Unusual Paradigms in Selective Synthesis: Part 1: Toward the Synthesis of Racemic and Enantioenriched HIOC; Part 2: Fluorinated Alcohols: Powerful Promoters for the Ring-Opening Reactions of Epoxides with Carbon Nucleophiles Open Access

Dover, Taylor (Spring 2021)

Permanent URL: https://etd.library.emory.edu/concern/etds/d504rm57z?locale=en


N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) exhibits protective activity against light-induced retinal damage in animal models, and thus has considerable therapeutic potential. Due to its stereogenic center, asymmetric synthesis methods are of great interest. This thesis will describe improvements in the synthesis of racemic HIOC, as well as the development of asymmetric synthesis methods for two analogs of the carboxylic acid precursor. Our selective synthesis strategy employs porcine liver esterase (PLE) in two different capacities: selective hydrolysis of the ester precursor and a multi-step process that includes an enzymatic desymmetrization and a cyclization step. We also discuss preliminary computational studies of PLE, and the challenges associated with these efforts.

The coupling of terminal alkynes and epoxides using mild catalytic methods is a long-standing challenge in synthetic chemistry. As part of initial efforts toward a strategy employing dual activation of the alkyne nucleophile and the epoxide electrophile, we developed an extensive review of fluorinated alcohol solvents in epoxide ring-opening reactions with carbon nucleophiles. The unique physical properties of these solvents enable interesting reactivity paradigms, which are rarely observed in typical organic solvents.

Table of Contents

Chapter 1: Developments Toward an Optimized Synthesis of Racemic HIOC

           1.1 Background & Physiology of the BDNF/TrkB Interaction                                        1

           1.2 Overview of Relevant Small-Molecule, Serotonin-Derived Therapeutics             5

           1.3 Overview of the Published HIOC Synthesis                                                                 6

           1.4 Mechanistic Concerns in the CDI Coupling                                                                 7

           1.5 Initial Attempts at HIOC Synthesis                                                                               8

           1.6 Revisions to the Synthesis of 2-Oxopiperidine-3-carboxylic Acid                          9

           1.7 A Variant Route to 2-Oxopiperidine-3-carboxylic Acid                                            11

           1.8 Revisions to the Final Step of the HIOC Synthesis                                                    12

           1.9 Conclusions                                                                                                                  13

Chapter 2: Developments Toward an Enantioselective Synthesis of HIOC                                     

           2.1 The Importance of Stereochemistry in Therapeutics                                               14

           2.2 Chemoenzymatic Assays for Enantioselective Hydrolysis                                       15

           2.3 Time Trials and Attempts at Configurational Assignment                                       17

           2.4 Progress toward preparing the Cα-methyl derivative of HIOC                                18

           2.5 Relevant Background for the Analysis of PLE Enantioselectivity                           23

           2.6 Initial Challenges in the Analysis of PLE Enantioselectivity                                   25

           2.7 Computational Molecular Docking Studies                                                                26

           2.8 Further Challenges in the Analysis of PLE Enantioselectivity                                27

           2.9 Concluding Thoughts                                                                                                   29

Chapter 3: Fluorinated Alcohols: Powerful Promoters for Ring-Opening Reactions of Epoxides with Carbon Nucleophiles       

           3.1 Overview                                                                                                                      31

           3.2.1 Introduction                                                                                                               34

           3.2.2 Properties of Fluorinated Alcohol Solvents                                                             36

           3.2.3 Safety of Fluorinated Alcohol Solvents and Implications in Green Chemistry  37

           3.3.1 Intermolecular Carbon-Carbon Bond-Forming Reactions                                    38

           3.3.2 Intramolecular carbon-carbon bond-forming reactions                                        44

           3.4.1 Ring-opening reactions with organopalladium intermediates arising from directed C-H functionalization   51

           3.4.2 Scope of reactions and conditions                                                                             53

           3.4.3 Mechanistic Proposals                                                                                               56

           3.5 Ring-opening reactions with terminal alkyne nucleophiles                                    59

           3.6 Ring-opening reactions of aziridines with carbon nucleophiles                             64

           3.7 Conclusions                                                                                                                  65

Chapter 4: Experimental Details                                                                                                       

           4.1 Notes                                                                                                                             67

           4.2 Protocols                                                                                                                       67

           4.3 Computational Details                                                                                                  72

References                                                                                                                                      73

Figures, Schemes, Tables, and Equations


           Figure 1.1.1: (A) Illustration of the “Neurotrophic Factor Hypothesis”: neurons that obtain the necessary target-derived neurotrophic factors ultimately survive and differentiate, while those that do not eventually die off. (B) Illustration of alternative routes of obtaining neurotrophic factors, including autocrine and paracrine routes.....2

