Plenary Session, Award lecture
PS-005

Catalysis as Key Enabler for the Stereoselective Synthesis of GDC-6599

K. Püntener1, J. C. Timmerman2, A. Y. Hong2, A. Glass1, F. Gosselin2, S. Hildbrand1
1Department of Process Chemistry & Catalysis, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland, 2Department of Synthetic Molecule Process Chemistry, Genentech, Inc., South San Francisco, CA 94080, United States

     This presentation provides insight into the impact of catalysis as a key enabler for the stereoselective synthesis of Genentech’s orally bioavailable, potent, and highly selective TRPA1 inhibitor GDC-6599 (1)1 -  predicted to decrease neurogenic inflammation, airway smooth muscle contraction, and sensory hypersensitivity.
     We highlight the challenges encountered with the Discovery Chemistry route, where early-step enzymatic KRED transformations delivered the trans-triol building block 2 with high enantio- and diastereoselectivity in four steps but contributed to an overall low-yield (2.5%), multi-step process. This was compounded by safety hazards from first-generation nucleophilic cyanation yielding intermediate 3 and poor selectivities in the final SN reaction. Process research activities tackled these issues by comparing two distinct, highly efficient catalytic routes developed to access the drug substance key building block N-hydroxyamidine intermediate 42-5. For an efficient synthesis thereof, a new process was designed to obviate the safety hazards of nucleophilic cyanation. This new 5-step route towards 4 leverages an enantioselective Pd-catalyzed Hayashi-Heck arylation followed by a stereo- and regioselective Rh-catalyzed hydroformylation to establish the key stereochemical dyad of the tetrahydrofuran core. The optimized sequence proceeds in 38% overall yield and provides robust impurity control. With this second-generation process at hand, 8 kg of 1 have been produced with greatly reduced PMI and >10-fold increaded overall yield to support clinical phase 2 studies.
     The second methodology led - together with great improvements achieved on the cyanation step -  to a third-generation process, which involves the asymmetric hydrogenation of 4-(4-chlorophenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester to optically pure trans-triol building block 2 in a one-pot, consecutive sequence. This short-cut to 3, offered a highly efficient, low-cost alternative to the original KRED route. The employed rationally designed dual-catalyst system - comprising Ir/(S)-SpiroPAP as lead catalyst and Ir/(R,R)-MsDPEN as assistant catalyst - led to higher diastereoselectivity (18:1 trans/cis) and higher yield (77%) for 2 than the lead catalyst employed in single-use mode (8:1 trans/cis, 71% yield). For further cost reduction, novel lead catalysts bearing new, readily accessible BINAN/MeOBIPHAN ligands were designed and extensively characterized, furnishing the product in comparable quality, highest yield (81%), and lowest possible cost. To the best of our knowledge, this represents the first known utilization of such a dual catalytic system in the stereoselective synthesis of a pharmaceutical intermediate.

1) a) J.A. Terret et al., J. Med. Chem. 2021, 64 (7), 3843. b) J.A. Terrett et al., J. Med. Chem. 2024, 67 (5), 3287.
2) J.J. Dotson, L. Dijk, J.C. Timmerman, S. Grosslight, R.C. Walroth, F. Gosselin, K. Püntener, K.A. Mack, M.S. Sigman, J. Am. Chem. Soc. 2023, 145, 110.
3) A.Y. Hong, K.A. Piechowicz, J.C. Timmerman, H. Zhang, C. Molinaro, F. Gosselin, Org. Process Res. Dev. 2024, 28 (6), 2325.
4) K. Püntener, A.L. Glass, L. Tensi, B. Chen, K.A. Piechowicz, M. Binder, S. Chin, A.Y. Hong, A. Macchioni, S. Hildbrand. J. Am. Chem. Soc. 2025, 147, 43041.
5) J.C. Timmerman,  A.Y. Hong, K. Piechowicz, K. Püntener, A.L. Glass, S. Tonazzi, M. Guillemot-Plass, J. Napolitano, B. Conklin, H. Zhang, F. Gosselin. Org. Process  Res. Dev. 2026 – accepted for publication.