Total synthesis and structural confirmation of homo- and heterodimeric bispyrrolidinoindoline dioxopiperazine alkaloids isolated from fungi and bacteria, namely, ditryptoleucine A, ditryptoleucine B (11), the N,N′-bis-demethylated analogue (+)-12, (−)-dibrevianamide F (13), (−)-SF-5280-451 (14), tetratryptomycin A (15), (−)-tryprophenaline (17), and (−)-SF-5280-415 (18), has been carried out starting from the corresponding bispyrrolidinoindolines derived from tryptophan. Our efforts to synthesize all possible diastereomers of the natural ditryptoleucine isolates uncovered structural factors that determine the rate and efficiency of dioxopiperazine ring formation, leading in some cases to mixtures of diastereomers by concomitant epimerization, to the formation of their putative monomeric dioxopiperazine dipeptide biogenetic precursors, and to the alternative formation of a dimer with a fused 1,3,5-triazepan-6-one heterocycle.

Bifunctional unsaturated reagents designed to undergo palladium‐catalyzed cross‐coupling reactions with complementary polyenyl connective fragments are highly useful for the undoubtedly challenging synthesis of polyenes. The current toolkit of building blocks for the bidirectional formation of Csp2−Csp2 single bonds of polyenes includes homo‐bisfunctionalized reagents with equal or unequal reactivity (due to steric and/or electronic factors), and hetero‐bisfunctionalized counterparts containing either two different nucleophiles, two electrophiles or one of these functionalities and a latent nucleophile that can be unmasked when desired. The combination of these bifunctional linchpin reagents using tactics that modulate the reactivity of each terminus in order to achieve the required connection have streamlined the synthesis of polyenes of great complexity using (iterative) cross‐coupling methods for Csp2−Csp2 bond formation. Reaction conditions for the Pd‐catalyzed cross‐coupling reactions are mild and functional‐group‐tolerant, and therefore these protocols allow to construct the polyene structures using shorter unsaturated reactants with the desired geometries, since in general the products preserve the stereochemical information of the connected cross‐coupling partners.

Mono‐ and difunctionalized alkenyl linchpins are continuously being developed with the purpose of connecting components of complementary reactivity as a general strategy for the synthesis of polyenes by Csp2−Csp2 single‐bond construction. In their Review on page 13543 ff., A. R. de Lera et al. outline some of the recent strategies and protocols for fragment cross‐coupling for the stereoselective construction of a range of polyunsaturated products.