Design, synthesis and biomedical applications of Azabicycloalkanone Amino Acid Peptidomimetics

Peptidomimetics are promising structures that replicate peptide function and conformation. They offer the potential to improve molecular-recognition, to enhance transport across biological membranes, and to resist metabolism. Among peptidomimetic classes, azabicyclo[X.Y.0]alkanone amino acids are particularly attractive, because of their capacity to rigidify backbone and side-chain geometry to replicate specific secondary structures such as turn conformations.  This thesis reveals an effective means for synthesizing azabicycloalkanone amino acids having different ring sizes. Strategies for adding ring substituents to the bicyclic ring system have been developed to mimic side-chain function. Finally, a set of indolizidin-2-one amino acid (I2aa) analogs has been made based on a lead allosteric modulator of the prostaglandin-F2α (PGF2α) receptor (FP) with the goal to address the unmet biomedical need of preterm birth.  A study of transannular cyclization of unsaturated lactams has provided access to a series of constrained bicyclic peptide surrogates using a common synthetic strategy featuring preparation of the cyclic precursor by coupling of enantiomerically pure ω-unsaturated amino acids followed by ring closing metathesis. Transannular iodoamidation and iodoacetoxylation of different unsaturated lactams have been accomplished where regioselectivity and diastereoselectivity was contingent on ring size, olefin position, solvent, amine protection and the use of a hypervalent iodine(III) additive. Transannular iodolactamization of different 8-, 9- and 10-member unsaturated lactams gave access to fused 5,5-, 5,6-, 6,4-, 6,5-, 6,6- and 7,5-bicycles. Although 8- and certain 9-membered lactams were resistant to iodoamidation using iodine in different solvents, transannular cyclization was achieved by adding (diacetoxyiodo)benzene to the reaction mixture.  X-ray crystallographic and spectroscopic analyses of 8-, 9-, and 10-member macrocycles, and 5,5-, 5,6-, 6,5- and 7,5-bicycles have demonstrated the potential of these constrained dipeptides to mimic the central residues of ideal type I, II’, II and VI β-turn geometries. Different methods were investigated to introduce functionality onto these ring systems with the purpose of replicating side-chain presentation at such turn regions. For example, copper-catalyzed SN2' reaction of the zincate from N-(Boc)iodo-alanine onto (Z)-1,4-dichlorobut-2-ene has provided methyl 2-N-(Boc)amino-4-(chloromethyl)hexenoate. Intra- and intermolecular displacement of the chloride from this ω-unsaturated amino acid building block has given effective entry to enantiomerically pure 4-vinylproline (Vyp) and 4-vinylornithine (Von) derivatives. Side-chain diversity has also been added by C-H bond activation and allylic oxidation of dehydro-indolizidin-2-one residues. In the pursuit of agents to prolong labor and prevent preterm birth (so-called tocolytics), diversity-oriented methods were developed to prepare a series of analogues of the I2aa FP modulator PDC113.824. A series of ten different I2aa analogs was synthesized to study structure-activity relationships for FP modulation in a myometrial contraction assay. The addition of substituents was achieved on both the five and six membered rings. Certain I2aa analogues exhibited activity and efficacy in inhibiting myometrial contractions likely by way of FP modulation. An effective, atom-economical means for producing lactam and bicyclic peptidomimetics of different ring sizes has been developed using a common synthetic strategy. A wealth of X-ray structural data of the different peptidomimetics has been obtained indicating potential for turn mimicry. Mechanistic insights into the transannular cyclization to make the bicycles may have general utility for the organic chemistry community engaged in alkaloid natural product synthesis.  The applications of specific azabicycloalkanone amino acids in medicinal chemistry was demonstrated by the synthesis of FP modulators possessing ring-substituted I2aa residues with the objective of developing therapeutics to delay labour and inhibit preterm birth. This thesis has thus addressed important issues in organic reactivity for the synthesis of heterocycles, in peptide science with respect to mimicry of secondary structure, and in medicinal chemistry towards treatment of the unmet medical need of preterm birth.

Keyphrases: Azabicycloalcanes (quinolozidinone, pyrrolizidinone, indolizidinone), Prostaglandine F2α, Transannular cyclizations, Azabicyclo[X.Y.0]alkanone amino acid (Quinolozidinone, Pyrrolizidinone, Indolizidinone), Iodolactamization, Prostaglandin F2a, Allosterism, Tocolytic, Premature delivery