Table of Contents Summary List of Schemes List of Tables List of Figures List of Abbreviations Chapter Catalytic Asymmetric Ring Opening of meso-Aziridines 1.1 Metal catalyzed asymmetric ring opening of meso-aziridines --------------------- 1.2 Organocatalytic asymmetric ring opening of meso-aziridines -------------------- 11 1.3 Conclusion ------------------------------------------------------------------------------ 19 Chapter Guanidine Catalyzed Enantioselective Desymmetrization of meso-Aziridines with Thiols 2.1 Bicyclic guanidine catalyzed enantioselective desymmetrization of meso N-tosyl aziridines with thiols ------------------------------------------------------------------- 24 2.2 Synthesis of novel chiral guanidines ------------------------------------------------- 36 2.3 Guanidine catalyzed enantioselective desymmetrization of meso N-acyl aziridines with thiols ------------------------------------------------------------------- 40 2.4 Guanidine catalyzed enantioselective desymmetrization of cis-aziridine-2,3dicarboxylates with thiols ------------------------------------------------------------- 48 2.5 Conclusion ------------------------------------------------------------------------------ 53 Chapter Guanidine Catalyzed Enantioselective Desymmetrization of meso-Aziridines with Carbamodithioic Acids 3.1 Introduction ----------------------------------------------------------------------------- 60 3.2 Guanidine catalyzed enantioselective desymmetrization of meso-aziridines with in situ generated carbamodithioic acids --------------------------------------------- 64 i 3.3 Synthesis of chiral β-amino sulfonic acid ------------------------------------------- 69 3.4 Conclusion ------------------------------------------------------------------------------ 71 Chapter Experimental 4.1 General Procedures --------------------------------------------------------------------- 76 4.2 Preparation of the aminoindanol derived guanidines ------------------------------ 77 4.3 Desymmetrization of meso N-acyl aziridines with thiols ------------------------- 80 4.4 Preparation of chiral allylic amide --------------------------------------------------- 90 4.5 Preparation and desymmetrization of cis-aziridine-2,3-dicaboxylates ---------- 92 4.6 Desymmetrization of meso N-acyl aziridines with carbamodithioic acids ----- 99 4.7 Preparation of chiral β-amino sulfonic acid --------------------------------------- 107 4.8 X-ray crystallographic analysis ---------------------------------------------------- 109 Appendix Ⅰ Chapter Enantioselective Catalytic Intramolecular Michael Additions: Asymmetric Synthesis of Chiral γ-Lactones 5.1 Introduction ---------------------------------------------------------------------------- 116 5.2 Synthesis of substrates --------------------------------------------------------------- 118 5.3 TBD catalyzed intramolecular Michael Additions ------------------------------- 118 5.4 Cinchona alkaloids catalyzed intramolecular Michael Additions -------------- 120 5.5 Conclusion------------------------------------------------------------------------------ 123 5.6 Experimental -------------------------------------------------------------------------- 124 Appendix Ⅱ Copies of NMR Spectrum ------------------------------------------------------------------ 141 Publications ---------------------------------------------------------------------------------- 179 ii Summary The aim of this study is to develop highly enantioselective desymmetrization of meso-aziridines using chiral guanidines as catalysts. Chiral guanidine 79b was easily synthesized in two steps from