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A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-d-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with l-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.

The research, development, and scale-up of the broad-spectrum antibacterial candidate sulopenem are presented. An enabled medicinal chemistry synthesis of this active pharmaceutical ingredient was utilized for Phase 1 and early Phase 2 manufacture but was not conducive to larger scale. The limitations associated with the first-generation synthesis were partially addressed in an improved second-generation synthesis of the target molecule where the penem ring is constructed via a modified Eschenmoser sulfide contraction sequence. Other highlights of the second-generation process include an improved synthesis of an important trithiocarbonate intermediate and a superior process for Pd-catalyzed deallylation of the penultimate ester to obtain low levels of residual palladium.

Previous synthetic processes for the preparation of sulopenem involved multistep linear sequences in which the chiral sulfoxide side chain was introduced early in the process. This contribution summarizes the development of a practical and convergent process for the large-scale preparation of 1. The key step in the synthesis involves cyclization of an oxalimide intermediate to provide the thiopenem core. This convergent strategy allows for late introduction of the expensive and labile chiral sulfoxide subunit. Additionally, a regioselective sulfur oxidation and an improved deprotection sequence were developed. The latter provides API of high purity without the need for recrystallization.

The intermolecular Friedel–Crafts acylation of electron-rich aromatic rings can be difficult in the presence of easily ionized groups. During these studies directed toward the synthesis of colchicine, it was observed that the stability of the cation is key to controlling alternative competing processes.

Stereospecific [2,3]-Sigmatropic rearrangements occurring via ylides generated from the decomposition of α-diazoamides provided good yields of substituted azabicyclo[3.3.0]octanes. In addition some of the non-rearranged cyclopropanes were formed.

A novel approach to azacyclooctene and azacyclononene containing substrates has been achieved via the intermediacy of a spirocyclic ammonium ylide derived from the diazodecomposition of a tethered α-diazoester moiety.

The intermolecular Friedel–Crafts acylation of electron-rich aromatic rings can be difficult in the presence of easily ionized groups. During these studies directed toward the synthesis of colchicine, it was observed that the stability of the cation is key to controlling alternative competing processes.