Peptide mimicry employing a combination of aza-amino acyl proline and indolizidinone residues has been used to develop allosteric modulators of the prostaglandin F2α receptor. The systematic study of the N-terminal phenylacetyl moiety and the conformation and side chain functions of the central turn dipeptide residue has demonstrated the sensitive relationships between modulator activity and topology. Examination of aza-Gly-Pro and aza-Phe-Pro analogs 2a and 2b in a murine preterm labor model featuring treatment with lipopolysaccharide demonstrated their capacity to extend significantly (>20 h) the average time of delivery offering new prototypes for delaying premature birth.

Sets of azabicyclo[X.Y.0]alkanone amino acids have been effectively used to identify active conformers in peptide-based drug discovery, but they usually require multiple routes to synthesize. Employing a common method from the same nine-membered unsaturated lactam precursor, we developed conditions for stereo-and regiochemical transannular cyclizations to synthesize three different indolizidin-2-and 9-one amino acid (I 2 aa and I 9 aa) analogues. For example, (3S,5R,6R,9S)-and (3S,5S,6S,9S)-I 2 aa diastereomers were prepared from hexahydro-1H-azonines by using iodine in THF and in MeCN with DIB as an additive. The regioselectivity of the transannular cyclization was influenced by amine protection to favor the synthesis of the I 9 aa isomer. Moreover, side chains were added onto the I 2 aa and I 9 aa ring systems by way of olefin intermediates that underwent Pd-catalyzed C−H bond activation and allylic oxidation.

An efficient method for synthesizing different functionalized azabicyclo[X.Y.0]alkanone amino acid derivatives has been developed employing electrophilic transannular cyclizations of 8-, 9-, and 10-membered unsaturated macrocycles to form 5,5-, 6,5-, 7,5-, and 6,6-fused bicylic amino acids, respectively. Macrocycles were obtained by a sequence featuring peptide coupling of vinyl-, allyl-, homoallyl-, and homohomoallylglycine building blocks followed by ring-closing metathesis. X-ray crystallographic analyses of the 8-, 9-, and 10-membered macrocyclic lactam starting materials as well as certain bicyclic amino acid products provided insight into their conformational preferences as well as the mechanism for the diastereoselective formation of specific azabicycloalkanone amino acids by way of transannular iodolactamization reactions.

Azacyclo- and azabicycloalkanone peptidomimetics were synthesized regio- and diastereoselectively by iodoacetoxylation and transannular amidation reactions on unsaturated lactam precursors contingent on ring size, olefin position, solvent, and hypervalent iodine(III) reagent. 4-Iodopyrrolizidinone 1, 7-iodoindolizidinone 2, and 4-iodo-5-acetoxylactams (e.g., 6 and 7) were made stereospecifically from 7-9-membered olefins 16, iodine, and hypervalent iodine(III) in acetonitrile or toluene, respectively. X-ray crystallography demonstrated potential for mimicry of natural peptide turn side chain and backbone conformations.

Enantiomerically pure 4-vinylproline (Vyp) was synthesized by a five-step approach from N-(Boc)­iodo-alanine (2) featuring copper-catalyzed SN2′ substitution of the corresponding zincate onto (Z)-1,4-dichlorobut-2-ene to prepare methyl 2-N-(Boc)­amino-4-(chloromethyl)­hexenoate (3). Intra- and intermolecular displacement of the chloride provided respectively Vyp and methyl 2-N-(Boc)­amino-4-(azidomethyl)­hexenoate (7) suitable for the synthesis of constrained peptide analogs.

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