commercially available (1R,2R)-1-amino-2-indanol. It was found to be an efficient Brønsted base catalyst for the enantioselective desymmetrization of meso N-acyl aziridines with benzenethiols. High yields (90-94%) and enantioselectivities (88-95% ee) were achieved. The enantiopure 1,2-difunctionalized products obtained can be used to generate chiral allylic amides via simple transformations. Desymmetrization of cis-N-tosyl-aziridine-2,3-dicarboxylates with arenethiols was also developed as a direct synthetic approach towards β-substituted aspartates, with ees up to 90%. The nucleophile scope of the chiral guanidine catalyzed desymmetrization of meso-aziridines was expanded to include carbamodithioic acid, which was generated in situ from an amine and CS2. Moderate to high yields (up to 98%) and good enantioselectivities (up to 90% ee) were also achieved. The optical purity of the ring-opened products could be enhanced to excellent ee values (up to 99%) after a single recrystallization. This is the first time on the use of carbamodithioic acid as a nucleophile in the asymmetric ring opening of aziridines. The methodology also provided a novel and practical protocol for the synthesis of enantiomerically enriched β-amino sulfonic acids. iii List of Schemes Scheme 1.1 Catalytic asymmetric ring opening of aziridines. Scheme 1.2 Et2Zn-dialkyl tartrate complex promoted asymmetric ring opening of meso-aziridines with thiols developed by Oguni and co-workers. Scheme 1.3 Copper-catalyzed desymmetrization of meso N-Ts aziridine 4a with MeMgBr developed by Müller and co-workers. Scheme 1.4 Chromium-catalyzed desymmetrization of meso-aziridines with TMSN3 developed by Jacobsen and co-workers. Scheme 1.5 Proposed mechanism of gadolinium-catalyzed desymmetrization of meso-aziridines with TMSCN. Scheme 1.6 Gadolinium-catalyzed desymmetrization of meso-aziridines with TMSCN developed by Shibasaki and co-workers Scheme 1.7 Yttrium-catalyzed desymmetrization of meso-aziridines TMSN3 developed by Shibasaki and co-workers Scheme 1.8 Desymmetrization of meso-aziridines with TMSCN catalyzed by Gd complexes derived from ligand 14 and 15 developed by Shibasaki and co-workers. Scheme 1.9 Niobium-catalyzed desymmetrization of meso-aziridines with aniline developed by Kobayashi and co-workers. Scheme 1.10 Yttrium-catalyzed desymmetrization of meso-aziridines with TMSCN and TMSN3 developed by RajanBabu and co-workers. Scheme 1.11 Chiral phosphoric acid-catalyzed desymmetrization of mesoaziridines with TMSN3 developed by Antilla and co-workers. Scheme 1.12 Chiral phosphoric acid-catalyzed desymmetrization of mesoaziridines with TMS-SPh developed by Della Sala and co-workers. Scheme 1.13 Chiral phosphoric acid-catalyzed desymmetrization of mesoaziridines with thiols developed by Antilla and co-workers. Scheme 1.14 Desymmetrization of meso-aziridines with thiols under phasetransfer conditions developed by Hou and co-workers. iv with Scheme 1.15 Asymmetric ring opening of unsubstituted aziridine with 1,3dicarbonyl compounds under phase-transfer conditions developed by Dixon and co-workers. Scheme 1.16 Quinine-catalyzed desymmetrization of meso-aziridines with thiols developed by Wu and co-workers. Scheme 1.17 Prolinol-catalyzed desymmetrization of meso-aziridines with thiols developed by Della and co-workers. Scheme 2.1 Synthesis of symmetrical chiral bicyclic guanidine 39. Scheme 2.2 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl maleimide with 1,3-diketones, β-ketoesters, dithiomalonates. Scheme 2.3 Chiral bicyclic guanidine catalyzed Michael reactions of cyclic enones and furanone with