In 2014, Zhang, Wu, Hong, Ai, Wang, Li and Lei showed that the build/couple/pair (B/C/P) logic of diversity-oriented synthesis, driven by the functional-group pairing patterns (FGPPs) hidden in Lycopodium alkaloids, delivers four natural products and six skeletally distinct unnatural scaffolds in parallel from a single multifunctional precursor in 7–9 steps (2–16 mg each). They explicitly expected the strategy to transfer to other complex natural products possessing FGPPs and to furnish natural-product-like libraries for chemical genetics and drug discovery. As of August 2026 the FGPP-inspired B/C/P design remains a single-family demonstration: no natural-product family other than the Lycopodium alkaloids has yet been shown to support it, later diversity-oriented syntheses of other natural-product families used different design logics, and the FG-pairing concept spread to privileged-heterocycle library synthesis rather than to new natural-product families. The open problem is to establish the strategy's scope: execute the FGPP/B/C/P design on complex natural products other than the Lycopodium alkaloids that possess hidden FGPPs — for instance, an additional natural-product family — so that, as in the source demonstration, several functional-group pairing pathways from a single common multifunctional precursor deliver genuine members of the new target and skeletally distinct natural-product-like scaffolds in parallel.

Background

Diversity-oriented synthesis (DOS) is the deliberate, forward-synthetic construction of small-molecule collections that are skeletally and stereochemically diverse, aiming to populate the sparsely sampled regions of chemical space occupied by natural products, which commercial screening libraries largely miss. The dominant planning framework for DOS is the build/couple/pair (B/C/P) strategy introduced by Burke and Schreiber (Angew. Chem. Int. Ed. 2004, 43, 46–58): simple chiral building blocks are made ('build'), joined in all combinations ('couple') to give a densely functionalized intermediate, and then intramolecularly connected in different ways ('pair') to yield many distinct molecular skeletons. The idea of exploiting 'functional group pairing' — letting the many functional groups of a multifunctional scaffold react with one another in alternative combinations — as a source of skeletal diversity goes back to Porco and co-workers (Org. Lett. 2007, 9, 2123–2126). Lycopodium alkaloids are a large family of polycyclic, nitrogen-bearing plant metabolites (club mosses) with dense stereochemistry and celebrated bioactivities, including the Alzheimer's drug candidate huperzine A; members such as serratezomine A, serratinine, 8α-hydroxyfawcettimine and lycoposerramine-U share C–C, C–N and C–O bonds that can be viewed as different 'pairings' of a common set of functional groups. Zhang, Wu, Hong, Ai, Wang, Li and Lei (Nat. Commun. 2014, 5, 4614) fused these threads: they identified the hidden functional group pairing patterns (FGPPs) — the alternative ways functional groups pair into connecting bonds — across the Lycopodium family, 'depaired' them retrosynthetically to one unified multifunctional precursor reached in build/couple phases from 4-aminobutan-1-ol, and then executed multiple pairing pathways from that single precursor to obtain, in parallel, four natural products and six natural-product-like scaffolds (10 distinct skeletons) within seven to nine steps and 2–16 mg per compound — enough for characterization and most biological assays but not for a screening collection. The authors state the expectation that 'this new strategy will be applied both to other complex natural products possessing FGPPs and to generating natural product-like chemical libraries of skeletally complex and diverse molecules for chemical genetics and drug discovery'. What the source leaves open — and what later literature has not closed — is how widely this design protocol transfers: identifying a hidden FGPP in a different natural-product target, collapsing it to one multifunctional precursor, and divergently re-pairing that precursor into genuine members plus new scaffolds in parallel.

Problem Statement

Establish the generality of the FGPP-inspired build/couple/pair strategy posed by Zhang et al. (Nat. Commun. 2014, 5, 4614): apply the full design protocol — (i) identify the hidden functional group pairing patterns (FGPPs) in complex natural products other than the Lycopodium alkaloids that possess FGPPs, for instance an additional natural-product family; (ii) 'depair' them retrosynthetically to a single multifunctional precursor furnished by build/couple phases; and (iii) execute multiple functional-group pairing pathways from that single precursor so that genuine members of the new target and skeletally distinct unnatural natural-product-like scaffolds are obtained in parallel — to at least one such additional target. In analogy with the source demonstration, which drew four natural products and six unnatural scaffolds (10 distinct skeletons in total) from one precursor through different pairing pathways, the demonstration must exhibit the parallel divergence that defines the strategy: several pairing pathways from the single common precursor delivering at least three genuine natural products of the new target alongside at least three distinct unnatural skeletons. Which structural characteristics of natural products or natural-product families enable or defeat the design is an interpretive question that a single transfer demonstration can inform but not settle; it is not part of the completion criterion here. Likewise, the source's expectation that the strategy will serve 'generating natural product-like chemical libraries ... for chemical genetics and drug discovery' is motivation for the question rather than an added deliverable: the source describes the 2–16 mg per compound of its own campaign as 'sufficient for characterizations and most biological assays' and imposes no larger material scale or screening campaign as a condition for a transfer demonstration.

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