           Figure 1.1.2: Simplified illustration of the TrkB receptor domain and the tyrosine residues implicated in some of the downstream signaling pathways.....3

           Figure 1.2.1: Structures of N-acetylserotonin (NAS) and N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC), two serotonin derivatives with activity as TrkB agonists.....6

           Figure 1.4.1: (A) Summary of the literature-proposed mechanisms for the CDI (5) coupling of carboxylic acids 7 with amines 12 to produce amides 13. (B) The exact mechanism of the reaction remains undetermined, with the second phase (8→11) remaining contested in the chemical literature.....8

           Figure 2.1.1: Structures of (R)- and (S)-thalidomide. While the (R) enantiomer is therapeutic, the (S) enantiomer exhibits teratogenic properties.....14

           Figure 2.3.2: Structure of the Cα-methyl derivative of HIOC (18).....18

           Figure 2.4.1: Structures of nipecotic acid (19), 2-oxopiperidine-3-carboxylic acid (4), and the Cα-methyl derivative of 2-oxopiperidine-3-carboxylic acid (21).....18

           Figure 2.5.1: Schematic illustration of the revised Jones model for the selectivity of PLE. The HL (hydrophobic, large) sector has undergone significant revision since the original specification of ≈33 cubic Å given in ref. 62.....23

           Figure 2.5.2: Application of the Jones Model to 24, which illustrates the cause of the preferential production of (R)-25.....24

           Figure 2.7.1: Methyl 2-phenylacetate (28) and ethyl 2-phenylacetate (29)—two substrates used as our model system. The computed binding affinities and the literature-reported Michaelis constants are also shown.....26

           Figure 2.7.2: Structure of phenylacetic acid, the hydrolysis product of both 28 and 29.....26

           Figure 2.8.1: Structure of PLE, with the particularly troublesome external cavity highlighted. To induce binding within the binding pocket, the Gridbox in AutoDock Vina was set to exclude this region.....28

           Figure 2.9.1: Illustration of the Entrance Channel, flanked by the two entrance helices, highlighted in blue and red.....30

           Figure 3.1.1: Proposed structures for bastimolide A and bastimolide B, two antimalarial natural products with moderate activity against drug-resistant P. falciparum strains.....31

           Figure 3.1.2: Excerpt from the synthesis of RK-397, an anti-cancer natural product.....33

           Figure Structures of fluorinated alcohol solvents.....35

           Figure Aggregation of HFIP, depicting hydrogen bond donation with 1,4-dioxane.....37

           Figure The electrophilic aromatic alkylation mechanism promoted by hydrogen bonding and the ionizing power of TFE.....40

           Figure Possible mechanisms for cycloisomerization.....48

           Figure Directing groups for palladium acetate-catalyzed C-H functionalization / epoxide alkylation.....52

           Figure Representative epoxides for palladium-catalyzed C-H functionalization / epoxide alkylation.....53

           Figure Partial catalytic cycles involving 2-phenylpyridine alkylation, with a Pd(IV) intermediate (path a) vs. redox-neutral pathway (path b). Determined at the B2PLYP/DGDZVP level of theory, in acetic acid (e = 6.25).....58

           Figure 3.5.2: Scope of product dihydropyrans (124-127) arising from epoxide substrates 37 (a) and 101 (b).....62

           Figure 3.5.3: Individual steps via alkynyl alcohols 128 and 129.....63

           Figure 4.3.1: Sample Workflow for AutoDock Vina Docking Calculations.....72


           Scheme 1.3.1: Synthetic route to HIOC from a commercially available ester precursor, ethyl 2-oxopiperidine-3-carboxylate (3).....7

           Scheme 1.6.1: Conversion of ethyl 2-oxopiperidine-3-carboxylate (3) into 2-oxopiperidine-3-carboxylic acid (4) as reported by Setterholm et al.....9

           Scheme 1.6.2: Condensed scheme leading to the isopropyl ester byproduct 14 in the work-up protocol for 4.....10

           Scheme 1.7.1: Synthesis of 4 from tert-butyl 2-oxopiperidine-3-carboxylate (15) using an acidic hydrolysis.....12

           Scheme 1.8.1: Step two of the synthetic protocol yielding HIOC.....12

           Scheme 2.3.1: Steglich esterification procedure with (1R,2S)-trans-2-phenyl-1-cyclohexanol (16) to provide derivatized product 17.....17

           Scheme 2.4.2: Synthetic route to provide diethyl 2-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2-methylmalonate (24) from the substitution reaction between diethyl 2-methylmalonate (22) and N-(3-bromopropyl)phthalimide (23).....19

           Scheme 2.4.3: Synthetic route to provide (R)-5-(1,3-dioxoisoindolin-2-yl)-2-(ethoxycarbonyl)-2-methylpentanoic acid ((R)-25) from the PLE-catalyzed desymmetrization of 2-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2-methylmalonate (24).....20

