Asymmetric Rearrangement Strategies in Natural Product Synthesis

Asymmetric rearrangement strategies have emerged as pivotal tactics in the construction of complex molecular frameworks characteristic of many natural products. By harnessing intramolecular shifts—such as 1,2-anionotropic migrations, Wagner–Meerwein rearrangements, α-ketol/α-iminol transpositions and semipinacol or benzilic acid rearrangements—chemists can induce rapid and controlled changes in connectivity while simultaneously introducing stereochemical information. These processes often proceed under mild conditions and can be orchestrated in tandem or domino sequences to minimise purification steps and maximise overall efficiency. When coupled with chiral catalysts or auxiliary-controlled approaches, asymmetric rearrangements enable the enantioselective formation of quaternary stereocentres, desymmetrisation of prochiral substrates and ring expansions that deliver medium to large cycles otherwise challenging to access. The resulting structural complexity underpins the synthesis of diverse alkaloids, terpenes and polyketide scaffolds with high step economy. In addition, mechanistic understanding—often informed by computational studies—has driven the rational design of new catalysts and reaction conditions, broadening the scope of migrating groups and enhancing enantioselectivity. Ultimately, these methods not only shorten synthetic routes but also open avenues to analogues with improved biological profiles, thus impacting drug discovery and agrochemical development on a global scale.

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Asymmetric Rearrangement Strategies in Natural Product Synthesis publication trend

The graph below shows the total number of articles in asymmetric rearrangement strategies in natural product synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

1,2-Anionotropic rearrangement: A migration of an alkyl or aryl group bearing an electron pair to an adjacent carbocation or radical centre, yielding a constitutional isomer.

Domino reaction: A sequence of two or more bond-forming steps that occur under the same conditions without isolation of intermediates.

α-Ketol rearrangement: An acid- or base-catalysed 1,2-shift of an alkyl or aryl group from an α-hydroxy ketone to give an α-diketone and a new alcohol.

Desymmetrization: A process that converts a symmetric or prochiral substrate into an enantioenriched product by selectively reacting one of two identical groups.

Wagner–Meerwein rearrangement: A cationic 1,2-shift of an alkyl group within a carbocation intermediate, used to reorganise carbon frameworks and generate new stereocentres.

References

1. Natural Product Synthesis Enabled by Domino Processes Incorporating a 1,2-Rearrangement Step. ACS Central Science (2021).
2. Absence of Intermediates in the BINOL-Derived Mg(II)/Phosphate-Catalyzed Desymmetrizative Ring Expansion of 1‑Vinylcyclobutanols. The Journal of Organic Chemistry (2021).
3. α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions. Beilstein Journal of Organic Chemistry (2021).