Ring-Closing Metathesis in Pharmaceutical Development: Fundamentals, Applications, and Future Directions

Abstract

Ring-closing metathesis (RCM) has become indispensable in organic synthesis for both academic investigations and industrial applications. This review provides an overview of RCM reactions, focusing on the practical aspects that researchers in an industrial environment may find of interest. Key elements of reaction design and lessons learned from these applications are discussed to help those considering implementing RCM reactions on scale, particularly in manufacturing active pharmaceutical ingredients (APIs). Advances in the development of more effective catalysts and new methodologies, such as enantioselective RCM and stereoselective macrocyclic RCM, are also briefly discussed.

4‐Methyltetrahydropyran (4‐MeTHP): Application as an Organic Reaction Solvent

“…The last example is the ring‐closing metathesis (RCM) of diene 38 , giving the cyclized product 39 in 92 % yield. RCM has now become one of the most applicable methods for providing various carbocycles and heterocycles, and it is widely used in pharmaceutical development, but normally in DCM or toluene. Although the generality remains to be confirmed, the example shown in Equation (8) indicates the applicability of 4‐MeTHP in RCM chemistry.…”

“…T oo ur knowledge, these condensation reactions are usually carriedo ut in halogenatedo r aproticp olar solventp robably duet oh igh solubility of organic salt intermediates.T he last example is the ring-closing metathesis (RCM) [62] of diene 38,g iving the cyclized product 39 in 92 %y ield. RCM has now become one of the most applicable methods for providing variousc arbocycles and heterocycles, and it is widely used in pharmaceutical development, [63] but normally in DCM or toluene. Althought he generality remains to be confirmed, the example shown in Equation (8)…”

Synthesis, Profiling, and Bioactive Conformation of trans‐Cyclopropyl Epothilones

“…Heating of 11a/11b in toluene in the presence of Grubbs II catalyst (for reviews see refs. [29,30] ) then led to smooth conversion into protected macrolactones 12a and 12b, both of which were obtained in yields > 90 %; as for the ringclosure reaction of the corresponding diene intermediate in the synthesis of dimethylbenzimidazole-based analog 1-BT, the (E) olefin was the only detectable cyclization product in both cases. Highly (E)-selective ring-closing olefin metathesis (RCM)-mediated macrocyclizations at the C(9)À C(10) site have also been reported for other epothilone-related macrocycles.…”

“…These considerations led us to explore two strategies towards the synthesis of aldehyde 14 that would include the establishment of the C(10)-C(11) connection either in the cyclization step or as part of the building block assembly process (Scheme 3) (rather than being included in the building block synthesis as for 9a/9b). In the former scenario, the site for a ringclosing metathesis reaction [29,30] is shifted by one bond (compared to our previous synthesis of analogs 1), thus leading to diene 15 as the RCM substrate. Ideally, the cyclization product should then be converted into 14 through concomitant reduction of the newly formed double bond and cleavage of the benzyl ether moiety; alternatively, if the reductive conditions required for these simultaneous transformations would not be compatible with the presence of the cyclo-propane ring, these steps would be carried out separately.…”

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

“…Alkene and alkyne metathesis [1][2][3][4], constituting highly versatile and powerful catalytic processes for constructing complex organic molecules [5][6][7][8][9][10][11][12], have found broad application in the fields of pharmaceutical synthesis [13][14][15], materials science [16][17][18][19][20], or in advanced techniques and technologies [21][22][23][24][25][26][27][28][29][30]. Thus, numerous multistep total syntheses of organic compounds, including bioactive molecules [31][32][33][34][35] and natural products [36,37], have been performed in a highly chemo-and stereoselective manner through metathesis routes [38][39][40][41][42][43].…”