Conformationally restricted amino acid analogues based on lactams
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
This thesis describes the synthesis of enamino esters 3(S)-(E)-benzoylamino-3-benzyl- 5-ethoxycarbonylmethylidene-1-methylpyrrolidin-2-one 77, and 3(S)-(E)-benzoylamino-3-benzy 1-5-ethoxycarbonylmethylidene-1-2, 4-dimethoxybenzy lamino-pyrrolidin-2-one 79. These were designed as a new class of conformationally restricted amino acid analogue. Chapter one gives a general introduction to the importance of peptides in nature and the pivotal role peptides play in drug discovery and design. A number of examples are examined to provide an insight into key elements required in peptidomimetic design. Chapter two introduces the process of peptidomimetic design, in particular that of cisamide bond mimics. The synthesis of a new class of conformationally restricted peptidomimetic based on lactams is examined. Chapter 3 discusses the synthesis of succinic acid-derived, and aspartic acid-derived, β-keto esters and amides 23, 24, 28, via a Meldrum's acid procedure. This method provides the basis for the preparation of cyclic enamino esters. The preparation of the β-keto amide methyl-5-(N-ethoxycarbonylmethylcarbamoyl)-4-oxo-pentanoate 24 allowed chain extension in the C-direction in one easy step. Chapter 4 examines the importance of ene-lactams in nature and the synthesis of enamino esters 55, 56, 59, 61, and enamino amides 63 and 64,.via the reaction of a β-keto ester, or amide, with an amine. Compounds 59 and 61 represent examples of 3- substituted cis-amide bond mimics that allow chain extension in both the N and C directions and subsequent incorporation into a peptide sequence. Chapter 5 describes the synthesis of the target phenylalanine-derived 3,3-disubstituted enamino esters 77 and 79, using the methodology established in chapter 4. Reaction of the enolate derived from (2R, 4S)-2-phenyl-3-benzoyl-4-benzyl-1,3-oxazolidin-5-one 65, with tert-butylbromoacetate gave (2R, 4S)-2-phenyl-3-benzoyl-4-benzyl-4-(tertbutyloxycarbonylmethyl)-1,3-oxazolidin-5-one 67. An x-ray crystal structure of 67 revealed that the reaction had proceeded with an inversion of configuration at C4, with the oxazolidinone ring being essentially planar in the solid state. This also revealed that the stereochemistry at C3 could be determined by the stereochemistry of the amino acid from which it was derived. The tert-butyl ester was hydrolyzed and the resulting acid was converted to the β-keto ester 71 upon reaction with meldrum's acid and EtOH. The β-keto ester (2R, 4S)-2-pheny 1-3 -benzoy 1-4-benzy 1-4-(3 -ethoxycarbony 1-2-oxopropyl)-1 ,3-oxazolidin-5-one 71, was reacted with either methylamine, or 2,4- dimethoxybenzylamine (DMBNH₂), and heated at 150°C, under reduced pressure, to give the target 3,3-disubstituted enamino esters 77 and 79. The target enamino ester 77 and 79 allow chain extension in both the N and C-directions and are designed to be incorporated into a peptide sequence to mimic a cis-amide bond and allow investigation into the bio-active conformation of a specific peptide.