Mechanisms and Synthetic Applications of Cyclic, Nonstabilized Isodiazenes: Nitrogen-Atom Insertion into Pyrrolidines and Related Rearrangements.

Reactive intermediates that can promote nonintuitive bond disconnections underpin advancements in skeletal editing methodologies. Accordingly, a detailed understanding of their reactivity and its underlying mechanisms is central to progress in this space. Herein, we catalog and study the reactivity of nonstabilized cyclic isodiazene intermediates generated via the reaction of cyclic secondary amines with an anomeric amide reagent.

Bridging the pyridine-pyridazine synthesis gap by skeletal editing.

Pairs of heterocycles differing by a single constitutive ring atom can exhibit stark differences in the retrosynthetic disconnections available for their preparation. Such a synthesis gap is exemplified by pyridine and pyridazine. Pyridine (a six-membered CN ring) has risen to prominence in discovery chemistry, its ease of assembly spurring further synthetic development.

Accessing sulfonamides via formal SO insertion into C-N bonds.

Functional group interconversions are particularly sought after by medicinal chemists as a means to enable both lead optimization and library diversification. Here we report SO insertion into the C-N bond of primary amines, enabling the direct synthesis of primary sulfonamides without preactivation and effectively inverting the nitrogen's properties (acidity, hydrogen bonding and so on). The key to this transformation is the implementation of an anomeric amide as a dual-function reagent that both serves to cleave the initial C-N bond and delivers a nitrogen atom to the product after SO incorporation.

Regioretention Probes Distinguish Ring Scission Mechanisms in Nitrogen Insertion Reactions.

Atom insertion reactions into ring systems may occur via one of two pathways, proceeding either through initial cyclization to form a 3-membered ring intermediate followed by cleavage of the ring-fusion bond, or through initial ring-scission followed by recyclization onto the inserting atom. Herein, we demonstrate the use of regioretention probes, substrates with latent symmetry that is unveiled only in the case of ring scission and are thus able to distinguish between possible mechanisms for atom insertion. We apply these probes to a handful of previously reported nitrogen insertion methods and in each case unambiguously establish whether the reaction proceeds through aziridination or C=C cleavage.

Carbon-Atom Scavengers Enable Divergent, Selective Carbon Deletion of Azaarenes.

Divergent synthesis is a powerful strategy that provides simultaneous access to multiple derivatives of a given substrate. However, the emerging developments in skeletal editing have largely delivered methods that lack this potential for diversification. Herein, we report the serendipitous discovery of reagent-controlled selective deletion of C3 or C2 carbon atoms of quinolines, affording indoles.

Strategic atom replacement enables regiocontrol in pyrazole alkylation.

Pyrazoles are heterocycles commonly found as key substructures in agrochemicals and medicinally active compounds alike. Despite their pervasiveness, established methods fall notably short in delivering complex pyrazoles selectively due to issues of differentiation during either assembly or N-functionalization. This is a direct consequence of a dominant synthetic strategy that attempts to control selectivity-determining bonds between poorly differentiated starting materials.

Redox-Tunable Ring Expansion Enabled By A Single-Component Electrophilic Nitrogen Atom Synthon.

Controllable installation of a single nitrogen atom is central to many major goals in skeletal editing, with progress often gated by the availability of an appropriate N-atom source. Here we introduce a novel reagent, termed DNIBX, based on dibenzoazabicycloheptadiene (dbabh), which allows the electrophilic installation of dbabh to organic substrates. When indanone β-ketoesters are aminated by DNIBX, the resulting products undergo divergent ring expansions depending on the mode of activation, producing heterocycles in differing oxidation states under thermal and photochemical conditions.

Retrosynthetic Simplicity.

Retrosynthetic simplicity is introduced as a metric by which methods can be evaluated. An argument in favor of reactions which are retrosynthetically simple is put forward, and recent examples in the context of skeletal editing from my own laboratory as well as contributions from others are analyzed critically through this lens.

Gastrointestinal manifestations in Williams syndrome: A prospective analysis of an adult and pediatric cohort.

Williams syndrome (WS) is a multi-system condition caused by the deletion of 25-27 coding genes on human chromosome 7. Irritability, gastrointestinal (GI) reflux and slow growth are commonly reported in infants with WS, but less data exist regarding GI concerns in older children and adults with the condition. This study evaluates 62 individuals with WS (31 children aged 3-17, and 31 adults aged 18-62) as well as 36 pediatric and adult controls to assess current and historical rates of common GI symptoms.

Increased heart rate fragmentation in those with Williams-Beuren syndrome suggests nonautonomic mechanistic contributors to sudden death risk.

Williams-Beuren syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multisystem disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis (SVAS).

Evidence for Dearomatizing Spirocyclization and Dynamic Effects in the Quasi-stereospecific Nitrogen Deletion of Tetrahydroisoquinolines.

