Stereoselective Synthesis of Tricyclic Diproline Analogues that Mimic a PPII Helix: Structural Consequences of Ring‐Size Variation

Abstract

Polycyclic proline‐derived scaffolds (ProMs) have recently demonstrated their value as conformationally defined dipeptide analogs for the modular construction of secondary structure mimetics, specifically interfering with PPII helix‐mediated protein–protein interactions. We disclose the stereoselective synthesis of two new tricyclic amino acid scaffolds (ProM‐4 and ProM‐8) that differ from the first generation scaffold ProM‐1 by the size of ring A. Conformational preferences and subtle structural differences of the three homologous scaffolds were analyzed by X‐ray crystallography, computational calculations, and NMR spectroscopy. N‐tert‐butoxycarbonyl(Boc)‐3‐(1‐propenyl)azetidine‐2‐carboxylic acid was prepared from L‐aspartic acid through β‐lactam intermediates. The corresponding piperidine‐based building block rac‐N‐Boc‐3‐vinylpipecolic acid was synthesized by Cu‐catalyzed 1,4‐addition of vinyl‐MgBr to methyl N‐Boc‐2,3‐dehydropipecolate. Target molecules were prepared through peptide coupling of the respective ring A building blocks with cis‐5‐vinylproline tert‐butyl ester and subsequent ring‐closing metathesis. Selective deprotection of a tert‐butyl carbamate (N‐Boc protecting group) in the presence of a tert‐butyl ester was achieved with trifluoroacetic acid at 0 °C.

Phase Diagrams to Evaluate the Opportunity for Enantiomeric Enrichment of Some Nonracemic Mixtures of Amino Acid Benzyl Esters by Crystallization as p-Toluenesulfonate Salts

“…Amino acids are very important chiral platform molecules, and the enantiomers of their benzyl esters are key starting materials for the chemical and chemoenzymatic synthesis of dipeptides and polypeptides , and for building more complex nonpeptide molecules including, for instance, mono- or polyheterocyclic diazepinic or azetidinonic substructures. − Recently, we have studied the esterification of 11 amino acids (Asp, Glu, Lys, Ala, Phe, Tyr, Phg, Val, Leu, Met, and Ser) by reaction with excess benzyl alcohol and little more than stoichiometric p -toluenesulfonic acid in boiling solvents, which form heterogeneous water azeotropes and can thus remove water resulting from esterification. , By this procedure, we prepared the dibenzyl ester p -toluenesulfonates of l -aspartic acid ( l - 1 ) and l -glutamic acid ( l - 2 ), the benzyl ester di- p -toluenesulfonate of l -lysine ( l - 3 ), and the benzyl ester p -toluenesulfonates of l -alanine ( l - 4 ), l -phenylalanine ( l - 5 ), l -tyrosine ( l - 6 ), d -phenylglycine ( d - 7 ), l -valine ( l - 8 ), l -leucine ( l - 9 ), l -methionine ( l - 10 ), and l -serine ( l - 11 ) (Chart ).…”

Mortiamides A–D, Cyclic Heptapeptides from a Novel Mortierella sp. Obtained from Frobisher Bay

“…Benzylation of amino acids was accomplished according to literature precedent. , All dipeptide coupling reactions were carried out using benzyl ester protected amino acids and purchased N -Boc-protected amino acids according to modified literature precedent …”

“…Benzylation of amino acids was accomplished according to literature precedent. 23,24 All dipeptide coupling reactions were carried out using benzyl ester protected amino acids and purchased N-Boc-protected amino acids according to modified literature precedent. 25 Deprotection of all dipeptides was accomplished first by hydrogenolysis with ∼20% w/w of 10% Pd/C in CH 2 Cl 2 under a H 2 atmosphere for 24−48 h at room temperature, to produce the corresponding free carboxylic acid.…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…256) [665], homoisofagomines and analogs [666], cycloheptenes derived from two proline units [667], tuberostemospiroline and stemona lactone R [668], a cyclic α-amino acid derivative (e.g. 257) [669], tetrapetolone (through a diastereoselective RCM employing a substrate with diastereotopic vinyl groups using a chiral molybdenum complex catalyst) [670], and tricyclic IAP inhibitors (e.g.…”