040(2)       3802(1)       9266(1)       19(1)           C(16)        7671(2)       3597(1)       8621(1)       19(1) 189            C(17)        3343(2)       4419(2)      10068(1)       34(1)           C(18)        9477(2)       3981(2)       9827(1)       27(1)           C(19)        4004(2)       2335(1)       5801(1)       23(1)           C(20)        3455(3)       1873(2)       4638(1)       46(1)           N(1)         4864(1)       2541(1)       7014(1)       19(1)           O(1)          743(1)       5986(1)       6935(1)       27(1)           O(2)         1721(1)       2879(1)       6963(1)       23(1)           O(3)         6939(1)       1680(1)       6522(1)       22(1)           O(4)         4927(1)       4104(1)       9990(1)       24(1)           O(5)         7841(1)       3886(1)       9874(1)       23(1)           O(6)         4503(1)       3282(1)       5640(1)       28(1)           O(7)         3432(2)       1538(1)       5364(1)       35(1)           O(8)         2210(1)        896(1)       8667(1)       29(1)          ________________________________________________________________    190             Table 3.  Bond lengths [A] and angles [deg] for mc049.            _____________________________________________________________               C(1)-C(2)                     1.503(2)             C(1)-C(6)                     1.524(2)             C(1)-H(1A)                    0.9900             C(1)-H(1B)                    0.9900             C(2)-O(1)                     1.2215(18)             C(2)-C(3)                     1.470(2)             C(3)-C(4)                     1.328(2)             C(3)-H(3)                     0.9500             C(4)-C(5)                     1.5233(19)             C(4)-H(4)                     0.9500             C(5)-N(1)                     1.4956(18)             C(5)-C(12)                    1.5378(18)             C(5)-C(6)                     1.5561(19)             C(6)-O(2)                     1.4252(17)             C(6)-H(6)                     1.0000             C(7)-O(2)                     1.4176(18)             C(7)-C(8)                     1.516(2)             C(7)-H(7A)                    0.9900             C(7)-H(7B)                    0.9900             C(8)-N(1)                     1.4632(18)             C(8)-C(19)                    1.526(2)             C(8)-H(8)                     1.0000             C(9)-O(3)                     1.2254(17) 191              C(9)-N(1)                     1.3679(18)             C(9)-C(10)                    1.5082(19)             C(10)-C(11)                   1.5067(19)             C(10)-H(10A)                  0.9900             C(10)-H(10B)                  0.9900             C(11)-C(12)                   1.3903(19)             C(11)-C(16)                   1.396(2)             C(12)-C(13)                   1.4046(19)             C(13)-C(14)                   1.3832(19)             C(13)-H(13)                   0.9500             C(14)-O(4)                    1.3614(16)             C(14)-C(15)                   1.408(2)             C(15)-O(5)                    1.3653(16)             C(15)-C(16)                   1.376(2)             C(16)-H(16)                   0.9500             C(17)-O(4)                    1.4348(18)             C(17)-H(17A)                  0.9800             C(17)-H(17B)                  0.9800             C(17)-H(17C)                  0.9800             C(18)-O(5)                    1.4334(17)             C(18)-H(18A)                  0.9800             C(18)-H(18B)                  0.9800             C(18)-H(18C)                  0.9800             C(19)-O(6)                    1.1979(18)             C(19)-O(7)                    1.3305(18)             C(20)-O(7)                    1.4453(19) 192              C(20)-H(20A)                  0.9800             C(20)-H(20B)                  0.9800             C(20)-H(20C)                  0.9800             O(8)-H(8A)                    0.89(2)             O(8)-H(8B)                    0.86(2)               C(2)-C(1)-C(6)              111.32(11)             C(2)-C(1)-H(1A)             109.4             C(6)-C(1)-H(1A)             109.4             C(2)-C(1)-H(1B)             109.4             C(6)-C(1)-H(1B)             109.4             H(1A)-C(1)-H(1B)            108.0             O(1)-C(2)-C(3)              122.00(13)             O(1)-C(2)-C(1)              122.50(13)             C(3)-C(2)-C(1)              115.42(12)             C(4)-C(3)-C(2)              122.11(13)             C(4)-C(3)-H(3)              118.9             C(2)-C(3)-H(3)              118.9             C(3)-C(4)-C(5)              124.96(13)             C(3)-C(4)-H(4)              117.5             C(5)-C(4)-H(4)              117.5             N(1)-C(5)-C(4)              108.76(11)             N(1)-C(5)-C(12)             106.32(10)             C(4)-C(5)-C(12)             