Nucleophilic/electrophilic cascades are
defined as the cascade sequences in which the key step constitutes a nucleophilic
or electrophilic attack.
An example of such a cascade is seen in the short enantioselective synthesis of the broad-spectrum antibiotic (–)-chloramphenicol, reported by Rao et al. (Scheme 1). Herein, the chiral epoxy-alcohol 1 was first treated with dichloroacetonitrile in the presence of NaH. The resulting intermediate 2 then underwent a BF·EtO-mediated cascade reaction. Intramolecular opening of the epoxide ring yielded intermediate 3, which, after an in situ hydrolysis facilitated by excess BF·EtO, afforded (–)-chloramphenicol (4) in 71% overall yield.
A nucleophilic cascade was also employed in the total synthesis of the natural product pentalenene (Scheme 2). In this procedure, squarate ester 5 was treated with (5-methylcyclopent-1-en-1-yl)lithium and propynyllithium. The two nucleophilic attacks occurred predominantly with trans addition to afford intermediate 6, which spontaneously underwent a 4π-conrotatory electrocyclic opening of the cyclobutene ring. The resulting conjugated species 7 equilibrated to conformer 8, which more readily underwent an 8π-conrotatory electrocyclization to the highly strained intermediate 9. The potential to release strain directed protonation of 9 such that species 10 was obtained selectively. The cascade was completed by an intramolecular aldol condensation that afforded product 11 in 76% overall yield. Further elaboration afforded the target (±)-pentalenene (12).