Substituted Imidazo[1,2‑<i>a</i>]pyridines as β‑Strand Peptidomimetics

New conformationally extended dipeptide surrogates based on an imidazo[1,2-<i>a</i>]pyridine scaffold are described. Efficient synthesis and incorporation into host peptides affords structures with native side-chain functionality and hydrogen bonding elements on one face of the backbone. Structural analysis by NMR suggests that model peptidomimetics adopt a β-strand-like conformation in solution

Total Synthesis of L‑156,373 and an oxoPiz Analogue via a Submonomer Approach

The first chemical synthesis of L-156,373 (<b>1</b>), a potent oxytocin receptor antagonist isolated from Streptomyces silvensis, is reported. Assembly of the unusual d-Piz-l-Piz dipeptide subunit was achieved through a sequential electrophilic amination–acylation–deprotection strategy followed by late-stage Piz ring formation. Synthesis and incorporation of a novel <i>N</i>-hydroxy-l-isoleucine building block is also described. This submonomer approach was further applied to the expedient synthesis of a di-δ-oxopiperazic acid analogue of <b>1</b> starting from Fmoc-Glu­(<i>t</i>Bu)-OH building blocks

An Ester Enolate–Claisen Rearrangement Route to Substituted 4-Alkylideneprolines. Studies toward a Definitive Structural Revision of Lucentamycin A

Substituted 4-alkylideneprolines represent a rare class of naturally occurring amino acids with promising biological activities. Lucentamycin A is a cytotoxic, marine-derived tripeptide that harbors a 4-ethylidine-3-methylproline (Emp) residue unique among known peptide natural products. In this paper, we examine the synthesis of Emp and related 4-alkylideneprolines employing a versatile ester enolate–Claisen rearrangement. The scope and selectivity of the key rearrangement reaction are described with a number of diversely substituted glycine ester substrates. Treatment of the allyl esters with excess NaHMDS at ambient temperature gives rise to highly substituted α-allylglycine products with good to excellent diastereoselectivities. Resolution of dipeptide diastereomers and cyclization to form the pyrrolidine rings provide rapid access to stereopure prolyl dipeptides. We have applied this strategy to the synthesis of four Emp-containing isomers of lucentamycin A in pursuit of a definitive stereochemical revision of the natural product. Our studies indicate that the Emp stereogenic centers are not the source of structural misassignment. The current strategy should find broad utility in the synthesis of additional natural product analogues and related 3-alkyl-4-alkylidene prolines

Solid-Phase Synthesis of Tetra­hydro­pyridazine­dione-Constrained Peptides

The design and solid-phase synthesis of tetrahydropyridazine-3,6-dione (Tpd) peptidomimetics derived from backbone-aminated peptides is reported. The described protocol features the synthesis of chiral α-hydrazino acids suitable for chemoselective incorporation into growing peptide chains. Acid-catalyzed cyclization to form the Tpd ring during cleavage affords the target peptidomimetics in good yield and purity. The scope of Tpd incorporation is demonstrated through the synthesis of constrained peptides featuring nucleophilic/electrophilic side chains and sterically encumbered α-substituted hydrazino acid residues

Access to Enantiopure α‑Hydrazino Acids for <i>N</i>‑Amino Peptide Synthesis

Backbone <i>N</i>-methylation of α-peptides has been widely employed to enhance the bioavailability and bioactivity of parent sequences. Heteroatomic peptide amide substituents have received less attention due, in part, to the lack of practical synthetic strategies. Here, we report the synthesis of α-hydrazino acids derived from 19 out of the 20 canonical proteinogenic amino acids and demonstrate their use in the solid-phase synthesis of <i>N-</i>amino peptide derivatives

Total Synthesis and Structural Revision of Lucentamycin A

Lucentamycin A is a marine-derived peptide natural product harboring a unique 4-ethylidene-3-methylproline (Emp) subunit. The proposed structure of lucentamycin A and the core Emp residue have recently been called into question through synthesis. Here, we report the first total synthesis of lucentamycin A, which confirms that the ethylidene substituent in Emp bears an <i>E</i> geometry, in contrast to the originally assigned <i>Z</i> configuration. Synthesis of the desired (<i>E</i>)-Emp subunit required the implementation of a novel strategy starting from Garner’s aldehyde

Total Synthesis and Structural Revision of Lucentamycin A

Lucentamycin A is a marine-derived peptide natural product harboring a unique 4-ethylidene-3-methylproline (Emp) subunit. The proposed structure of lucentamycin A and the core Emp residue have recently been called into question through synthesis. Here, we report the first total synthesis of lucentamycin A, which confirms that the ethylidene substituent in Emp bears an <i>E</i> geometry, in contrast to the originally assigned <i>Z</i> configuration. Synthesis of the desired (<i>E</i>)-Emp subunit required the implementation of a novel strategy starting from Garner’s aldehyde

Structure Assignment of Lucentamycin E and Revision of the Olefin Geometries of the Marine-Derived Lucentamycins

A new lucentamycin analogue, lucentamycin E (<b>5</b>), was isolated from the culture broth of the marine-derived actinomycete <i>Nocardiopsis lucentensis</i>, strain CNR-712. The absolute stereostructure of <b>5</b> was assigned by comprehensive analyses of NMR data and by application of the advanced Marfey’s method. The planar structure of <b>5</b> was analogous to lucentamycins A–D, whereas the olefin geometry of the 3-methyl-4-ethylideneproline moiety was found to be <i>E</i>, opposite of that previously reported. Consequently, a reinvestigation of the olefin geometries of the 3-methyl-4-ethylideneproline residues of lucentamycins A–D showed that the olefin geometries of the substituted proline functionalities must be revised to (2<i>S</i>,3<i>R</i>,<i>E</i>)-3-methyl-4-ethylideneproline

Synthesis of Novel Tricyclic Chromenone-Based Inhibitors of IRE‑1 RNase Activity

Inositol-requiring enzyme 1 (IRE-1) is a kinase/RNase ER stress sensor that is activated in response to excessive accumulation of unfolded proteins, hypoxic conditions, calcium imbalance, and other stress stimuli. Activation of IRE-1 RNase function exerts a cytoprotective effect and has been implicated in the progression of cancer via increased expression of the transcription factor XBP-1s. Here, we describe the synthesis and biological evaluation of novel chromenone-based covalent inhibitors of IRE-1. Preparation of a family of 8-formyl­tetrahydro­chromeno­[3,4-<i>c</i>]­pyridines was achieved via a Duff formylation that is attended by an unusual cyclization reaction. Biological evaluation in vitro and in whole cells led to the identification of <b>30</b> as a potent inhibitor of IRE-1 RNase activity and XBP-1s expression in wild type B cells and human mantle cell lymphoma cell lines