109.24(11)             N(1)-C(5)-C(6)              109.42(11)             C(4)-C(5)-C(6)              110.72(11) 193              C(12)-C(5)-C(6)             112.23(11)             O(2)-C(6)-C(1)              103.48(11)             O(2)-C(6)-C(5)              111.75(11)             C(1)-C(6)-C(5)              112.78(11)             O(2)-C(6)-H(6)              109.6             C(1)-C(6)-H(6)              109.6             C(5)-C(6)-H(6)              109.6             O(2)-C(7)-C(8)              109.73(11)             O(2)-C(7)-H(7A)             109.7             C(8)-C(7)-H(7A)             109.7             O(2)-C(7)-H(7B)             109.7             C(8)-C(7)-H(7B)             109.7             H(7A)-C(7)-H(7B)            108.2             N(1)-C(8)-C(7)              110.90(12)             N(1)-C(8)-C(19)             110.70(12)             C(7)-C(8)-C(19)             112.18(12)             N(1)-C(8)-H(8)              107.6             C(7)-C(8)-H(8)              107.6             C(19)-C(8)-H(8)             107.6             O(3)-C(9)-N(1)              121.45(13)             O(3)-C(9)-C(10)             121.54(13)             N(1)-C(9)-C(10)             117.00(12)             C(11)-C(10)-C(9)            111.68(11)             C(11)-C(10)-H(10A)          109.3             C(9)-C(10)-H(10A)           109.3             C(11)-C(10)-H(10B)          109.3 194              C(9)-C(10)-H(10B)           109.3             H(10A)-C(10)-H(10B)         107.9             C(12)-C(11)-C(16)           120.31(13)             C(12)-C(11)-C(10)           119.08(12)             C(16)-C(11)-C(10)           120.41(12)             C(11)-C(12)-C(13)           118.75(12)             C(11)-C(12)-C(5)            117.40(12)             C(13)-C(12)-C(5)            123.83(12)             C(14)-C(13)-C(12)           120.88(13)             C(14)-C(13)-H(13)           119.6             C(12)-C(13)-H(13)           119.6             O(4)-C(14)-C(13)            125.32(13)             O(4)-C(14)-C(15)            114.92(12)             C(13)-C(14)-C(15)           119.76(13)             O(5)-C(15)-C(16)            125.36(12)             O(5)-C(15)-C(14)            115.20(12)             C(16)-C(15)-C(14)           119.43(13)             C(15)-C(16)-C(11)           120.83(13)             C(15)-C(16)-H(16)           119.6             C(11)-C(16)-H(16)           119.6             O(4)-C(17)-H(17A)           109.5             O(4)-C(17)-H(17B)           109.5             H(17A)-C(17)-H(17B)         109.5             O(4)-C(17)-H(17C)           109.5             H(17A)-C(17)-H(17C)         109.5             H(17B)-C(17)-H(17C)         109.5 195              O(5)-C(18)-H(18A)           109.5             O(5)-C(18)-H(18B)           109.5             H(18A)-C(18)-H(18B)         109.5             O(5)-C(18)-H(18C)           109.5             H(18A)-C(18)-H(18C)         109.5             H(18B)-C(18)-H(18C)         109.5             O(6)-C(19)-O(7)             125.41(14)             O(6)-C(19)-C(8)             125.96(13)             O(7)-C(19)-C(8)             108.62(12)             O(7)-C(20)-H(20A)           109.5             O(7)-C(20)-H(20B)           109.5             H(20A)-C(20)-H(20B)         109.5             O(7)-C(20)-H(20C)           109.5             H(20A)-C(20)-H(20C)         109.5             H(20B)-C(20)-H(20C)         109.5             C(9)-N(1)-C(8)              114.45(12)             C(9)-N(1)-C(5)              120.95(11)             C(8)-N(1)-C(5)              122.05(11)             C(7)-O(2)-C(6)              110.29(10)             C(14)-O(4)-C(17)            116.79(11)             C(15)-O(5)-C(18)            117.37(11)             C(19)-O(7)-C(20)            115.29(13)             H(8A)-O(8)-H(8B)            104(2)            _____________________________________________________________              Symmetry transformations used to generate equivalent atoms: 196      Table 4.  Anisotropic displacement parameters (A^2 x 10^3) for mc049.     The anisotropic displacement factor exponent takes the form:     -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]       _______________________________________________________________________                 U11        U22        U33        U23        U13        U12     _______________________________________________________________________       C(1)     18(1)      25(1)      19(1)      -2(1)      -2(1)      -2(1)     C(2)     23(1)      21(1)      19(1)      -5(1)      -6(1)      -1(1)     C(3)     27(1)      19(1)      14(1)      -1(1)      -2(1)      -1(1)     C(4)     22(1)      20(1)      13(1)      -2(1)      -1(1)      -4(1)     C(5)     21(1)      17(1)      16(1)      -1(1)      -1(1)      -1(1)     C(6)     20(1)      21(1)      17(1)       1(1)      -3(1)      -4(1)     C(7)     28(1)      20(1)      24(1)      -3(1)      -3(1)      -5(1)     C(8)     28(1)      