A subcategory of nucleophilic/electrophilic sequences is constituted by organocatalytic
cascades, in which the key nucleophilic attack is driven by organocatalysis.
An organocatalytic cascade was employed in the total synthesis of the natural product harziphilone, reported by Sorensen et al. in 2004 (Scheme 3). Herein, treatment of the enone starting material 13 with organocatalyst 14 yielded intermediate 15 via conjugate addition. Subsequent cyclization by the intramolecular Michael addition of the enolate into the triple bond of the system gave species 16, which afforded intermediate 17 after proton transfer and tautomerization. The cascade was completed by elimination of the organocatalyst and a spontaneous 6π-electrocyclic ring closure of the resultant cis-dienone 18 to (+)-harziphilone (19) in 70% overall yield.
An outstanding triple organocatalytic cascade was reported by Raabe et
al. in 2006. Linear aldehydes (20),
nitroalkenes (21) and α,β-unsaturated
aldehydes (22) could be condensed
together organocatalytically to afford tetra-substituted
cyclohexane carbaldehydes (24) with
moderate to excellent diastereoselectivity and complete enantiocontrol (Scheme
4). The transformation is mediated by the readily
available proline-derived organocatalyst 23.
The transformation was proposed to
proceed via a Michael addition/Michael addition/aldol condensation sequence
(Scheme 5). In the first step, Michael addition of
aldehyde 20 to nitroalkene 21 occurs through enamine catalysis,
yielding nitroalkane 25. Condensation
of α,β-unsaturated aldehyde 22 with the organocatalyst then
facilitates the conjugate addition of 25
to give intermediate enamine 26,
which is prone to undergo an intramolecular aldol condensation to iminium
species 27. Organocatalyst 23 is regenerated by hydrolysis, along
with the product 24, thus closing
the triple cascade cycle.