Tetrahedron Letters

Investigation of a strategy to streamline the synthesis of peptides containing α,β-dehydroamino acids (ΔAAs) is reported. The key step involves generating the alkene moiety via elimination of a suitable precursor after it has been inserted into a peptide chain. This process obviates the need to prepare ΔAA-containing azlactone dipeptides to facilitate coupling of these residues. Z -dehydroaminobutyric acid ( Z -ΔAbu) could be constructed most efficiently via EDC/CuCl-mediated dehydration of Thr. Formation of Z -ΔPhe by this or other dehydration methods was unsuccessful...

Herbal medicine is used as a complement to modern medicine for the treatment of human diseases suchas cancer, inflammation, and diabetes. Nutraceutical components in foods such as vanillin produceantioxidant and anticancer activities and many of these produce minimal adverse effects in humans.Therefore, strategies that combine both herbal medicine and nutraceutical components could producecompounds that exhibit reduced toxicity. Recently, we developed GZ16.007, which is a combination ofharmaline and curcumin that is currently undergoing clinical evaluation for the treatment of cancer...

Inspired by reports of water sculpted Tn antigen (α-GalNAc- O -Ser/Thr) epitopes and our interest in producing metabolically more stable C -linked analogs of Tn, we explored the utility of C2 functionality on α-Gal- C -alkenes to deliver hydroxyl to the pendant alkenyl chain. Toward this end, a cyclic carbonate approach gave rise to a single C -linked α-Gal-1'(S)-hydroxyethane in 3 steps, and use of a 2-(hydroxyimino)galactoside cyclization transferred an oxygen to a pendant cis -substituted C -linked alkene affording the R -configuration at the newly formed stereocenter (7:1 dr)...

A short de novo synthesis of an l-lemonose thioglycoside is described starting from d-threonine. The synthesis leverages a Dieckmann condensation and Stork-Danheiser transposition to arrive at a key vinylogous ester intermediate on gram scale. Ensuing 1,2-addition diastereoselectively establishes the C3 tetra-substituted center and subsequent glycal hydration allows for anomeric functionalization to the thioglycoside. 1 H and NOESY NMR analyses reveal that the major α-anomer of thioglycoside deviates from the expected 1 C4 conformation...

Earth abundant metal catalysts hold advantages in cost, environmental burden and chemoselectivity over precious metal catalysts. Differences in reactivity for a given metal center result from ligand field strength, which can promote reaction through either open- or closed-shell carbon intermediates. Herein we report a simple protocol for cobalt-catalyzed alkene reduction. Instead of using an oxidative turnover mechanism that requires stoichiometric hydride, we find a reductive turnover mechanism that requires stoichiometric proton...

Chemical investigation of an organic extract of a fungus isolated from submerged wood collected from fresh water (strain G173), identified as a Talaromyces amestolkiae (Eurotiales; Trichocomaceae), led to the isolation of three coumarins, three dihydroisocoumarins, a dibenzo- α -pyrone, a meroterpenoid, and a merodrimane. Three of the isolated compounds, namely 7-chloropestalasin A ( 3 ), 4-hydroxyaspergillumarin ( 6 ), and ent -thailandolide B ( 9 ) were new. The structures were elucidated using a combination of spectroscopic and spectrometric techniques...

[This corrects the article PMC7665082.].

Rhodojaponin III is a grayanane-type diterpenoid natural product with a novel chemical scaffold. It shows potent antinociceptive activity and may represent a new class of natural non-opioid analgesics with a novel mode of action. We explored the Au(I)-catalyzed Conia-ene cyclization and the Mn(III)-mediated radical cyclization of alkynyl ketones for the synthesis of the bicyclo[3.2.1]octane fragment of rhodojaponin III. These strategies will be applicable in the synthesis of rhodojaponin III and analogs for future biological studies...

A series of 2-(1 H -1,2,4-triazol-3-yl)acetates, as well as 4-mono- and 4,4-disubstituted 5-amino-2,4-dihydro-3 H -pyrazol-3-ones (including spirocyclic derivatives) have been synthesized using the Pinner reaction strategy. α-Mono- and α,α-disubstituted ethyl cyanoacetates were converted into the corresponding carboxyimidate salts that served as the key intermediates. Their further reaction with formylhydrazide or hydrazine hydrate provided triazolylacetates or aminopyrazolones (including spirocyclic derivatives), depending on the structure of the starting Pinner salt and the nature of the nucleophile...

This article describes the action of iodine(III) reagents [diacetoxyiodobenzene, PhI(OAc)2 , and iodosobenzene, (PhIO)n ] in conjunction with TMSBr which act as functional bromine equivalents in unique oxidations of saturated, carbamate protected N -heterocycles. Interestingly, during this work, treatment of the same carbamates with molecular bromine alone afforded similar products, which were sequestered by the solvent methanol.

A Davis-Beirut reaction inspired nitroso Diels-Alder protocol is reported. The starting material for the procedure is a nitrophenyl moiety with the para position appropriately substituted with a 2°-amine (see 5 ) or 2°-alcohol (see 6 ). Deprotonation at the benzylic position followed by concomitant oxidation of the benzylic position and reduction of the nitro moiety delivers a nitrosophenyl intermediate, which subsequently undergoes a nitroso Diels-Alder reaction. This one-pot procedure delivers aryldihydro-1,2-oxazines in moderate yields...