18(1)      18(1)      -1(1)      -5(1)      -2(1)     C(9)     26(1)      18(1)      12(1)       4(1)       1(1)       2(1)     C(10)    20(1)      21(1)      17(1)       1(1)       2(1)       0(1)     C(11)    21(1)      15(1)      18(1)       1(1)       2(1)      -2(1)     C(12)    21(1)      15(1)      16(1)       1(1)      -1(1)      -2(1)     C(13)    17(1)      21(1)      18(1)       2(1)       0(1)      -2(1)     C(14)    21(1)      20(1)      16(1)       1(1)       2(1)      -2(1)     C(15)    20(1)      19(1)      16(1)       2(1)      -2(1)      -2(1)     C(16)    19(1)      19(1)      19(1)       2(1)       1(1)      -1(1)     C(17)    22(1)      60(1)      19(1)      -4(1)       3(1)       6(1) 197      C(18)    17(1)      41(1)      24(1)      -2(1)      -3(1)      -3(1)     C(19)    28(1)      19(1)      20(1)      -2(1)      -6(1)       3(1)     C(20)    88(2)      32(1)      19(1)       2(1)     -20(1)      -7(1)     N(1)     23(1)      18(1)      15(1)      -1(1)      -2(1)       0(1)     O(1)     23(1)      28(1)      30(1)      -1(1)      -7(1)       4(1)     O(2)     24(1)      22(1)      22(1)      -3(1)      -6(1)      -3(1)     O(3)     30(1)      21(1)      15(1)      -1(1)       2(1)       3(1)     O(4)     19(1)      37(1)      15(1)       0(1)       1(1)       0(1)     O(5)     19(1)      36(1)      16(1)       0(1)      -3(1)      -1(1)     O(6)     41(1)      23(1)      19(1)       2(1)      -4(1)      -5(1)     O(7)     62(1)      24(1)      19(1)       1(1)     -15(1)      -7(1)     O(8)     23(1)      43(1)      19(1)       1(1)       1(1)       0(1)     _______________________________________________________________________    198           Table 5.  Hydrogen coordinates ( x 10^4) and isotropic          displacement parameters (A^2 x 10^3) for mc049.            ________________________________________________________________                            x             y             z           U(eq)          ________________________________________________________________             H(1A)         513          4294          7774          25           H(1B)        1996          4823          8153          25           H(3)         3596          6138          6570          24           H(4)         5431          4824          6792          22           H(6)         2379          2785          7957          23           H(7A)        1640          1369          6441          29           H(7B)        2264          1235          7222          29           H(8)         4368          1022          6526          25           H(10A)       8443          2850          7403          23           H(10B)       7607          3970          7064          23           H(13)        3439          3894          8792          23           H(16)        8748          3496          8578          23           H(17A)       3098          5073          9753          50           H(17B)       3149          4662         10549          50           H(17C)       2698          3737          9954          50           H(18A)       9901          3241          9646          41           H(18B)       9903          4138         10289          41           H(18C)       9744          4631          9512          41 199            H(20A)       2961          2644          4582          70           H(20B)       2900          1282          4364          70           H(20C)       4518          1920          4476          70           H(8A)        2090(30)       981(19)      9127(13)      48(6)           H(8B)        1300(30)       921(19)      8504(11)      41(6)          ________________________________________________________________    200           Table 6.  Torsion angles [deg] for mc049.          ________________________________________________________________             C(6)-C(1)-C(2)-O(1)                                 140.59(13)           C(6)-C(1)-C(2)-C(3)                                 -42.66(16)           O(1)-C(2)-C(3)-C(4)                                -168.66(13)           C(1)-C(2)-C(3)-C(4)                                  14.58(19)           C(2)-C(3)-C(4)-C(5)                                   1.6(2)           C(3)-C(4)-C(5)-N(1)                                 131.32(14)           C(3)-C(4)-C(5)-C(12)                               -113.03(15)           C(3)-C(4)-C(5)-C(6)                                  11.06(18)           C(2)-C(1)-C(6)-O(2)                                 -65.27(13)           C(2)-C(1)-C(6)-C(5)                                  55.65(15)           N(1)-C(5)-C(6)-O(2)                                 -42.96(15)           C(4)-C(5)-C(6)-O(2)                                  76.90(14)           C(12)-C(5)-C(6)-O(2)                               -160.74(10)           N(1)-C(5)-C(6)-C(1)                                -159.05(11)           C(4)-C(5)-C(6)-C(1)                                 -39.19(15)           C(12)-C(5)-C(6)-C(1)                                 83.18(14)           O(2)-C(7)-C(8)-N(1)                                  50.69(15)           O(2)-C(7)-C(8)-C(19)                                -73.67(14)           O(3)-C(9)-C(10)-C(11)                              -147.18(13)           N(1)-C(9)-C(10)-C(11)                                32.02(16)           C(9)-C(10)-C(11)-C(12)                              -34.81(17)           C(9)-C(10)-C(11)-C(16)                              139.97(12)           C(16)-C(11)-C(12)-C(13)                              -0.49(19) 201            C(10)-C(11)-C(12)-C(13)                             174.29(12)           C(16)-C(11)-C(12)-C(5)                             -179.17(12)           C(10)-C(11)-C(12)-C(5)                               -4.39(18)           N(1)-C(5)-C(12)-C(11)                                43.58(15)           C(4)-C(5)-C(12)-C(11)                               -73.62(15)           C(6)-C(5)-C(12)-C(11)                               163.18(12)           N(1)-C(5)-C(12)-C(13)                              -135.03(13)           C(4)-C(5)-C(12)-C(13)                               107.77(14)           C(6)-C(5)-C(12)-C(13)                               -15.43(18)           C(11)-C(12)-C(13)-C(14)                               1.8(2)           C(5)-C(12)-C(13)-C(14)                             -179.58(12)           C(12)-C(13)-C(14)-O(4)                              178.89(13)           C(12)-C(13)-C(14)-C(15)                              -1.3(2)           O(4)-C(14)-C(15)-O(5)                                 0.48(18)           C(13)-C(14)-C(15)-O(5)                             -179.31(12)           O(4)-C(14)-C(15)-C(16)                              179.29(12)           C(13)-C(14)-C(15)-C(16)                              -0.5(2)           O(5)-C(15)-C(16)-C(11)                             -179.47(13)           C(14)-C(15)-C(16)-C(11)                               1.8(2)           C(12)-C(11)-C(16)-C(15)                              -1.4(2)           C(10)-C(11)-C(16)-C(15)                            -176.06(12)           N(1)-C(8)-C(19)-O(6)                                -13.2(2)           C(7)-C(8)-C(19)-O(6)                                111.24(17)           N(1)-C(8)-C(19)-O(7)                                166.29(12)           C(7)-C(8)-C(19)-O(7)                                -69.24(15)           O(3)-C(9)-N(1)-C(8)                                  -8.10(18) 202            C(10)-C(9)-N(1)-C(8)                                172.70(11)           O(3)-C(9)-N(1)-C(5)                                -170.37(12)           C(10)-C(9)-N(1)-C(5)                                 10.43(18)           C(7)-C(8)-N(1)-C(9)                                 163.83(12)           C(19)-C(8)-N(1)-C(9)                                -70.97(15)           C(7)-C(8)-N(1)-C(5)                                 -34.12(17)           C(19)-C(8)-N(1)-C(5)                                 91.08(15)           C(4)-C(5)-N(1)-C(9)                                  69.78(15)           C(12)-C(5)-N(1)-C(9)                                -47.75(15)           C(6)-C(5)-N(1)-C(9)                                -169.16(12)           C(4)-C(5)-N(1)-C(8)                                 -91.13(14)           C(12)-C(5)-N(1)-C(8)                                151.35(12)           C(6)-C(5)-N(1)-C(8)                                  29.94(17)           C(8)-C(7)-O(2)-C(6)                                 -68.79(14)           C(1)-C(6)-O(2)-C(7)                                -173.08(11)           C(5)-C(6)-O(2)-C(7)                                  65.30(14)           C(13)-C(14)-O(4)-C(17)                              -10.2(2)           C(15)-C(14)-O(4)-C(17)                              170.06(13)           C(16)-C(15)-O(5)-C(18)                               11.9(2)           C(14)-C(15)-O(5)-C(18)                             -169.38(13)           O(6)-C(19)-O(7)-C(20)                                 0.7(2)           C(8)-C(19)-O(7)-C(20)                              -178.79(15)          ________________________________________________________________     203  Table 7.  Hydrogen Bonds  Donor --- H....Acceptor [    ARU  ]      D - H      H...A      D...A  D - H...A     -------------------------------------------------------------------------------- O(8)  --H(8A)  ..O(4)   [  3457.01]    0.90(2)    2.54(3) 3.2589(15)     138(2) O(8)  --H(8A)  ..O(5)   [  3457.01]    0.90(2)    2.03(3) 2.8679(15)     155(2) O(8)  --H(8B)  ..O(1)   [  4546.01]    0.85(3)    1.97(3) 2.8252(16)     176(2)    Translation of ARU-code to Equivalent Position Code ===================================================    [  3457. ]  = -1/2+x,1/2-y,2-z    [  4546. ]  = -x,-1/2+y,3/2-z      

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.24.1-0363880/manifest

Comment

Related Items