The present work reports the first example of the use of the chemistry of radical cations under nonoxidative conditions in total synthesis. Using a late-stage tandem radical/polar crossover reaction, a highly stereoselective total synthesis of cephalosporolide E (which is typically obtained admixed with cephalosporolide F) was accomplished. The reaction of a phthalimido derivative with triphenyltin radical in refluxing toluene engenders a contact ion-pair (radical cation) that leads, in the first instance, to the cephalosporolide F, which is transformed into the cephalosporolide E via a stereocontrolled spiroketal isomerization promoted by the diphenylphosphate acid that is formed during the tandem transformation.
The
stereocontrolled synthesis of naturally occurring products
containing a 5,5-spiroketal molecular structure represents a major
synthetic problem. Moreover, in a previous work, the stereocontrolled
synthesis of cephalosporolide E (ceph E), which presumably was obtained
from its epimer congener (ceph F) through an acid-mediated equilibration
process, was reported. Consequently, we performed a theoretical investigation
to provide relevant information regarding the title question, and
it was found that the higher thermodynamic stability of ceph E, relative
to ceph F, is caused by an n → π* interaction between
a lone electron pair of the oxygen atom of the spiroketal ring (nO) and the antibonding orbital of the carbonyl group (π*C=O). Although similar stereoelectronic interactions have been
disclosed in other molecular structures, its presence in ceph E, and
very likely in other related naturally occurring products, represents
a novel nonanomeric stabilizing effect that should be introduced into
the chemical literature.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.