Structural diversity using amino acid “Customizable Units”: conversion of hydroxyproline (Hyp) into nitrogen heterocycles

Abstract

The ability of amino acid “customizable units” to generate structural diversity is illustrated by the conversion of 4-hydroxyproline (Hyp) units into a variety of nitrogen heterocycles. After a first common step, where the unit underwent a one-pot decarboxylation–alkylation reaction to afford 2-alkylpyrrolidines with high stereoselectivity, a divergent step was carried out. Thus, the deprotected 4-hydroxy group was used either to initiate a radical scission that afforded aliphatic β-amino aldehydes, or to carry out an elimination reaction, to give 2-alkyl-2,5-dihydro-1H-pyrroles. In the first case, the amines underwent a tandem reductive amination–cyclization to afford β-amino-δ-lactams, an efficient rigidifying unit in peptides. Different lactam N-substituents, such as alkylamines, peptides, and alkenyl chains suitable for olefin metathesis were introduced this way. In the second case, the pyrrole derivatives were efficiently converted into alkaloid and iminosugar derivatives in good global yields and with excellent stereoselectivity.

Conversion of Hydroxyproline “Doubly Customizable Units” to Hexahydropyrimidines: Access to Conformationally Constrained Peptides

“…The recent introduction of hydroxyproline “doubly customizable units” allows the generation of a variety of modified amines and peptides in good yields and very few steps (Scheme , conversion 1 → 3 ). , A first modification (conversion 1 → [4] → 2 ) is carried out using an oxidative radical decarboxylation, which generates acyliminium intermediate 4 . This ion reacts with carbon nucleophiles to afford 2-alkyl pyrrolidines in good yield and excellent 2 R or 2 S purity due to the control provided by the stereogenic center at C-4 .…”

“…The resulting products 5 have an N , O -acetal and an α-lateral chain with a terminal carbonyl group. Both chains can be functionalized independently, , and thus, we have reported the formation of acyclic products 3 with three different, tailor-made substituents…”

“…This transformation is not trivial, since the aldehyde group was the first to react, and the resulting linear chain extended away from the relatively bulky N -acetoxymethyl group. Therefore, non-cyclic products 3 were obtained. , In this paper, we report a change in the reductive amination–cyclization conditions that allows the transformation of aldehydes 5 into hexahydropyrimidines 6b , which in addition to their pharmacological utility, can be valuable units to modulate a peptide secondary structure.…”

“…Therefore, non-cyclic products 3 were obtained. 1 , 3 In this paper, we report a change in the reductive amination–cyclization conditions that allows the transformation of aldehydes 5 into hexahydropyrimidines 6b , which in addition to their pharmacological utility, can be valuable units to modulate a peptide secondary structure.…”