Synthesis of Polycyclic Olefinic Monomers from Norbornadiene for Inverse Vulcanization: Structural and Mechanistic Consequences.

The preparation of high-sulfur content organosulfur polymers has generated considerable interest as an emerging area in polymer science that has been driven by advances in the inverse vulcanization polymerization of elemental sulfur with organic comonomers. While numerous new inverse vulcanized polysulfides have been made over the past decade, insights into the mechanism of inverse vulcanization and structural characterization of the high-sulfur-content copolymers remain limited in scope. Furthermore, the exploration of new molecular architectures for organic comonomer synthesis remains an important frontier to enhance the properties of these new polymeric materials.

An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013-2023).

This Perspective is a continuation of our analysis of U.S. FDA-approved small-molecule drugs (1938-2012) containing nitrogen heterocycles.

Dithiophosphoric Acids for Polymer Functionalization.

Dithiophosphoric acids (DTPAs) are an intriguing class of compounds that are sourced from elemental sulfur and white phosphorus and are prepared from the reaction of phosphorus pentasulfide with alcohols. The electrophilic addition of DTPAs to alkenes and unsaturated olefinic substrates is a known reaction, but has not been applied to polymer synthesis and polymer functionalization. We report on the synthesis and application of DTPAs for the functionalization of challenging poly-enes, namely polyisoprene (PI) and polynorbornene (pNB) prepared by ring-opening metathesis polymerization (ROMP).

Stereoselective Synthesis of Conjugated Di- and Trienamides via a Dienolate Enabled Anionic Cascade.

We report a stereoselective synthesis of conjugated di- and trienamides from the direct one pot γ-selective union of a dienolate and chiral nonconjugated and conjugated sulfinyl imines, respectively. This class of anionic cascades was uncovered as part of efforts to challenge the steric limitations of an anionic asymmetric amino-Cope rearrangement platform. Reaction scope studies have uncovered the substitution patterns essential for starting chiral tri- and -disubstituted conjugated and nonconjugated sulfinyl imines to be matched for the anionic cascade.

On the Mechanism of the Inverse Vulcanization of Elemental Sulfur: Structural Characterization of Poly(sulfur--(1,3-diisopropenylbenzene)).

Organosulfur polymers, such as those derived from elemental sulfur, are an important new class of macromolecules that have recently emerged via the inverse vulcanization process. Since the launching of this new field in 2013, the development of new monomers and organopolysulfide materials based on the inverse vulcanization process is now an active area in polymer chemistry. While numerous advances have been made over the last decade concerning this polymerization process, insights into the mechanism of inverse vulcanization and structural characterization of the high-sulfur-content copolymers that are produced remain challenging due to the increasing insolubility of the materials with a higher sulfur content.

One Step Selective Counterion Dependent Formation of Conjugated Chiral N-Sulfinylimines from Aldehydes.

We report a detailed study on the synthesis and aldehyde vinylogation applications of chiral N-sulfinyl imine phosphonate reagents. Two complementary scalable reagent routes, from trialkyl phosphites and methyl phosphonates, respectively, are presented. This reagent class enables significant streamlining in synthesis of conjugated Ellman imines from aldehydes, which can now be accomplished in a single step compared to a more classic 4-step redox-based approach.

Sulfenyl Chlorides: An Alternative Monomer Feedstock from Elemental Sulfur for Polymer Synthesis.

A polymerization methodology is reported using sulfur monochloride (SCl) as an alternative feedstock for polymeric materials. SCl is an inexpensive petrochemical derived from elemental sulfur (S) but has numerous advantages as a reactive monomer for polymerization vs S. This new process, termed sulfenyl chloride inverse vulcanization, exploits the high reactivity and miscibility of SCl with a broad range of allylic monomers to prepare soluble, high molar-mass linear polymers, segmented block copolymers, and crosslinked thermosets with greater synthetic precision than achieved using classical inverse vulcanization.

Anionic Amino-Cope Rearrangement Cascade Synthesis of 2,4-Substituted Benzoate Esters from Acyclic Building Blocks.

We report a new anionic cascade for assembling 2,4-substituted benzoate esters in one pot from racemic β-fluoro-substituted conjugated -butylsulfinyl imines and 3-substituted methyl 2-butenoates. Dienolate formation triggers a Mannich addition followed by an amino-Cope like rearrangement, which results in immediate elimination of fluoride by a lithiated enamine. The newly formed 1,4-diene intermediate contains a highly acidic proton which is spontaneously deprotonated, leading to a facile intramolecular cyclization followed by sulfinamide group elimination and aromatization.

Phenols in Pharmaceuticals: Analysis of a Recurring Motif.

Phenols and phenolic ethers are significant scaffolds recurring both in nature and among approved small-molecule pharmaceuticals. This compendium presents the first comprehensive compilation and analysis of the structures of U.S.

Polymerizations with Elemental Sulfur: From Petroleum Refining to Polymeric Materials.

The production of elemental sulfur from petroleum refining has created a technological opportunity to increase the valorization of elemental sulfur by the synthesis of high-performance sulfur-based plastics with improved optical, electrochemical, and mechanical properties aimed at applications in thermal imaging, energy storage, self-healable materials, and separation science. In this Perspective, we discuss efforts in the past decade that have revived this area of organosulfur and polymer chemistry to afford a new class of high-sulfur-content polymers prepared from the polymerization of liquid sulfur with unsaturated monomers, termed inverse vulcanization.

