The design and synthesis of acylated enamino esters as potential inhibitors of serine proteases
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
This thesis examines the synthesis of bromo acylatad enamino asters, of the type (4.01), and protio acylatad enamino esters, of the type (4.02), designed as a new class of potential mechanism-based inactivators and alternate substrata inhibitors, respectively, of chymotrypsin. [Diagram] Chapter 1 describes the synthesis of succinic-, glutaric- and phthalic-basad, bromo and chloro enollactones (1.11-1.15, 1.17) via a new reaction involving halo enollactonization of keto acid phosphoranes (1.06-1.10). The phthalic bromo enollactones (1.17) are also synthesized via the reaction of Ph₃P=CBrCO₂Et with 4,5-dichlorophthalic anhydride. The reactions are extensions of the SCOOPY and Wittig anhydride carbonyl olefination reactions. Chapter 2 describes the synthesis of simple succinimide- and phthallmide-based protio and chloro enamino asters (2.09, 2.63-2.75, 2.93, 2.95, 2.98) via a versatile new reaction in which an enollactone (2.33, 1.11, 2.115) and amine react to form an isolable keto-amide (2.37-2.47, 2.94, 2.96, 2.116) and/or hydroxy lactam (2.48-2.50, 2.97) intermediate. Subsequent elimination of H₂O on heating gives the enamino aster via an overall insertion process. Chapter 3 describes the synthesis of simple succinimide-basad protio and bromo enamino asters (2.66, 2.71, 3.02-3.03) from the reaction of β-keto ester (3.01), via an isolable enamine intermediate (3.07-3.10). The synthesis of α 3-substituted enamino aster (3.04) via the insertion and β-keto ester routes is also described. Chapter 4 describes the synthesis of the target 3,3-disubstituted enamino esters (4.01-4.07) via the insertion reaction and a TiCl₄ mediated β-keto ester reaction. The benzyl group at position 3, required for recognition by chymotrypsin, is introduced stereoselectively using methodology developed largely by Seebach and coworkers for the asymmetric synthesis of α,α;-disubstituted amino acids. By changing this residue other serine proteases can be targeted. The proposed inhibitors (4.01-4.07) are designed to be incorporated into an oligopeptide having optimum interaction with the target enzyme. Preliminary testing of enamino esters and enollactones (2.71, 3.04, 4.01- 4.02, 4.03, 4.06, 4.42, 4.43) for chymotrypsin Inhibition is also described. Chapter 5 examines trends in the ¹³CNMR, ³¹PNMR and FAB mass spectra of keto acid and keto ester phosphoranes (4.15, 4.26, 4.40-4.41, 5.04-5.06); key intermediates to enamino esters and enollactones (eg 4.01-4.06, 4.42, 4.43).