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Synthetic studies towards homotyrosinol sulfonamide derivatives via Heck-Mizoroki coupling reactions Zhou, Yuan 2009

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SYNTHETIC STUDIES TOWARDS HOMOTYROSINOL SULFONAMIDE DERIVATIVES VIA HECK-MIZOROKI COUPLING REACTIONS  by  YUAN ZHOU  B. Sc., University of Science and Technology of China, 2006  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Chemistry)   THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  December 2009 © YUAN ZHOU, 2009  ii Abstract  Homotyrosine, as a nonproteinogenic α-amino acid, is present as a component of diverse natural products that have important biological activities. Therefore, homotyrosine and its derivatives are important precursors for the total synthesis of some natural products. However, up to now, there was no report concerning a reliable synthetic route towards the synthesis of homotyrosine or its derivatives in a preparative scale.   In this thesis, a robust method was developed for the preparation of homotyrosinol derivatives and related intermediates through a Mizoroki-Heck coupling reaction between an aryl iodide and appropriate amino acid-derived olefins in the presence of N-phenylurea as the ligand. In addition, a preparative scale protocol for the oxidative cyclization of the homotyrosinol sulfonamide derivative was established. These results are essential for various synthetic efforts towards more complicated natural products ongoing in our laboratory.          iii Table of Contents Abstract.............................................................................................................................. ii Table of Contents .............................................................................................................. ii List of Tables ......................................................................................................................v List of Figures................................................................................................................... vi List of Schemes ...................................................................................................................x List of Abbreviations ...................................................................................................... xii Acknowledgments .......................................................................................................... xvi Chapter 1. Introduction.....................................................................................................1 1.1. Homotyrosine as an important precursor for total synthesis of natural products .........4 1.2. Previous syntheses towards homotyrosine and its derivatives .....................................8 1.2.1. Catalytic enantioselective hydrogenation route .........................................................8 1.2.2. Organometallic route ...............................................................................................12 1.2.3. Hydroboration-Suzuki cross coupling route ............................................................14 1.2.4. Friedel-Crafts acylation route ..................................................................................20 1.2.5. Michael addition route .............................................................................................22 1.2.6. 1, 3-dipolar cycloaddition route...............................................................................23 Chapter 2. Discussion ......................................................................................................26 2.1. Objectives and approach .............................................................................................26 2.2. Synthesis of vinyl glycinol derivatives .......................................................................27 2.3. Study on the alkene metathesis approach ...................................................................28 2.4. The Suzuki coupling route ..........................................................................................30 2.5. The Heck coupling route.............................................................................................32  iv 2.5.1. Ligand screening......................................................................................................35 2.5.2. Substrate scope.........................................................................................................38 2.5.3. The base ...................................................................................................................40 2.5.4. The breakthrough: N-Phenylurea as ligand..............................................................41 2.5.5 The determination of optical purity ..........................................................................42 2.5.6 Literature procedure..................................................................................................44 2.6. Synthesis of N-mesyl-O-silyl homotyrosinol .............................................................46 2.7. Synthesis of other analogues using a similar approach ..............................................47 2.8. Oxidative cyclization of homotyrosinol derivative 2.48.............................................49 References .........................................................................................................................50 Appendix: Experimental Section....................................................................................56              v List of Tables  Table 2.1. Conversion and yields by different catalysts ...................................................31 Table 2.2. Ligands screen with Pd(OAc)2 in Heck coupling reaction ..............................37 Table 2.3. Reaction using SPhos as ligand........................................................................39 Table 2.4. Substrate scope for Pd(OAc)2 catalyzed Heck coupling reaction....................40 Table 2.5. Reaction using N-Phenylurea as ligand............................................................43 Table 2.6. Heck reaction of 2.17 with 2.33 under Gobel conditions ................................46 Table 2.7. Heck reaction of 2.33 with 2.50 with a Pd-phenylurea complex .....................50                vi List of Figures  Figure 1.1. Nonproteinogenic amino acids……………………………………………….1 Figure 1.2. ACE inhibitors and Luzopeptins……………………………………………..2 Figure 1.3. Luzopeptin E2: Natural Products Containing N-Methyl-3-Hydroxyvaline and Piperazic Acid……………………………………………………………………………..2 Figure 1.4. Microcystins………………………………………………………………….3 Figure 1.5. Lyngbyastatin 4………………………………………………………………4 Figure 1.6. Structure of (-)-lepadiformine………………………………………………..7 Figure 2.1. Grubbs and Hoveyda catalysts .......................................................................30 Figure 2.2. 19F-NMR spectrum of 2.44 .............................................................................44 Figure 2.3. The Gobel synthesis of compounds 2.46 by Heck reaction ...........................45 Figure 2.4. The crystal structure of compound 2.64 .........................................................53 Figure A.1.1H NMR spectrum of 2.6 ................................................................................63 Figure A.2. 13C NMR spectrum of 2.6 ..............................................................................63 Figure A.3. IR spectrum of 2.6 .........................................................................................64 Figure A.4. 1H NMR spectrum of 2.7…………………………………………………...66 Figure A.5. 13C NMR spectrum of 2.7 ..............................................................................66 Figure A.6. IR spectrum of 2.7 .........................................................................................67 Figure A.7. 1H NMR spectrum of 2.11 .............................................................................69 Figure A.8. 13C NMR spectrum of 2.11 ............................................................................69 Figure A.9. IR spectrum of 2.11 .......................................................................................70 Figure A.10. 1H NMR spectrum of 2.10 ...........................................................................72  vii Figure A.11. 13C NMR spectrum of 2.10 ..........................................................................72 Figure A.12. IR spectrum of 2.10 .....................................................................................73 Figure A.13. 1H NMR spectrum of 2.9 .............................................................................75 Figure A.14. 13C NMR spectrum of 2.9 ............................................................................75 Figure A.15. IR spectrum of 2.9 .......................................................................................76 Figure A.16. 1H NMR spectrum of 2.15 ...........................................................................78 Figure A.17. 13C NMR spectrum of 2.15 ..........................................................................79 Figure A.18. IR spectrum of 2.15 .....................................................................................79 Figure A.19. 1H NMR spectrum of 2.16 ...........................................................................81 Figure A.20. 13C NMR spectrum of 2.16 ..........................................................................82 Figure A.21. IR spectrum of 2.16 .....................................................................................82 Figure A.22. 1H NMR spectrum of 2.17 ...........................................................................84 Figure A.23. 13C NMR spectrum of 2.17 ..........................................................................85 Figure A.24. IR spectrum of 2.17 .....................................................................................85 Figure A.25. 1H NMR spectrum of 2.37e .........................................................................87 Figure A.26. 13C NMR spectrum of 2.37e ........................................................................87 Figure A.27. IR spectrum of 2.37e....................................................................................88 Figure A.28. 1H NMR spectrum of 2.34 ...........................................................................91 Figure A.29. 13C NMR spectrum of 2.34 ..........................................................................91 Figure A.30. IR spectrum of 2.34 .....................................................................................92 Figure A.31. 1H NMR spectrum of 2.35 ...........................................................................94 Figure A.32. 13C NMR spectrum of 2.35 ..........................................................................94 Figure A.33. IR spectrum of 2.35 .....................................................................................95  viii Figure A.34. 1H NMR spectrum of 2.39b.........................................................................97 Figure A.35. 13C NMR spectrum of 2.39b........................................................................97 Figure A.36. IR spectrum of 2.39b ...................................................................................98 Figure A.37. 1H NMR spectrum of 2.39e .......................................................................100 Figure A.38. 13C NMR spectrum of 2.39e ......................................................................100 Figure A.39. IR spectrum of 2.39e..................................................................................101 Figure A.40. 1H NMR spectrum of 2.42 .........................................................................104 Figure A.41. 13H NMR spectrum of 2.42........................................................................104 Figure A.42. IR spectrum of 2.42 ...................................................................................105 Figure A.43. 1H NMR spectrum of 2.44 .........................................................................107 Figure A.44. 13H NMR spectrum of 2.44........................................................................107 Figure A.45. 19F NMR spectrum of 2.44 ........................................................................108 Figure A.46. IR spectrum of 2.44 ...................................................................................108 Figure A.47. 