How is retinol produced?

The retinol derives its name from the word "retina", due to the role it plays in vision, particularly night vision. Interestingly, in the past, Egyptians used to apply beef liver compresses, which contain retinol, to the eyes of the blind in an attempt to cure blindness. This, of course, has not been scientifically proven. Since the 20th century, retinol and retinoids in general have been used in dermatology to reduce acne, thanks to their action on cell renewal.

Later, the retinol became a staple in skincare for combating signs of ageing. In addition to its effect on epidermal renewal, it has the ability to stimulate the production of collagen and elastin by fibroblasts, thus contributing to achieving smoother, firmer, and more elastic skin. Moreover, retinol is recognised for its antioxidant properties, useful for preventing photoageing, as well as for its regulatory action on melanogenesis, helping to reduce the appearance of brown spots that can appear with age.

Retinol can be derived from a 100% chemical reaction or biosynthesis, detailed below.

Retinol can be obtained through chemical synthesis. This method is widely used in the pharmaceutical and skincare industry as it allows for the production of large quantities of retinol with high purity and controlled cost. It's worth noting that retinol is an unstable molecule that is sensitive to oxygen, light, and heat. Therefore, its synthesis requires specific conditions, including an inert atmosphere (nitrogen or argon) and a low temperature to prevent its degradation. Several industrial processes have been described in scientific literature. Despite variations, the synthesis methods share a common initial step: the production of β-ionone, a key precursor.

1. Synthesis of β-ionone : The β-ionone (C13H20O) is a natural terpene ketone found in certain plants. It is responsible for the floral violet aromas in wines and is the most common chemical starting point for synthesising retinol. Industrially, it is obtained by condensing acetone with isobutene, followed by cyclisation and oxidation stages.

2. Conversion of β-ionone into retinol : The β-ionone must then be transformed to extend its carbon chain and introduce the polyenic system, that is, the alternation of double bonds, characteristic of retinol. There are three main methods for this: the Grignard reaction, the Julia reaction, or the Wittig reaction.

   • The Grignard reaction: β-Ionone is reacted with a propargyl halide, such as a bromide, in the presence of zinc or a magnesium/mercury amalgam. This step generates an alkyne intermediate via a Grignard reaction, which is usually protected by an acetal to avoid side reactions. The resulting alkyne is then reduced by catalytic hydrogenation using palladium on carbon or Raney nickel, forming a saturated carbon chain.

   • The Julia reaction: This process is based on the alkylation of a sulfone, enabling the formation of double bonds in a desired configuration. Stereoselectivity is a critical parameter here, as retinol has 16 theoretical stereoisomers, but only one configuration is biologically active.

   • The Wittig reaction: This pathway involves a phosphorus ylide, allowing the formation of a carbon-carbon bond between β-ionone and a polyene fragment. This reaction is known for its ability to form double bonds with relatively good control.