Carbon-carbon bond formation reactions. Part I : classical aldol reaction. Part II : contemporary C-H bond activation/functionalization

• Main Author: Chok, Yew Keong
• Other Authors: Loh Teck Peng
• Format: Theses and Dissertations
• Language: English
• Published: 2015
• Subjects: DRNTU::Science::Chemistry::Organic chemistry::Organic synthesis
• Online Access: https://hdl.handle.net/10356/65479
• Institution: Nanyang Technological University

Since the serendipitous synthesis of urea by Frederich Wöhler in 1828, which marked the birth of organic synthesis, this craft had been perfected by synthetic chemistry to such an extent where not only can such biomacromolecules as proteins and genes be manipulated and assembled in vitro at will, but also natural products of seemingly boundless complexity and intrigue can be synthesized in the laboratory following logical approaches from readily available starting materials. Nevertheless, regardless of how elaborated contemporary organic synthesis may look, deep down at its core, it is still business as usual, where the forging of carbon–carbon bonds take centre stage. Assembly of the carbon skeletal framework of even a seemingly simple organic compound represents a critical component of its synthesis, and is not simply a task of piecing together the correct number of carbon atoms. Organic chemists are blessed to have experienced a supernova of novel and robust organic reactions and reagents, which opens up an innumerable number of carbon–carbon bond-forming reactions. Examples include the variety of organometallic reagents, aldol reaction, Wittig reaction, Diels-Alder reaction, the huge class of palladium-catalyzed carbon–carbon bond-forming reactions, olefin metathesis, and the list goes on. Herein, we will explore the chemistry of two carbon–carbon bond forming reactions, one classical – the aldol reaction involving the use of organocatalysts, and the second a contemporary rendition of palladium-catalyzed reactions involving C–H bond activation and functionalization. We managed to develop a simple organocatalytic system, consisting of diethylenetriamine and tartaric acid (40 mol%), to effect the ketone aldol addition to aldehyde in water. The system is amenable to catalysing the one-pot Mannich reaction of aromatic amines in water as well and subsequently successfully applied to effect the ketone aldol reaction of N-terminally modified tetrapeptides. This serves as a plausible model for subsequent application to N-terminally modified proteins, to effect conjugation. Next, we also successful developed the first olefination of enamides at the β-position with electron-deficient alkenes catalyzed by Pd(OAc)2 and 1 atm oxygen as the sole oxidant. The reaction proceeded smoothly to provide products in moderate to high yields and with excellent β-regioselectivities. An in-depth study of the mechanism was also undertaken by means of 1H NMR spectroscopic analysis. This novel method generates highly functionalized, versatile compounds which holds potential for organic synthesis. Our synthetic study of (–)-quinocarcin commenced with the synthesis of (R)-phenylglycinol (11) which is then O-methyl protected and finally amidated to furnish picolinamide 2a, the substrate for our next stage of exploration – ligand-directed aryl C–H activation. The synthesis of 2a in good yields and reproducibility enable us to easily advance to the C–H functionalization stage. Building upon our group’s previous unpublished work, acrylation was tested and optimized to give satisfactory results. Subsequent acetoxylation, however, does not proceed as smoothly as we had expected, suffering from severe undesired competing side reactions. Suspecting that the carbon–carbon double bond interferes with the reaction, we attempted reduction of the double bond prior to acetoxylation. Indeed, very slightly higher yield was achieved, but more importantly, much cleaner product was obtained, which tallies with our hypothesis that the double bond affect the reaction in an undesirable manner. Therefore, moving forward, new solutions to circumvent this problem have to be thought out.