1H NMR spectrum of 2.47 .........................................................................111 Figure A.48. 13H NMR spectrum of 2.47........................................................................111 Figure A.49. IR spectrum of 2.47 ...................................................................................112 Figure A.50. 1H NMR spectrum of 2.48 .........................................................................114 Figure A.51. 13H NMR spectrum of 2.48........................................................................114 Figure A.52. IR spectrum of 2.48 ...................................................................................115 Figure A.53. 1H NMR spectrum of 2.51a .......................................................................118 Figure A.54. 13H NMR spectrum of 2.51a......................................................................118 Figure A.55. 1H NMR spectrum of 2.51b.......................................................................120 Figure A.56. 13H NMR spectrum of 2.51b .....................................................................120  ix Figure A.57. 1H NMR spectrum of 2.51c .......................................................................122 Figure A.58. 13H NMR spectrum of 2.51c ......................................................................122 Figure A.59. 1H NMR spectrum of 2.64 .........................................................................124 Figure A.60. 13H NMR spectrum of 2.64........................................................................124                     x List of Schemes  Scheme 1.1. Synthesis of (+)-PHNO from L-homotyrosine derivative ..............................5 Scheme 1.2. Synthetic route to (-)-cylindricine precursor ..................................................6 Scheme 1.3. Retrosynthetic logic for (-)-lepadiformine......................................................8 Scheme 1.4. Enantioselective hydrogenation....................................................................10 Scheme 1.5. DPAMPP catalyzed enantioselective hydrogenation ...................................10 Scheme 1.6. R-H8-MonoPhos catalyzed enantioselective hydrogenation .........................12 Scheme 1.7. Synthesis of homotyrosine derivative from organozinc reagent ..................13 Scheme 1.8. Synthesis of homophenylalanine from organolithium reagent .....................14 Scheme 1.9. Example of organozinc reagent and by-product in the synthetic path..........15 Scheme 1.10. The Taylor synthesis of Garner aldehyde and the derived organoborane ..16 Scheme 1.11. Homotyrosine precursor synthesis with Cbz-borane ..................................17 Scheme 1.12. Synthesis of homotyrosine derivative using Suzuki coupling ....................18 Scheme 1.13. Preparation and kinetic resolution of alcohol 1.82 .....................................19 Scheme 1.14. Synthesis of organoborone and Suzuki coupling reaction..........................20 Scheme 1.15. Synthesis steps towards 1.91 ......................................................................20 Scheme 1.16. The Nordlander synthesis of a homotyrosine derivative ............................21 Scheme 1.17. The Melillo synthesis of homotyrosine methyl ether .................................22 Scheme 1.18. The Hashimoto approach to homotyrosine derivatives ..............................23 Scheme 1.19. The Yamada synthesis of homotyrosine using Michael addition ...............24 Scheme 1.20. Synthesis of husing 1, 3-dipolar cycloaddition...........................................25  xi Scheme 2.1. Strategies for the synthesis of homotyrosinol sulfonamides explored in the course of this study ............................................................................................................27 Scheme 2.2. Synthesis of vinyl glycinol derivatives.........................................................28 Scheme 2.3. General alkene metathesis ............................................................................29 Scheme 2.4. Alkene metathesis .........................................................................................31 Scheme 2.5. Boron derivatives synthesis ..........................................................................32 Scheme 2.6. Approach to 1.32 by a heck reaction ............................................................33 Scheme 2.7. Presumed mechanism of the Heck reaction..................................................34 Scheme 2.8. Reduction of Pd(II) to Pd(0) according to Amatore .....................................34 Scheme 2.9. Heck coupling reaction .................................................................................35 Scheme 2.10. Heck coupling reaction with base NaHCO3 ...............................................41 Scheme 2.11. Optical purity of Heck coupling product ....................................................44 Scheme 2.12. Synthesis of L-homotyrosine derivative .....................................................47 Scheme 2.13. Tetrahentate Phosphine Ligand used in Pd-catalyzed Heck Reactions of Vinyl Sulfide Derivatives ..................................................................................................49 Scheme 2.14. Bidentate Phosphine Ligand used in Pd-catalyzed Heck Reactions of Vinyl Sulfide Derivatives.............................................................................................................49 Scheme 2.15. Oxidative Cyclization of Sulfonamide Derivatives of Homotyrosinol ......51 Scheme 2.16. Presumed Mechanism of Oxidative Cyclization of 2.57 ............................52 Scheme 2.17. Oxidative Cyclization of 2.63 .....................................................................53     xii List of Abbreviations  Å   angstrom Ac   acetyl aq.   aqueous atm   atmosphere br   broad Bn   benzyl Boc   tert-butyloxycarbonyl Bu   butyl oC   degrees Celsius calcd   calculated cat.   catalytic cm-1   wave-number(s) conc.   concentrated Cy   cyclohexyl δ   chemical shift in parts per million downfield of tetramethylsilane d   doublet DBU   1,8-Diazabicyclo[5.4.0]undec-7-ene DIB   diacetoxyiodobenzene DIPAMP (S)-(2-methoxyphenyl)-[2-[(2-methoxyphenyl) phenylphosphanyl]ethyl]-phenylphosphane DMAC  N,N-dimethylacetamide  xiii DMF   N, N-dimethylformamide DMSO   dimethyl sulfoxide DPPE   1,2-bis(diphenylphosphino)ethane DPAMPP N-((1S,2R)-2-(diphenylphosphinooxy)-1,2-diphenylethyl)-N- methyl-1,1-diphenylphosphinamine dppf   1,1'-Bis(diphenylphosphino)ferrocene e.e   enantiomeric excess equiv.   equivalent ESI   electrospray ionization Et   ethyl g   gram(s) gem   geminal hex   hexane HMDS   hexamethyldisilazane HRMS   high resolution mass spectrum Hz   Hertz i   iso IR   infrared J   coupling constant LAH   lithium aluminaum hydride m   meta m   multiple M   molar (moles per litre); mega  xiv Me   methyl mol   mole(s) mp   melting point Ms   methylsulfonyl MS   mass spectrum n   normal NMR   nuclear magnetic resonance Nu   nucleophile o   ortho p   para PCC   pyridinium chlorochromate PG   protecting group Ph   phenyl PMB   p-methoxyphenylmethyl ppm   parts per million Pr   propyl Py   pyridine q   quartet quant.   quantitative r.t.   room temperature s   secondary s   singlet sat.   saturated  xv t   tertiary TBAF   tetra-n-butylammonium fluoride TBAB   tetrabutylammonium bromide TBDPS  tert-butyl-diphenylsilyl TBS   tert-butyl-dimethylsilyl Tf   triflate TFA   trifluoroacetic acid THF   tetrahydrofuran TLC   thin layer chromatography TMS   trimethylsilyl tol   toluene Ts   p-toluenesulfonyl UV   ultra-violet m   micro           xvi Acknowledgements   First and foremost, I am deeply grateful to my supervisor, Dr. Marco. A. Ciufolini, for his mentorship and encouragement throughout the course of my degree.  Without his hard work, patience, dedication and encouragement, this work would have been impossible for me to finish.   I am also grateful to my co-workers in the Ciufolini’s lab. Thanks Dr. Steven Liang for teaching me name reactions; Dr. Jianmin Zhang for providing useful advice; Simon Kim, Veeru Aulakh, Jacyln Chau and Charles Turner for innumerable useful discussions. Because of them, my time here was made to be much more pleasurable and productive than it would otherwise have been.   Many collaborators in the chemistry department deserve thanks: Dr. Yun Ling for providing high resolution mass spectrum and elemental analysis; Dr. Brian Patrick for obtaining the crystal structure for me.   I am eternally grateful for all of the support from my family. To my parents far away in China and the most important person here Ran, so thanks to you all.      1  Chapter 1: Introduction  As their name implies, the so-called nonproteinogenic α-amino acids are α-amino acids that are not commonly found in proteins, even though they may be observed as components of diverse natural products and drug molecules. Examples include homophenylalanine, 1.1,1 α-aminobutyric acid, 1.2,2 homotyrosine, 1.3, 3-hydroxy-N- methylvaline, 1.4, piperazic acids, 1.5,3 and so on. For instance, a number of angiotensin-  COOH NH2 1.1 L-homophenylalanine OH O NH2 1.2 -Aminobutyric acid COOH NH2 1.3 L-homotyrosine HO H N O OH OH 1.4 3-hydroxy-N-methylvaline N H NH O OH 1.5 piperazic acid  Figure 1.1: Nonproteinogenic Amino Acids  converting enzyme (ACE) inhibitors, which are used for the treatment of hypertension and congestive heart failure,4,5 incorporate L-homophenylalanine (1.1).  Examples include Benazepril (1.6) and Enalapril (1.7), which are widely used in clinical practice.  2   Figure 1.2: ACE inhibitors Incorporating Homophenylalanine   The aminoacid, N-methyl-3-hydroxyvaline is found, e.g., in luzopeptins, peptide natural products that exhibit potent antiretroviral activity.6 These substances also display piperazic acid residues, which are widespread among natural products.7  H N Me N O O O N Me OH O H N HO Me N N H O O HO H 1.8 luzopeptin E2 O HN N O O H N O N OH MeO H H O NH N N H O N H OH OMe HO   Figure 1.3: Luzopeptin E2: Natural Products Containing N-Methyl-3-Hydroxyvaline and Piperazic Acid   3  Homotyrosine can be found in a variety of natural products, especially cyclic peptides isolated from cyanobacteria. Notable examples are the microcystins (MC, Figure 1.4), a class of toxic cyclic heptapeptides produced by organisms of the genera Anabaena, Microcystis, and Oscillatoria (Planktothrix) and Nostoc.8 Homotyrosine is present in MCs such as oscillamide Y (1.10),9 cyanopeptolins 880 (1.11)10 and anabaenopeptins 915 (1.12).11    Figure 1.4: Microcystins   4 Homotyrosine is also present as a component of lyngbyastatin 4 (1.13), a depsipeptide isolated from the marine cyanobacterium Lyngbya confervoides.12 This natural product is a highly selective inhibitor of elastase13 and chymotrypsin,14 with IC50  HO N N H O HO N O O O NH O O O H N OH H N O N H O OSO3H OH 1.13 Lyngbyastatin 4 HN O   Figure 1.5: Lyngbyastatin 4  values of 0.03 and 0.30 μM, respectively, while it is essentially inactive toward other serine protease such as trypsin and thrombin.  The synthesis of nonproteinogenic α-amino acids and their derivatives continues to attract the interest of the synthetic community15 on account of their considerable potential as building blocks in natural product and medicinal chemistry. In addition, a number of these compounds have important biological functions.16  1.1 Homotyrosine as an important precursor for total synthesis of natural products  Homotyrosine and its derivatives are also useful as chiral intermediates for the synthesis of medicinal agents and natural products. For example, the Melillo synthesis  5 17of (R, R)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO, 1.18], a dopamine agonist with therapeutic potential in the treatment of Parkinson’s disease,18 started from D- homotyrosine. As seen in Scheme 1.1, this aminoacid undergoes Friedel-Crafts cyclization to 1.15, which is elaborated into the final 1.18 in a straightforward manner. The pharmacologically active R, R enantiomer is thus obtained directly.    (a) Oxalyl chloride/CH2Cl2/DMF; (b) TiCl4/CH2Cl2; H3O+; silica gel; (c) NaAlH2(OCH2CH2OCH3)2/t-BuOMe/tol; (d) KOH/MeOH/H2O; (e) (EtCO)2O; (f) BH3Me2S/THF; NaOH/H2O; (g) ClCH2COCl/Na2CO3/H2O/tol; (h) NaOH/H2O/tol/n- Bu4NCl; (i) NaAlH2(OCH2CH2OCH3)2/tol; NaOH/H2O; (j) HCl; (k) MeSO3H/ methionine.  