Total Synthesis of Natural Products and Alkaloids

Total synthesis of natural products and alkaloids underpins the discovery and development of therapeutics, agrochemicals and molecular probes by recreating complex molecular architectures in the laboratory. This endeavour not only secures access to scarce or structurally novel targets but also illuminates biosynthetic logic and enables modification of core scaffolds for improved activity or selectivity. Contemporary approaches combine convergent assembly, cascade cyclisations and late‐stage functionalisation to forge polycyclic frameworks and install multiple stereocentres with high precision. Advances in catalytic enantioselective methods, bio‐inspired and contra-biosynthetic strategies, and computationally guided reaction design have dramatically shortened synthetic sequences and expanded the chemical space accessible to chemists. These innovations continue to influence global health and sustainability initiatives by providing scalable routes to lead compounds and by inspiring new reaction paradigms drawn from nature’s own toolkit.

Research from Nature Portfolio

Recent studies have demonstrated a contra-biosynthetic skeletal modification that converts benzenoid frameworks into seven-membered troponoid congeners. Computational analyses guided the development of a Büchner–Curtius–Schlotterbeck transformation of p-quinol methylethers, culminating in a concise two-step total synthesis of the sesquiterpenoid harringtonolide from a common precursor. Insights into Lewis-acid and nucleophile selection revealed unconventional selectivity trends that are expected to inform future skeletal editing strategies. A complementary report has established scalable syntheses of low-abundance Isodon diterpenoids, including eriocalyxin B, neolaxiflorin L and xerophilusin I. A streamlined sequence enabled multigram preparation of each target, facilitating in-depth bioevaluation. This platform identified neolaxiflorin L as a promising anticancer lead, underscoring the power of efficient total synthesis to unlock the therapeutic potential of complex natural scaffolds.

Total Synthesis of Natural Products and Alkaloids publication trend

The graph below shows the total number of articles in total synthesis of natural products and alkaloids across all publications each year (not limited to Nature Index journals).

Technical terms

Total synthesis: The complete chemical assembly of a complex natural compound from simple precursors.

Alkaloid: A nitrogen-containing natural product, often endowed with significant biological activity.

Dearomative cyclization: A ring-forming transformation that converts an aromatic system into a non-aromatic cyclic structure.

Oxyallyl cation: A reactive three-carbon intermediate bearing a positive charge delocalised over an oxygen and adjacent carbons, employed in cycloaddition reactions.

Enantioselective: A process that preferentially produces one enantiomer over its mirror image.

Contra-biosynthesis: A synthetic strategy that reverses a biosynthetic step to access complex molecular frameworks.

References

1. Late-stage benzenoid-to-troponoid skeletal modification of the cephalotanes exemplified by the total synthesis of harringtonolide. Nature Communications (2024).
2. Efficient syntheses of (−)-crinine and (−)-aspidospermidine, and the formal synthesis of (−)-minfiensine by enantioselective intramolecular dearomative cyclization. Chemical Science (2017).
3. Synthesis of Cyclohepta[b]indoles by (4 + 3) Cycloaddition of 2‑Vinylindoles or 4H‑Furo[3,2‑b]indoles with Oxyallyl Cations. The Journal of Organic Chemistry (2020).
4. Scalable synthesis enabling multilevel bio-evaluations of natural products for discovery of lead compounds. Nature Communications (2018).