The olefin metathesis reaction is finding increasing use in drug discovery and process chemistry, with a number of applications now implemented at commercial manufacturing scale. Catalyst improvements over the past decade have allowed use of the metathesis reaction with highly functionalized substrates, allowing chemists to access increasingly diverse chemical space, including most notably macrocycles, constrained small ring spirocycles, and fused-ring systems. For scientists employed in the pharmaceutical industry, the patent literature is the primary avenue for communication of synthetic routes to drug candidates. While most examples of the metathesis reaction in the patent literature offer only sketchy experimental details and provide little context on reaction development, the wide scope of substrates within the pharmaceutical patent literature provides a true indication of reaction scope and functional group compatibility. The current article reviews applications of the metathesis reactions in drug discovery and development in the pharmaceutical industry disclosed in the patent literature from January 2016 to August 2017.

N-heterocyclic carbenes are well known for their role in catalyzing benzoin and Stetter reactions: the generation of acyl anion equivalents from simple aldehydes to react with a variety of electrophiles. However, when an aldehyde bearing a leaving group or unsaturation adjacent to the acyl anion equivalent is subjected to an NHC, a new avenue of reactivity is unlocked, leading to a number of novel transformations which can generate highly complex products from simple starting materials, many of which are assembled through unconventional bond disconnections. The field of these new reactions - those utilizing α-reducible aldehydes to access previously unexplored catalytic intermediates – has expanded rapidly in the past eight years. This review aims to provide the reader with a historical perspective on the underlying discoveries that led to the current state of the art, a mechanistic description of these reactions, and a summary of the recent advances in this area.

To support the application of ruthenium-catalyzed olefin metathesis in drug development, we present a summary of the metal removal techniques employed in metathesis reactions intended for clinical or commercial API synthesis. Both extractive and adsorptive methods are discussed in the context of chemical process development leading to successful drug substance deliveries with sufficiently low residual ruthenium to meet regulatory specifications.

The scope of the NHC-redox amidation has been expanded to include a variety of α,β-unsaturated aldehydes, including α-fluoro α,β-unsaturated aldehydes which give rise to enantioenriched α-fluoroamides in good to excellent yield and enantioselectivity (up to 97% ee). Enantioenriched amines may be elaborated to either diastereomer of the product in high diastereoselectivity (up to 99:1). Functionalization of the amide products to amines and fluorohydrins is also demonstrated with retention of enantioenrichment at the fluorine stereocenter.

A practical synthesis of the phthalazine-based p38 MAP kinase inhibitor [(S)-2] was needed for an ongoing program. Vibrational circular dichroism provided the assignment of the absolute stereochemistry of the target compound. The selected synthetic route for (S)-2 required identification of efficient reaction conditions for the construction of carbon-oxygen, carbon-carbon, and carbon-nitrogen bonds to connect the key building blocks. An efficient two-step method (chlorodehydroxylation, aromatic nucleophilic substitution) for the synthesis of arylether [(S)-10] was developed. PAT (in situ Raman spectroscopy) was utilized to monitor and control the formation of a lithium alkoxide in this reaction. The synthesis of (S)-2 was completed using high-yielding Suzuki-and amide-coupling reactions. The isolation conditions for these steps were optimized to obtain material of very high purity without the need for any complicated workup procedures.