Scheme 1.1: Synthesis of (+)-PHNO from L-homotyrosine derivative  The Ciufolini synthesis of (-)-cylindricine C (1.20) and (-)-2-epicylindricine C (1.21)19 illustrates an application of homotyrosine in natural product chemistry. Cylindricines are structurally unique alkaloids produced by the ascidian, Clavelina  6 cylindrical.20 They have elicited considerable interest in the synthetic arena due to their unusual architecture and moderate cytotoxic activity.  A key sequence in the Ciufolini synthesis of the common precursor 1.26 was the oxidative cyclization of derivative 1.22 of D-homotyrosine (Scheme 1.2).  N O n-C6H13 H OH H N O H OH H n-C6H13 1.20 (-)-Cylindricine C 1.21 (-)-2-Epicyclindricine C HN OTBDPS n-C6H13 O B O O H 1.26 1.22 MsN O OTBDPS N O2 S OTBDPS N O2 S OTBDPS n-C6H13 O 1.23 1.24 1.25 a-f g-i j-k l HO NH2 COOH   (a) SOCl2/MeOH; (b) MsCl/TEA (excess), CH2Cl2, 0oC, 91% over two steps; (c) NaBH4/EtOH/THF, 94%; (d) NaOH/dioxane, 80oC, 90%; (e) PhI(OAc)2, (CF3)2CHOH, room temperature; (f) tBuPh2SiCl, imidazole, DMF, room temperature, 82% over two steps; (g) KHMDS, THF, -100oC, 89% (d.r.=7:1); (h) PhSH, BF3OEt2 (cat.), CH2Cl2, 0oC, 77%; (i) Raney Ni, EtOH/THF, 77%; (j) tBuLi, THF, -78oC, (+/-)-1-octene oxide,  7 BF3OEt2; (k) DMP, CH2Cl2, room temperature, 88% over two steps; (l) 1. DBU, DMF; 2. bis(pinacolyl)diboronate, CuCl, KOAc, room temperature, 86%.  Scheme 1.2: Synthetic Route to (-)-Cylindricine Precursor  An ongoing effort in these laboratories aims to achieve the synthesis of (-)- lepadiformine (1.27). This substance was isolated in 1994 by Biard et al. from the tunicate, Clavelina lepadiformis,21 and it was subsequently found to possess moderate cytotoxicity against KB and non-small-cell lung carcinoma cells. In addition, it was also found to be a cardiac K+-channel blocker.22    Figure 1.6: Structure of (-)-Lepadiformine  Structurally and biosynthetically, lepadiformine is related to the cylindricines (1.20 and 1.21).20,23 Accordingly, our group’s strategy for the synthesis of 1.27 also rests on the oxidative amidation of homotyrosine derivative 1.32 to generate the nitrogen- containing spirocyclic unit of the molecule, as outlined in Scheme 1.3. Either enantiomeric form of homotyrosine and of various derivatives is article of commerce; however, they are expensive ($500 for 5 g). Given their central role in  8 ongoing efforts in our laboratory, we decided to develop a practical synthesis from readily available intermediates. Indeed, the objective of this study was to establish a reliable avenue to homotyrosinol, which is the starting point of a number of our current synthetic efforts.    Scheme 1.3: Retrosynthetic Logic for (-)-Lepadiformine  1.2. Previous syntheses of homotyrosine and its derivatives  Past asymmetric syntheses of homotyrosine have relied primarily on Noyori-type asymmetric catalytic hydrogenation to create the N-bearing stereogenic center, or on Negishi or Suzuki coupling reactions of a chiral organometallic agent with an appropriate aryl building block. Alternative approaches have involved Friedel-Crafts reaction of an aromatic substrate with an aminoacid-derived acylating agent, Michael additions of α- methylbenzylamine to appropriate unsaturated dicarbonyl compounds, and 1,3-dipolar  9 cycloadditions of chiral nitrones to styrenes. The following paragraphs illustrate representative syntheses of homotyrosine and derivatives using these technologies.  1.2.1 Catalytic enantioselective hydrogenation route  Melillo et al. achieved the catalytic asymmetric hydrogenation of acrylate derivative 1.39 with chiral rhodium catalysts (Scheme 1.4).17 Thus, condensation of 1.34 with methyl carbamate in the presence of a catalytic amount of p-toluenesulfonic acid (toluene, 80 oC) provided a mixture of (Z)-olefin 1.35, (E)-olefin 1.36 and dicarbamate adduct 1.37 in a ratio of 3:3:4. Treatment of this mixture with gaseous HCl induced both the elimination of one molecule of methyl carbamate from 1.37 to form the acrylate-type product, as well as the isomerization of 1.36 to 1.35. Stereochemically pure 1.35 was then subjected to Rh-catalyzed asymmetric hydrogenation. Depending on the nature of the ligand utilized in the latter step, either enantiomer of the desired product could be obtained in 80-90% ee. To illustrate, a complex obtained through the interaction of [Rh(NBD)2]ClO4 with 1 equivalent of (R,R)-DIPAMP afforded (S)-1.39 of 90% ee, while the use of (S,S)-Chiralphos provided (R)-1.38 of 82% ee. The structures of the rhodium complex and the ligands appear in the scheme 1.4.   10   (a) Mg/THF; (b) (EtO2C)2, H3O+; (c) HOAc: 10% aq. H2SO4=1:1, 80% over three steps; (d) H2NCO2Me/ p-TSA/tol/reflux/-H2O; (e) HCl/tol/80 oC, 90% over two steps; (f) H2/[Rh(NBD)-((S,S)-chiraphos)]ClO4, MeOH, 80%; (g) H2/[Rh(NBD)2-((R,R)- DIPAMP)]ClO4, MeOH, 90%.  Scheme 1.4: Enantioselective Hydrogenation   11   Scheme 1.5: DPAMPP Catalyzed Enantioselective Hydrogenation  Jiang et al. extended the study of this asymmetric hydrogenation and applied it to the enantioselective synthesis of L-homophenylalanine 1.44,24 which is structurally similar to homotyrosine. Best results in this reaction were obtained by the use of a complex of Rh(I) with ligand 1.43 (DPAMPP; Scheme 1.5).  The DPAMPP ligand was introduced by Chan et al., who also produced monodentate ligands such as H8-MonoPhos (1.38). Rhodium complexes of the latter proved to be effective catalysts in asymmetric hydrogenation.25,26 Thus, enantioselectivities as high as 98.4% e.e. were observed in the hydrogenation of the substrates shown in Scheme 1.6, at a catalyst loading as low as 0.01 mol %.   12   Scheme 1.6: R-H8-MonoPhos Catalyzed Enantioselective Hydrogenation  1.2.2 Organometallic routes  Much progress has been made in the use of functionalized zinc reagents in the organic synthesis in the past two decades. Such organometallics are now readily prepared under mild conditions by the direct insertion of activated zinc into carbon-halogen bonds.27 For instance, functionalized zinc reagent 1.52, derived from protected L- iodoalanine 1.51, can be prepared as detailed in Scheme 1.7.  This material undergoes efficient Negishi-type coupling with benzoyl chloride to afford enantiopure ketone 1.53. The latter may be smoothly hydrogenated to furnish homotyrosine derivative 1.54 in a quantitative yield. The sequence proceeded with no erosion of optical purity.   13   (a) Zn/ Cu in benzene-dimethylacetamide at 60 oC; (b) 4-methoxy-benzoyl chloride, 6 mol% (Ph3P)2PdCl2, 63%; (c) H2, Pd/C, quant.  Scheme 1.7: Synthesis of Homotyrosine Derivative from Organozinc Reagent   Organozinc reagent 1.51 (Scheme 1.7) has found widespread use in the preparation of enantiopure, nonproteinogenic amino acids. However, it suffers from limitations such as a restricted range of compatible electrophiles, low reactivity in the absence of palladium or copper catalysts and poor nucleophilicity toward simple aldehydes and ketones. To palliate these difficulties, Taylor et al. investigated organolithium reagent 1.59 (Scheme 1.8), which added efficiently to aldehydes (e.g., benzaldehyde) and ketones, including cyclohexanone and cyclobutanone, in yields ranging from 75 to 98%.28 These workers did not demonstrate a synthesis of homotyrosine using 1.59; however, they did describe the preparation of homophenylalanine.   14   (a) MeOH; (b) Boc2O, Et3N, quant over two steps; (c) C2Cl6, Ph3P; (d) LiBH4, THF, 69% over two steps; (e) SEMCl, 80%; (f) n-BuLi; (g) Lithium naphthalenide; (h) benzaldehyde, 98% (3:2 ratio); (i) 0.1 M HCl in MeOH, 3h 79%.  Scheme 1.8: Synthesis of Homophenylalanine from Organolithium Reagent   Jackson et al. developed organozinc reagent 1.63 that behaves as a carrier of an amino acid γ-anion synthon (Scheme 1.9).27,29 Negishi coupling with aryl iodides proceeded as expected to give homotyrosine or homophenylalanine derivatives 1.66 in high optical purity. However, chemical yields were moderate. A major side reaction was protonolysis, resulting in formation of variable quantities of 1.67.   15   (a) activated Zn, r.t, 4-12h, 90%; (b) ArI, Pd2(dba)3 (0.625 mol%), P(o-tol)3 (2.5 mol%), THF, 50oC, 1h, 26-65%; (c) LiOMe (1 equiv.), MeOH, -10oC, 1h, 90%; (d) Et3SiH, Boc2O, Et3N, EtOH, 60 oC, 7d.  Scheme 1.9: Example of Organozinc Reagent and by-product in the Synthetic Path  1.2.3 Hydroboration-Suzuki cross coupling route  The Suzuki cross-coupling reaction30 constitutes an efficient and mild method for the synthesis of unnatural α-amino acids through union of an organoborane derivative of an amino acid with an appropriate vinyl or aryl halide. This chemistry has been largely developed by Taylor, et al.,31 and Johnson et al.32  The Taylor technology involves the elaboration of the Garner aldehyde, 1.70,33 into vinyl derivative 1.71, which subsequently undergoes hydroboration to produce 1.72  16 (Scheme 1.10). In this connection, Taylor also devised an improved procedure for the preparation of 1.7034 via LAH reduction of Weinreb amide 1.69.    (a) MeO(CH3)NH-HCl, EDCI, N-methylmorpholine; (b) DMP, acetone, BF3-OEt2, 90% over two steps; (c) LiAlH4; (d) Ph3P=CH2, 77% over two steps; (e) 9-BBN-H, THF, 0 oC to r.t, 2h.  Scheme 1.10: The Taylor Synthesis of Garner Aldehyde and the Derived Organoborane  The coupling of organoborane 1.72 with aryl halides provides rapid access to homotyrosine and homophenylalanine derivatives. However, the reaction with 4- iodoanisole leading to homotyrosine precursor 1.73 was moderate yielding and kinetically slow, overshadowing the application of the method for preparative purposes.  17   (a) 4-iodoanisole, PdCl2(dppf).CHCl3, DMF, 16h, 71%; (b) Jones’ Oxidation; (c) CH2N2 or TMSCHN2, 64% over two steps.  Scheme 1.11: Homotyrosine Precursor Synthesis with Cbz-borane   It should be noted that a Boc-protected analog of 1.75 was also prepared and studied.31 This borane proved to be inferior as a building block for amino acid synthesis in that the oxidation of 1.76 to 1.77 under Jones conditions35 promoted release of the Boc group (recall, the Jones reagent is strongly acidic). The premature liberation of the primary amino function during Jones oxidation resulted in diminished yields of 1.78. On the other hand, two N-Cbz and N-Boc versions of the borane underwent coupling in identical yield (71% and 72%, respectively).   18   (a) Ph3PCH3Br, KHMDS, THF, -78 oC to r.t, 2h, 80%; (b) 9-BBN-H, THF, 0 oC to r.t, 2h; (c) 4-iodoanisole, PdCl2(dppf).CHCl3, DMF, 16h, 72% over two steps; (d) Jones’ Oxidation; (e) CH2N2 or TMSCHN2, 54% over two steps; (f) 6M aq. HCl, anisole, 70 oC, 5h, 88%.  Scheme 1.12: Synthesis of Homotyrosine Derivative using Suzuki Coupling   Johnson et al. devised an alternative route to either enantiomer of building block 1.85 through lipase-catalyzed kinetic resolution of alcohol 1.82.32 The preparation of the latter started with an Overman-type36 rearrangement of bis-trichloroimidate derivative 1.80 of cis-2-butene-1,4-diol. In the present case, the rearrangement occurred under Pd- catalyst. The key step, the enantioselective acylation of (S)-1.82 promoted by Amano PS- 30 lipase, afforded 1.83 in 48% chemical yield and 96% ee, plus unreacted (R)-1.82, denoted in the scheme below as compound 1.84, in 46% chemical yield and 97% ee. It is  19   (a) CCl3CN, KH, 90-93%; (b) PdCl2(CH3CN)2, THF, 85%; (c) 6N HCl; (d) Boc2O, 60% over two steps; (e) PS-30 lipase, isopropenyl acetate, 48% for 1.83, 46% for 1.84; (f) KCN, MeOH, 93%; (g) 2,2-dimethoxypropane, acetone, BF3-Et2O, quant.  Scheme 1.13: Preparation and Kinetic Resolution of Alcohol 1.82  worthy of note that the resolution step was less efficient with an analog of 1.82 in which a Cbz group was present in lieu of a Boc protecting group.  Johnson also reported that the hydroboration of 1.86 with 9-BBN was considerably more efficient when carried out in toluene instead of THF, as indicated earlier by Taylor. The resultant 1.87 underwent smooth coupling with p-bromoanisole as well with a variety of other aryl halides and triflates. Two examples are shown in Scheme  20   (a) 9-BBN, Toluene, reflux, 0.5h; (b) 3.2N NaOH, 3 mol% Pd(PPh3)4, 90 oC, overnight. 1-bromo-4-methoxybenzene, 94% over two steps; 4-methoyxyphenyl trifluoromethane- sulfonate, 85% over two steps.  Scheme 1.14: Synthesis of Organoborone and Suzuki Coupling Reaction  1.14.  The conversion of 1.89 into homotyrosine derivative 1.91 proceeded in excellent overall yield via Dess-Martin oxidation of 1.90 to an aldehyde and subsequent Pinnick oxidation of the latter to a carboxylic acid (Scheme 1.15).34    (a) HCl, MeOH, r.t, over night, 80%; (b) i. Dess-Martin/THF; ii. NaClO2, NaH2PO4; (c) H2, Pd/C, 81% over three steps.  