Diversification of Simple Arenes into Complex (Amino)cyclitols.

Highly oxygenated cyclohexanes, including (amino)cyclitols, are featured in natural products possessing a notable range of biological activities. As such, these building blocks are valuable tools for medicinal chemistry. While de novo synthetic strategies have provided access to select compounds, challenges including stereochemical density and complexity have hindered the development of a general approach to (amino)cyclitol structures. This work reports the use of arenophile chemistry to access dearomatized intermediates which are amenable to diverse downstream transformations. Practical guidelines were developed for the synthesis of natural and non-natural (amino)cyclitols from simple arenes through a series of strategic functionalization events.

Total Synthesis and Computational Investigations of Sesquiterpene-Tropolones Ameliorate Stereochemical Inconsistencies and Resolve an Ambiguous Biosynthetic Relationship.

The sesquiterpene-tropolones belong to a distinctive structural class of meroterpene natural products with impressive biological activities, including anticancer, antifungal, antimalarial, and antibacterial. In this article, we describe a concise, modular, and cycloaddition-based approach to a series of sesquiterpene mono- and bistropolones, including (-)-epolone B, (+)-isoepolone B, (±)-dehydroxypycnidione, and (-)-10-epi-pycnidione. Alongside the development of a general strategy to access this unique family of metabolites were computational modeling studies that justified the diastereoselectivity observed during key cycloadditions. Ultimately, these studies prompted stereochemical reassignments of the pycnidione subclass and shed additional light on the biosynthesis of these remarkable natural products.

Enantioselective polyene cyclizations.

The cyclization of polyolefins represents a powerful tool for the rapid generation of molecular complexity. Within the last decade, significant discoveries have been made in the development of methods for converting prochiral polyene substrates into the corresponding polycyclic products with high levels of enantiocontrol. This review highlights advances in the area of enantioselective polyene cyclizations and their use in the synthesis of complex secondary metabolites.

Reactivity and Selectivity of Azaspirocycles in Radical C-H Functionalization.

Investigations of saturated spirocycles toward selective C-H functionalization reactions are scarce, despite their potential applications. In this work, we uncovered fundamental reactivity and selectivity differences between saturated heterocycles and their spirocyclic analogues using a model radical C-H xanthylation coupled with computational analysis. Ultimately, this study sheds light on the fundamental, understudied radical reactivity of spirocycles, thereby allowing for a pronounced chemical tunability that will prove to be advantageous in the expansion of their chemical space and applications in medicinal chemistry.

Synthesis of (+)-ribostamycin by catalytic, enantioselective hydroamination of benzene.

Aminoglycosides (AGs) represent a large group of pseudoglycoside natural products, in which several different sugar moieties are harnessed to an aminocyclitol core. AGs constitute a major class of antibiotics that target the prokaryotic ribosome of many problematic pathogens. Hundreds of AGs have been isolated to date, with 1,3-diaminocyclohexanetriol, known as 2-deoxystreptamine (2-DOS), being the most abundant aglycon core. However, owning to their diverse and complex architecture, all AG-based drugs are either natural substances or analogues prepared by late-stage modifications. Synthetic approaches to AGs are rare and lengthy; most studies involve semi-synthetic reunion of modified fragments. Here we report a bottom-up chemical synthesis of the 2-DOS-based AG antibiotic ribostamycin, which proceeds in ten linear operations from benzene. A key enabling transformation involves a Cu-catalyzed, enantioselective, dearomative hydroamination, which set the stage for the rapid and selective introduction of the remaining 2-DOS heteroatom functionality. This work demonstrates how the combination of a tailored, dearomative logic and strategic use of subsequent olefin functionalizations can provide practical and concise access to the AG class of compounds.

Development of a Scalable and Sublimation-Free Route to MTAD.

The cyclic azodicarbonyl 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) is a versatile and powerful reagent used mainly in cycloaddition chemistry. Though known for more than 50 years, its unsafe preparation, as well as purification by sublimation, hampered its widespread applicability on a larger scale. Herein we report a scalable and safe route to MTAD, which avoids the generation of methyl isocyanate. Moreover, we demonstrate that sublimation can be circumvented by the application of judicious oxidation conditions, followed by simple filtration. Overall, up to 25 g of MTAD was prepared in a single batch from commercial starting materials in three steps, with recrystallization serving as the only purification in the sequence. When employed in dearomative methodologies, the MTAD obtained by this protocol displayed synthetic efficiency equivalent to that of MTAD purified by sublimation.