Synthesis Strategies for Prostaglandin Analogues

Prostaglandin analogues represent a class of bioactive lipids with broad clinical applications, including antiglaucoma, anti-inflammatory and antiplatelet therapies. Synthetic strategies have evolved from classical multistep sequences using lactone intermediates to modern approaches that harness catalysis, biocatalysis and cascade reactions for enhanced efficiency and selectivity. Central to most routes is the construction of the chiral cyclopentane core, often achieved via asymmetric aldol cascades, Diels–Alder cycloadditions or metal-catalysed couplings. Chemoenzymatic methods combine enzyme-mediated stereocontrol with chemical transformations to streamline access to key intermediates, while organocatalytic and transition-metal-catalysed processes enable pot-economical and enantioselective sequences. Recent innovations have focused on consolidating steps, minimising protecting-group manipulations and improving scalability to facilitate drug development and manufacture.

Research from Nature Portfolio

A concise chemoenzymatic synthesis has been developed that delivers representative prostaglandins in five to seven steps on a multi‐gram scale. A single bromohydrin intermediate, prepared in two steps via enzyme-catalysed stereoselective oxidation, serves as a versatile scaffold. Subsequent nickel-catalysed cross-couplings introduce lipid chains with high enantioselectivity, and Wittig olefination completes the prostaglandin framework. This route reduces overall step count, improves atom economy and offers cost advantages, promising broader access to prostaglandin analogues for pharmaceutical applications.

Synthesis Strategies for Prostaglandin Analogues publication trend

The graph below shows the total number of articles in synthesis strategies for prostaglandin analogues across all publications each year (not limited to Nature Index journals).

Technical terms

Chemoenzymatic synthesis: Combined use of chemical reactions and enzyme-catalysed steps to construct complex molecules with high stereocontrol.

Enantioselectivity: Preference for the formation of one mirror-image form (enantiomer) over the other in a chiral synthesis.

Cross-coupling reaction: Metal-catalysed joining of two molecular fragments to form a new carbon–carbon bond.

Diels–Alder reaction: Cycloaddition between a conjugated diene and a dienophile to generate a six-membered ring with defined stereochemistry.

Organocatalysis: Acceleration of chemical transformations by small organic molecules rather than metal-based catalysts or enzymes.

Olefin metathesis: Exchange of alkene fragments via breaking and reforming of carbon–carbon double bonds, typically catalysed by metal carbenes.

References

1. A concise and scalable chemoenzymatic synthesis of prostaglandins. Nature Communications (2024).
2. De Novo Synthesis of Dihydrobenzofurans and Indolines and Its Application to a Modular, Asymmetric Synthesis of Beraprost. Journal of the American Chemical Society (2023).
3. Organocatalyst-mediated, pot-economical total synthesis of latanoprost. Chemical Science (2023).
4. A General Catalyst Controlled Route to Prostaglandin F2α. Organic Letters (2022).