Scheme 1.15: Synthetic Steps towards 1.91  21 1.2.4. Friedel-Crafts acylation route The potent dopamine agonist, 2-amino-6,7-dihydoxy-1,2,3,4- tetrahydronaphthalene (ADTN, 1.96) is of interest as a potential treatment for Parkinson’s disease.37 An asymmetric synthesis of this material by Nordlander et al. started with the creation of homotyrosine derivative 1.95 through the Friedel-Crafts acylation of 1,2-dimethoxybenzene 1.92 with aspartic acid-derived anhydride 1.93.38 The reaction occurred regioselectively at the carbonyl group farther removed from the nitrogenous functionality. Ketone 1.94 was thus obtained as a single isomer in 55% yield after recrystallization.    (a) AlCl3, CH2Cl2, r.t, 80h, then HCl, 20min, 55%; (b) Et3SiH, CF3CO2H, reflux, 2h, 72%.  Scheme 1.16: The Nordlander Synthesis of a Homotyrosine Derivative   A later paper by Melillo et al. described the application of the same chemistry to the synthesis of homotyrosine methyl ether, 1.101.17 In accord with Nordlander, these workers observed that the Friedel-Crafts acylation of anisole with anhydride 1.102  22 occurred selectively at the carbonyl group away from the NCOOMe group; however, the ortho-para selectivity with respect to the aromatic substrate was poor (ca. 2:1 in favor of the desired isomer).  The problem was corrected by engaging chloroanisole 1.98 in the reaction, whereupon only product 1.99 (X = Cl) was obtained.  Hydrogenolysis of the aryl ketone and of the chloro substituent took place simultaneously when 1.99 (X = Cl) was hydrogenated in the presence of Pd(C).    (a) AlCl3, CH2Cl2, MeNO2; H3O+; 94%; (b) H2 (3 atm)/i-PrOH/Pd-C; 94%  Scheme 1.17: The Melillo Synthesis of Homotyrosine Methyl Ether   In the course of studies directed toward the synthesis of homophenylalanine, Hashimoto et al. encountered difficulties in the acylation of benzene (less reactive than anisole derivatives) with the above aspartic-acid-derived anhydrides under Nordlander or Melillo conditions (AlCl3 as the catalyst). To correct the problem, they investigated the  23 use of strong Bronsted acids as promoters. Neat trifluoromethane sulfonic acid induced formation of a mixture of 1.102 and 1.103, which were isolated in 54% and 3% yield, respectively. When acid chloride 1.104 was employed in lieu of the anhydride, the desired 1.102 emerged in 98% yield; however, the transposition of these results to the homotyrosine series gave disappointing results, affording a 5:4 mixture of regioisomers 1.105 and 1.106.39    (a) PhH, neat TfOH, 0 oC, 1h, 54% for 1.102, 3% for 1.103; (b) anisole, neat TfOH, 0 oC, 1h, 97% combined yield.  Scheme 1.18: The Hashimoto Approach to Homotyrosine Derivatives     24 1.2.5. Michael addition route The observation that compounds of the type 1.109 may be efficiently hydrogenated to yield homotyrosine derivatives induced Yamada et al. to explore a route to 1.110 involving the addition of a chiral nitrogen nucleophile to intermediate 1.108.40 The latter substance is readily prepared by Friedel-Crafts acylation of anisole with maleic anhydride. Furthermore, the more electrophilic keto carbonyl directs subsequent 1, 4- additions. Accordingly, reaction of 1.108 with (S)- α-methylbenzylamine afforded 1.109 in 90% yield and 97% d.e. Subsequent hydrogenolysis delivered 110.    (a) Anisole (yields and selectivity was not mentioned in the paper); (b) 1.1 eq. (S)-α- methylbenzylamine, 60 oC, 16h, 90%, 97% d.e.; (c) 10% Pd/C, H2, EtOH, r.t, 24h, 90%.  Scheme 1.19: the Yamada Synthesis of Homotyrosine using Michael Addition     25 1.2.6. 1, 3-dipolar cycloaddition route  Baldwin et al. have utilized nitrone 1.112 as a chiral glycine template for the synthesis of non natural α-amino acids.41 The substance may be prepared in 70-80% yiled by oxidation of lactone 1.111 with the urea-hydrogen peroxide complex in the presence of a catalytic amount of methyltrioxorhenium, according to the procedure of Goti42 and Murray.43 Nitrone 1.112 undergoes the anticipated 1,3-dipolar cycloaddition with various olefins; in particular, with styrenes. While the faciality of the process with respect to nitrone is excellent (exclusive attack anti to the phenyl substituent), the topological control in the reaction is moderate, at least with styrenes.    (a) H2NCONH2, H2O2, MeReO3 (cat); (b) Ph3P, CHCl3, reflux, 3h, 84%, 5:1=exo: endo; (c) H2, Pd(OH)2/C, dioxane/TFA, 45%  Scheme 1.20: Synthesis of Homotyrosine using 1, 3-dipolar Cycloaddition  26 For instance, a 5:1 mixture of exo (major) and endo cycloadducts were obtained in the reaction of 1.112 with 1.113. Fortunately, this was immaterial in the context of a synthesis of homotyrosine. Indeed, catalytic hydrogenation of the mixture of 1.113 (exo and endo) affords the same end product 1.117.  Two aspects of the final step merit comment.  First, the authors uncovered evidence that the reaction proceeded through an initial cleavage of the N-O bond, followed by rapid translactonization to give γ-lactone 1.116. This was followed by hydrogenolysis of the benzylic C-O and C-N bonds. Second, the phenolic acetyl protecting group was lost during the reaction, providing the desired homotyrosine directly (Scheme 1.20).                27 Chapter 2: Results and Discussions  2.1 Objectives and approach As indicated in the Introduction (p. 8), the objective of this study was to devise a practical synthesis of homotyrosinol. Specifically, we required an entry to sulfonamide derivatives of homotyrosinol, because those are the actual substrates for oxidative cyclization of interest to us (Scheme 1.2).  To that end, we focused on three approaches (Scheme 2.1): a Suzuki coupling reaction of boranes 2.2 in a manner reminiscent of Taylor (Scheme 1.11) and Johnson (Scheme 1.14), an alkene metathesis reaction between 2.4 and a styrene, and a Heck reaction of 2.4 with an aryl halide. Because borane 2.2 would be prepared by hydroboration of 2.4, our first concern became the preparation of the latter intermediate, which is recognized as a derivative of vinylglycinol.    Scheme 2.1: Strategies for the synthesis of homotyrosinol sulfonamides explored in the course of this study  28 2.2. Synthesis of vinyl glycinol derivatives  Vinylglycinol derivatives can be easily synthesized from L-methionine by thermal elimination of the corresponding sulfoxide.44,45 We presumed that the literature methods devised to access carbamate derivatives of 2.15-2.17 could be adapted to the sulfonamide series, even though the CAS database records no occurrences of compound 2.6, 2.7 or 2.8. This proved to be the case. Reaction of L-methionine methyl ester hydrochloride 2.5 with CH3SO2Cl afforded the expected 2.6 in virtually quantitative yield. Reduction with LiAlH4 provided 2.7, which was converted into three different O-protected derivatives, 2.9-2.10. Sulfoxide formation from the latter occurred smoothly upon reaction with  S OMe NHMs S OMe NH2 HCl O a 2.5 O b S OH NHMs 2.6 2.7 OPG NHMs c not isolated2.8 S OPG NHMs d S OPG O NHMs e 2.3 PG=OAc 2.9 PG=OTBS 2.10 PG=OTBDPS 2.11 PG=OAc 2.12 PG=OTBS 2.13 PG=OTBDPS 2.14 PG=OAc 2.15 PG=OTBS 2.16 PG=OTBDPS 2.17  (a) MsCl, Et3N, CH2Cl2, 0°C to RT (99%); (b) LiAlH4, THF, 0°C to RT (90%) (c) TBDPSCl/TBSCl/Ac2O, Imidazole, DMF, RT; 2.9: 95%; 2.10: 90%; 2.11: 98%; (d); NaIO4, MeOH, H2O, RT; (e); Na2CO3, 1,2-dichlorobenzene, 180°C; 2.15: 72%; 2.16: 85%; 2.17: 70-83%.  Scheme 2.2: Synthesis of vinyl glycinol derivatives  29 NaIO4, and thermolysis of the products in refluxing 1, 2-dichlorobenzene afforded vinylglycinol derivatives 2.15-2.17 in excellent overall yield (Scheme 2.2). It is noted that the sulfoxide thermolysis was carried out in the presence of Na2CO3 as the base. An experiment in which K2CO3 was employed instead of Na2CO3 during the thermolysis of sulfoxide 2.14 produced the desired 2.17 in significantly lower yield (30%-40% instead of 83 %). Consequently, all other such reactions were only carried out with Na2CO3. The overall sequence appeared to be robust: large-scale reactions starting with 30 mmol of methionine ester 2.5 proceeded in 70% yield over 5 steps.  2.3 Study on the alkene metathesis approach The work described in this section was carried out by Dr. Huan (Steven) Liang, of our group.  Olefin metathesis is a reaction between a pair of alkenes, which undergo formal double bond cleavage and statistical redistribution of alkylidene fragments (Scheme 2.3). Pioneering work by Schrock46,47, and especially Grubbs48, has rendered this transformation as central to modern synthetic practice as the more classical reactions of organic chemistry. The transformation is promoted by a variety of metal-carbene complexes; i.e., organometallic compounds containing the functional group Mt=C (Mt = Ti, Ni, Mo, Rh, Ru …).    Scheme 2.3: General Alkene Metathesis  30 P(Cy)3 Ru P(Cy)3 Cl Ph Ru P(Cy)3 Cl Ph NN Me Me Me Me Me MeCl P(Cy)3 Ru Cl O Ru Cl NN Me Me Me Me Me MeCl O 2.17 Grubbs Catalyst 1st Generation 2.18 Grubbs Catalyst 2nd Generation 2.19 Hoveyda Catalyst 1st Generation 2.20 Hoveyda Catalyst 2nd Generation Cl Cl   Figure 2.1: Grubbs and Hoveyda Catalysts  However, the majority of metathesis reactions of interest in synthetic organic chemistry rely on the so-called Grubbs catalysts and their Hoveyda variants. These ruthenium complexes possess the structures shown in Figure 2.1. Their popularity derives from their good stability, excellent tolerance of spectator functionality (carbonyls, amides, carbamates, alcohol, ether, borane, silane), applicability in a broad range of solvents, and from the high yields that they generally afford.  Initial experiments aiming to induce cross-metathesis between styrene 2.21 and 2.22 in the presence of the Grubbs first generation complex 2.17 produced disappointing results. The choice of catalyst was dictated by its greater air stability relative to its congeners, which makes handling very convenient, as well as its lower cost. These  31 advantages are offset by a lower activity relative to other catalysts. In our case, heating a mixture of 2.21 and 2.22 at 100 oC for 24 h in the presence of variable amounts of   Reaction conditions: catalyst (5 mol %), vinyl moiety (0.5 mmol), styrene moiety (0.6 mmol), CH2Cl2, room temperature or 100 oC (in sealed tube).  Scheme 2.4: Alkene Metathesis  catalyst as much as 100 mol% – resulted at most in a modest 15% conversion (NMR) and in 8% isolated yield of desired 2.23. This was clearly unacceptable. Unfortunately, the use of more active second-generation catalysts did not cure the problem. As seen in the table below, the highest yield of 2.23 ever recorded was 20% at 40% conversion. These  Catalyst  Conversion Yield Grubbs I 15% 8% Grubbs II 40% 20% Hoveyda I 25% 11% Hoveyda II 35% 21%  Table 2.1: Conversion and Yields by different Catalysts  32 setbacks induced us to abandon the metathesis approach.  2.4. The Suzuki coupling route In order to proceed the Suzuki coupling reaction, first should convert 2.22 into a borane suitable for the conduct of a Suzuki-type reaction according to Taylor and Johnson. Regrettably, the hydroboration of 2.22 failed. Thus, the substrate was immune to the action of 9-BBN, catecholborane, or pinacolborane, either alone or in conjunction with the Wilkinson catalyst.49 At room temperature, no reaction took place; at higher temperatures, the substrate decomposed. Recall that the hydroboration of a carbamate derivative of vinylglycinol was achieved without incident (Scheme 1.11). Evidently, this reaction is intolerant of secondary sulfonamide functionality. While the reasons for this behavior were escaped from us, it is possible that the significant acidity of the N-H bond in 2.22(pKa of similar sulfonamides = 10-12, according to Evans’ pKa table) induced    Scheme 2.5: Boron Derivatives Synthesis  33 protonolysis of the borane and formation of an N-boryl derivative of the substrate (cf. 2.25). The resulting steric congestion engendered around the vinyl group could well suppress any further reaction.  2.5. The Heck coupling route  The above failures induced us to refocus our attention on a Heck reaction of 2.22 to the formation of 2.26 (Scheme 2.6).    