As part of our ongoing research on bioactive fungal metabolites, two new metabolites were isolated from a fungus of the Stictidaceae (strain MSX62440), dasyscyphins F and G ( 1 and 3 ), and the known dasyscyphin C ( 2 ). Compound 1 was characterized by HRMS and 1D and 2D NMR data, and its absolute configuration established by ECD spectroscopy. A structural revision of dasyscyphin C ( 2 ) was based on NMR data and verified by ECD calculations. Compound 3 was reported previously as a synthetic product, and its identity confirmed by comparison with NMR data in the literature, and its absolute configuration was established by ECD spectroscopy...

(-)-Cannabidiol [(-)-CBD] has recently gained prominence as a treatment for neuro-inflammation and other neurodegenerative disorders; interest is also developing in its synthetic enantiomer, (+)-CBD, which has a higher affinity to CB1 / CB2 receptors than the natural stereoisomer. We have developed an inexpensive, stereoselective route to access ent -CBD derivatives using (+)-carvone as a starting material. In addition to (+)-CBD, we report the first syntheses of (+)-cannabidivarin, (+)-cannabidiphorol as well as C-6 / C-8 homologues...

This report describes the direct synthesis of dihydro-pyrrolo-pyrazole heterocycles from allylic azides and methyl vinyl sulfone. The product results from a complex cascade reaction that is operationally straightforward, with aromatization being the result of a concomitant elimination step. A variety of azides could participate in this reaction (12 examples) and the isolated yields of the desired product ranged from 51%-72%. Lastly the ethylene sulfone group could be removed by heating the product in pyrrolidine...

Cysteine-directed covalent ligands have emerged as a versatile category of chemical probes and drugs that leverage thiol nucleophilicity to form permanent adducts with proteins of interest. Understanding the scope of cysteines that can be targeted by covalent ligands, as well as the types of electrophiles that engage these residues, represent important challenges for fully realizing the potential of cysteine-directed chemical probe discovery. Although chemical proteomic strategies have begun to address these important questions, only a limited number of electrophilic chemotypes have been explored to date...

Three novel 8-oxo-dGTP bisphosphonate analogues of 3 in which the bridging β,γ-oxygen is replaced by a methylene, fluoromethylene or difluoromethylene group ( 4-6 , respectively) have been synthesized from 8-oxo-dGMP 2 by reaction of its morpholine 5'-phosphoramidate 14 or preferably, its N -methylimidazole 5'-phosphoramidate 15 with n -tributylammonium salts of the appropriate bisphosphonic acids, 11-13 . The latter method also provides a convenient new route to 3 . Analogues 4-6 may be useful as mechanistic probes for the role of 3 in abnormal DNA replication and repair...

Plakortinic acids C ( 3 ) and D ( 4 ), two unprecedented peroxide-polyketides with 7,8-dioxatricyclo[4.2.2.02,5 ]dec-9-ene scaffold, as well as known biogenetically related congeners, plakortinic acids A ( 1 ) and B ( 2 ), were isolated from a two-sponge association of Plakortis symbiotica-Xestospongia deweerdtae . Upon chemical derivatization, the structures and relative configurations of 3 and 4 were characterized by analysis of HRESIMS and NMR spectroscopic data, molecular modeling studies, and chiroptical comparisons with known natural products and published values of [α]D of related synthetic analogs...

A convenient protocol for amide bond formation for electron deficient amines and carboxylic acids is described. Amide coupling of aniline derivatives has been investigated with a number of reagents under a variety of reaction conditions. The use of 1 equivalent of EDC and 1 equivalent of DMAP, catalytic amount of HOBt and DIPEA provided the best results. This method is amenable to the synthesis of a range of functionalized amide derivatives with electron deficient and unreactive amines.

Our continued synthetic interest in this class of retinoids, CD437 and its analogs, against methicillin-resistant Staphylococcus aureus (MRSA) has brought us to explore further isosteric substitutions within the scaffold. Although our previous findings have shown promising activity against gram-positive pathogens, their therapeutic viability remained an issue. Specifically, through preliminary analysis, our best performing compound, analog 2, displayed low solubility within serum as well as high affinity for retinoid binding proteins with a concentration dependent relationship...

Aryl-substituted esters of a racemic diprotected 2-azido-1-alkanol were submitted to the Staudinger/aza-Wittig reaction in order to assess scope and establish conditions for their cyclization to the corresponding 2,4,5-trisubstituted oxazolines. Following the cyclization study, the (2 R ,3 R )-antipode of the azidoalkanol was obtained in high ee by incubation of the corresponding racemic azidoacetate with pig liver esterase (PLE). The p -nitrobenzoate of the enantioenriched 2-azido-1-alcohol was cyclized by the Staudinger/aza-Wittig to give the corresponding (4 R ,5 R )-disubstituted-2-(4-nitrophenyl) oxazoline...