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Stereodivergent and enantiodivergent pathways for the Friedel–Crafts reactions were computationally studied with DFT methods. This study aims to explain recently observed solvent-dependent regioselectivity, and enantioselectivity when cinchona catalyst is used. Deprotonation reaction, Frontier Kohn-Sham orbitals, dual descriptors, Mulliken charges, and Hirshfeld atomic charge for reactant were calculated and analyzed. The most probable position of electrophilic attack and nucleophilic attack in-silico predicted aligns with experimental observations. The calculation of the transition states on the anionic and neutral model in a vacuum show preference for the electrophilic attack in the para position. In comparison to the anionic system, the presence of potassium cation improves ortho/para selectivity and increases the energy barrier. For the key enantioselective step, 12 transition states were calculated which covers 4 representative product such: (R)-ortho, (S)-ortho, (R)-para, and (S)-para. The computational study suggests, that the presence of the cesium cation is essential for the arrangement of the reactant and catalyst in the transition state, which leads to observed selectivity.

Ring-opening polymerization (ROP) is a promising approach to accessing well-defined polyesters with superior (bio)degradability and recyclability. However, the living/controlled polymerization of glycolide (GL), a well-known sustainable monomer derived from carbon mono/di-oxide, has never been reported due to the extremely low solubility of its polymer in common solvents. Herein, we report the first living/controlled anionic ROP of GL in strong protic fluoroalcohols (FAs), which are conventionally considered incompatible with anionic polymerization. Well-defined polyglycolide (PGA, Ð < 1.15, Mn up to 55.4 kg mol-1) and various PGA-based macromolecules are obtained at room temperature for the first time. NMR titration and computational studies revealed that FAs simultaneously activate the chain-end and monomer without being involved in initiation. Low boiling point FAs and PGA can be recycled through simple distillation and sublimation at 220 oC in vacuo, respectively, providing a promising sustainable alternative for tackling plastic pollution problems. Well-defined multicrystalline multiblock polymers are essential model polymers for advancing crystallization physics, phase separation, self-assembly, and improving the mechanical properties of materials. However, due to the different chain properties and incompatible synthetic methodology, multicrystalline multiblock polymers with more than two crystallites are rarely reported. Herein, by combining polyhomologation, ring-opening polymerization, and “catalyst switch” strategy, we synthesized the first pentacrystalline pentablock quintopolymer, polyethylene-b-poly(ethylene oxide)-b-poly(e-caprolactone)-b-poly(L-lactide)-b-polyglycolide (PE-b-PEO-b-PCL-b-PLLA-b-PGA). The novel “fluoroalcohol-assisted catalyst switch” enables the first successful incorporation of a high melting point polyglycolide into the complex multiblock polymer. Solid-state NMR spectroscopy, X-ray diffraction, and differential scanning calorimetry revealed the existence of five different crystalline phases.

This doctoral thesis focuses on applying different organocatalysts in several enantioselective reactions and aerobic photooxidations using visible light. Chapter 1 describes using a chiral primary amine-salicylamide derived from (1R,2R)-cyclohexane-1,2-diamine as chiral organocatalyst in the asymmetric conjugate Michael addition of aldehydes and ketones to maleimides, giving the corresponding enantioenriched succinimides. The same organocatalyst is used in the enantioselective Michael addition of aldehydes to nitroalkenes, yielding enantiopure γ-nitroaldehydes. Furthermore, these Michael additions of aldehydes to maleimides and nitroalkenes are carried out employing sustainable and environmentally friendly deep eutectic solvents (DES), being able to reuse the catalytic system for several cycles. Chapter 2 describes using a chiral primary-amine monocarbamate derived from (1R,2R)-cyclohexane-1,2-diamine as chiral organocatalyst in the enantioselective α-amination of aldehydes with azodicarboxylates, obtaining the corresponding α,α-disubstituted aldehydes with the absence of solvent under mild conditions. This simple orgacatalytic system’s applicability is demonstrated by preparing a chiral oxazolidinone precursor of amino acids. The reaction is also successfully scaled-up. In addition, theoretical calculations were performed to demonstrate how the absolute configuration of the final adducts is produced. Chapter 3 shows how riboflavin tetraacetate, a cheap vitamin B2 derivative, is an appropriate metal-free photocatalyst in the aerobic photooxidation of xanthenes, thioxanthenes and dihydroacridines under visible light irradiation. / This research work has been possible thanks to funding from the Spanish Ministerio de Economía y Competitividad (PGC2018-096616-B-100, CTQ201788171-P), the Generalitat Valenciana (AICO 2021/013) and the University of Alicante (VIGROB-173). The author wishes to express his gratitude to the Institute of Organic Synthesis for a research contract (I-PI/21-20) and to the University of Alicante-Banco Santander consortium for a grant to spend a three-months research period in the Chemistry Interdisciplinary Project research center (ChIP) of the University of Camerino (Italy) under the supervision of Dr. Matteo Tiecco.

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Enzymes are some of nature's most powerful tools in chemical processes. However, their molecular complexity makes them difficult to synthesize and complicates their application in traditional organic synthesis. Peptides, a building block of enzymes, can be rapidly synthesized and have been used as a possible alternative in achieving enzyme-like catalysis. However, most peptide-based catalysts are limited in reaction-scope and are unable to incorporate traditional organic catalysts. We have designed a helical peptide scaffold capable of being functionalized with a wide variety of organocatalysts as well as transition-metal based catalysts. In order to understand how the peptide structure effects reactivity and selectivity we designed and studied a helical peptide functionalized with enamine and thiourea catalysts for the conjugate addition reaction of a variety of nitroolefins to cyclohexanone. By rationally engineering the peptide backbone, we were able to achieve up to 95%ee. Our studies emphasized the crucial role the peptide secondary structure plays in this reaction and its potential to serve as a general catalytic platform for future reaction development. Progress particularly toward the development of peptide scaffolds capable of binding transition-metals and performing organometallic catalysis is also described. Peptides are promising motifs in therapeutics. They are more specific and are able to bind to a larger range of targets than small-molecule based drugs while also having lower immunogenicity than larger biologic-based drugs. However, their poor in vivo stability is problematic for their more widespread use. Peptide stapling has been shown to increase peptide stability by covalently linking two ends of the peptide. Squaric esters are commonly used in conjugation chemistry and have shown to selectively react with primary amine nucleophiles, such as those on lysine sidechains. However, their potential to act as peptide stapling reagents has remained unexplored. We have developed a method whereby helical peptides can be stapled with squaric methyl ester on-resin. Peptides can be stapled at the i+1, i+4, and i+7 positions in good yields. The staple is also stable under the highly acidic conditions used to cleave the peptides from resin. Circular dichroism studies show that the staple is able to increase peptide helicity when compared with an unstapled control.