Scheme 2.6: Approach to 1.32 by a Heck reaction   Since R. F. Heck’s publication of a landmark 1972 paper entitled “Palladium- catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides,” what is now known as the Heck-Mizoroki, or more simply the Heck, reaction50,51 has become one of the premier methods for the arylation of olefins. New ligands and palladium catalysts developed over the years have greatly expanded the scope and efficiency of the reaction, which, through the important work of Overman has even been extended to the intramolecular regime.52-55 Mechanistically, the process is believed to start with an oxidative addition of a Pd(0) complex into the aryl-X (or vinyl-X) bond. In cases where the Pd catalyst is introduced as a Pd(II) compound, preliminary reduction of the metal to the zerovalent  34 oxidation state is believed to occur. The resultant arylpalldium(II) halide complex may then promote carbonpalladation of an appropriate olefin, resulting in the formation of a putative arylpalladium(II) alkyl intermediate.  The presence of a β-H atom in the latter permits the occurrence of a β-H elimination of a halopalladium(II)hydride complex, which ultimately undergoes reductive elimination of a Pd(0) complex and concomitant    Scheme 2.7: Presumed mechanism of the Heck reaction.  formation of a molecule of H-X. The reaction is therefore carried out in the presence of an appropriate base to absorb the H-X thus produced. This sequence of events is exemplified in Scheme 2.7. Notable stereochemical aspects of the reaction are the syn course of both the carbopalladation (cf. 2.29 Æ 2.30) and the β-H elimination (cf. 2.30 Æ 2.32) steps.   35  Scheme 2.8: Reduction of Pd(II) to Pd(0) according to Amatore  Our initial attempts to produce compound 2.35 through the union of 2.22 and 2.33 employed a widely used catalytic system composed of Pd(OAc)2 and triphenylphosphine in a 1 : 2 molar ratio.56 As shown by Amatore,57-59 the interaction of these two agents induces reduction of Pd(II) to Pd(0).  Specifically, the two combine to produce a Pd(0) complex plus one equivalent each of triphenylphosphine oxide and acetic anhydride (Scheme 2.8). The reaction was carried out in DMF, a common solvent for this transformation, in the presence of K2CO3 as the base and at a temperature of 105 oC. Again, these are common literature conditions.60 The conversion of the starting materials into the product was monitored by NMR, which showed that the reaction was complete in four and a half hours. As seen in Scheme 2.8, two products were thus obtained: the anticipated 2.34 and the corresponding deacetylated analogue 2.35. While both products  OTBDPS NHMs AcO I + OTBDPS NHMs2.34 R=Ac2.35 R=H2.33 2.22 RO  Conditions: Pd (OAc)2 (20 mol %), Ph3P (40 mol %), 1.2 equiv. K2CO3, de-gassed DMF ([C] = 0.35 /vinyl moiety), 105 oC, vinyl moiety (0.5 mmol), phenol (0.6 mmol).  Scheme 2.9: Heck Coupling Reactions   36 are useful, inasmuch as they both can be advanced to desired 1.32, the total yield of the two was only around 40%, which was unacceptably low for our purposes. The balance of the olefinic substrate was converted to polymeric materials that we were unable to characterize. These observations validated the Heck approach, but they also signaled that the conditions employed in these test experiments were inappropriate. Consequently, we carried out a screen of ligands, sources of metal, bases, and protecting groups on both aryl and vinyl components in order to optimize the reaction.  2.5.1 Ligand screening  A total of ten ligands were examined in a reaction carried out under the following standard conditions: 0.5 mmol (200 mg) of vinyl component 2.22, 1.5 mL of degassed DMF (substrate concentration = 0.3 M), 0.6 mmol (1.2 equiv.) of aryl moiety 2.33, Pd(OAc)2 (20 mol % relative to 2.22), Ph3P (40 mol % relative to 2.22, 2 equiv. relative to Pd(OAc)2), 0.6 mmol (1.2 equiv.) of K2CO3, 105 oC, NMR monitoring, reported yields refer to chromatographically purified products. The results of experiments that employed Ph3P, n-Bu3P, trifurylphosphine, JohnPhos, cyclohexyl JohnPhos, XPhos, DavePhos, and an unnamed phosphine as ligands are summarized in Table 2.2. Among these eight ligands, only tributylphosphine and XPhos afforded good (> 80%) yields. Reactions run with n-Bu3P were more selective, in that only the acetylated product 2.35 was obtained, while XPhos consistently furnished an approximately 2:1 mixture of acetylated and deacetylated materials. Recall, this is not a major concern, because the acetyl group is destined to be released anyway. Trifurylphosphine and the JohnPhos ligands performed especially poorly, while reactions run in the presence of DavePhos stalled at about 70%  37 OTBDPS NHMs AcO I + OTBDPS NHMs2.34 R=Ac 2.35 R=H 2.33 2.22 entry ligand reaction isolated yield isolated yield time of 2.34 of 2.35 P(tert-Bu)2 (JohnPhos) (cyclohexyl JohnPhos) PCy2 XPhos i-Pr i-Pr i-Pr (DavePhos) Ph3P n-Bu3P O P3 PCy2 PCy2i-PrO O-i-Pr PCy2Me2N a b c d e f g h 4.5 4 7 9 9 4 4 5 (72% conv.) 31 87 (0.5 mmol scale) 58 (6.7 mmol scale) < 10 19 22 58 55 24 9 0 0 < 5 0 0 24 5 20 RO   Table 2.2: Ligands Screen with Pd(OAc)2 in Heck Coupling Reaction   38 conversion to form a 1:1 mixture of 2.34 and 2.35. The good results observed with Bu3P induced us to scale up the reaction by an order of magnitude. Unfortunately, the yield of product dropped significantly when 6.7 mmol of 2.22 were thus processed (58% vs. 87%), all other reaction parameters being equal. No attempts were made to scale up the reaction involving XPhos on accounts of the considerable cost of this substance. Besides proceeding in unsatisfactory yield, the above reactions also required a large quantity of palladium (20 mol%) to proceed reasonably rapidly. In our continuing search for an improved procedure that would afford high yields and require a diminished quantity of precious metal, we evaluated to the use of SPhos and the recently described phenylurea as ligands.  Results of reactions that employed SPhos are summarized in Table 2.3. These experiments were carried out as described earlier: 0.5 mmol (200 mg) of vinyl component 2.22, 1.5 mL of degassed DMF (substrate concentration = 0.3 M), 0.6 mmol (1.2 equiv.) of aryl moiety 2.33, 0.6 mmol (1.2 equiv.) of K2CO3, 105 oC, NMR monitoring, reported yields refer to chromatographically purified products. However, the source and amount of metal, as well as the ratio of metal to ligand was varied as indicated. It should be noted that the reactions tended to stall when run at temperatures lower than 100-105 oC.  The use Pd(OAc)2 as the source of metal afforded the highest conversions and yields. Furthermore, yields remained essentially constant regardless of the metal / ligand ratio or, more importantly, the quantity of metal used, down to a metal loading around 3%. Below this level, yields dropped. A reaction carried out with 4.7 grams (11.7 mmol) of 2.22 afforded a 1.5: 1 mixture of 2.34 and 2.35 in 86% total yield, indicating that the  39 OTBDPS NHMs AcO I + OTBDPS NHMs2.34 R=Ac 2.35 R=H 2.33 2.22 ligand (SPhos) PCy2MeO MeO entry a b c d e f g h i j isolated yield of 2.34 91 52 (11.7 mmol scale) 73 40 9 49 21 43 34 31 isolated yield of 2.35 0 34 11 0 0 0 62 40 52 21 mol% of Pd 20 20 10 10 10 10 10 5 3 1 mol ratio Pd / ligand 1 : 2 1 : 2 1 : 2 1 : 2 1 : 2 1 : 2 1 : 1 1 : 2 1 : 1 1 : 2 " (70% conv. after 9h) " " " " " source of Pd Pd(OAc)2 Pd2(dba)3 Pd(PPh3)4 PdCl2(PPh3)2 Pd(OAc)2 (80% conv. after 4h) (30% conv. after 4h) (65% conv. after 4h) " " " " " " " " RO   Table 2.3: Reactions using SPhos as Ligand  reaction was probably scalable.  40 2.5.2 Substrates scope  The foregoing observations encouraged us to examine the coupling of variously  2.36entry a b c d e f isolated yield of 2.38, R =Ac 73 0 41 0 0 15 2.37 OP' NHMs R-O X + OP' NHMs2.36 2.37 2.38 AcO I OTBDPS NHMs AcO I OTBS NHMs AcO I OAc NHMs HO I OTBDPS NHMs HO I OH NHMs AcO Br OTBDPS NHMs isolated yield of 2.39, R = H 11 21 0 10 36 0 RO   Table 2.4: Substrate Scope for Pd(OAc)2 Catalyzed Heck Coupling Reaction  41 protected substrates under the catalytic influence of the Pd – SPhos system. These experiments were motivated by a desire to avoid the use of a costly TBDPS protecting group on the vinyl component. Table 2.4 summarizes the results of reactions carried out under the following standard conditions: 0.5 mmol of vinyl component, 1.5 mL of degassed DMF ([2.37] = 0.35 M), 10 mol % Pd(OAc)2, 20 mol% SPhos, 0.6 mmol of aryl moiety, 0.6 mmol K2CO3, 105 oC, 4 h, NMR monitoring, yields of chromatographically purified products. It is apparent from the data shown that the reaction proceeded best with TBDPS-protected 2.37 and the acetate ester of 4-iodophenol (entry a). As seen previously in Table 2.3, this reaction afforded a ca. 7: 1 mixture of acetylated and deacetylated product. Recall, reactions run with a 20% load of Pd complex afforded no deacylated product. However, deacetylated material was the only product observed in entry b.  2.5.3 The base   (a) 0.5 mmol of 2.22, 1.5 mL of degassed DMF ([2.22] = 0.35 M), 10 mol % Pd(OAc)2, 20 mol% SPhos, 0.6 mmol of 2.33, 0.6 mmol NaHCO3, 105 oC, 4 h, NMR monitoring, yields of chromatographically purified products.  Scheme 2.10: Heck Coupling Reaction with Base NaHCO3  42 As mentioned above, the formation of mixtures of acetylated and deacetylated products is inconsequential.  However, we questioned whether replacing the stronger base, K2CO3, with a weaker one could improve product selectivity even further. It was found that the use of NaHCO3 in lieu of K2CO3 greatly reduced the extent of deacetylation (Scheme 2.10).  2.5.4. The breakthrough: N-Phenylurea as ligand A recent report by Guo, et al., described the use of inexpensive N-phenylurea as an effective ligand for Pd.61 In the context of a Heck reaction, the use of this ligand resulted in a 99% yield (determined by GC) of stilbene through the coupling of bromobenzene with styrene. When 0.5 mmol of 2.22 in 1.5 mL of degassed DMF ([2.22] = 0.35 M) containing 10 mol % Pd(OAc)2, 20 mol% N-phenylurea, 0.6 mmol of 2.33, and 0.6 mmol K2CO3 was heated at 105 oC (NMR monitoring), complete consumption of 2.22 was detected after about 2h. Chromatographic purification of the crude product delivered 2.34 in 38% yield and 2.35 in 48% yield (86% overall entry a). Replacing the base with the milder NaHCO3 resulted in exclusive formation of 2.34 in an 84% yield after chromatography. Clearly, this inexpensive alternative to the costly SPhos afforded even better results. Table 2.5 summarizes a brief study of reaction conditions. The new ligand permitted the use of only 5 mol % of Pd(OAc)2 even on substantial scales (entry e). For preparative purposes (entry f), we utilized the conditions of entry e: 5 mol% of metal, 10 mol% ligand, K2CO3 as the base, 2 h reaction time, affording in 83% chromatographed yield a mixture of 2.34 (63% by NMR) and 2.35 (20% by NMR).  43 OTBDPS NHMs AcO I + OTBDPS NHMs2.34 R=Ac 2.35 R=H 2.33 2.22 ligandentry a b c d e f isolated yield of 2.34 38 76 84 23 59 63 isolated yield of 2.35 48 13 0 0 28 20 mol% of Pd 10 10 10 10 5 5 base K2CO3 NaHCO3 NaHCO3 Na2HPO4 (conv. = 30%) K2CO3 K2CO3 " " " " " Ph N H O NH2 mmol of 2.22 0.5 0.5 0.5 0.5 2.5 11.0 (ratio by 1H NMR) time ( h ) 4 4 2 8 2 2 RO   Table 2.5: Reactions using N-Phenylurea as Ligand  2.5.5 The determination of optical purity  The degree of enantiomeric purity of product 2.42 was determined by the Mosher method. Accordingly, the TBDPS group in 2.34 was released (TBAF) and the resulting alcohol 2.42 was esterified with (R)-MTPA chloride (Scheme 2.11). The emerging ester 2.44 was assayed by 19F-NMR spectroscopy, whereupon only one signal was detected  44 (Figure 2.2). This established that the optical integrity of the molecule had been preserved during the coupling reaction.   Et3N, HOBT, EDCI, CH2Cl2, 0 oC to r.t. 70 %.  Scheme 2.11: Optical Purity of Heck Coupling Product  Figure 2.2: 19F-NMR Spectrum of 2.44  45 2.5.6 Literature procedure  At this juncture of our research, a publication from the laboratories of Gobel appeared, which disclosed a similar Heck route to non-natural aromatic aminoacids through the coupling of aryl bromides with Cbz-protected vinylglycinol 2.45 in aqueous DMF and in the presence of K2CO3.62 A noteworthy aspects of the Gobel reaction is the use of a ligand-free catalytic system that comprises Pd(OAc)2 and a phase-transfer agent, such as Bu4N+ - OTf. Representative examples are shown in Figure 2.3.  