Stereo- and Regiochemical Transannular Cyclization of a Common Hexahydro-1H-azonine to Afford Three Different Indolizidinone Dipeptide Mimetics

Abstract

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.

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

“…In spite the possibility of improved regioselectivity in the oxirane ring opening, the route (Scheme 2) was, however, deemed inefficient due to the complications engendered from the lack of diastereomeric selectivity in the epoxidation of olefins 11. Prompted by earlier success using transannular iodolactamization to prepare azabicyclo[X.Y.0]alkan-2-one ring systems [15,35], and related iodoamination protocols for preparing iodomethyl pyrrolidines and piperidines [36][37][38], ∆ 4 -diaminoazelate 11a was subjected to iodine and NaHCO3 at −20 °C (Scheme 3). The ring opening of the iodonium intermediate by one of the two carbamate-protected nitrogen appeared to be a method for selectively obtaining proline 15 instead of the azetidine counterpart; however, a mixture of diastereomeric iodolactones 16 was also produced as a competing side product.…”

“…In peptide science, 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 approaches for creating constrained dipeptides that employ steric [ 2 , 3 ], stereo-electronic [ 4 , 5 ], and covalent constraints [ 1 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], the use of azabicyclo[X.Y.0]alkanone amino acids offers unique potential for locking the polyamide backbone into specific orientations that may mimic natural secondary structures such as β-turns.…”

“…In peptide science, 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 approaches for creating constrained dipeptides that employ steric [ 2 , 3 ], stereo-electronic [ 4 , 5 ], and covalent constraints [ 1 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], the use of azabicyclo[X.Y.0]alkanone amino acids offers unique potential for locking the polyamide backbone into specific orientations that may mimic natural secondary structures such as β-turns. Among such bicyclic systems, the azabicyclo[4.3.0]alkanone amino acids, so-called indolizidine-2-one amino acid (I 2 aa) analogs and their ring-substituted derivatives (e.g., 1 – 3 , Figure 1 ), are among the most studied for utility in dissecting the backbone geometry and side chain alignment responsible for peptide activity towards the development of receptor ligands (e.g., 4 ) and enzyme inhibitors (e.g., 5 – 7 ) [ …”

“…Several synthetic methods have been developed to introduce substituents at the 5- and 7-positions along the I 2 aa ring system ( Figure 1 ) [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. For example, 5-hydroxy-5-phenyl I 2 aa analogs were synthesized by diastereoselective photochemical cyclization of carbamate-protected β-benzoylalaninyl prolinates [ 13 ].…”

“…Furthermore, 5-hydroxymethyl, 5-azidomethyl, 5-formyl, 5-carboxy, 5-benzyl, 7-hydroxymethyl, 7-hydroxypropyl, 7-azidopropyl and 7-benzyl, as well as 5,7-dibenzyl I 2 aa derivatives were all synthesized diastereoselectively by routes featuring, respectively, intramolecular displacements and reductive aminations of 4-substituted 5-methanesulfonyl and 5-keto 2,8-diaminoazelates to form 5-substituted prolines, which reacted in lactam cyclization [ 10 , 11 , 12 ]. Furthermore, 5-iodo I 2 aa diastereomers were respectively prepared by transannular iodolactamization of hexahydro-1H-azonines [ 15 ]. Iodide elimination afforded the corresponding ∆ 5 -indolizidine-2-one, which was subsequently arylated at the 5-position by oxidative Heck chemistry [ 16 ].…”