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.

Keywords: Alkaloids; Amino-δ-lactams; Customizable units; Hydroxyproline; Iminosugars; N-Acyliminium ion; Nitrogen heterocycles; Radical fragmentation; Structural diversity.

Scheme 1

Conversion of 4-hydroxyproline (Hyp) customizable unit into structurally diverse nitrogen heterocycles

Scheme 2

Simplified procedure for the scission-alkylation and 4-hydroxy group deprotection

Scheme 3

Simplified procedure to obtain β-amino-δ-lactams

Scheme 4

Formation of α,α-disubstituted β-amino-δ-lactams

Scheme 5

Formation of ( +)-sedamine analogues 21 and 22

Scheme 6

Formation of (−)-coniine analogues 26 and 27

Scheme 7

Synthesis of iminosugar derivatives