The transposition of this alternative methodology to the methanesulfonamide derivative of vinylglycinol as the substrate revealed three major drawbacks. First, the reaction had to be carefully monitored to avoid degradation of the product by the catalytic  Br Br Br Br OTBS NHCbz Ar Br + Ar OTBS NHCbz 2.462.45 Pd(OAc)2 aq. DMF, Bu4N OTf Br N Br MeO (87%) (83%) (30%) (77%) (89%) (80%)  Figure 2.3: The Gobel Synthesis of Compounds 2.46 by Heck Reaction  46 system. Prolonged heating of reaction mixtures beyond the time at which complete disappearance of the vinyl component had occurred (about 4 h, 1H NMR) caused an unacceptable loss of product to polymerization. Variable amounts of polymeric materials were evident in the spectra of crude products even if the reaction was stopped immediately upon disappearance of 2.22. The problem was especially acute when operating with more than 1 mmol of substrate, whereupon the separation of desired  OTBDPS NHMs AcO I + OTBDPS NHMs2.34 R=Ac 2.35 R=H 2.33 2.22 entry a b isolated yield of 2.34 63 0 isolated yield of 2.35 21 46 mmol of 2.22 1.0 5.0 a RO   (a) Reaction conditions: DMF: H2O= 20:1, [2.22] = 0.07M, phenol/vinyl ration=1.2:1, 10 mol % Pd (OAc)2, 12 mol % Bu4NOTf (1.2 equiv. vs. Pd(OAc)2), K2CO3 (2.4 equiv. vs. 2.22), 100 oC, 4 h (1H NMR monitoring). Yields refer to chromatographically purified products.  Table 2.6: Heck Reaction of 2.22 with 2.33 under Gobel Conditions  47 product from polymeric material (column chromatography) became very troublesome. Secondly, the Gobel procedure prescribes a concentration of vinylglycine substrate equal to 0.07 M. Such a degree of dilution is entirely impractical for the conduct of preparative work. Third, 10 mol % of Pd(OAc)2 were required instead of 5%. Two examples of reactions carried out under Gobel conditions are provided in Table 2.6. The yield of a preparative run of the reaction was about half of that obtained by our optimized procedure.  2.6 Synthesis of N-mesyl-O-silyl homotyrosinol  Having established a robust preparative route to 2.34, we turned our attention to its conversion into the desired 2.48. This transformation entails the hydrogenation of the olefin and the release of the protecting groups. The proper order of these steps was determined through experiment. Thus, hydrogenation of a mixture of 2.34 and 2.35 over Pd(C) in MeOH containing suspended K2CO3 afforded compound 2.47 in 95% yield (Scheme 2.12). The K2CO3 utilized in this step served to promote the cleavage of the phenolic acetate. The desilylation of the primary alcohol occurred significantly more efficiently in the presence of 70% HF in pyridine (80% yield after chromatography) relative to the customary TBAF (ca. 70% yield). The use of HF in pyridine also facilitated the purification of the final 2.48, which was obtained in 76% overall yield. An improvement in overall efficiency obtained when the desylation was carried out prior to hydrogenation. Treatment of a mixture of 2.34 and 2.35 with suspended K2CO3 in MeOH (release of the phenolic acetate) then with HF – pyridine, followed by hydrogenation over Pd(C) afforded compound 2.48 in 90% overall yield after chromatography. In summary,  48 the desired 2.48 was now available in four steps from 2.17 and 2.33 (Heck reaction, HF- pyr, H2/Pd(C)/MeOH/K2CO3) in 4.5 g batches with an overall yield of 77%.     Scheme 2.12: Synthesis of L-Homotyrosine Derivative   2.7 Synthesis of other analogues using a similar approach  The optimized three-step sequence thus devised was extended to the preparation of other intermediates of current interest in our laboratory. Table 2.7 provides four such examples. The substrates for this study, compounds 2.50a – d, were prepared by Dr. H. Liang, of our group. The successful preparation of 2.51d merits comment. This molecule and its vinyl precursor 2.50d incorporate a dialkyl sulfide functionality. The presence of  49   Conditions: [PdCl(CH2CH=CH2)]2/Tedicyp (1:2) (0.01 mmol), aryl halide (1 mmol), ethyl vinyl sulfide (2 mmol), base (2 mmol), 130 oC, 20h, argon, isolated yield.  Scheme 2.13: Tetradentate Phosphine Ligand used in Pd-catalyzed Heck Reactions of Vinyl Sulfide Derivatives     Conditions: 2-methylene-1,3-dithiane 1-oxide (0.5 mmol), aryl iodide (1.2eq), palladium acetate (5mol%), DPPE (5mol%), potassium carbonate (1.2eq), TBAB (1.2eq), DMF (2.0ml), argon, isolated yield.  Scheme 2.14: Bidentate Phosphine Ligand used in Pd-catalyzed Heck Reactions of Vinyl Sulfide Derivatives   50 such sulfur centers may hamper the progress of transition metal-mediated reactions. In some cases, special tetradentate phosphine ligands (Scheme 2.13) had to be employed to circumvent the problem,63 but in others, a more common bidentate phosphine proved to  R NHMs AcO I + R NHMs 2.33 2.50 entry a b c d overall yield 89 84 66 44 a - c R i-Pr Me Ph-CH2 MeS-CH2-CH2 2.51 OH   (a) 0.4 – 0.5 mmol of 2.50, DMF, [2.50] = 0.35 M, phenol/vinyl ration=1.2:1, 5 mol % Pd (OAc)2, 10 mol % PhNHCONH2, (2 equiv. vs. Pd(OAc)2), K2CO3 (1.2 equiv. vs. 2.50), 100-105 oC, 2 h (1H NMR monitoring). (b) MeOH, 1.2 equiv. K2CO3, rt, 1h. (c) H2, Pd(C), overnight. Yields refer to chromatographically purified products.  Table 2.7: Heck Reaction of 2.33 with 2.50 with a Pd - Phenylurea Complex  51 be quite effective (Scheme 2.14).50 In the case of 2.50d, the Heck coupling proceeded in about 45-50% yield. Indeed, the overall yield of 2.51d, 44%, reflects substantially the efficiency of the Heck step, in that the subsequent hydrogenation reaction was essentially quantitative.64  2.8 Oxidative cyclization of homotyrosinol derivative 2.48.  As discussed in the introductory section, our interest in a synthesis of homotyrosinol derivatives was motivated by their importance as substrates for an oxidative cyclization that converts them into dienones 2.53 (Scheme 2.15). In its original format,65 the reaction involved the use of iodobenzene diacetate (“DIB”) as the oxidant    Scheme 2.15: Oxidative Cyclization of Sulfonamide Derivatives of Homotyrosinol  and of very costly 1,1,1,3,3,3-hexafluoro-2-propanol as the solvent. This chemistry is central to a total synthesis of cylindricine C.19 More recently, Dr. Liang from our laboratory discovered that the reaction may be carried out in inexpensive trifluoroacetic acid with excellent results.66  Mechanistically, the reaction is believed to involve a Bronsted acid catalyzed exchange of an acetoxy ligand on DIB with the phenolic substrate. The resultant 2.58   52 H+ Ph I O O O O +- Ph I O O O OH Ph I O O H++- Ph I O O HN SO2R O H++- Ph I O OH HN SO2R O Ph I HN SO2R O - AcOH - AcOH - Ph-I HN SO2R O O N SO2R - H+ HN SO2R HO + 2.54 2.55 2.56 2.57 2.58 2.59 2.60 2.61 2.62   Scheme 2.16: Presumed Mechanism of Oxidative Cyclization of 2.57  subsequently undergoes acid-catalyzed dissociation to a presumed cationic intermediate 2.61, which is then captured by the sulfonamide (Scheme 2.16).  A final aspect of the research described here centered on the exploration of conditions suitable for the conduct of the oxidative cyclization of 2.57 on preparative scales. The choice of 2.63 as the substrate was dictated by its importance as an intermediate for an ongoing synthesis of (-)-lepadifomine.  Slow dropwise addition of a 0.16 M solution of 2.63 (0.3 mmol) in TFA to a 0.16 M solution of DIB also in TFA (final concentration of reactants = 0.08 M), at room temperature, induced a virtually instantaneous reaction that produced dienone 2.64 in 95% yield. The reaction was clearly quite efficient; however, from a preparative standpoint, it was impractical to operate at such a high dilution during large scale  53 reactions. Experiment revealed that there was no need for high dilution. Indeed, reactions run at a final concentration of 0.3 M of substrate (2.63) were also as high-yielding as 95%. A semipreparative run with 3.8 mmol (1 g) of substrate afforded 2.64 in a 75% yield (Scheme 2.17). The structure of 2.64 was ascertained by X-ray diffractometry.   Reaction conditions: 1.05 eq. DIB, TFA, [C] = 0.3 M, yield 75%  Scheme 2.17:  Oxidative Cyclization of 2.63   Figure 2.4: The Molecular Structure of Compound 2.64   54  In summary, this research defined a robust method for the preparation of homotyrosinol derivatives and related intermediates through a Mizoroki-Heck coupling between an aryl iodide and appropriate aminoacid-derived olefins. A key aspect of the work is the use of inexpensive N-phenylurea as the ligand for Pd during Heck reaction. In addition, a preparative scale procedure for the oxidative cyclization of the methanesulfonamide derivative of homotyrosinol was established. The results obtained in the course of these studies are essential to the progress of various synthetic efforts ongoing in our laboratory.                 55 REFERENCES   (1) Weller, H. N.; Gordon, E. M. J. Org. Chem 1982, 47, 4160.  (2) Abderhalden, E. W., E. HOPPE-SEYLERS ZEITSCHRIFT FUR PHYSIOLOGISCHE CHEMIE 1912, 82, 167.  (3) Bevan, K. D., J. S.; Hassall, C. H.; Morton, R. 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Chemical shifts are reported in parts per million (ppm) on the δ scale and coupling constants, J, are in hertz (Hz). Multiplicities are described as “s” (singlet), “d” (doublet), “t” (triplet), “q” (quartet), “dd” (doublet of doublets), “dt” (doublet of triplets), “m” (multiplet), “br” (broad). Infrared (IR) spectra (cm-1) were recorded on Nicolet 4700 Fourier transform spectrophotometer from neat films of analyte deposited on NaCl plates. Low-resolution mass spectra (m/z) were obtained in the electrospray (ESI) and atmospheric pressure chemical (APCI) mode on a Waters Micromass ZQ mass spectrometer. High-resolution mass spectra (m/z) were recorded in the electrospray (ESI) mode on a Micromass LCT mass spectrometer by the UBC Mass Spectrometry laboratory. Melting points (uncorrected) were measured on a Mel-Temp apparatus. All reagents and solvents were commercial products and used without further purification except THF (freshly distilled from Na/benzophenone under argon) and CH2Cl2 (freshly distilled from CaH2 under argon). Flash chromatography was performed on Silicycle 230 – 400 mesh silica gel. Analytic and preparative TLC was carried out with Merck silica gel 60 plates with fluorescent indicator. Spots were visualized with UV light or KMnO4. All reactions were performed under dry Ar in oven-dried flasks equipped with TeflonTM stirbars. All flasks were fitted with rubber septa for the introduction of substrates, reagents, and solvents via syringe.    61 Preparation of 2.6 NHMs S O OMe    To a solution of L-Methionine methyl ester hydrochloride (10 g, 50.3 mmol) and triethylamine (13.9 ml, 100 mmol) in DCM (150 ml) at 0°C, methanesulfonyl chloride (5.8 ml, 75 mmol) was drop-wise added over a period of 10 minutes. At the end of the addition, the solution turned to yellow. The reaction mixture was warmed up to room temperature and stirred over night. The mixture was quenched by aq. Sat. NH4Cl (50 ml) and extracted with EtOAc (3* 75 ml). The combined extracts were sequentially washed with aq. sat. NH4Cl (3* 50 ml), aq. sat. NaCl (50 ml), dried over MgSO4 and concentrated to afford 12.1 g (49.8 mmol, 99%) product as a colorless solid.  1H NMR (CDCl3): 5.40 (d, J=9, 1H); 4.31-4.21 (m, 1H); 3.77 (s, 3H); 2.96 (s, 3H); 2.61 (br, 2H); 2.08 (s, 3H); 2.19-1.86 (m, 2H)  13C NMR (CDCl3): 172.6; 54.7; 52.9; 41.2; 32.1; 29.7; 15.2  IR: 3278; 1740l; 1317; 1109  HRMS: calcd. for C7H15NO4S2:    264.0340 [M+Na]+ found:                               264.0338 [M+Na]+  M.P. 41-42oC  [α]D23 -19.2 ° (CHCl3, c= 0.85)   62   Figure A.1: 1H NMR spectrum of 2.6    Figure A.2: 13C NMR spectrum of 2.6  63    Figure A.3: IR spectrum of 2.6                          64 Preparation of 2.7 NHMs S OH    To a stirring solution of 2.6 (12.1 g, 49.8 mmol) in THF (150ml) in an ice bath, lithium aluminum hydride powder (2.55 g, 67.2 mmol) was slowly added over a period of 30 minutes. Then reaction mixture was warmed up to room temperature and stirred over night under Argon protection. Upon the completion of the reaction, the mixture was cooled down to 0 °C. First, H2O (2.55 ml) was added to quench the reaction. Then 30 minutes later, 15% NaOH solution (2.55 ml), H2O (7.65 ml) and 5 tps of drying reagent (MgSO4) was sequentially added in the interval of half an hour with vigorous stirring. The suspension solution was filtered through Celite using acetone. The crude light yellow colored solution was evaporated to afford 9.54 g (44.8 mmol, 90%) product as orange colored oil which was used without further purification.  1H NMR (CDCl3): 5.34 (br, 1H); 3.79-3.70 (m, 1H); 3.65-3.53 (m, 2H); 3.05 (s, 3H); 3.00 (br, 1H); 2.68-2.52 (m, 2H); 2.09 (s, 3H); 1.87-1.74 (m, 2H).  