Abstract
The constrained dipeptide surrogates 5- and 7-hydroxy indolizidin-2-one N-(Boc)amino acids have been synthesized from L-serine as a chiral educt. A linear precursor ∆4-unsaturated (2S,8S)-2,8-bis[N-(Boc)amino]azelic acid was prepared in five steps from L-serine. Although epoxidation and dihydroxylation pathways gave mixtures of hydroxy indolizidin-2-one diastereomers, iodolactonization of the ∆4-azelate stereoselectively delivered a lactone iodide from which separable (5S)- and (7S)-hydroxy indolizidin-2-one N-(Boc)amino esters were synthesized by sequences featuring intramolecular iodide displacement and lactam formation. X-ray analysis of the (7S)-hydroxy indolizidin-2-one N-(Boc)amino ester indicated that the backbone dihedral angles embedded in the bicyclic ring system resembled those of the central residues of an ideal type II’ β-turn indicating the potential for peptide mimicry.
Highlights
5-hydroxy-5phenyl indolizidine-2-one amino acid (I2 aa) analogs were synthesized by diastereoselective photochemical cyclization of carbamate-protected β-benzoylalaninyl prolinates [13]
A 5-chloro methyl I2 aa derivative was synthesized by the treatment of phthalimido allylglycinyl 5-methoxyprolinate with
12b, hydrogenolytic cleavage of the carbamate using hydrogen and palladium-on-carbon ethanol commenced an an epoxide ring opening andand lactam formation sequence, which was in ethanol commenced epoxide ring opening lactam formation sequence, which followed by Boc as described aboveabove to afford four isomers of 8 and which was followed by protection
Summary
Conformationally constrained dipeptides serve effectively as tools for structure–activity relationship studies to identify biologically active conformers [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. Among different oxidation approaches yielding access to 5-hydroxy and 7-hyof diastereoselective iodolactonization chemistry inspired by the seminal research of the droxy I2aa derivatives, useful routes to (3S,5S,6S,9S)-2 and (3S,6S,7S,9S)-3 were conceived. Molecules 2022, 26, x FOR PEER REVIEW by way of diastereoselective iodolactonization chemistry inspired by the seminal research of the Bartlett laboratory [24]
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