Lithiation/stannylation of optically active N-propargyloxazolidinones produced optically active alpha-oxazolidinonylallenylstannanes. Reaction of these with aldehydes in the presence of BF(3).OEt(2) produced beta-hydroxypropargylamines with high syn diastereoselectivity and ee. These were converted to gamma-hydroxy-beta-amino acids by oxidative cleavage of the alkyne.
Conditions for the oxidative ring expansion of a-alkoxy-1-vinyl-1-cyclobutanols have been established using palladium(II) acetate as catalyst. The ring expansion of several 1-vinyl-1-cyclobutanols and an a-monosubstituted-1-vinyl-1-cyclobutanol are reported.Substituted cyclopentenones are found in a variety of naturally occurring, biologically active compounds, and a range of synthetic approaches to this class of compounds exist. 1 In the mid 1980s, Clark showed that palladium(II) could be used to oxidatively ring expand 1-vinyl-1-cyclobutanols to the corresponding cyclopentenones. 2 This reaction, which proceeds with migration of the more substituted a-carbon (eq. 1), has been studied in some detail. 3 Equation 1When 1-vinyl-cyclobutanols 1 having geminal substituents on the migrating carbon are used the product of this reaction is a methylene cyclopentanone 2. When one of the substituents on the migrating carbon is a proton, the initially formed methylene cyclopentanone double bond will isomerize to give a methyl cyclopentenone 3.This type of ring expansion of a-heteroatom-substituted 1-vinyl-1-cyclobutanols has not been examined. These a-heteroatom-1-vinyl-1-cyclobutanols are readily available from addition of vinyl anions to photolytically generated a-alkoxy cyclobutanones. 4 In this work, the results of studies on the ring expansion of a-alkoxy-1-vinyl-1-cyclobutanols using palladium(II) acetate catalyst and 2,3-dichloro-5,6-dicyanoquinone (DDQ) as the oxidizing agent are reported.Cyclobutanones, due to their inherent ring strain, readily undergo many reactions, and the ketone moiety of these molecules is particularly reactive to anion addition reactions. 5 Treatment of cyclobutanones 4a-c 6 with vinyl magnesium bromide in THF produced 1-vinyl-1-cyclobutanols 5a-c in modest to high yields (eq. 2) as single diastereomers. 7 NOE experiments on 1-vinyl-1-cyclobutanol 5a led to assignment of the newly formed stereocenter as shown (Figure). The stereochemistry of 1-vinyl-1-cyclobutanols 5b-c was assigned by analogy with 5a. Equation 2 FigureTreatment of 1-vinyl-1-cyclobutanol 5a with bis(acetonitrile) palladium(II) chloride and 1,4-benzoquinone (BQ) in THF, 3c produced none of the desired methylene cyclopentanone 6a. Only methyl cyclopentenone 7a was obtained (eq. 3). The formation of this product represents loss of one of the existing stereocenters of the starting cyclobutanone. Equation 3This is believed to occur via re-addition of a palladium(II) hydride species to methylene cyclopentanone 6a followed by b-elimination of palladium(II) methoxide (Scheme). 1.4 % 5a 0 % 9 10 0 % Downloaded by: East Carolina University. Copyrighted material.
Intermolecular inverse electron demand cycloadditions of 2-substituted imidazoles with various 1,2,4-triazines produced both imidazo[4,5-c]pyridines (3-deazapurines) and pyrido[3,2-d]pyrimid-4-ones (8-deazapteridines). The product distribution was controlled by reactant substituents and influenced by reaction temperature. A regioselective method for the preparation of 6-unsubstituted 1,2,4-triazines was also developed. By using this route to 8-deazapteridines, a new 8-deazafolate analogue was prepared.
In our earlier work (Golden et al., 2021), we showed 70–80% accuracies for several skin sensitization computational tools using human data. Here, we expanded the data set using the NICEATM human skin sensitization database to create a final data set of 1355 discrete chemicals (largely negative, ∼70%). Using this expanded data set, we analyzed model performance and evaluated mispredictions using Toxtree (v 3.1.0), OECD QSAR Toolbox (v 4.5), VEGA’s (1.2.0 BETA) CAESAR (v 2.1.7), and a k-nearest-neighbor (kNN) classification approach. We show that the accuracy on this data set was lower than previous estimates, with balanced accuracies being 63% and 65% for Toxtree and OECD QSAR Toolbox, respectively, 46% for VEGA, and 59% for a kNN approach, with the lower accuracy likely due to the higher percentage of nonsensitizing chemicals. Two hundred eighty seven chemicals were mispredicted by both Toxtree and OECD QSAR Toolbox, which was approximately 20% of the entire data set, and 84% of these were false positives. The absence or presence of metabolic simulation in OECD QSAR Toolbox made no overall difference. While Toxtree is known for overpredicting, 60% of the chemicals in the data set had no alert for skin sensitization, and a substantial number of these chemicals were in fact sensitizers, pointing to sensitization mechanisms not recognized by Toxtree. Interestingly, we observed that chemicals with more than one Toxtree alert were more likely to be nonsensitizers. Finally, a kNN approach tended to mispredict different chemicals than either OECD QSAR Toolbox or Toxtree, suggesting that there was additional information to be garnered from a kNN approach. Overall, the results demonstrate that while there is merit in structural alerts as well as QSAR or read-across approaches (perhaps even more so in their combination), additional improvement will require a more nuanced understanding of mechanisms of skin sensitization.
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