Transfer of 1‑Alkenyl Groups between Secondary Amines. Relative Stability and Reactivity of Enamines from Popular Organocatalysts

Enamines from 3-methylbutanal and several Pro- and Phe-derived secondary amines were prepared in DMSO-<i>d</i>₆, CD₃CN, and CDCl₃. For the first time, the relative thermodynamic stabilities of these and other enamines were compared, and rapid exchanges of 1-alkenyl groups were demonstrated. Competition experiments showed that the most favored enamines (without significant steric inhibition of resonance) react more rapidly with electrophiles

Importance of the Electron Correlation and Dispersion Corrections in Calculations Involving Enamines, Hemiaminals, and Aminals. Comparison of B3LYP, M06-2X, MP2, and CCSD Results with Experimental Data

While B3LYP, M06-2X, and MP2 calculations predict the Δ<i>G</i>° values for exchange equilibria between enamines and ketones with similar acceptable accuracy, the M06-2X/6-311+G­(d,p) and MP2/6-311+G­(d,p) methods are required for enamine formation reactions (for example, for enamine <b>5a</b>, arising from 3-methylbutanal and pyrrolidine). Stronger disagreement was observed when calculated energies of hemiaminals (<i>N</i>,<i>O</i>-acetals) and aminals (<i>N</i>,<i>N</i>-acetals) were compared with experimental equilibrium constants, which are reported here for the first time. Although it is known that the B3LYP method does not provide a good description of the London dispersion forces, while M06-2X and MP2 may overestimate them, it is shown here how large the gaps are and that at least single-point calculations at the CCSD­(T)/6-31+G­(d) level should be used for these reaction intermediates; CCSD­(T)/6-31+G­(d) and CCSD­(T)/6-311+G­(d,p) calculations afford Δ<i>G</i>° values in some cases quite close to MP2/6-311+G­(d,p) while in others closer to M06-2X/6-311+G­(d,p). The effect of solvents is similarly predicted by the SMD, CPCM, and IEFPCM approaches (with energy differences below 1 kcal/mol)

Relative Tendency of Carbonyl Compounds To Form Enamines

Equilibria between carbonyl compounds and their enamines (from <i>O</i>-TBDPS-derived prolinol) have been examined by NMR spectroscopy in DMSO-<i>d</i>₆. By comparing the exchange reactions between pairs (enamine A + carbonyl B → carbonyl A + enamine B), a quite general scale of the tendency of carbonyl groups to form enamines has been established. Aldehydes quickly give enamines that are relatively more stable than those of ketones, but there are exceptions to this expected rule; for example, 1,3-dihydroxyacetone acetals or 3,5-dioxacyclohexanones (2-phenyl-1,3-dioxan-5-one and 2,2-dimethyl-1,3-dioxan-5-one) show a greater tendency to afford enamines than many α-substituted aldehydes

Total Synthesis of Amphidinolide K, a Macrolide That Stabilizes F‑Actin

The total synthesis of (−)-amphidinolide K (<b>1</b>) based on asymmetric addition of allylsilane <b>C1</b>–<b>C8</b> to enal <b>C9</b>–<b>C22</b> is reported. The 1,9,18-tris-<i>O</i>-TBDPS ether was converted into the desired 9,18-dihydroxy acid. Its macrolactonization was accomplished by the Shiina method. Compound <b>1</b> together with 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. Compound <b>1</b> behaves as a stabilizer of actin filaments (F-actin) in vitro