13C NMR (CDCl3): 64.9; 54.6; 41.5; 30.9; 30.3; 15.3 IR: 3285; 1308; 1100  HRMS: calcd. for C6H15NO3S2:    236.0391 [M+Na]+ found:                               236.0393 [M+Na]+  [α]D20 -34.5° (CH2Cl2, c= 1.13)   65   Figure A.4: 1H NMR spectrum of 2.7    Figure A.5: 13C NMR spectrum of 2.7  66   Figure A.6: IR spectrum of 2.7             67 Preparation of 2.11 NHMs S OTBDPS    To a solution of 2.7 (9.54 g 44.8 mmol) and imidazole (6.1 g, 89.6 mmol) in DCM (100 ml) at 0°C, TBDPSCl (15.4 ml, 58.24 mmol) was drop-wise added over a period of 10 minutes. Then the reaction mixture was warmed up to room temperature and stirred over night. The mixture was quenched by aq. Sat. NH4Cl (50 ml) and extracted with EtOAc (3* 75 ml). The combined extracts were sequentially washed with aq. sat. NH4Cl (3* 50 ml), aq. sat. NaCl (50 ml), dried over MgSO4 and concentrated to afford orange-color oil. Then the oil was dissolved in acetonitrile, washed with hexanes (3 * 50 ml) and evaporated to afford product as light orange oil (19.81 g, 43.9 mmol, 98%) without request for further purification.  1H NMR (CDCl3): 7.67-7.61 (m, 4H); 7.49-7.37 (m, 6H); 4.64 (d, J=8.6, 1H); 3.80-3.63 (m, 2H); 3.61 (br, 1H); 2.87 (s, 3H); 2.55 (br, 2H); 2.08 (s, 3H); 1.92-1.82 (m, 2H); 1.08 (s, 9H)  13C NMR (CDCl3): 135.5; 132.67; 132.65; 130.1; 127.95; 127.92; 65.8; 54.3; 41.5; 31.5; 30.3; 26.9; 19.2; 15.2  IR: 3283; 2930; 1323; 1152 HRMS: calcd. for C22H33NO3SiS2    474.1569 [M+Na]+ found:                                   474.1573 [M+Na]+  [α]D19 -26.4° (CH2Cl2, c = 0.94)   68   Figure A.7: 1H NMR spectrum of 2.11    Figure A.8: 13C NMR spectrum of 2.11  69   Figure A.9: IR spectrum of 2.11             70 Preparation of 2.10 NHMs S OTBS    To a solution of 2.7 (4.0g, 18.9 mmol) and imidazole (2.59 g, 38.0 mmol) in DCM (40 ml) at 0°C, TBSCl (3.72 g, 24.7 mmol) was added. The reaction mixture was warmed up to room temperature and stirred over night. Then mixture was quenched by aq. sat. NH4Cl (10 ml) and extracted with EtOAc (3* 25 ml). The combined extracts were sequentially washed with aq. sat. NH4Cl (3* 25 ml), aq. sat. NaCl (25 ml), dried over MgSO4 and concentrated. Chromatography of the residue (EtOAc: hexanes = 1: 3) gave 5.56 g (17.0 mmol, 90 %) product as light yellow oil.  1H NMR (CDCl3):  4.65 (br, 1H); 3.78-3.54 (m, 2H); 3.61 (br, 1H); 3.00 (s, 3H); 2.62 (br, 2H); 2.10 (s, 3H); 1.87-1.76 (m, 2H); 0.89 (s, 9H); 0.079 (s, 3H); 0.072 (s, 3H)  13C NMR (CDCl3):  65.3; 54.3; 41.6; 31.4; 30.3; 25.8; 18.3; 15.2; -5.45; -5.48  IR: 3283; 2928; 1317; 1152  HRMS: calcd. for C12H29NO3SiS2    328.1436 [M+H]+ found:                                   328.1445 [M+H]+  [α]D19 -31.8° (CH2Cl2, c = 0.83)     71   Figure A.10: 1H NMR spectrum of 2.10    Figure A.11: 13C NMR spectrum of 2.10  72   Figure A.12: IR spectrum of 2.10              73 Preparation of 2.9    To a solution of 2.7 (0.852, 4.0 mmol) and pyridine (0.49 ml, 6.0 mmol) in DCM (8ml) at 0°C, acetic anhydride (0.45 ml, 4.8 mmol) was added. The reaction mixture was warmed up to room temperature and stirred over night. Then mixture was quenched by aq. sat. NaHCO3 (5 ml) and extracted with EtOAc (3* 15 ml). The combined extracts were sequentially washed with aq. sat. NaHCO3 (3* 10 ml), aq. sat. NaCl (10 ml), dried over MgSO4 and concentrated. Chromatography of the residue (EtOAc: hexanes = 1: 2) gave 0.918g (3.6 mmol, 95 %) product as light yellow oil.  1H NMR (CDCl3):  5.23 (d, J=9, 1H); 4.12-3.99 (m, 2H); 3.79-3.66 (m, 1H); 2.96 (s, 3H); 2.64-2.46 (m, 2H); 2.03 (s, 3H); 2.01 (s, 3H); 1.84-1.64 (m, 2H)  13C NMR (CDCl3):  170.8; 66.2; 51.8; 41.6; 31.4; 29.9; 20.7; 15.2  IR: 3281; 1739; 1316; 1150  HRMS: calcd. for C8H11NO4S2         278.0497 [M+Na]+ found:                                   278.0494 [M+Na]+  [α]D20 -33.6° (CH2Cl2, c = 1.63)      74   Figure A.13: 1H NMR spectrum of 2.9    Figure A.14: 13C NMR spectrum of 2.9  75    Figure A.15: IR spectrum of 2.9                          76 Preparation of 2.15     Sodium periodate (0.847 g, 3.96 mmol) in de-ionized water (11 ml) in addition funnel was slowly added to a solution of compound 2.9 (0.918 g, 3.6 mmol) in MeOH (11 ml), at 0 °C with good stirring. The reaction mixture was warmed up to room temperature and stirred for 4 hours. Once the reaction was completed, the mixture was diluted in 30 ml EtOAc. The organic layer was separated and sequentially washed with aq. sat. NaHCO3 (3* 10 ml), aq. sat. NaCl (10 ml), dried over MgSO4 and concentrated. Then the crude product was dissolved in 1, 2 – dichlorobenzene (5 ml), and Na2CO3 powder (0.763 g, 7.2 mmol) was added. The reaction was heated up to 190 °C to keep refluxing and stirred overnight under the protection of Argon. Once the reaction was completed, NH4Cl (10 ml) was added to quench the reaction. The mixture was diluted with 15 ml EtOAc, washed with aq. sat. NH4Cl (3* 10 ml), aq. sat. NaCl (10 ml), dried over MgSO4 and concentrated. Chromatographic purification of the residue (1: 1 = EtOAc: Hexane) was provided 2.15 (0.537 g, 72% over two steps) as light yellow oil.  1H NMR: 5.87-5.73 (m, 1H); 5.41 (d, J=17, 1H); 5.32 (d, J=10, 1H); 4.89 (br, 1H); 4.25 (br, 1H); 4.21-4.09 (m, 1H); 2.98 (s, 3H); 2.09 (s, 3H)  13C NMR: 170.8; 134.0; 118.6; 65.8; 55.2; 42.1; 20.8  IR: 3280; 1741; 1319; 1147  77 HRMS: calcd. for C7H13NO4S:       230.0463 [M+Na]+ found:                                 230.0457 [M+Na]+  [α]D20  -20.3° (CH2Cl2, c = 1.25)             Figure A.16: 1H NMR spectrum of 2.15  78   Figure A.17: 13C NMR spectrum of 2.15       Figure A.18: IR spectrum of 2.15  79 Preparation of 2.16     Sodium periodate (3.95 g, 18.7 mmol) in de-ionized water (40 ml) in addition funnel was slowly added to a solution of compound 2.10 (5.55 g, 17 mmol) in MeOH (50 ml), at 0 °C with good stirring. The reaction mixture was warmed up to room temperature and stirred for 4 hours. Once the reaction was completed, the mixture was concentrated on roto vap and then diluted in 100 ml EtOAc. The organic layer was separated and sequentially washed with aq. sat. NaHCO3 (3* 25 ml), aq. sat. NaCl (25 ml), dried over MgSO4 and concentrated. Then the crude product was dissolved in 1, 2 – dichlorobenzene (20ml), and Na2CO3 powder (3.64 g, 34 mmol) was added. The reaction was heated up to 190 °C to keep refluxing and stirred overnight under the protection of Argon. Once the reaction was completed, NH4Cl (10 ml) was added to quench the reaction. The mixture was diluted with 30 ml EtOAc, washed with aq. sat. NH4Cl (3* 25 ml), aq. sat. NaCl (25 ml), dried over MgSO4 and concentrated. Additional extraction was performed using hexanes (30 ml) and acetonitrile (30 ml) to remove the excess 1, 2 – dichlorobenzene. Chromatographic purification of the residue (1: 4 = EtOAc: Hexane) provided 2.16 (2.77 g, 85% over two steps) as light yellow oil.  1H NMR (CDCl3): 5.88-5.74 (m, 1H); 5.33 (d, J=17, 1H); 5.25 (d, J= 10.3, 1H); 4.82 (br, 1H); 3.99 (br, 1H); 3.78-3.54 (m, 2H); 2.96 (s, 3H); 0.88 (s, 9H); 0.067 (s, 3H); 0.059 (s, 3H)  13C NMR (CDCl3): 135.5; 117.9; 65.7; 57.8; 41.9; 25.8; 18.2; -5.5; -5.4  IR: 3284; 2857; 1325; 1154  80 HRMS: calcd for C11H25NO3SSi:    302.1222 [M+Na]+ found:                                  302.1222 [M+Na]+  [α]D20 14.7° (CH2Cl2, c = 1.08)             Figure A.19: 1H NMR spectrum of 2.16  81   Figure A.20: 13C NMR spectrum of 2.16          Figure A.21: IR spectrum of 2.16  82 Preparation of 2.22    Sodium periodate (6.33g, 29.6 mmol) dissolved in de-ionized water (80 ml) was slowly added to the solution of compound 2.11 (12.14 g, 26.9 mmol) in MeOH (80 ml), at 0 °C with good stirring. The mixture was warmed up to room temperature and stirred for 4 hours. Once the reaction was completed, the mixture was concentrated and then diluted in EtOAc (100 ml). The organic layer was separated and sequentially washed with aq. sat. NaHCO3 (3* 35 ml), aq. sat. NaCl (35 ml), dried over MgSO4 and concentrated. Then the crude product was dissolved in 1, 2 – dichlorobenzene (30 ml), and Na2CO3 powder (5.7g, 53.8 mmol) was added. The reaction was heated up to 190 °C to keep refluxing and stirred overnight under Argon protection. Then, NH4Cl (20 ml) was added to quench the reaction. The mixture was diluted with 50 ml EtOAc, washed with aq. sat. NH4Cl (3* 35 ml), aq. sat. NaCl (35 ml) dried over MgSO4 and concentrated. Additional extraction was performed using hexanes (50 ml) and acetonitrile (50 ml) to remove excess 1, 2 – dichlorobenzene. Chromatographic purification of the residue (1: 4 = EtOAc: Hexane) provided 2.22 (7.59 g, 18.8 mmol, 70% over two steps) as an orange solid.  1H NMR (CDCl3): 7.71-7.62 (m, 4H); 7.51-7.37 (m, 6H); 5.91-5.77 (m, 1H); 5.36 (d, J=17, 1H); 5.27 (d, J= 10, 1H); 4.94 (br, 1H); 4.06 (br, 1H); 3.83-3.63 (m, 2H); 2.94 (s, 3H); 1.09 (s, 3H)  13C NMR (CDCl3): 135.58; 135.55; 135.46; 132.69; 132.66; 130.03; 130.02; 127.9; 127.8; 118.1; 66.3; 57.8; 41.9; 26.9; 26.8; 19.3  IR: 3290; 2931; 1361  83 HRMS: calcd. for C21H29NO3SSi    426.1535 [M+Na]+ found                                  426.1525 [M+Na]+  M.P.: 71.5-72.5 °C [α]D23 -10.12 ° (CHCl3, c= 1.00)              Figure A.22: 1H NMR spectrum of 2.17  84   Figure A.23: 13C NMR spectrum of 2.17          Figure A.24: IR spectrum of 2.17  85 Preparation of 2.37e  NHMs OH    In ice bath, 1 M TBAF solution in THF (1.2 ml, 1.2 mmol) was slowly added into a solution of 2.22 (484 mg, 1.2 mmol) in THF (3 ml). Then the reaction mixture was warmed up to room temperature and stirred over night. The reaction was quenched by 5 ml aq. sat. NH4Cl and diluted with EtOAc (15 ml), washed with aq. Sat. NH4Cl (3* 10 ml), aq. sat. NaCl (10 ml), dried over MgSO4 and concentrated. Chromatography of the residue (EtOAc: Hexane = 1:1) gave 181 mg (1.1 mmol, 93 %) product as light yellow oil.  1H NMR (CDCl3): 5.89-5.73 (m, 1H); 5.52-5.43 (m, 1H); 5.38 (d, J=17, 1H); 5.30 (d, J=10, 1H); 4.11-4.00 (m, 1H); 3.82-3.52 (m, 2H); 3.00 (s, 3H)  13C NMR (CDCl3): 134.8; 118.3; 64.9; 58.1; 41.8  IR: 3280  HRMS: calcd. for C5H11NO3S:       188.0357 [M+Na]+ found:                                 188.0358 [M+Na]+  [α]D20 -21.81° (CH2Cl2, c = 0.94)     86   Figure A.25: 1H NMR spectrum of 2.37e     Figure A.26: 13C NMR spectrum of 2.37e  87   Figure A.27: IR spectrum of 2.37e                          88 General procedure for Heck coupling   Pd (OAc) 2 (10 mol %), ligand (20 mol %), and potassium carbonate (0.6 mmol) was added to the solution of 4-iodine phenol (0.6 mmol) and vinyl glycinol derivative (0.5 mmol) in degassed DMF (1.5 ml). The reaction mixture was heated up to 105 °C- 110 °C under Argon protection. After 2-4 hours stirring (NMR was used to monitor the reaction), the mixture was cooled down to room temperature, quenched with aq. sat. NH4Cl (10 mL) and then extracted with EtOAc (15 ml). The combined extracts were sequentially washed with aq. sat. NH4Cl (10 mL), aq. sat. NaCl (10 ml) dried with MgSO4 and concentrated. Chromatography (1:3 = EtOAc: Hexane) of the residue afforded desired coupling products.                            89 Preparation of 2.34    Light yellow oil  1H NMR (CDCl3): 7.68-7.60 (m, 4H); 7.49-7.31 (m, 8H); 7.06 (d, J=8.6, 2H); 6.62 (d, J=15.7, 1H); 6.07 (dd, J=15.7, 7.5, 1H); 4.93 (d, J=6.7, 1H); 4.25-4.15 (m, 1H); 3.90-3.68 (m, 2H); 2.93 (s, 3H); 2.31 (s, 3H); 1.08 (s, 9H) 13C NMR (CDCl3): 169.4; 150.4; 135.56; 135.54; 133.7; 132.5; 132.3; 130.07; 130.04; 127.95; 127.90; 127.50; 126.5; 121.8; 66.4; 57.4; 42.2; 26.8; 21.1; 19.2 IR: 3288; 2931; 1750; 1324; 1156  HRMS: calcd. for C29H35NO5SSi:      560.1903 [M+Na]+ found:                                    560.1894 [M+Na]+  EA: Calcd. for C29H35NO5SSi:     C, 64.77; H, 6.56; N, 2.60 Found:                                   C, 64.50; H, 6.52; N, 2.79  [α]D20  -16.6 ° (CH2Cl2, c= 1.17)    90   Figure A.28: 1H NMR spectrum of 2.34    Figure A.29: 13C NMR spectrum of 2.34  91   Figure A.30: IR spectrum of 2.34             92 NHMs OTBDPS HO Preparation 2.35     Light orange oil. Chromatographic solvent: EtOAc: Hexane = 1: 2.  