Cyclic products can be obtained through the intramolecular version of the Nicholas reaction, which requires having the nucleophile connected to the alkyne unit. Here, we report the synthesis of ...1-oxa-3-cyclooctynes starting from commercially available (1
,3
)-camphoric acid. The strategy is based on the initial preparation of propargylic alcohols, complexation of the triple bond with Co
(CO)
, and treatment with BF
·Et
O to induce an intramolecular Nicholas reaction with the free hydroxyl group as nucleophile. Finally, oxidative deprotection of the alkyne afforded the cyclooctynes in good yields. Notably, large-sized R substituents at the chiral center connected to the O atom were oriented in such a way that steric interactions were minimized in the cyclization, allowing the formation of cyclooctynes exclusively with
configuration, in good agreement with theoretical predictions. Moreover, preliminary studies demonstrated that these cyclooctynes were reactive in the presence of azides yielding substituted triazoles.
Transition metal-free oxidation with air at room temperature has been achieved by simply using ascorbate (vitamin C) and catalytic amounts of menadione (vitamin K3). A combination of the mentioned ...vitamins transforms atmospheric oxygen into hydrogen peroxide, which is able to oxidize arylboronic acids and other chemical moieties.
Although the agmatine deiminase system (AgDI) has been investigated in Enterococcus faecalis, little information is available with respect to its gene regulation. In this study we demonstrate that ...the presence of exogenous agmatine induces the expression of agu genes in this bacterium. In contrast to the homologous and extensively characterized AgDI system of S. mutants, the aguBDAC operon in E. faecalis is not induced in response to low pH. In spite of this, agmatine catabolism in this bacterium contributes by neutralizing the external medium while enhancing bacterial growth. Our results indicate that carbon catabolic repression (CCR) operates on the AgDI system via a mechanism that involves interaction of CcpA and P-Ser-HPr with a cre site found in an unusual position considering the aguB promoter (55 nt upstream the +1 position). In addition, we found that components of the mannose phosphotransferase (PTS.sup.Man) system also contributed to CCR in E. faecalis since a complete relief of the PTS-sugars repressive effect was observed only in a PTS.sup.Man and CcpA double defective strain. Our gene context analysis revealed that aguR is present in oral and gastrointestinal microorganisms. Thus, regulation of the aguBDAC operon in E. faecalis seems to have evolved to obtain energy and resist low pH conditions in order to persist and colonize gastrointestinal niches.
Positive cooperativity between host conformational equilibria and guest binding has been widely reported in protein receptors. However, reported examples of this kind of cooperativity in synthetic ...hosts are scarce and largely serendipitous, among other things because it is hard to envision systems which display this kind of cooperativity. In order to shed some light on the correlation between conformational equilibria of free host and guest binding, selected structural modifications have been performed over a family of nonpreorganized hosts in order to induce conformational changes and to analyze their effect on the binding affinity. The conformational effect was evaluated by a theoretical conformational search and correlated with the ability of the receptors. All data suggest that those receptors that display the best association constants are able to sample folded conformations analogous to the conformational requirements for the binding of the guests. On the contrary, for those receptors where folded conformers are scarce, then the association constant and enantioselectivity clearly drop.
The concept of molecular simplification as a drug design strategy to shorten synthetic routes, while keeping or enhancing the biological activity of the lead drug, has been applied to (+)-muconin, an ...acetogenin with remarkable cytotoxicity. A novel approach that enables the stereoselective synthesis of such a natural compound or its enantiomer from a common precursor is described. An additional advantage of the method is complete stereochemical control and the decrease in the number of chemical steps required, thus providing an enhancement of the overall yield. Antiproliferative studies against the human solid tumor cell lines showed that the aliphatic chain-THF/THP fragment of (+)-muconin has modest cytotoxic activity. The strategy opens the way to preparing novel bioactive acetogenin analogues by shorter synthetic routes.
Molecular simplification of any given natural or synthetic template helps medicinal chemists designing shorten synthetic routes while keeping or enhancing the biological activity. This strategy is ...exemplified with simplified analogs of naturally occurring catalpol.
Two iridoid scaffolds were synthesized enantioselectively using as key step an l-proline-catalyzed α-formyl oxidation. The in vitro antiproliferative activities were evaluated against a representative panel of human solid tumor cell lines. Both iridoids induced considerably growth inhibition in the range 0.38–1.86μM. Cell cycle studies for these compounds showed the induction of cell cycle arrest at the G1 phase. This result was consistent with a decrease in the expression of cyclin D1. Damaged cells underwent apoptosis as indicated by specific Annexin V staining.
A new iron(III) halide-promoted aza-Prins cyclization between γ,δ-unsaturated tosylamines and aldehydes provides six-membered azacycles in good to excellent yields. The process is based on the ...consecutive generation of γ-unsaturated-iminium ion and further nucleophilic attack by the unsaturated carbon−carbon bond. Homoallyl tosylamine leads to trans-2-alkyl-4-halo-1-tosylpiperidine as the major isomer. In addition, the alkyne aza-Prins cyclization between homopropargyl tosylamine and aldehydes gives 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines as the only cyclic products.
Enantiomerically pure anti-β-amino alcohols were synthesized from optically pure α-(N,N-dibenzylamino)benzyl esters, derived from α-amino acids, by the sequential reduction to aldehyde with DIBAL-H ...at -78 °C and subsequent in situ addition of Grignard reagents. Besides anti-β-amino alcohols, anti-2-amino-1,3-diols and anti-3-amino-1,4-diols were obtained in good yields (60-95%) and excellent stereoselectivity (de > 95%). Our technique is compatible with free hydroxyl groups present in the substrate. To demonstrate the versatility of the method, spisulosine and sphinganine were synthesized in two steps from the appropriate N,N-dibenzyl-l-aminobenzyl ester in 42% and 45% yield, respectively.
Copper oxides have been of considerable interest as electrocatalysts for CO2 reduction (CO2R) in aqueous electrolytes. However, their role as an active catalyst in reducing the required overpotential ...and improving the selectivity of reaction compared with that of polycrystalline copper remains controversial. Here, we introduce the use of selected-ion flow tube mass spectrometry, in concert with chronopotentiometry, in situ Raman spectroscopy, and computational modeling, to investigate CO2R on Cu2O nanoneedles, Cu2O nanocrystals, and Cu2O nanoparticles. We show experimentally that the selective formation of gaseous C2 products (i.e., ethylene) in CO2R is preceded by the reduction of the copper oxide (Cu2OR) surface to metallic copper. On the basis of density functional theory modeling, CO2R products are not formed as long as Cu2O is present at the surface because Cu2OR is kinetically and energetically more favorable than CO2R.
PDF