dithiomalonate 41f. Scheme 2.4 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl trans-4-oxo-4-arylbut-2-enoates. Scheme 2.5 Chiral bicyclic guanidine catalyzed Michael reactions of 2-cyclopenten-1-one with various 1,3-dicarbonyl compounds. Scheme 2.6 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl maleimide with benzoylacetate using triethylamine as solvent. Scheme 2.7 Chiral bicyclic guanidine catalyzed phospha-Michael additions of various diaryl phosphine oxides to conjugated aryl nitroalkenes. Scheme 2.8 Chiral bicyclic guanidine catalyzed protonation of 1-phthalimidoacrylate with thiophenols. Scheme 2.9 Chiral bicyclic guanidine catalyzed protonation of itaconimides with diaryl phosphine oxides. Scheme 2.10 Chiral bicyclic guanidine catalyzed protonation of axially chiral N-(2-tert-butylphenyl)itaconimide. Scheme 2.11 Chiral bicyclic guanidine catalyzed Michael reactions of dithranol 57. v Scheme 2.12 Chiral bicyclic guanidine catalyzed Diels-Alder reactions of anthrones. Scheme 2.13 Synthesis of guanidine from DMC 69 and amine. Scheme 2.14 Synthesis of bis-guanidinium salt 73·2HBF4. Scheme 2.15 Synthesis of guanidinium salt from aminoindanol. Scheme 2.16 Synthesis of O-Bn aminoindanol. Scheme 2.17 Synthesis of guanidinium salts from O-protected aminoindanols. Scheme 2.18 Preparation of chiral allylic amide 83. Scheme 2.19 Proposed catalytic cycle of chiral desymmetrization of meso-aziridines. Scheme 2.20 Synthesis of cis-aziridine-2,3-dicarboxylates. Scheme 3.1 Synthesis of dithiocarbamates. Scheme 3.2 Reaction of 2-aminomethyloxiranes with carbon disulfide. Scheme 3.3 One-pot reaction of epoxides with amine/CS2. Scheme 3.4 Synthesis of carbodithioic acid esters of fluoxetine. Scheme 3.5 Ring opening reaction of meso N-tosyl aziridine 4a with amines and CS2. Scheme 3.6 Preparation of chiral β-amino sulfonic acid 99. Scheme 5.1 Synthesis of γ-lactones via tandem radical addition-cyclization reaction. Scheme 5.2 Synthesis of γ-lactones via intramolecular Michael addition. Scheme 5.3 Synthesis of γ-lactones via 1,5-electrocyclic ring closure reaction. Scheme 5.4 Synthesis of donor–acceptor functionalized substrates 102. vi guanidine catalyzed List of Tables Table 2.1 Various chiral guanidines catalyzed desymmetrization of meso N-tosyl aziridine 4c with benzenethiol 63a. Table 2.2 Solvent effect on the chiral guanidine 39 catalyzed desymmetrization of meso N-tosyl aziridine 4a with benzenethiol 63a. Table 2.3 Temperature and concentration effects on the chiral guanidine 39 catalyzed desymmetrization of meso N-tosyl aziridines 4a, 4d with benzenethiol 63a. Table 2.4 Chiral guanidines catalyzed desymmetrization of meso-aziridines 4a, 1a with bethiol 63a. Table 2.5 Desymmetrization of meso N-acyl aziridines 21a, 12a with benzenethiol 63a catalyzed by chiral guanidine 79b. Table 2.6 Desymmetrization of meso N-acyl aziridine 12a with various thiols catalyzed by chiral guanidine 79b. Table 2.7 Effect of catalyst loading on the desymmetrization of meso N-acyl aziridine 12a with benzenethiol 63d. Table 2.8 Desymmetrization of various meso N-3,5-dinitrobenzoyl aziridines 12 with benzenethiol 63d catalyzed by guanidine 79b. Table 2.9 Chiral guanidine 79a catalyzed desymmetrization of various cisaziridine-2,3-dicarboxylates 91a-d with benzenethiol 63a. Table 2.10 Solvent and concentration effects on the desymmetrization of cisaziridine-2,3-dicarboxylate 91d with benzenethiol 63c catalyzed by guanidine 79b. Table 2.11 Desymmetrization of cis-aziridine-2,3-dicarboxylate 91d with various thiols catalyzed by guanidine 79b. Table 3.1 Chiral guanidine 79b catalyzed