The tendency of carbonyl compounds to form iminium ions by reaction with pyrrolidine or chiral pyrrolidine derivatives (in other words, the relative stability to hydrolysis of these iminium ions) has been computationally examined, mainly using the M06-2X/6-311+G(d,p) method. We have thus obtained the equilibrium positions for R–CH=O + CH 2 =CH–CH=N + R 2 * → R–CH=N + R 2 * + CH 2 =CH–CH=O reactions and for related exchanges. In these exchanges, there is a transfer of a secondary amine between two carbonyl compounds. Their relative energies may be used to predict which iminium species can be predominantly formed when two or more carbonyl groups are present in a reaction medium. In the catalytic Michael additions of nucleophiles to iminium ions arising from conjugated enals, dienals, and trienals, if the formation of the new Nu–C bond is favorable, the chances of amino-catalyzed reactions to efficiently proceed, with high conversions, depend on the calculated energy values for these exchange equilibria, where the iminium tetrafluoroborates of the adducts (final iminium intermediates) must be more prone to hydrolysis than the initial iminium tetrafluoroborates. The density functional theory (DFT) calculations indicate that the MacMillan catalysts and related oxazolidinones are especially suitable in this regard.
Chiral nitroalkenes are used for the first time in Michael additions of aldehydes, catalyzed by pyrrolidine derivatives. They yield the same major stereoisomer with either (S)-proline or (R)-proline, but this asymmetric induction does not overcome the effect of sterically more congested catalysts. Nitrocyclobutane intermediates are often formed, which are more stable than those from (E)-1-nitro-2-phenylethene. The cyclobutanes and final products were characterized by 2D NMR and chemical correlations.A SciFinder-n search indicates that over 1,000 articles contain additions of carbonyl/carboxyl compounds to (E)-1-nitro-2-phenylethene (-nitrostyrene), although the number is reduced to ca. 670 or 170 if the words "asymmetric" or "organocatalytic", respectively, are entered. In fact, to check the performance of chiral catalysts, the reaction of cyclohexanone with -nitrostyrene has been used as a paradigmatic example. 1 The nitro-Michael reactions of aldehydes and nitroalkenes, as Seebach, Hayashi et al. 2 and Burés, Amstrong, and Blackmond demonstrated, 3 are (2+2)-cycloadditions (formal or stepwise). 4 Depending on the temperature, solvent polarity, and concentration of H2O and organic acid in the medium, these cyclobutanes undergo quick or slow ring opening and hydrolysis to 4nitrobutanals, as summarized in Scheme 1.
Amphidinolides and iriomoteolides are complex macrolides isolated from cultured marine dinoflagellates of the genus Amphidinium sp. [1][2][3][4]. All of them are cytotoxic against several cancer cell lines, especially those with larger rings, with activities in the nanomolar range. Some years ago, we started a research program directed towards the synthesis and elucidation of the biological mechanism of action of several members of this family of natural products [5][6][7][8][9]. As part of this research effort, we have completed the total synthesis of some amphidinolides. Work is underway in our laboratories to complete the total synthesis of amphidinolide B2 and iriomoteolide 2a.Amphidinolide K and some of its stereoisomers and analogues were subjected to evaluation of the possible disruption of the α,β-tubulin-microtubule and/or G-actin-F-actin equilibria. Preliminary studies suggest that amphidinolide K behaves as a stabilizer of F-actin in vitro. The interaction of several of these macrolides with actin has also been studied computationally in our laboratories.
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