We report an optimized protocol for the solid-phase synthesis of backbone-N-aminated peptides. Electrophilic N-amination amino acid zwitterions provides crude -hydrazino acids that can be used directly in SPPS. In situ formation Fmoc-protected chlorides with Ghosez’s reagent enables base-free couplings to on automated system. TFA-free cleavage and global deprotection affords poly-N-amino peptides high purity a fraction time required by previously reported methods.

We describe the first investigation of collagen mimetic peptides harboring proline surrogates with heteroatoms at δ-position. While dehydro-δ-azaproline and (N-methyl)-δ-azaproline destabilized parent structure, replacement Xaa proline...

The unique role of proline in modulating protein folding and recognition makes it an attractive target for substitution to generate new proteomimetics. design, synthesis, conformational analysis non-canonical surrogates can also aid parsing the prolyl stereoelectronic effects on structure. We recently described synthesis dehydro-δ-azaproline (ΔaPro), a novel unsaturated analogue featuring planar dehydropyrazine ring. When incorporated into host sequences, this backbone N-aminated surrogate...

Stereocontrolled synthesis of cis and trans-substituted prolines by a divergent approach, leads to the preparation cis-(4S)- trans-(4R)-trifluoromethyl-L-proline from hydroxyproline. The key pyrroline intermediates were subjected hydrogenation (see scheme; A=sterically directed hydrogenation, B=hydroxy-directed hydrogenation; Boc=tert-butoxycarbonyl, TBS=tert-butyldimethylsilyl), afford products in high diastereomeric excess.

The first enantiocontrolled total synthesis of the marine sponge metabolite chlorodysinosin A is described. structure and absolute configuration are identical to those dysinosin except for presence a novel 2S,3R-3-chloroleucine residue in former. concise stereocontrolled new chlorine-containing amino acid fragment was developed. An X-ray cocrystal synthetic with enzyme thrombin confirms assignment achieved through synthesis. Within aeruginosin family natural products, most potent inhibitor...

Abstract The Mycobacterium tuberculosis RNA polymerase (MtbRNAP) is the target of first-line anti-tuberculosis inhibitor rifampin, however, emergence rifampin resistance necessitates development new antibiotics. Here, we communicate first single-molecule characterization MtbRNAP elongation and its inhibition by three diverse small-molecule inhibitors: N(α)-aroyl-N-aryl-phenylalaninamide (D-IX216), streptolydigin (Stl), pseudouridimycin (PUM) using high-resolution optical tweezers. Compared...

The utility of 4-substituted prolinols and their corresponding prolines in peptides, peptidomimetics, natural products has motivated researchers to find new efficient routes for preparation. Herein, we report a general approach the synthesis Boc-protected 4-alkylprolinols via divergent asymmetric hydrogenation strategy. Intermediate exocyclic olefins were prepared by Wittig-type reactions with ketone 6 subjected hydroxyl sterically directed reductions. Crabtree catalyst (Ir[COD]PyPCy3PF6)...

N-Acyloxyiminium ions generated from 4-substituted l-pyroglutamic esters with 4-(3-butenyl), 4-(3-butynyl), 4-(3-cinnamylmethyl), and 4-allenic tethers undergo rapid Lewis acid mediated carbocyclization to give stereodefined azacyclic compounds depending on the nature of nucleophilic tether. In general, reactions alkenes alkynes terminal alkyl or aryl substituents, as well allenes, proceed through transient vinylic carbocations that are attacked internally by N-Boc group tricyclic...

Tauopathies are a class of neurodegenerative diseases resulting in cognitive dysfunction, executive and motor disturbance. The primary pathological feature tauopathies is the presence neurofibrillary tangles brain composed tau protein aggregates. Moreover, aggregates can spread from neuron to lead propagation pathology. Although numerous small molecules known inhibit aggregation block cell-to-cell transmission, it still challenging use them for therapeutic applications due poor specificity...

A rapid and stereoselective enolate-Claisen rearrangement provides access to the 4-ethylidene-3-methylproline (Emp) subunit of lucentamycin A. Synthesis putative structure cytotoxic natural product suggests need for structural revision.

A condensation−ring-close−ring-open sequence was employed for the synthesis of orthogonally protected meso-2,6-diaminopimelic acid, starting from easily accessible chiral synthons. Condensation suitably l-allylglycine and d-vinylglycinol derivatives followed by Grubbs' ring-closing metathesis to generate key lactam intermediate. This strategy has been applied a concise total potent immunostimulatory peptide FK565.

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

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

Tauopathies are a class of neurodegenerative disorders whose predominant feature is tau protein deposits in the brain. Misfolded has capacity to seed fibrillization naïve tau, leading prion-like spread aggregates. Tau protomers within filaments always exhibit cross-beta amyloid structure, but distinct conformations often correlate with specific diseases. An understanding how these impact seeding activity remains elusive. Identification minimal epitopes required for transcellular propagation...

The aggregation of amyloids into toxic oligomers is believed to be a key pathogenic event in the onset Alzheimer's disease. Peptidomimetic modulators capable destabilizing propagation an extended network β-sheet fibrils represent potential intervention strategy. Modifications amyloid-beta (Aβ) peptides derived from core domain have afforded inhibitors both antagonizing and reducing amyloid toxicity. Previous work our laboratory has shown that peptide backbone amination stabilizes...

Functionalized octahydroindoles were synthesized from (±)-cyclohex-2-en-1-ol as potential intermediates for convergent syntheses of several alkaloids plants the <i>Daphnyphyllum </i>genus.

We report the chemical synthesis of pseudouridimycin (1), an antimicrobial natural product that potently and selectively inhibits bacterial RNA polymerase. Chemical stability studies revealed intramolecular hydroxamate bond scission to be a major decomposition pathway for 1 in aqueous buffer. Replacement with tertiary amide, as 16, afforded conformational isostere resistant degradation. These pave way design analogues improved biological activity.

Two configurationally stable carbon-based analogues of pyochelin have been prepared from Boc-pyroglutamic acid-tert-butyl ester in 11 and 13 steps. Introduction the amino group was achieved by a highly diastereoselective electrophilic azidation reaction to afford novel bis-α-amino acid proline derivatives.

Den Knick im Peptid modellieren: Um nichtnatürliche cis- und trans-substituierte Proline zu synthetisieren, wurden zunächst ausgehend von Hydroxyprolin Pyrrolin-Zwischenprodukte hergestellt. Diese ließen sich durch asymmetrische Hydrierung mit zwei unterschiedlichen Methoden hohen Diastereomerenüberschüssen zum cis-(4S)- trans-(4R)-Trifluormethyl-L-prolin umsetzen (siehe Schema; A=sterisch kontrollierte Hydrierung, B=Hydroxygruppen-gesteuerte Hydrierung).

Backbone amide hydroxylation of peptide strands enhances β-hairpin folding.