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Review
. 2025 Apr 11;90(14):4781-4795.
doi: 10.1021/acs.joc.4c02919. Epub 2025 Apr 1.

From Cortisone to Enlicitide: A Journey of Synthetic Chemistry Innovations at Merck

Louis-Charles Campeau  1
Affiliations
Review

From Cortisone to Enlicitide: A Journey of Synthetic Chemistry Innovations at Merck

Louis-Charles Campeau. J Org Chem. .

Abstract

Necessity is the mother of invention. Most synthetic chemistry innovations are driven by our desire to make molecules. In the first half of the 20th century, much of this work was inspired by natural products, but as we started to understand the impact that specific molecules could have on biology and human health, a new stimulus for invention appeared. The pharmaceutical industry first brought mass production and formulation of natural products for medicinal purposes but quickly started tinkering with molecular structure to modify compounds' properties, eventually designing molecules from scratch. This necessity for invention of new molecules to improve human health and to manufacture them on large scale is an excellent stimulus for synthetic chemistry innovations. In this Perspective, examples from Merck's chemistry groups are used to highlight the types of innovations that can arise from these endeavors.

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Conflict of interest statement

The author declares no competing financial interest.

Figures

Scheme 1
Scheme 1. Key Oxidations in the Total Synthesis of Cortisone
Scheme 2
Scheme 2. Initial Approach to Thienamycin Core (R = o-Nitrobenzyl)
Scheme 3
Scheme 3. Rh-Carbenoid N–H Insertion Approach to the Total Synthesis of Thienamycin (R = p-Nitrobenzyl)
Scheme 4
Scheme 4. Cinchonium Catalyzed Phase-Transfer Alkylation in the Synthesis of Indacrinone
Scheme 5
Scheme 5. Initial Approaches to Explore Trifluoroethyl Amine SAR
Scheme 6
Scheme 6. Diverse Approaches to Chiral Trifluoroethylamine Pharmacophore in Odanacatib
Scheme 7
Scheme 7. Diastereoselective Reductive Amination Approach to Odanacatib
Scheme 8
Scheme 8. Generations of F-Leucine Synthesis
Scheme 9
Scheme 9. Initial Approach to Sitagliptin via Mitsunobu Inversion
Scheme 10
Scheme 10. Novel Asymmetric Hydrogenation Approach to Sitagliptin
Scheme 11
Scheme 11. Transamination of Pro-Sitagliptin Ketone
Figure 1
Figure 1
Strategies for the synthesis of nucleoside analogues.
Scheme 12
Scheme 12. Original Route to Uprifosbuvir
Scheme 13
Scheme 13. Approach to 2′-Ketouridine and its Elaboration to 2′-Chloro-2′-Methyl Uridine
Scheme 14
Scheme 14. Design for a Dynamic Phosphorylation Strategy
Scheme 15
Scheme 15. Dimeric Chiral Imidazole Catalyst for Selective Synthesis of ProTide in Uprifosbuvir
Scheme 16
Scheme 16. Vorbrüggen-Type Glycosylation in the Synthesis of Islatravir
Scheme 17
Scheme 17. Retrosynthetic Proof-of-Concept for the Biocatalytic Glycosylation Reaction
Scheme 18
Scheme 18. Adapting the Nucleoside Salvage Pathway into a Biocatalytic Cascade in the Preparation of Islatravir
Scheme 19
Scheme 19. Synthesis of Islatravir via Biocatalytic Cascade
Scheme 20
Scheme 20. Initial Approach from Uridine to Molnupiravir
Scheme 21
Scheme 21. Novel Approach to Molnupiravir
Scheme 22
Scheme 22. Phosphate Recycling Approach to Biocatalytic Glycosylation in the Preparation of Molnupiravir
Figure 2
Figure 2
Evolution of PSCK9 chemical matter with a primary method of synthesis.
See this image and copyright information in PMC

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