Cycloadditions that involve more than six π electrons are termed higher-order cycloadditions and are an excellent tool for solving complex synthetic challenges, as they provide direct access to polycyclic scaffolds that contain medium-sized rings. They have interesting synthetic potential for the discovery of new bioactive molecules and in natural product synthesis. It is peculiar that stereocontrolled [8+2] and [6+4] cycloadditions have been largely neglected for the past 50 years. Here we demonstrate a cross-dienamine activation of 2-cyclopentenone and the unprecedented endocyclic linear-dienamine activation of 2-cyclohexenones and 2-cycloheptenones. These dienamine intermediates undergo aminocatalytic stereoselective [8+2], [6+4] and formal [4+2] cycloadditions with various heptafulvenes. The periselectivities of the cycloadditions are controlled based on the ring size of the 2-cycloalkenones and the substitution patterns of the heptafulvenes. The chiral products obtained undergo various chemical and photochemical single-step transformations that give access to other classes of all-carbon polycyclic scaffolds.

High on cycloaddi(c)tions: The impact of the Woodward-Hoffmann [4n+2] rule for thermally allowed cycloaddition reactions and the challenges associated with moving from six to ten electrons are discussed in this Essay.

Further studies are reported on the utilization of the versatile reaction between chiral sulfinimines and alkyldiphenylsilyl lithium reagents with the goal of preparing a wide range of silanediol-based protease inhibitors. In particular, focus has been placed to demonstrate how a number of genetically encoded amino acid side chains such as serine, threonine, tyrosine, lysine, proline, arginine, aspartate and asparagine might be incorporated into the overall approach. Efforts to apply this synthetic methodology for accessing biologically relevant silanediol dipeptide mimics are also described. This includes the synthesis of a potential inhibitor of the human neutrophil elastase, as well as a diphenylsilane mimic of a hexapeptide fragment of the human islet amyloid polypeptide.

Reductive lithiation of methyl-substituted diarylmethylsilanes using lithium naphthalenide represents a practical method for the preparation of the corresponding silyl lithium reagents. Their addition to chiral sulfinimines affords versatile precursors to silanols and silanediols. The replacement of the currently used diphenylsilane motif by a more labile diarylsilane moiety allows the selective hydrolysis of one or two aryl groups by treatment with TFA.

The mechanisms and origins of chemo- and stereo­selectivities of the organocatalytic [6+4] cycloaddition between 2-cyclopentenone and tropone have been investigated by a combined computational and experimental study. In the presence of a cinchona alkaloid primary amine catalyst and an acid additive, 2-cyclopentenone forms a cross-dienamine intermediate that subsequently undergoes a stepwise [6+4] cycloaddition reaction via a zwitterionic intermediate. The rate-determining transition state features a strong hydrogen-bonding interaction between the tropone oxygen atom and the protonated quinuclidine directing the reaction course leading to a highly periselective [6+4] cycloaddition. The importance of the strong hydrogen-bonding interaction is also demonstrated by the influence of the concentration of the acid additive on the yields and enantio­selectivities of the reaction. The corresponding [4+2] cycloaddition reaction has a much higher energy barrier. The enantio­selectivity of the [6+4] cycloaddition originates from different repulsive hydrogen–hydrogen interactions that distinguish the diastereomeric transition states.