Synthesis of an olefin-containing cyclic peptide using the solid-phase Horner-Emmons reaction

Linear and cyclic olefin peptides containing the substrate sequence for human T-cell leukemia virus type-1 (HTLV-1) were efficiently synthesized on a solid support using the Horner-Emmons reaction. The precursor peptide aldehyde was prepared by oxidation of the corresponding peptide alcohol with Dess-Martin periodinane. The oxidation reaction proceeded quantitatively on a cross-linked ethoxylate acrylate resin (CLEAR) support instead of a polystyrene-based support. Cyclization on the solid support was achieved via an amide bond formation mediated by EDC/HOAt to yield a single major product. The linear olefin peptide was cleaved by HTLV-1 protease at the scissile site, whereas the cyclic olefin peptide functions as a competitive inhibitor rather than a substrate.     

Solid-phase synthesis of peptidomimetic inhibitors for the hepatitis C virus NS3 protease.

The NS3 serine protease enzyme of the hepatitis C virus (HCV) is essential for viral replication. Short peptides mimicking the N-terminal substrate cleavage products of the NS3 protease are known to act as weak inhibitors of the enzyme and have been used as templates for the design of peptidomimetic inhibitors. Automated solid-phase synthesis of a small library of compounds based on such a peptidomimetic scaffold has led to the identification of potent and highly selective inhibitors of the NS3 protease enzyme.     

Solid-phase synthesis of HTLV-1 protease inhibitors containing hydroxyethylamine dipeptide isostere

An efficient method has been developed for the first solid-phase synthesis of HTLV-1 protease inhibitors that contain hydroxyethylamine isostere as a transition-state mimetic. The synthetic procedure was designed to allow the evaluation of stereostructure-activity relationships at the scissile site. All the possible configurations at the hydroxy- and side chain-bearing asymmetric centers of the isostere were constructed by an ester-derived asymmetric aldol reaction. Each inhibitor containing the isostere backbone was synthesized on solid support by using the newly developed succinate ester linker. The configuration at the hydroxy- and side chain-bearing asymmetric center showed remarkable effects on the inhibitory activity; the K(i) value changed with approximately 2 orders of magnitude. The described approach enables an efficient preparation of the inhibitors containing secondary alcohol as a transition-state mimetic.     

Cross metathesis assisted solid-phase synthesis of glycopeptoids

A solid-phase synthesis of glycopeptoids was explored through olefin cross metathesis (CM). Peptoids and sugar derivatives with appropriate olefin moieties were coupled in the presence of an olefin metathesis catalyst to afford glycopeptoids in good yields. This systematic solid-phase CM study can provide facile access to the molecular sources of glycopeptidomimetics and postchemical modifications on various molecular scaffolds.     

N-to-C solid-phase peptide and peptide trifluoromethylketone synthesis using amino acid tert-butyl esters

Solid-phase peptide synthesis in the N-to-C direction, opposite to the classical C-to-N direction of peptide synthesis, provides the synthetically versatile C-terminal carboxyl group for further modification into C-terminally modified peptide mimetics. These are of general interest as potential bioactive agents, particularly as protease inhibitors. Elaboration of peptide mimetics on the solid-phase would facilitate synthesis of peptide mimetic combinatorial libraries. This report describes an effective strategy for solid-phase inverse peptide synthesis based on readily available amino acid tert-butyl esters. The potential of this approach for peptide mimetic synthesis is demonstrated by the solid-phase synthesis of two peptide trifluoromethylketones.     

Convenient access to glutamic acid side chain homologues compatible with solid phase peptide synthesis

[reaction: see text] Preparation of several side chain length variants of glutamic acid is achieved via olefin cross metathesis of allyl glycine derivatives. The products are suitably protected for direct use in Fmoc solid-phase peptide synthesis, as demonstrated by successful synthesis of test sequences.     

Total synthesis of (+)-kuhistaferone

The first, enantiocontrolled total synthesis of (+)-kuhistaferone was achieved using an aluminum-based Lewis acid mediated rearrangement for the construction of a quaternary stereogenic center, an ene-reaction and an intramolecular Horner-Emmons reaction as the key steps.     

