Concise synthesis of ()-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis

• Published in: Chemical science (Cambridge) 2023-09, Vol.14 (36), p.9863-9871
• Main Authors: Cigan, Emmanuel, Pletz, Jakob, Berger, Sarah A, Hierzberger, Bettina, Grilec-Zlamal, Michael, Steiner, Alexander, Oroz-Guinea, Isabel, Kroutil, Wolfgang
• Format: Article
• Language: English
• Subjects: Biomimetics; Chemistry; Organic chemistry; Reductases
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d3sc02304d

Efficient access to the morphinan scaffold remains a major challenge in both synthetic chemistry and biotechnology. Here, a biomimetic chemo-enzymatic strategy to synthesize the natural promorphinan intermediate (+)-salutaridine is demonstrated. By combining early-stage organic synthesis with enzymatic asymmetric key step transformations, the prochiral natural intermediate 1,2-dehydroreticuline was prepared and subsequently stereoselectively reduced by the enzyme 1,2-dehydroreticuline reductase obtaining ( R )-reticuline in high ee and yield (>99% ee, up to quant. conversion, 92% isol. yield). In the final step, membrane-bound salutaridine synthase was used to perform the selective ortho-para phenol coupling to give (+)-salutaridine. The synthetic route shows the potential of combining early-stage advanced organic chemistry to minimize protecting group techniques with late-stage multi-step biocatalysis to provide an unprecedented access to the medicinally important compound class of promorphinans. Designing an alternative access to the morphinan scaffold by taking advantage of biocatalysis for asymmetric C&z.dbd;N reduction and oxidative C-C bond formation.