1H NMR (CDCl3): 7.70-7.61 (m, 4H); 7.48-7.34 (m, 6H); 7.16 (d, J=8.6, 2H); 6.78 (d, J=8.6, 2H); 6.54 (d, J=15.4, 1H); 5.98-5.85 (m, 2H); 5.01 (d, J=6.5, 1H); 4.24-4.13 (m, 1H); 3.89-3.67 (m, 2H); 2.95 (s, 3H); 1.09 (s, 9H)  13C NMR (CDCl3): 155.9; 135.58; 135.56; 132.9; 132.65; 132.63; 130.07; 130.03; 128.5; 127.97; 127.94; 127.91; 123.4; 115.6; 66.5; 57.8; 42.2; 26.9; 19.3  IR: 3295; 2931; 1362; 1152  HRMS: calcd. for C27H33NO4SSi:        518.1797 [M+Na]+ found:                                         518.1797 [M+Na]+  E.A. : calcd. for C27H33NO4SSi:        C, 65.42; H, 6.71; N, 2.83 found:                                          C, 65.23; H, 6.36; N, 2.69  [α]D21 -3.76 ° (acetone, c = 1.75)    93   Figure A.31: 1H NMR spectrum of 2.35      Figure A.32: 13C NMR spectrum of 2.35  94   Figure A.33: IR spectrum of 2.35                          95 Preparation 2.39b      Chromatographic solvent (EtOAc: Hexanes = 1:2), light yellow oil.  1H NMR (d6-acetone): 8.47 (br, 1H); 7.31 (d, J=8.6, 2H); 6.82 (d, J=8.6, 2H); 6.67 (d, J=15.8, 1H); 6.13 (d, J=15.8, 1H); 6.12-6.07 (m, 1H); 4.22-4.16 (m, 1H); 3.80 (d, J=5.7, 2H); 2.94 (s, 3H); 0.92 (s, 9H); 0.11 (s, 3H); 0.10 (s, 3H)  13C NMR (d6-acetone): 157.3; 131.8; 128.3; 127.7; 124.4; 115.4; 66.3; 57.9; 41.0; 25.4; 18.0; -6.1  IR: 3380  HRMS: calcd. for C17H29NO4SSi:           394.1484 [M+Na]+ found:                                         394.1493 [M+Na]+  [α]D20  +20.70 ° (acetone, c = 1.15)        NHMs OTBS HO  96   Figure A.34: 1H NMR spectrum of 2.39b     Figure A.35: 13C NMR spectrum of 2.39b  97   Figure A.36: IR spectrum of 2.39b                          98 Preparation of 2.39e     Chromatographic solvent (EtOAc: Hexanes = 3: 1), light yellow solid.  1H NMR (d6-acetone): 8.46 (br, 1H); 7.30 (d, J=8.6, 2H); 6.82 (d, J=8.6, 2H); 6.65 (d, J=16, 1H); 6.17-6.06 (m, 2H); 4.21-4.06 (m, 2H); 3.76-3.62 (m, 2H); 2.96 (s, 3H)  13C NMR (d6-acetone): 157.2; 131.7; 128.3; 127.7; 124.5; 115.4; 65.1; 58.3; 41.0 IR: 3426; 1644 HRMS:  calcd. for C11H15NO4S:           280.0619 [M+Na]+ found:                                     280.0616 [M+Na]+ EA: calcd. for C11H15NO4S:           C, 51.35; H, 5.88; N, 5.44 found:                                     C, 51.75; H, 5.80; N, 5.49  M.P. 142-143 °C  [α]D23  -63.6° (acetone, c = 0.79)     99   Figure A.37: 1H NMR spectrum of 2.39e    Figure A.38: 13C NMR spectrum of 2.39e  100   Figure A.39: IR spectrum of 2.39e             101 General procedure for silyl group deprotection   HF-Pyridine solution (70 % HF, 2ml) was drop-wise added into the solution of coupling product (1mmol) in THF (3ml) which was cooled in the ice bath. The reaction mixture was warmed up to room temperature and stirred over night under Argon protection. Once the reaction was completed, the mixture was neutralized with solid NaHCO3 (a tsp of base was slowly added every two minute especially for larger scale reaction) until there was no bubble coming out any more. Then the mixture was filtrated through celite and concentrated under reduced pressure. Chromatography (EtOAc: Hexanes = 3: 1) of the residue afforded the desired products.        Preparation 2.39e     Chromatographic solvent (EtOAc: Hexanes = 3: 1), light yellow solid. See page 99 for characterization data and spectrums.  102 Preparation of 2.42   Light yellow solid, 95 % yield.  1H NMR (CDCl3): 7.39 (d, J=8.6, 2H); 7.06 (d, J=8.6, 2H); 6.68 (d, J=16, 1H); 6.10 (dd, J=16, 7.2, 1H); 4.27-4.17 (m, 1H); 3.88-3.62 (m, 2H); 2.99 (s, 3H); 2.30 (s, 3H)  13C NMR (CDCl3): 169.4; 150.5; 133.5; 132.5; 127.6; 125.7; 121.9; 65.2; 57.7; 42.1; 21.1  IR: 3504; 3284; 1754  HRMS: calcd. for C13H17NO5S:             322.0725 [M+Na]+ found:                                        322.0722 [M+Na]+ HRMS: calcd. for C13H17NO5S:             C, 52.16; H, 5.72; N, 4.68 found:                                        C, 52.10; H, 5.74; N, 4.66  M. P. 125.5-126.5 °C [α]D23 -63.7 ° (CHCl3, c = 0.73)      103   Figure A.40: 1H NMR spectrum of 2.42   Figure A.41: 13C NMR spectrum of 2.42  104   Figure A.42: IR spectrum of 2.42             105 Preparation (s)-MPTA ester 2.44 O NHMs O OMe CF3 AcO    Triethylamine (0.033mL, 0.24 mmol) was slowly added to a solution of 2.42 (50mg, 0.17 mmol) in DCM (1mL) with DMAP (29mg, 0.24 mmol) and (R)-MTPACl (50mg, 0.2 mmol), at 0 oC and with good stirring. Then the reaction mixture was warmed up to room temperature and stirred over night under Argon protection. Upon the completion of the reaction, the mixture was diluted with EtOAc (15mL), and then was sequentially washed with aq. sat. NH4Cl (3*10 mL), aq. sat. NaCl (10 mL) dried over MgSO4 and concentrated. Chromatography of the residue (EtOAc/Hex=1/2) gave 61 mg (0.12 mmol, 70%) product as light yellow oil.  1H NMR (CDCl3): 7.53-7.46 (m, 2H); 7.45-7.30 (m, 5H); 7.06 (d, J=8.5, 2H); 6.66 (d, J=16, 1H); 4.81-4.73 (m, 1H); 4.53-4.41 (m, 3H); 3.53 (s, 3H); 2.89 (s, 3H); 2.31 (s, 3H)  13C NMR (CDCl3): 169.3; 166.4; 150.7; 133.3; 133.0; 131.7; 129.8; 128.6; 127.6; 127.2; 124.4; 121.9; 84.7; 67.7; 55.5; 54.7; 42.2; 21.1  F-NMR -71.66  HRMS: calcd. for C23H24NO7F3S:             538.1123 [M+Na]+ found:                                          538.1132 [M+Na]+ IR 1751  [α]D20 -6.09 ° (CH2Cl2, c = 0.92)  106   Figure A.43: 1H NMR spectrum of 2.44    Figure A.44: 13C NMR spectrum of 2.44  107  Figure A.45: 19F NMR spectrum of 2.44     Figure A.46: IR spectrum of 2.44  108 General procedure for hydrogenation   Compound 2.34 and 2.35 (1 mmol), palladium (10 wt % on activated carbon, 106 mg, and 0.1 mmol) and potassium carbonate (276mg, 2 mmol) was added to a pre-dried round-bottom flask with Argon protection on top. MeOH (5ml) was slowly added at room temperature. Hydrogen gas was bubbled into the solution for half an hour on sonicator. Then the reaction mixture was stirred at room temperature for overnight. Once upon the completion of the reaction, the mixture was quickly filtrated through 2-inch celite pad with Hexanes and concentrated. EtOAc (20 ml) and aq. sat. NH4Cl (10 mL) were added into the crude yellow oil. The mixture was separated and extracted with EtOAc (3*10 ml). The combined organic layer was sequentially washed with aq. sat. NH4Cl (10 mL), aq. sat. NaCl (10 ml) dried with MgSO4 and concentrated. The products were carried over the next step without further purification.            109 Preparation of 2.47 NHMs OTBDPS HO   95 % yield, light yellow oil.  1H NMR (CDCl3): 7.67-7.59 (m, 4H); 7.49-7.36 (m, 6H); 7.00 (d, J=8.6, 2H); 6.74 (d, J=8.6, 2H); 4.56 (d, J=8, 1H); 3.77-3.62 (m, 2H); 3.49-3.38 (m, 1H); 2.82 (s, 3H); 2.67-2.49 (m, 2H); 1.94-1.81 (m, 2H); 1.08 (s, 9H)  13C NMR (CDCl3): 153.8; 135.5; 133.1; 132.7; 130.0; 129.4; 127.94; 127.91; 115.3; 65.7; 55.1; 41.7; 34.4; 31.0; 26.9; 19.21 IR: 3294; 2930; 1316; 1113 HRMS: calcd. for C27H35NO4SSi:        520.1954 [M+Na]+ found:                                      520.1967 [M+Na]+ [α]D23 -15.8° (acetone, c = 1.51)        110  Figure A.47: 1H NMR spectrum of 2.47    Figure A.48: 13C NMR spectrum of 2.47  111  Figure A.49: IR spectrum of 2.47              112 Preparation of 2.48 NHMs OH HO   95 % yield, light yellow to white solid  1H NMR (d6-acetone):    8.08 (br, 1H); 7.07 (d, J=8.5, 2H); 6.75 (d, J=8.5, 2H); 5.94 (d, J=8.5, 1H); 3.99 (br, 1H); 3.63 (d, J=5.5, 2H); 3.49-3.38 (m, 1H); 2.98 (s, 3H); 2.81-2.56 (m, 2H); 1.98-1.65 (m, 2H)  13C NMR (d6-acetone): 155.4; 132.7; 129.2; 115.1; 64.7; 55.8; 40.8; 34.4; 30.9  IR: 3417; 1644;  HRMS: calcd. for C11H17NO4S:           282.0776 [M+Na]+ found:                                      282.0778 [M+Na]+ E.A.: calcd. for C11H17NO4S:           C, 50.95; H, 6.61; N, 5.40 found:                                     C, 50.98; H, 6.59; N, 5.39 M.P.: 112.5-113.5 °C  [α]D23 -6.03° (acetone, c = 0.63)   113  Figure A.50: 1H NMR spectrum of 2.48    Figure A.51: 13C NMR spectrum of 2.48  114  Figure A.52: IR spectrum of 2.48                   115 General procedure for the synthesis of 2.51    Pd (OAc) 2 (5 mol %), N-phenylurea (10 mol %), and potassium carbonate (0.6 mmol) was added to the solution of 4-iodine phenol (0.6 mmol) and vinyl 2.50 (0.5 mmol) in degassed DMF (1.5 ml). The reaction mixture was heated up to 100 °C-105 °C under Argon protection. After 2 hours’ stirring (NMR was used to monitor the reaction), the mixture was cooled down to room temperature, quenched with aq. sat. NH4Cl (10 mL) and then extracted with EtOAc (15 ml). The combined extracts were sequentially washed with aq. sat. NH4Cl (10 mL), aq. sat. NaCl (10 ml) dried with MgSO4 and concentrated. The crude product was dissolved in MeOH with suspended K2CO3 (0.6 mmol) and stirred for one hour at room temperature. Upon the reaction the completion of the reaction, the mixture was filtrated through celite and concentrated under reduced pressure. Chromatography of the residue gave the corresponding desired product.  The pure coupling product, palladium (10 wt % on activated carbon, 26.5mg, and 0.025 mmol) was added to a pre-dried round-bottom flask with Argon protection on top. MeOH (5ml) was slowly added at room temperature. Hydrogen gas was bubbled into the solution for 15 minutes on sonicator. Then the reaction mixture was stirred at room temperature for overnight. Once upon the completion of the reaction, the mixture was quickly filtrated through 2-inch celite pad with Hexanes and concentrated. EtOAc (10 ml) and aq. sat. NH4Cl (5 mL) were added into the crude yellow oil. The mixture was separated and extracted with EtOAc (3*5 ml). The combined organic layer was sequentially washed with aq. sat. NH4Cl (5 mL), aq. sat. NaCl (5 ml) dried with MgSO4 and concentrated.   116 Preparation of 2.51a   89 % yield over 3 steps; very light yellow foam.  1H NMR (d6-acetone):    7.07 (d, J=8.6, 2H); 6.76 (d, J=8.6, 2H); 3.32-3.23 (m, 1H); 2.94 (s, 3H); 2.80-2.52 (m, 2H); 2.01-1.66 (m, 3H); 0.95 (dd, J=9.1, 6.7, 6H)  13C NMR (d6-acetone): 154.1; 133.1; 129.3; 115.4; 59.4; 42.0; 34.3; 31.6; 31.4; 18.5; 17.6 HRMS: calcd. for C13H21NO3S:           294.1140 [M+Na]+ found:                                     294.1143 [M+Na]+          117   Figure A.53: 1H NMR spectrum of 2.51a    Figure A.54: 13C NMR spectrum of 2.51a  118 Preparation of 2.51b   84% yield over three steps; light yellow oil.  1H NMR (d6-acetone):    8.11 (br, 1H); 7.07 (d, J=8.1, 2H); 6.76 (d, J=8.1, 2H); 5.94 (d, J=8.2, 1H); 3.54-3.39 (m, 1H); 2.92 (s, 3H); 2.75-2.55 (m, 2H); 1.88-1.68 (m, 2H); 1.28 (d, J=6.5, 3H)  13C NMR (d6-acetone): 155.4; 132.6; 129.2; 115.0; 49.5; 40.6; 39.7; 31.2; 21.7  HRMS: calcd. for C11H17NO3S:           266.0827 [M+Na]+ found:                                     266.0821 [M+Na]+         119  Figure A.55: 1H NMR spectrum of 2.51b     Figure A.56: 13C NMR spectrum of 2.51b  120 Preparation of 2.51c NHMs Ph OH   66% yield over three steps; light yellow oil.  1H NMR (d6-acetone): 8.13 (br, 1H); 7.38-7.17 (m, 5H); 7.03 (d, J=8.3, 2H); 6.74 (d, J=8.3, 2H); 6.10 (d, J=8.9, 1H); 3.71-3.55 (m, 1H); 2.99-2.54 (m, 4H); 2.45 (s, 3H); 1.93-1.68 (m, 2H)  13C NMR (d6-acetone): 155.4; 139.1; 132.6; 129.7; 129.1; 128.3; 126.3; 115.1; 56.0; 41.9; 40.2; 37.9; 31.0  HRMS: calcd. for C17H21NO3S:           342.1140 [M+Na]+ found:                                     342.1138 [M+Na]+         121  Figure A.57: 1H NMR spectrum of 2.51c    Figure A.58: 13C NMR spectrum of 2.51c  122 Preparation of 2.64    A 0.16 M solution of 2.63 (0.3 mmol) in TFA was added slowly, dropwise into a 0.16 M solution of DIB also in TFA (final concentration of reactants = 0.08 M), at room temperature. Upon the completion of the reaction, the crude mixture was evaporated to dryness under reduced pressure. Chromatography of the residue (1% MeOH in EtOAc) would afford a light yellow solid 2.64 in a 95% yield.  1H NMR (d6-acetone): 7.26 (dd, J=9.8, 3.0, 1H); 7.04 (dd, J=9.9, 3.0, 1H); 6.16 (dd, J=9.9, 2.3, 1H);6.10 (dd, J=10.1, 2.1, 1H); 4.15 (br, 1H); 4.12- 4.04 (m, 1H); 3.82-3.72 (m, 2H); 3.00 (s, 3H); 2.61-2.33 (m, 2H); 2.24-2.13 (m, 1H); 1.99-1.89 (m, 1H)  13C NMR (d6-acetone): 184.4; 152.7; 148.7; 127.7; 127.3; 64.2; 63.9; 63.1; 39.3; 37.7; 26.5  IR: 3417; 2929; 1667; 1328  HRMS: calcd. for C11H15NO4S:           280.0619 [M+Na]+ found:                                     280.0619 [M+Na]+ [α]D22 -20.35o (acetone, c = 1.103)    123  Figure A.59: 1H NMR spectrum of 2.64    Figure A.60: 13C NMR spectrum of 2.64  124 X-RAY CRYSTALLOGRAPHY DATA  X-ray data of compound 2.64  Empirical Formula C11H15NO4S Formula Weight 257.30 Crystal Color, Habit colourless, needle Crystal Dimensions 0.12 X 0.20 X 0.25 mm Crystal System orthorhombic Lattice Type primitive Lattice Parameters a = 5.6476(6) Å  b = 9.7999(12) Å  c = 21.490(3) Å  α = 90o  β = 90o  γ = 90o  V = 1189.4(2) Å 3  Space Group P 212121 (#19) Z value 4 O N SO2CH3 OH  125 Dcalc 1.437 g/cm3 F000 544.00 μ(MoKα) 2.75 cm-1 Data Images 804 exposures @ 15.0 seconds Detector Position 36.00 mm 2θmax 56.2o No. of Reflections Measured Total: 10763 Residuals (refined on F2, all data): R1; wR2 0.047; 0.082 Goodness of Fit Indicator 1.03 No. Observations (I>2.00σ(I)) 2471 Residuals (refined on F); R1; wR2 0.035; 0.076  

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