Part 1. modular approach to obtaining diverse tetrahydroquinoline-derived polycyclic skeletons for use in high-throughput generation of natural-product-like chemical probes

A practical synthesis of a tetrahydroaminoquinoline scaffold (12) was developed that used a stereocontrolled aza Michael as the key reaction. Three tetrahydroquinoline alkaloid-like, tricyclic derivatives 16, 18, and 19 with different medium to macrocyclic ring skeletons were obtained, using this scaffold as the starting material, in a modular manner. The macrocyclic compounds with an isolated olefin and an electron-deficient olefin were obtained by ring-closing metathesis approaches. Compounds 16 and 18 are unique and contain bridged 10- and 12-membered functionalized rings. The NMR studies of these compounds revealed interesting information on the conformation of the bicyclic scaffolds that was dependent on the nature and the size of the macrocyclic rings. Finally, this modular methodology, using compound 21 anchored onto the solid support, successfully led to the generation of different macrocyclic derivatives, 23, 25, and 27 in solid-phase synthesis. The solid-phase synthesis approach outlined in this article has the potential to generate tetrahydroquinoline-based tricyclic compounds containing different medium to macrocyclic architectures.     

Synthesis of a key intermediate of novel galbonolide analogues via efficient construction of a conjugated diene system

The development of an efficient synthetic method enabled multi-gram synthesis of a key intermediate, which is useful for the modification at the C6-functional group of galbonolide analogues. The structure of a key intermediate including a conjugated diene was afforded by Horner-Emmons reaction, alkylation of Weinreb amide with alkyl lithium and a subsequent Wittig reaction.     

Characterizing the protonation states of the catalytic residues in apo and substrate-bound human T-cell leukemia virus type 1 protease

Human T-cell leukemia virus type 1 (HTLV-1) protease is an attractive target when developing inhibitors to treat HTLV-1 associated diseases. To study the catalytic mechanism and design novel HTLV-1 protease inhibitors, the protonation states of the two catalytic aspartic acid residues must be determined. Free energy simulations have been conducted to study the proton transfer reaction between the catalytic residues of HTLV-1 protease using a combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulation. The free energy profiles for the reaction in the apo-enzyme and in an enzyme – substrate complex have been obtained. In the apo-enzyme, the two catalytic residues are chemically equivalent and are expected to be both unprotonated. Upon substrate binding, the catalytic residues of HTLV-1 protease evolve to a singly protonated state, in which the OD1 of Asp32 is protonated and forms a hydrogen bond with the OD1 of Asp32′, which is unprotonated. The HTLV-1 protease–substrate complex structure obtained from this simulation can serve as the Michaelis complex structure for further mechanistic studies of HTLV-1 protease while providing a receptor structure with the correct protonation states for the active site residues toward the design of novel HTLV-1 protease inhibitors through virtual screening.     

Enantioselective total synthesis of the antitumor macrolide rhizoxin D

The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from gamma-butyrolactone. The central core of rhizoxin D was prepared via a chiral resolution/asymmetric aldol protocol. Several methods for the generation of the polyene fragment were explored, and the side-chain was ultimately prepared from serine in six steps. The unification of the left and right wings of the molecule was achieved using a one-step olefination protocol, and the macrocyclization was carried out using a Horner-Emmons olefination at the C(2)-C(3) olefin.     

Immobilized alpha-diazophosphonoacetate as a versatile key precursor for palladium catalyzed indole synthesis on a polymer support

Rh(II)-catalyzed N-H insertion reaction of immobilized alpha-diazophosphonoacetate with 2-haloanilines followed by Horner-Emmons reaction gave immobilized enaminoesters, which were efficiently cyclized to indoles via intramolecular palladium catalyzed reaction on a polymer support.     

A convergent and stereoselective synthesis of a seco-precursor of macrolactin A

A seco-precursor of macrolactin A was synthesized by coupling two advanced segments. Wittig reaction and Horner-Emmons reaction were utilized to construct the three characteristic E,Z and E,E dienes. The C₁-C₁₀ segment was synthesized through Horner-Emmons reaction with phosphonate reagent. The α-alkylation of sulfone stabilized anion with allyl bromide followed by desulfonation gave the C₁₁-C₂₄ segment.     