desymmetrization of meso N-tosyl aziridine 4a with various amines and CS2. Table 3.2 Chiral guanidine 79b catalyzed desymmetrization of meso N-acyl aziridine 12a with amines and CS2. vii Table 3.3 Chiral guanidine 79b catalyzed desymmetrization of various meso N-acyl aziridines 12 with amine and CS2. Table 5.1 TBD catalyzed intramolecular Michael addition reactions. Table 5.2 Optimization of the reaction conditions for intramolecular Michael addition reactions of α,β-unsaturated carbonyl compound 102b. Table 5.3 Preparation of various chiral γ-lactones by enantioselective intramolecular Michael addition reactions of α,β-unsaturated carbonyl compounds 102. viii List of Figures Figure 2.1 General sturcture of guanidine. Figure 2.2 Structural diversity of the aminoindanol isomers. Figure 2.3 O-protected aminoindanols. Figure 2.4 X-ray structure of 81c. Figure 2.5 Structure of aziridine-2,3-dicarboxylate and aspartic acid. Figure 3.1 General structure of dithiocarbamate. Figure 3.2 Structure of fluoxetine. Figure 5.1 Structure of γ-lactone. ix List of Abbreviations AcOH acetic acid Ac acetyl Ad adamantyl Ar aryl [] specific rotation aq. aqueous BINOL 2,2'-binaphthol Bn benzyl Boc tert-butoxycarbonyl t Bu tert-butyl o degrees (Celcius) C  chemical shift in parts per million Cbz carboxybenzyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N'-dicyclohexylcarbodiimide DCM dichloromethane DIPE diisopropyl ether DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethyl sulfoxide dd doublet of doublet x dr diastereomeric ratio ee enantiomeric excess eq. equivalent EI electron impact ionization ESI electro spray ionization Et ethyl FAB fast atom bombardment ionization FTIR Fourier transform infrared spectroscopy g grams h hour(s) HPLC high pressure liquid chromatography HRMS high resolution mass spectroscopy Hz hertz i.d. internal diameter IR infrared J coupling constant LRMS low resolution mass spectroscopy M mol∙l-1 Me methyl MeCN acetonitrile MeOH methanol mg milligram MHz megahertz xi min. minute(s) mL milliliter L microliter mmol millimole MTBE methyl tert-butyl ether MS mass spectroscopy NMR nulcear magnetic resonance Nu nucleophile PA phosphoric acid Ph phenyl ppm parts per million PG protecting group i Pr isopropyl rt room temperature TBD 1,5,7-Triazabicyclo[4.4.0]dec-5-ene TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl TsCl para-toluenesulfonyl chloride xii [...]... resolution mass spectroscopy M mol∙l -1 Me methyl MeCN acetonitrile MeOH methanol mg milligram MHz megahertz xi min minute(s) mL milliliter L microliter mmol millimole MTBE methyl tert-butyl ether MS mass spectroscopy NMR nulcear magnetic resonance Nu nucleophile PA phosphoric acid Ph phenyl ppm parts per million PG protecting group i Pr isopropyl rt room temperature TBD 1, 5,7-Triazabicyclo[4.4.0]dec-5-ene... million PG protecting group i Pr isopropyl rt room temperature TBD 1, 5,7-Triazabicyclo[4.4.0]dec-5-ene TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl TsCl para-toluenesulfonyl chloride xii . opening of meso- aziridines 3 1. 2 Organocatalytic asymmetric ring opening of meso- aziridines 11 1. 3 Conclusion 19 Chapter 2 Guanidine Catalyzed Enantioselective Desymmetrization of meso- Aziridines. Guanidine Catalyzed Enantioselective Desymmetrization of meso- Aziridines with Carbamodithioic Acids 3 .1 Introduction 60 3.2 Guanidine catalyzed enantioselective desymmetrization of meso- aziridines. Thiols 2 .1 Bicyclic guanidine catalyzed enantioselective desymmetrization of meso N-tosyl aziridines with thiols 24 2.2 Synthesis of novel chiral guanidines 36 2.3 Guanidine catalyzed enantioselective