[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 [2.2.2]-bicycle, which is then transformed to the [3.2.1]-bicyclic gibberellin core via a novel Lewis acid catalyzed rearrangement. Strategic synthetic handles allow for late-stage modification of the gibberellin skeleton and provides efficient access to this important family of natural compounds

Double-Diels–Alder Approach to Maoecrystal V. Unexpected C–C Bond-Forming Fragmentations of the [2.2.2]-Bicyclic Core

Synthetic studies toward maoecrystal V are reported. An oxidative dearomatization/Diels–Alder cascade to assemble the natural product carbocyclic core in one step is proposed. A facile electrocyclization is shown to suppress the intramolecular allene Diels–Alder pathway. This obstacle is alleviated via a stepwise approach with an allene equivalent to access the key cyclopentadiene-fused [2.2.2]-bicyclic core. Upon treatment with Lewis acid, the proposed intramolecular hetero-Diels–Alder reaction is cleanly and unexpectedly diverted either via C–C bond-forming fragmentation to the spiro-indene product (when R = OMe) or via elimination (when R = H)

Dearomatization Approach to 2‑Trifluoromethylated Benzofuran and Dihydrobenzofuran Products

A mild dearomatization enabled <i>ortho</i>-selective replacement of an aromatic C–H bond with a hexafluoro­acetylacetone (hfacac) substituent has been developed. This reaction is dependent on a hypervalent iodine generated phenoxonium intermediate, a critical choice of solvent, and reagent addition order. The fluorinated dihydrobenzofuran product can be transformed into dihydrobenzofuran and benzofuran products decorated with a 2-trifluoromethyl group. The 3-trifluoro­methylacyl substituted benzofurans rapidly form hydrates, which can be reduced to the corresponding alcohols

Beyond C, H, O, and N! Analysis of the Elemental Composition of U.S. FDA Approved Drug Architectures

The diversity of elements among U.S. Food and Drug Administration (FDA) approved pharmaceuticals is analyzed and reported, with a focus on atoms other than carbon, hydrogen, oxygen, and nitrogen. Our analysis reveals that sulfur, chlorine, fluorine, and phosphorous represent about 90% of elemental substitutions, with sulfur being the fifth most used element followed closely by chlorine, then fluorine and finally phosphorous in the eighth place. The remaining 10% of substitutions are represented by 16 other elements of which bromine, iodine, and iron occur most frequently. The most detailed parts of our analysis are focused on chlorinated drugs as a function of approval date, disease condition, chlorine attachment, and structure. To better aid our chlorine drug analyses, a new poster showcasing the structures of chlorinated pharmaceuticals was created specifically for this study. Phosphorus, bromine, and iodine containing drugs are analyzed closely as well, followed by a discussion about other elements

Data-Mining for Sulfur and Fluorine: An Evaluation of Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery

Among carbon, hydrogen, oxygen, and nitrogen, sulfur and fluorine are both leading constituents of the pharmaceuticals that comprise our medicinal history. In efforts to stimulate the minds of both the general public and expert scientist, statistics were collected from the trends associated with therapeutics spanning 12 disease categories (a total of 1969 drugs) from our new graphical montage compilation: disease focused pharmaceuticals posters. Each poster is a vibrant display of a collection of pharmaceuticals (including structural image, Food and Drug Administration (FDA) approval date, international nonproprietary name (INN), initial market name, and a color-coded subclass of function) organized chronologically and classified according to an association with a particular clinical indication. Specifically, the evolution and structural diversity of sulfur and the popular integration of fluorine into drugs introduced over the past 50 years are evaluated. The presented qualitative conclusions in this article aim to promote innovative insights into drug development

Intermolecular Oxonium Ylide Mediated Synthesis of Medium-Sized Oxacycles

Detailed in this account are our efforts toward efficient oxacycle syntheses. Two complementary approaches are discussed, with both employing chemoselective allyl ether activation and rearrangement as the key step. Vinyl substituted oxiranes and oxetanes provide a single step access to dihydropyrans and tetrahydrooxepines. Oxiranes proved to be poor substrates, while oxetanes were slightly better. An alternative approach using substituted allyl ethers proved successful and addressed the limitations encountered in the ring expansions

Asymmetric Vinylogous Aza-Darzens Approach to Vinyl Aziridines

A new asymmetric approach to assemble <i>cis</i>-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. The reaction is initiated by a <i>syn</i>-selective addition, affording <i>cis</i>-vinyl aziridine products after displacement of bromide. The low <i>syn</i>-diastereoselectivity is attributed to competing retro-Mannich pathways

Mechanism and the Origins of Stereospecificity in Copper-Catalyzed Ring Expansion of Vinyl Oxiranes: A Traceless Dual Transition-Metal-Mediated Process

Density functional theory computations of the Cu-catalyzed ring expansion of vinyloxiranes is mediated by a traceless dual Cu­(I)-catalyst mechanism. Overall, the reaction involves a monomeric Cu­(I)-catalyst, but a single key step, the Cu migration, requires two Cu­(I)-catalysts for the transformation. This dual-Cu step is found to be a true double Cu­(I) transition state rather than a single Cu­(I) transition state in the presence of an adventitious, spectator Cu­(I). Both Cu­(I) catalysts are involved in the bond forming and breaking process. The single Cu­(I) transition state is not a stationary point on the potential energy surface. Interestingly, the reductive elimination is rate-determining for the major diastereomeric product, while the Cu­(I) migration step is rate-determining for the minor. Thus, while the reaction requires dual Cu­(I) activation to proceed, kinetically, the presence of the dual-Cu­(I) step is untraceable. The diastereospecificity of this reaction is controlled by the Cu migration step. Suprafacial migration is favored over antarafacial migration due to the distorted Cu π-allyl in the latter

New Class of Anion-Accelerated Amino-Cope Rearrangements as Gateway to Diverse Chiral Structures

We report useful new lithium-assisted asymmetric anion-accelerated amino-Cope rearrangement cascades. A strategic nitrogen atom chiral auxiliary serves three critical roles, by (1) enabling in situ assembly of the chiral 3-amino-1,5-diene precursor, (2) facilitating the rearrangement via a lithium enolate chelate, and (3) imparting its influence on consecutive inter- or intramolecular C–C or C–X bond-forming events via resulting chiral enamide intermediates or imine products. The mechanism of the amino-Cope rearrangement was explored with density functional theory. A stepwise dissociation–recombination mechanism was found to be favored. The stereochemistry of the chiral auxiliary determines the stereochemistry of the Cope product by influencing the orientation of the lithium dienolate and sulfinylimine fragments in the recombination step. These robust asymmetric anion-accelerated amino-Cope enabled cascades open the door for rapid and predictable assembly of complex chiral acyclic and cyclic nitrogen-containing motifs in one pot

Biodistribution data obtained from the PET imaging experiment and from tissue harvest.

<p>(a) Plot of the 2-dimensional ROI data for all group I and II animals at 3 and 24 hours. Three regions per tissue per animal were collected and the average %ID/g and standard deviation determined. The average %ID/g tissue per animal was then used to determine an average %ID/g per tissue per group and the standard deviation within the group values was also calculated. (b) Plot of the 24 hour biodistribution data obtained from tissue harvest, weighing and counting of organs from group I, II, and III mice.</p