Recent developments in olefin cross-metathesis

Among the many types of transition-metal-catalyzed C-C bond-forming reactions, olefin metathesis has come to the fore in recent years owing to the wide range of transformations that are possible with commercially available and easily handled catalysts. Consequently, olefin metathesis is now widely considered as one of the most powerful synthetic tools in organic chemistry. Until recently the intermolecular variant of this reaction, cross-metathesis, had been neglected despite its potential. With the evolution of new catalysts, the selectivity, efficiency, and functional-group compatibility of this reaction have improved to a level that was unimaginable just a few years ago. These advances, together with a better understanding of the mechanism and catalyst-substrate interactions, have brought us to a stage where more and more researchers are employing cross-metathesis reactions in multistep procedures and in the synthesis of natural products. The recent inclusion of alkynes and hindered bicyclic olefins as viable substrates for bimolecular metathesis coupling, the discovery of enantioselective cross-metathesis and cross-metathesis in water, and the successful marriage of metathesis and solid-phase organic synthesis has further widened the scope of this versatile reaction.     

Synthesis of Unsaturated Carboxylic and Amino Acids of Adamantane Series with the Use of Organophosphorus Reagents

Sodium derivative of diethyl(3-amino-1-ethoxycarbonylpropane)phosphonic acid was obtained by reaction of triethyl phosphonoacetate with ethylene imine in the presence of sodium hydride. The compound obtained was brought into Horner-Emmons reaction with carbonyl derivatives of adamantane series to afford the corresponding unsaturated amino acids. From adamantanecarbonyl chlorides and triphenylphosphonium ethoxycarbonylmethylide were prepared new phosphorus acylylides that on thermolysis provide ethyl acetylenecarboxylates containing an adamantyl substituent.     

DIBAL-mediated reductive transformation of trans-dimethyl tartrate acetonide into ε-hydroxy α,β-unsaturated ester and its derivatives

Stepwise, selective DIBAL reduction of the acetonide diester derived from tartaric acid followed by the Horner-Emmons reaction effectively provided desymmetrized hydroxy mono-olefination products in a one-pot operation.     

A novel four-component reaction for the synthesis of functionalised dihydropyrimidines

In a multi-component reaction (MCR) of a phosphonate, nitriles, aldehydes and isocyanates, N3-functionalised dihydropyrimidines can be synthesised efficiently via a Horner-Emmons/aza Diels-Alder pathway.     

Synthesis and properties of cyclic ethylene-bridged 3,6-fluorene dimer and its linear analogues

Three oligomers of ethylene-bridged 3,6-fluorene were synthesized starting from phenanthrenequinone. McMurry reaction was applied to synthesize the cyclic compound. Horner-Emmons reaction was used to synthesize the linear compounds with all-trans configuration. The crystal structure of the cyclic compound was described. The optical and electronic properties of these compounds were fully characterized and compared.     

A convenient and stereoselective synthesis of 11Z-3,4-didehydroretinal by Horner-Emmons reaction using diphenyl phosphonate

A convenient synthesis of 3,4-didehydroretinal was developed. The Horner-Emmons reaction between 3,4-didehydro-beta-ionone and diphenyl phosphonate in the presence of crown ether gave the retinonitrile as an isomeric mixture, in which the newly produced double bond was predominantly 11Z-form. After separation of the 11Z-form retinonitrile, it was converted into the corresponding retinal in good yield without isomerization of the double bonds.     

High-Throughput Fluorescent Assay for Inhibitor Screening of Proteases from RNA Viruses

Spanish flu, polio epidemics, and the ongoing COVID-19 pandemic are the most profound examples of severe widespread diseases caused by RNA viruses. The coronavirus pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demands affordable and reliable assays for testing antivirals. To test inhibitors of viral proteases, we have developed an inexpensive high-throughput assay based on fluorescent energy transfer (FRET). We assayed an array of inhibitors for papain-like protease from SARS-CoV-2 and validated it on protease from the tick-borne encephalitis virus to emphasize its versatility. The reaction progress is monitored as loss of FRET signal of the substrate. This robust and reproducible assay can be used for testing the inhibitors in 96- or 384-well plates.