[4+4] Cycloaddition of Unsaturated Imines Activated by Hydroxy or Amino Groups: Synthetic Application and Biofunctions

<p> We have found that the unsaturated imines derived from the unsaturated aldehydes and ethanolamine derivatives, i.e., phenylglycinol or cis-1-amino-2-indanol, smoothly participated in the [4+4] cycloaddition reaction, providing the 2,6,9-triazabicyclo[3.3.1]nonanes or 1,5-diazaoctanes in almost quantitative yields. The reaction is significantly activated by the presence of the hydroxy groups of the unsaturated imines through (1) novel OH-pinteraction with the reacting imines, and (2) stabilization of the cyclization products. The [4+4] cycloaddition reaction could also proceed from the unsaturated imines containing the amino functionalities; thus, the reaction of acrolein with the polyamines, i.e., spermine or spermidine, readily produced the corresponding 1,5-diazaoctanes at ambient temperature. </p><p> It is known that the polyamines in and on the cells could readily be oxidized by the amine oxidase upon the oxidative stress, resulting in the production of acrolein. Acrolein is the cytotoxic aldehyde, which reacts with the amines or thiols of the biologically relevant molecules, further accelerating the process of oxidative stress. We hypothesized from the reactivity profiles of the unsaturated imines, that the acrolein, which is produced by the polyamines, could react with polyamines themselves, providing the 1,5-diazaoctane derivatives. Spermine as the representative polyamines, smoothly reacted with acrolein, initially producing the 1,5-diazaoctanes, and eventually the hydrogels through the sequential [4+4] polymerization reaction. The [4+4] products of polyamines showed cytotoxicity and promoted the oxidative stress. The results described in this symposium suggest the new mechanism of the oxidative stress underlying the acrolein production from polyamines.</p>