Constrained Dipeptide Surrogates: 5- and 7-Hydroxy Indolizidin-2-one Amino Acid Synthesis from Iodolactonization of Dehydro-2,8-diamino Azelates

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.

Keywords: heterocycle; indolizidin-2-one amino acids; iodolactonization; lactam; peptide mimic.

Figure 1

Indolizidine-2-one amino acid (Boc-I²aa-OH) isomers 1, 5- and 7-hydroxy I²aas 2 and 3, methyl ester counterparts 8 and 9, and biologically active 5- and 7-substituted I²aa NK-2 ligand 4 and thrombin inhibitors 5–7.

Scheme 1

Synthesis of protected epoxides 12.

Scheme 2

Syntheses of 5- and 7-hydroxy Boc-I²aa-OMe 8 and 9 from epoxide 12.

Scheme 3

Strategies featuring iodoamination and dihydroxylation of ∆⁴-diaminoazelate 11a.

Scheme 4

Synthesis of 5- and 7- hydroxy I²aa derivatives 2 and 3.

Figure 2

Strong (solid double-tipped arrows) and weak (dotted lines) through-space transfer of magnetization used to assign relative stereochemistry of (5S,6S)-8 and (6S,7S)-9.

Figure 3

Depictions of conformers in the X-ray structure of (6S,7S)-9.

Figure 4

X-ray-determined backbone dihedral angles of related I²aa systems and an ideal type II′ β-turn [11,44,45].