First isolated in the early 20th century, protolichesterinic acid has drawn scientific interest due to its diverse biological activities, including antimicrobial, antifungal, and anti-inflammatory properties.

Protolichesterinic acid is typically extracted from lichens such as Cetraria islandica using advanced chromatographic techniques and has been studied for its role in both natural product chemistry and pharmacology.

[1] Later work by Asano and Asahina established that natural protolichesterinic acid actually has a negative specific rotation ([α]D = −12.71°), indicating it is the (−)-(2S,3R) enantiomer, while the material studied by Zopf and Böhme was the (+)-(2R,3S) form.

Final purification employs centrifugal partition chromatography using a solvent system of n-heptane, ethyl acetate, and acetonitrile, achieving over 99% purity with yields exceeding 65%.

The method's reliability is confirmed by its high precision (0.78% relative standard deviation) and good recovery rate (90%), making it suitable for accurate determination of protolichesterinic acid content in biological samples.

It shows strong antibacterial effects against Klebsiella pneumoniae (minimum inhibitory concentration 0.25 μg/mL) and Vibrio cholerae (0.5 μg/mL), exceeding the potency of ciprofloxacin.

Structure-activity studies indicate that while the stereospecific side chain and exocyclic double bond are not essential for activity, the carboxylic acid group plays a crucial role.

[9] Research has revealed that protolichesterinic acid affects cancer cell metabolism by disrupting mitochondrial function through inhibition of oxidative phosphorylation and enhancement of glycolysis.

[10] Early biosynthesis studies in Cetraria islandica showed that protolichesterinic acid is produced in very small quantities (approximately 0.1%) in the whole lichen.

The extremely low levels of incorporation (approximately 0.004%) suggested that protolichesterinic acid biosynthesis represents a very minor metabolic pathway in C. islandica.

[12] A variety of synthetic approaches have progressively improved the efficiency and stereoselectivity of protolichesterinic acid synthesis while developing new methodologies for constructing similar lactone-containing natural products.

Their method employed bis(cyclopentadienyl)titanium(III) chloride to effect radical cyclization, forming key tetrahydrofuran intermediates.

The four-step sequence involved epoxide cyclization, protection, lactone formation, and Jones oxidation, achieving an 80% yield in the final step.

[16] In 2016, Fernandes and Nallasivam reported a protecting-group-free synthesis using palladium-catalysed Suzuki-Miyaura coupling to install a phenyl group as a masked carboxylic acid, followed by ruthenium-catalysed Sharpless epoxidation.