Integrating Fermentation Engineering and Organopalladium Chemocatalysis for the Production of Squalene from Biomass-Derived Carbohydrates as the Starting Material

The transition from fossil resources to renewable biomass for the production of valuable chemicals and biobased fuels is a crucial step towards carbon neutrality. Squalene, a valuable chemical extensively used in the energy, healthcare, and pharmaceutical fields, has traditionally been isolated from the liver oils of deep-sea sharks and plant seed oils. In this study, a biochemical synergistic conversion strategy was designed and realized to convert glucose to squalene by combining fermentation technology in yeast with reductive coupling treatment of dienes. First, glucose derived from hydrolysis of cellulose was used as a renewable resource, using genetically engineeredSaccharomyces cerevisiaeas the initial biocatalyst to produce β-farnesene with a titer of 27.6 g/L in a 2.5 L bioreactor. Subsequently, intermediate β-farnesene was successfully converted to squalene through the organopalladium-catalyzed reductive coupling reaction involving the formation of Pd(0)L2species. Under mild reaction conditions, impressive β-farnesene conversion (99%) and squalene selectivity (100%) were achieved over the Pd(acac)2catalyst at a temperature of 75 °C in an ethanol solvent after 5 h. This advancement may provide insights into broadening squalene production channels and accessing the complex skeletons of natural terpenoids from biorenewable carbon sources, offering practical significance and economic benefits.Keywords:squalene;β-farnesene;fermentation technology;reductive coupling of dienes;Saccharomyces cerevisiae