The first biomimetic enantioselective total synthesis of (−)-communesin F based on a late-stage heterodimerization and aminal exchange is described. Our synthesis features the expedient diazene–directed assembly of two advanced fragments to secure the congested C3a–C3a′ linkage in three steps, followed by a highly efficient biogenetically inspired aminal reorganization to access the heptacyclic communesin core in only two additional steps. Enantioselective syntheses of the two fragments were developed, with highlights including the catalytic asymmetric halocyclization and diastereoselective oxyamination reactions of tryptamine derivatives, a stereoselective sulfinimine allylation, and an efficient cyclotryptamine–C3a-sulfamate synthesis by either a new silver–promoted nucleophilic amination or a rhodium–catalyzed C–H amination protocol. The versatile synthesis of the fragments, their stereocontrolled assembly, and the efficient aminal–exchange as supported by in situ monitoring experiments, in addition to the final stage N1′-acylation of the communesin core provide a highly convergent synthesis of (−)-communesin F.

This manuscript describes the chemical process development and multi-kilogram synthesis of rovafovir etalafenamide (GS-9131), a phosphonamidate prodrug nucleotide reverse transcriptase inhibitor under investigation for the treatment of HIV-1 infection. Rovafovir etalafenamide is assembled in a four-step sequence beginning from the nucleoside core and an elaborated phosphonamidate alcohol. The assembly starts with a decarboxylative elimination of a β-hydroxyacid to yield the corresponding cyclic enol ether, which is subsequently coupled to a functionalized phosphonamidate alcohol in an iodoetherification reaction. Oxidative syn elimination then installs the required fluoroalkene, after which a final deprotection reaction yields the active pharmaceutical ingredient (API). Understanding the genesis, fate, and purge of the des-fluoro analog of the API, a mitochondrial toxin, proved to be a central driver in the development of the manufacturing route and impurity control strategy. Initial control strategies revolved around the use of silica gel chromatography or simulated moving bed chromatography to purge the des-fluoro impurity to an acceptable level, but ultimately a chromatography-free approach to mitigate the formation of this impurity was devised that expanded manufacturing flexibility. Design of experiments was used to improve the iodoetherification fragment coupling reaction and to reduce the level of the des-fluoro impurity formed in this step. Furthermore, several new crystalline intermediate forms were discovered and implemented as isolation points to bolster the overall impurity control strategy for standard, diastereomeric, and potentially mutagenic impurities as well as for the des-fluoro impurity. These processes were executed on multikilogram scale to produce API for clinical studies.

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