Mild Darzens Annulations for the Assembly of Trifluoromethylthiolated (SCF) Aziridine and Cyclopropane Structures.

We report mild new annulation approaches to trisubstituted trifluoromethylthiolated (SCF) aziridines and cyclopropanes via Darzens inspired protocols. The products of these anionic annulations, rarely studied previously, possess attractive features rendering them valuable building blocks for synthesis platforms. In this study, trisubstituted acetophenone nucleophiles bearing SCF and bromine substituents in their α position were shown to undergo [2 + 1] annulations with vinyl ketones and tosyl-protected imines under mild reaction conditions.

Dienolate Annulation Approach for Assembly of Densely Substituted Aromatic Architectures.

The efficient assembly of complex aromatic structures from simple acyclic building blocks is reported. An anion-cascade union of an enoate and a conjugated imine affords cyclohexenone products, which are readily aromatized to phenols. By engaging the intermediate cyclohexenones with Grignard reagents, a facile addition/elimination proceeds yielding chiral cyclohexadienes, which are then aromatized.

Oxidative Route to Indoles via Intramolecular Amino-Hydroxylation of -Allenyl Anilines.

A new intramolecular oxidative amino-hydroxylation of -allenyl anilines is reported. Treatment of carbamate-protected anilines with lead(IV) carboxylates in dichloromethane at room temperature results in facile tandem C-N (allene cyclization) and C-O bond formation (carboxylate trapping) to form indole products. Detailed reaction scope, mechanistic and kinetic studies suggest a reaction pathway involving an initial Wessely dearomatization step followed by cyclization and rearomatization.

Dramatic Effect of γ-Heteroatom Dienolate Substituents on Counterion Assisted Asymmetric Anionic Amino-Cope Reaction Cascades.

We report a dramatic effect on product outcomes of the lithium ion enabled amino-Cope-like anionic asymmetric cascade when different γ-dienolate heteroatom substituents are employed. For dienolates with azide, thiomethyl, and trifluoromethylthiol substituents, a Mannich/amino-Cope/cyclization cascade ensues to form chiral cyclohexenone products with two new stereocenters in an -relationship. For fluoride-substituted nucleophiles, a Mannich/amino-Cope cascade proceeds to afford chiral acyclic products with two new stereocenters in a -relationship.

A Structural Analysis of the FDA Green Book-Approved Veterinary Drugs and Roles in Human Medicine.

The FDA Green Book is a list of all drug products that have been approved by the FDA for use in veterinary medicine. The Green Book, as published, lacks structural information corresponding to approved drugs. To address this gap, we have compiled the structural data for all FDA Green Book drugs approved through the end of 2019.

Strategic Vinyl Sulfone Nucleophile β-Substitution Significantly Impacts Selectivity in Vinylogous Darzens and Aza-Darzens Reactions.

Vinylogous Darzens and aza-Darzens reactions employing a benzothiophene 1,1-dioxide nucleophile are reported. These new [2 + 1] annulation reactions, which proceed under mild reaction conditions, are γ-selective, affording -epoxides selectively and favoring -aziridines. The reactions are base-dependent, with KOtBu and CsCO being optimal for aldehyde and imine annulations, respectively.

A Survey of the Structures of US FDA Approved Combination Drugs.

Combination drugs are an important class of US FDA approved pharmaceuticals. These drugs have been on a continuous growth trajectory since the first combination drugs were approved in the 1940s. In this Perspective, we report the first comprehensive compilation and analysis of US FDA approved combination drugs, from the first approval in 1943 through 2018.

Asymmetric Vinylogous Aza-Darzens Approach to Vinyl Aziridines.

A new asymmetric approach to assemble cis-vinyl aziridines is reported. A reaction of strategically substituted dienolates, decorated with a γ-leaving group, with chiral sulfinimines afforded chiral vinyl aziridine products in good to excellent yields. This is the first systematic study toward the realization of a useful asymmetric vinylogous aza-Darzens reaction.

From Oxiranes to Oligomers: Architectures of U.S. FDA Approved Pharmaceuticals Containing Oxygen Heterocycles.

Oxygen heterocycles are the second most common type of heterocycles that appear as structural components of U.S. Food and Drug Administration (FDA) approved pharmaceuticals.

Review of synthetic approaches toward maoecrystal V.

Synthetic approaches toward the complex natural product diterpenoid maoecrystal V are reviewed, including successful total syntheses, published synthetic efforts, and efforts compiled from dissertations. The review focuses on general synthetic strategies and chronicles efforts toward the molecule since its isolation in 2004, summarizing key contributions of these efforts to the broader synthetic community.

[2.2.2]- to [3.2.1]-Bicycle Skeletal Rearrangement Approach to the Gibberellin Family of Natural Products.

Synthetic studies toward the gibberellin family of natural products are reported. An oxidative dearomatization/Diels-Alder cascade assembles the carbon skeleton as a [2.2.

Analysis of US FDA-Approved Drugs Containing Sulfur Atoms.

In this review, we discuss all sulfur-containing FDA-approved drugs and their structures. The second section of the review is dedicated to structural analysis and is divided into 14 subsections, each focusing on one type of sulfur-containing moiety. A concise graphical representation of each class features drugs that are organized on the basis of structural similarity, evolutionary relevance, and medical indication.