Development of a Crystallization-Induced Diastereomer Transformation of Oxime Isomers for the Asymmetric Synthesis of (1S,6R)-3,9-Diazabicyclo[4.2.1]nonane.

Herein we report a practical crystallization-induced diastereomer transformation (CIDT) of oxime isomers for the scalable asymmetric synthesis of the bicyclic diamine (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative that serves as a valuable building block in medicinal chemistry. The developed approach utilizes (S)-phenylethylamine as a chiral auxiliary handle for CIDT, and the starting nortropinone derivative is prepared in one step from commercially available materials. The resulting E-oxime is subjected to a stereospecific Beckmann rearrangement, followed by reduction of the resulting lactam with LiAlH4 to afford the monoprotected (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative. The development of the CIDT and understanding of the mechanistic implications leading to the high selectivity are reported.

Highly Selective Hydrogenation of C═C Bonds Catalyzed by a Rhodium Hydride.

Under mild conditions (room temperature, 80 psi of H2) Cp*Rh(2-(2-pyridyl)phenyl)H catalyzes the selective hydrogenation of the C═C bond in α,ß-unsaturated carbonyl compounds, including natural product precursors with bulky substituents in the ß position and substrates possessing an array of additional functional groups. It also catalyzes the hydrogenation of many isolated double bonds. Mechanistic studies reveal that no radical intermediates are involved, and the catalyst appears to be homogeneous, thereby affording important complementarity to existing protocols for similar hydrogenation processes.

The Development of Reaction Cascades to Synthesize Dimeric Coccinellid Alkaloids.

Over the course of the past decade, our group has been intensely interested in achieving the laboratory synthesis of varied members of the coccinellid alkaloid family of natural products. These compounds, produced by varied species of ladybugs throughout the world as defensive agents, include several polycyclic members that can formally be considered as either monomeric or dimeric with architectures that contain between 3 and 7 ring systems along with an array of stereocenters. As a result of their fascinating structures, many groups have achieved syntheses of varied monomeric members using a variety of synthetic strategies and tactics. However, no efforts to synthesize any of the dimeric structures had been reported at the time we began our studies, and only a modest amount of study had been performed as relates to their biosynthesis, with little knowledge of how the larger structures might actually arise in Nature. In this Account, we provide an overview of our general synthetic considerations to achieve a global synthesis of the collection, efforts that have led to date to the formal and total synthesis of 12 different members, 4 at the dimer level. Critical was (1) the identification of a key, common intermediate to enable access to a large number of monomeric substructures in short order, (2) careful thinking as to how the larger structures might arise biosynthetically to fuel building block design, and (3) the development of several reaction cascades that rapidly assembled the majority of their molecular complexity in single-pot operations. Key discoveries in the program include the finding that when efforts to achieve intermolecular dimerizations fail with advanced intermediates, attempts to couple more functionalized fragments earlier and then fold them into the desired structure can be an effective strategy. We also highlight suggestive evidence that a non-natural isomer we originally prepared from one of those cascades may, in fact, be a natural product. And, in particular, we will focus on how two key cascades were developed, as a result of synthetic challenges at varied points in our explorations, which proved capable of forging multiple bonds, rings, and stereocenters in the target structures. One of these includes a designed event that combined 9 different chemical reactions in a single pot and may prove useful for the synthesis of other targets.

Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors.

The pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to expand. Papain-like protease (PLpro) is one of two SARS-CoV-2 proteases potentially targetable with antivirals. PLpro is an attractive target because it plays an essential role in cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex, and disruption of host responses. We report a substantive body of structural, biochemical, and virus replication studies that identify several inhibitors of the SARS-CoV-2 enzyme. We determined the high resolution structure of wild-type PLpro, the active site C111S mutant, and their complexes with inhibitors. This collection of structures details inhibitors recognition and interactions providing fundamental molecular and mechanistic insight into PLpro. All compounds inhibit the peptidase activity of PLpro in vitro, some block SARS-CoV-2 replication in cell culture assays. These findings will accelerate structure-based drug design efforts targeting PLpro to identify high-affinity inhibitors of clinical value.

A Concise, Enantiospecific Total Synthesis of Chilocorine C Fueled by a Reductive Cyclization/Mannich Reaction Cascade.

Among defensive alkaloids isolated from ladybugs, the heterodimeric member chilocorine C possesses an alluring monomeric unit that combines quinolizidine and indolizidine substructures. Indeed, the overall stereochemical disposition of its ring fusions is distinct from those of related natural products. Herein we show that a carefully orchestrated sequence with several chemoselective transformations, including a designed cascade that accomplishes nine distinct chemical reactions in one-pot, can smoothly forge that domain and ultimately enable a 15-step, 11-pot enantiospecific synthesis of the natural product. Mechanistic studies, density functional theory calculations, and the delineation of several other unsuccessful approaches highlight its unique elements.

Mannich-type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine-containing Alkaloids.

Even though there are dozens of biologically active 2-substituted and 2,6-disubstituted piperidines, only a limited number of approaches exist for their synthesis. Herein is described two Mannich-type additions to nitrones, one using ß-ketoacids under catalyst-free conditions and another using methyl ketones in the presence of chiral thioureas, which can generate a broad array of such 2-substituted materials, as well as other ring variants, in the form of ß-N-hydroxy-aminoketones. Both processes have broad scope, with the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods, along with other critical steps, has enabled 8-step total syntheses of the 2,6-disubstituted piperidine alkaloids (-)-lobeline and (-)-sedinone.

(1,2-Diaminoethane-1,2-diyl)bis(N-methylpyridinium) Salts as a Prospective Platform for Designing Recyclable Prolinamide-Based Organocatalysts.

A new efficient and highly recyclable organocatalyst has been developed for asymmetric cross-aldol reactions under neat conditions in ketone-ketone, ketone-aldehyde, and aldehyde-aldehyde systems. The catalyst features two prolinamide fragments and a C2-symmetrical (1,2-diaminoethane-1,2-diyl)bis(N-methylpyridinium) group. The catalyst retained high activity and excellent stereoselection over the operating period of more than 830 h (25 cycles). An ab initio theoretical investigation explained the absolute configuration of the products and different stereoinduction levels for designed diastereomeric organocatalysts.