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

Emmanuel Cigan; Jakob Pletz; Sarah A Berger; Bettina Hierzberger; Michael Grilec-Zlamal; Alexander Steiner; Isabel Oroz-Guinea; Wolfgang Kroutil

doi:10.1039/d3sc02304d

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

Chem Sci. 2023 Aug 24;14(36):9863-9871. doi: 10.1039/d3sc02304d. eCollection 2023 Sep 20.

Authors

Emmanuel Cigan¹, Jakob Pletz¹, Sarah A Berger¹, Bettina Hierzberger¹, Michael Grilec-Zlamal¹, Alexander Steiner¹, Isabel Oroz-Guinea¹, Wolfgang Kroutil^{1

2}

Affiliations

¹ Institute of Chemistry, University of Graz, NAWI Graz, BioTechMed Graz Heinrichstrasse 28/II 8010 Graz Austria Wolfgang.Kroutil@uni-graz.at.
² Field of Excellence BioHealth, University of Graz 8010 Graz Austria.

Abstract

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.