Rigid Dipeptide Mimetics:  Efficient Synthesis of Enantiopure Indolizidinone Amino Acids

Abstract

An effective means to synthesize indolizidinone amino acids has been developed and furnishes all possible stereoisomers of these conformationally rigid mimetics of peptide secondary structures. Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/reductive amination/lactam cyclization sequence that furnished stereoselectively azabicyclo[3.4.0]alkane amino acid 1. Enantiopure (3S,6S,9S)- and (3R,6R,9R)-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylic acids ((3S,6S,9S)- and (3R,6R,9R)-1) were respectively synthesized from l- and d-N-(PhF)glutamates 2 (PhF = 9-(9-phenylfluorenyl)). Slow addition of sodium bis(trimethylsilyl)amide to 2 provided good to excellent yields of β-keto esters 3, which were subsequently hydrolyzed and decarboxylated to give symmetric α,ω-bis[N-(PhF)amino]azelate δ-ketones 5. Augmentation of hydrogen pressure increased diastereoselectivity in reductive aminations with 5 and afforded 5-alkylprolines 8 and 10. Lactam formation on exposure of 10 to triethylamine and N-protection with di-tert-butyl dicarbonate gave methyl 2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate (12) which on C-terminal ester hydrolysis with hydroxide ion gave enantiopure [N-(BOC)amino]indolizidinone acid 1. Alternatively, hydride addition to ketone 5a gave symmetric α,ω-bis[N-(PhF)amino]azelate δ-alcohol 7a, which upon mesylation and intramolecular SN2 displacement by the PhF amine gave specifically cis-5-alkylproline 15 that was similarly converted to (3S,6S,9S)-1. In addition, epimerization of the C-9 stereocenter of (3S,6S,9S)-[N-(BOC)amino]indolizidinone methyl ester 12 with NaN(SiMe3)2 and ester hydrolysis gave (3S,6S,9R)-indolizidinone amino acid (3S,6S,9R)-1. By providing efficient methodology for synthesizing all of the possible stereoisomers of enantiopure indolizidinone amino acid 1, our route is specifically designed to enhance the general use of these peptide mimetics in the exploration of conformation−activity relationships of various biologically active peptides.

A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway

“…1 and supplemental Fig. S1A) involved, in brief, a systematic analysis of the sequence using alanine and enantiomeric amino acid scans, which highlighted the importance of the Arg and Asp side chains; replacement of the hydrophobic termini with hydrocarbon pharmacophores and the Gly-His residue by different indolizidinone turn mimics (21)(22)(23)(24); and refinement near the Arg-Asp residue using different amino acid substitutions to arrive at the pyridylalanine-␤-homophenylalanine surrogate. The 3-phenylacetamido indolizidin-2-one 9-carboxyl and the pyridinylalaninyl-␤-homophenylalanine sections of PDC113.824 (Fig.…”

Synthesis and Evaluation of the β‐Turn Properties of 4‐Amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐ones and of Their Spirocyclic Derivative

“…[31] Other acidolytic conditions (TFA/H 2 O, 9:1 [32] and TFA/anisole, 3:1 [33] ) provided insufficient scavenging of the tBu cation and caused tert-butylation of the aromatic ring of o-CN-Phe.…”

Structure-Based Design, Synthesis, and Evaluation of Conformationally Constrained Mimetics of the Second Mitochondria-Derived Activator of Caspase That Target the X-Linked Inhibitor of Apoptosis Protein/Caspase-9 Interaction Site

“…Briefly, the key intermediates 5 and 6 were prepared according to the literature method. 19 Hydrolysis of the methyl ester groups in 5 and 6 followed by condensation with benzylamine gave two amides. Removal of the Boc protective groups in these two amides followed by condensation with N-tert-butoxycarbonyl-L-alanine yielded intermediates 7 and 8.…”