           Scheme 2.4.4: Synthetic route to provide 1-(tert-butyl) 3-ethyl (S)-2-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2-methylmalonate ((S)-26) from (R)-5-(1,3-dioxoisoindolin-2-yl)-2-(ethoxycarbonyl)-2-methylpentanoic acid ((R)-25).....21

           Scheme 2.4.5: Synthetic route to tert-butyl (S)-3-methyl-2-oxopiperidine-3-carboxylate ((S)-20) from 1-(tert-butyl) 3-ethyl (S)-2-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2-methylmalonate ((S)-26) via phthalimide cleavage and regioselective cyclization.....21

           Scheme 2.4.6: Synthetic route to (S)-3-methyl-2-oxopiperidine-3-carboxylic acid ((S)-21) from tert-butyl (S)-3-methyl-2-oxopiperidine-3-carboxylate ((S)-20) via acid hydrolysis.....22

           Scheme 2.4.7: Synthetic route to the (S) enantiomer of the Cα-methyl derivative of HIOC ((S)-18) via a CDI coupling of serotonin-HCl (6) with (S)-3-methyl-2-oxopiperidine-3-carboxylic acid ((S)-21).....22

           Scheme 2.6.1: Illustration of the enantioselective hydrolysis of 2-oxopiperidine-3-carboxylate esters 27 (where the dark blue circle represents one of a variety of linear and branched alkyl chains) to provide (R)- and (S)-2-oxopiperidine-3-carboxylic acid (4).....25

           Scheme Representative examples of epoxide electrophiles reacting with carbon nucleophiles, without fluorinated alcohol solvents.....35

           Scheme Representative scope of epoxide substrates in TFE-promoted alkylations of indoles.....41

           Scheme Alkylations of other electron-rich aromatic compounds with (R)-styrene oxide.....43

           Scheme 3 atom + 2 atom annulations of aryl-substituted epoxides with aryl alkenes.....44

           Scheme HFIP-promoted cyclization of the sensitive epoxyether 65.....45

           Scheme HFIP / Ph4PBF4-promoted cyclization of squalene oxide (80).....51

           Scheme Pd-catalyzed C-H functionalization with 2-pyridyl and N-methoxyamide directing groups, with regioselective epoxide alkylation.....54

           Scheme Pd-catalyzed C-H functionalization with carboxylic acid directing group, with regioselective epoxide alkylation.....55

           Scheme Pd-catalyzed C-H functionalization with an O-methyl ketoxime directing group, promoting regioselective epoxide alkylation.....55

           Scheme Pd-catalyzed C-H functionalization with N-acyl directing groups, with regioselective epoxide alkylation.....56

           Scheme Kinetic isotope rate study and a stoichiometric experiment with palladacycle 109 from 2-phenylpyridine (84).....57

           Scheme A stoichiometric experiment with palladacycle 115 from meta-toluic acid, and a mechanistic proposal based on the stereochemistry of 102.....59

           Scheme 3.6.1: Palladium-catalyzed C-H functionalization of an arylcarboxylic acid with addition to an N-tosylaziridine, promoted by HFIP.....64

           Scheme 3.6.2: Three-component coupling of an isonitrile, an N-tosylaziridine, and malononitrile (119) to form tetrahydropyridone imines, promoted by tetrabutylphosphonium acetate in HFIP.....65


           Table 2.1.1: Chemoenzymatic Condition Assays. Investigation of the enzymatic enantioselective hydrolysis of ethyl 2-oxopiperidine-3-carboxylate (3).....16

           Table Selected properties of HFIP and TFE, compared with ethanol and water.....36

           Table Toxicity of HFIP and TFE.....37

           Table TFE-promoted alkylations of indoles 36 with (R)-styrene oxide (37).....39

           Table Comparing the effects of TFE vs. HFIP and water on alkylation with spiroepoxyoxindole (48).....42

           Table Solvent screening for cycloisomerization of epoxide 63.....45

           Table Acid-catalyzed, HFIP-promoted cycloisomerization of neopentyl epoxide 67.....46

           Table Alkyl vs. ether tethers, and regioselectivity of monomethoxy aromatic substrates.....47

           Table Cycloisomerizations of methylcycloalkyl epoxide substrates 71.....47

           Table HFIP / additive-promoted tricyclizations of epoxydiene 76.....50

           Table 3.5.1: Three-component reactions of phenylacetylene with propylene oxide and active methylene compounds.....61


           Equation 4.1.1: 1H NMR conversion estimate for the PLE-catalyzed hydrolysis of ethyl 2-oxopiperidine-3-carboxylate.....67


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