Selectivity in organic chemistry is generally presumed to arise from energy differences between competing selectivity-determining transition states. However, in cases where static density functional theory (DFT) fails to reproduce experimental product distributions, dynamic effects can be examined to understand the behavior of more complex reaction systems. Previously, we reported a method for nitrogen deletion of secondary amines which relies on the formation of isodiazene intermediates that subsequently extrude dinitrogen with concomitant C-C bond formation via a caged diradical.

Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams-Beuren Syndrome.

Background: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity.

Carbon-to-nitrogen single-atom transmutation of azaarenes.

When searching for the ideal molecule to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom. Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines, but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis. Here, we report a transformation that enables the direct conversion of a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines.

Loss of Baz1b in mice causes perinatal lethality, growth failure, and variable multi-system outcomes.

BAZ1B is one of 25-27 coding genes deleted in canonical Williams syndrome, a multi-system disorder causing slow growth, vascular stenosis, and gastrointestinal complaints, including constipation. BAZ1B is involved in (among other processes) chromatin organization, DNA damage repair, and mitosis, suggesting reduced BAZ1B may contribute to Williams syndrome symptoms. In mice, loss of Baz1b causes early neonatal death.

Aromatic nitrogen scanning by -selective nitrene internalization.

Nitrogen scanning in aryl fragments is a valuable aspect of the drug discovery process, but current strategies require time-intensive, parallel, bottom-up synthesis of each pyridyl isomer because of a lack of direct carbon-to-nitrogen (C-to-N) replacement reactions. We report a site-directable aryl C-to-N replacement reaction allowing unified access to various pyridine isomers through a nitrene-internalization process. In a two-step, one-pot procedure, aryl azides are first photochemically converted to 3-azepines, which then undergo an oxidatively triggered C2-selective cheletropic carbon extrusion through a spirocyclic azanorcaradiene intermediate to afford the pyridine products.

Core-Labeling (Radio) Synthesis of Phenols.

We report a method that enables the fast incorporation of carbon isotopes into the carbon of phenols. Our approach relies on the synthesis of a 1,5-dibromo-1,4-pentadiene precursor, which upon lithium-halogen exchange followed by treatment with carbonate esters results in a formal [5 + 1] cyclization to form the phenol product. Using this strategy, we have prepared 12 1-C-labeled phenols, show proof-of-concept for the labeling of phenols with carbon-14, and demonstrate phenol synthesis directly from cyclotron-produced [C]CO.

A focus on 1-azahomocubane: the new kid on the block.

Strained hydrocarbons have recently regained interest as potential drug candidates. However, the study of their heteroatom analogs has remained limited, despite differing by only a single atom. The first synthesis of 1-azahomocubane by Williams, Eaton and co-workers (T.

Heart Rate Variability Analysis May Identify Individuals With Williams-Beuren Syndrome at Risk of Sudden Death.

Background: Williams-Beuren syndrome (WBS) (Online Mendelian Inheritance in Man #194050) is a rare genetic multisystem disorder resulting from a chromosomal microdeletion at 7q11.23. The condition is characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis.

Direct Deaminative Functionalization.

Selective functional group interconversions in complex molecular settings underpin many of the challenges facing modern organic synthesis. Currently, a privileged subset of functional groups dominates this landscape, while others, despite their abundance, are sorely underdeveloped. Amines epitomize this dichotomy; they are abundant but otherwise intransigent toward direct interconversion.

Unified Access to Pyrimidines and Quinazolines Enabled by N-N Cleaving Carbon Atom Insertion.

Given the ubiquity of heterocycles in biologically active molecules, transformations with the capacity to modify such molecular skeletons with modularity remain highly desirable. Ring expansions that enable interconversion of privileged heterocyclic motifs are especially interesting in this regard. As such, the known mechanisms for ring expansion and contraction determine the classes of heterocycle amenable to skeletal editing.

A Synthetic Cycle for Heteroarene Synthesis by Nitride Insertion.

Recent interest in skeletal editing necessitates the continued development of reagent classes with the ability to transfer single atoms. Terminal transition metal nitrides hold immense promise for single-atom transfer, though their use in organic synthesis has so far been limited. Here we demonstrate a synthetic cycle with associated detailed mechanistic studies that primes the development of terminal transition metal nitrides as valuable single-atom transfer reagents.

Single-atom logic for heterocycle editing.

Medicinal chemistry continues to be impacted by new synthetic methods. Particularly sought after, especially at the drug discovery stage, is the ability to enact the desired chemical transformations in a concise and chemospecific fashion. To this end, the field of organic synthesis has become captivated by the idea of 'molecular editing'-to rapidly build onto, change or prune molecules one atom at a time using transformations that are mild and selective enough to be employed at the late stages of a synthetic sequence.