Water–Organic Interfaces Drive Molecular Evolution from Squalene to Steroids

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Abstract
In living cells, the conversion of squalene to lanosterol requires two dedicated enzymes and proceeds through 2,3-oxidosqualene as an essential intermediate. We show that water microdroplets contacting immiscible organic solvents accomplish this same multistep transformation without enzymatic catalysis. We propose that the oriented electric field across the water–organic interface generates reactive oxygen species that epoxidize squalene and then initiates acid-catalyzed ring-opening of the epoxide followed by a cationic polyene cyclization cascade to yield lanosterol. H218O labeling traced oxygen from water into TEMPO-derived and peroxyacetate ions observed by real-time mass spectrometry. LC–HRMS/MS further revealed C18–C30 reaction products with spectral matches to oxygenated terpenoid and steroid-like structures. We find that ethyl acetate is the most effective organic solvent because it generates peroxyacetic acid at the interface. Simulations show that a preformed protonated 2,3-oxidosqualene model remains hydrated and oriented after placement at the ethyl acetate–water interface, and calculations on microsolvation models indicate that an interfacial water configuration preferentially stabilizes the epoxidation transition state relative to the reactant by approximately 3 kcal mol–1. These results establish a plausible, abiotic pathway for steroid emergence and diversification at water–organic interfaces.
Funding Information
  • Division of Chemistry (CHE-2203609)
  • Air Force Office of Scientific Research (AFOSR FA9550-21-1-0170)

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