Theoretical and Experimental Insights into the Tandem Mannich—Electrophilic Amination Reaction: Synthesis of Safirinium Dyes

Isoxazolo[3,4-b]pyridin-3(1H)-ones are ‘spring-loaded’ compounds that quantitatively react with iminium salts derived from formaldehyde and secondary amines to yield fluorescent Safirinium dyes. The mechanism and energetics of the above tandem Mannich–electrophilic amination reaction have been investigated experimentally and using theoretical methods. The hybrid B3LYP functional with GD3 empirical dispersion and range-separated hybrid functional ωB97XD, both combined with a PCM model, were applied to acquire the energetic profiles of the studied reaction with respect to the structure of secondary amine and isoxazolone used. Diastereoselectivity of the tandem reactions involving iminium salt derived from L-proline has been rationalized theoretically by means of density functional theory calculations.

Solid-Phase Synthesis of an Insect Pyrokinin Analog Incorporating an Imidazoline Ring as Isosteric Replacement of a trans Peptide Bond

A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization reaction of an iminium salt generated from the preceding amino acid and 2,4-diaminopropanoic acid (Dap).

Solid Phase Synthesis of an Insect Pyrokinin Analog Incorporating an Imidazoline Ring as Isosteric Replacement of a trans Peptide Bond

A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization reaction of an iminium salt generated from the preceding amino acid and 2,4-diaminopropanoic acid (Dap).

Stereoselective and Stereospecific Triflate Mediated Intramolecular Schmidt Reaction: Easy Access to Alkaloid Skeletons

The stereoselectivity and stereospecificity of the triflate mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1<i>H</i>-pyrrolo[1,2-a]azepine, the structural skeleton of several important families of alkaloids such as the <i>Stemona</i> alkaloids, has been examined. The reaction involves an initial intramolecular S_N2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N₂-elimination followed by hydride mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicylic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1<i>H</i>-pyrrolo[1,2-a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (–)-(<i>cis</i>)-3-propylindolizidine and (–)-(<i>cis</i>)-3-butyllehmizidine, two alkaloids found in the venom of workers of the ant <i>Myrmicaria melanogaster</i>, is reported.<br>

Stereochemical Control of the Triflate Mediated Intramolecular Schmidt Reaction

The stereoselectivity of the triflate mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1<i>H</i>-pyrrolo[1,2-a]azepine, the structural skeleton of several important families of alkaloids such as the <i>Stemona</i> alkaloids, has been examined. The reaction involves an initial intramolecular S_N2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N₂-elimination followed by hydride mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicylic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1<i>H</i>-pyrrolo[1,2-a]azepine. The origin of the stereoselectivity of is rationalized based on theoretical calculations.

Stereochemical Control of the Triflate Mediated Intramolecular Schmidt Reaction

The stereoselectivity of the triflate mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1<i>H</i>-pyrrolo[1,2-a]azepine, the structural skeleton of several important families of alkaloids such as the <i>Stemona</i> alkaloids, has been examined. The reaction involves an initial intramolecular S_N2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N₂-elimination followed by hydride mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicylic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1<i>H</i>-pyrrolo[1,2-a]azepine. The origin of the stereoselectivity of is rationalized based on theoretical calculations.

Cycloaddition reactions of acetylenic iminium salts and diazoacetates leading to pyrazole iminium salts

Acetylenic iminium triflates with the general formula [R–C≡ C–C(Ar)=N+R2 TfO−] were found to be excellent dipolarophiles in [3+ 2] cycloaddition reactions with diazoacetates leading to (1H-pyrazol-3(5)-yl)methanaminium triflates in high yields. The terminal acetylenic iminium salt (propyne iminium salt) [HC≡C–C(Ph)=N+Me2 TfO−] reacted with an equimolar amount of methyl diazoacetate instantaneously at 20°C to form the expected pyrazole in almost quantitative yield. When a 2:1 stoichiometry was applied, subsequent Michael addition of the pyrazole at the alkyne occurred and the bis(iminium) ditriflate 4 was obtained in high yield. By hydride reduction or hydrolysis of the iminium group, some of the highly hygroscopic pyrazole iminium salts were converted into neutral, twofold functionalized, di- and tri-C-substitued 1H-pyrazoles.