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Methods to functionalize arenes and heteroarenes in a site-selective manner are highly sought after for rapidly constructing value-added molecules of medicinal, agrochemical, and materials interest. One effective approach is the site-selective cross-coupling of polyhalogenated arenes bearing multiple, but identical, halogen groups. Such cross-coupling reactions have proven to be incredibly effective for site-selective functionalization. However, they also present formidable challenges due to the inherent similarities in the reactivities of the halogen substituents. In this Review, we discuss strategies for site-selective cross-couplings of polyhalogenated arenes and heteroarenes bearing identical halogens, beginning first with an overview of the reaction types that are more traditional in nature, such as electronically, sterically, and directing-group-controlled processes. Following these examples is a description of emerging strategies, which includes ligand- and additive/solvent-controlled reactions as well as photochemically initiated processes.

The synthesis of diverse N-fused heterocycles, including the pyrido[1,2-a]indole scaffold, using an efficient pyrone remodeling strategy is described. The pyrido[1,2-a]indole core was demonstrated to be a versatile scaffold that can be site-selectively functionalized. The utility of this novel annulation strategy was showcased in a concise formal synthesis of three fascaplysin congeners., The synthesis of diverse N-fused heterocycles, including the pyrido[1,2-a]indole scaffold, using an efficient pyrone remodeling strategy is described.

The positional isomerization of C–C double bonds is a powerful strategy for the interconversion of alkene regioisomers. However, existing methods provide access to thermodynamically more stable isomers from less stable starting materials. Here we report the discovery of a dual catalyst system that promotes contra-thermodynamic positional alkene isomerization under photochemical irradiation, providing access to terminal alkene isomers directly from conjugated, internal alkene starting materials. The utility of the method is demonstrated in the deconjugation of diverse electron rich/poor alkenes and through strategic application to natural product synthesis. Mechanistic studies are consistent with a regiospecific bimolecular homolytic substitution (SH2') mechanism proceeding through an allyl-cobaloxime intermediate.

The recognition of latent symmetry in delavatine A has enabled a short synthesis of the natural product starting from 3,5-dibromo-2-pyrone. The concise synthetic route features a cascade process involving a 6π electrocyclization to construct the indane core of delavatine A. In addition, we have conducted detailed experimental and computational studies to gain an in-depth understanding of the mechanism of the observed site-selective cross-coupling of 3,5-dibromo-2-pyrone. This insight may provide new avenues to achieve the selective cross-coupling of multiply halogenated heteroarenes.

We provide a full account of our synthetic studies targeting the hexacyclic calyciphylline B-type alkaloids, a subfamily of the Daphniphyllum natural products. Following an initial set of synthetic strategies focused on constructing the piperidine core of the calyciphylline B-type framework via a 6π-azaelectrocyclization, as well as exploiting the reactivity of underexplored oxazaborinine heterocycles, we ultimately designed a highly functionalized acyclic precursor which underwent carefully orchestrated and efficient cyclizations to forge the architecturally complex natural product scaffold. Our efforts have culminated in the development of the first total synthesis of (-)-daphlongamine H, provided access to its C5-epimer, (-)-isodaphlongamine H, and led to structural revision of deoxyisocalyciphylline B.

We describe a symmetry-inspired synthetic approach that has enabled a short synthesis of delavatine A and a formal synthesis of incarviatone A, which are two likely biosynthetically related natural products. The indane core of these natural products was constructed through a cascade sequence involving five transformations that occur in a single pot. Leveraging symmetry has allowed us to trace both natural products back to a versatile building block, 3,5-dibromo-2-pyrone, and studies related to site-selective cross-coupling of this polyhalogenated heterocycle are described. In addition, our strategy gave access to a putative biogenetic precursor, from which the syntheses of both natural products were attempted.

The first total synthesis of the complex hexacylic Daphniphyllum alkaloid (–)-daphlongamine H in enantioenriched form has been accomplished. Key to the success of the strategy are a complexity-building Mannich reaction, efficient cyclizations, and a highly diastereoselective hydrogenation to assemble multigram quantities of the tricyclic core bearing four contiguous stereocenters. Following construction of the hydro-indene substructure by means of a Pauson–Khand reaction, endgame redox manipulations delivered the natural product. Importantly, the synthetic studies have also given access to (–)-isodaphlongamine H and led to a revision of the reported structure of deoxyisocalyciphylline B, which resulted in the proposal of a modified biosynthetic pathway to the calyciphylline B-type alkaloids.

Reaction of thioamides (e.g., II) with benzynes generated by the hexadehydro-Diels-Alder (HDDA) cycloisomerization (e.g., I) produces dihydrobenzothiazines (e.g., III). It is postulated that the reaction proceeds via benzothietene (cf. IV) and o-thiolatoaryliminium (cf. V) intermediates and that the latter undergoes intramolecular 1,3-hydrogen atom migration to produce the penultimate isomeric iminium zwitterions VI.

We report here reactions of alkyl sulfides with benzynes thermally generated by the hexadehydro-Diels-Alder (HDDA) cycloisomerization. The initially produced 1,3-betaine (o-sulfonium/aryl carbanion) undergoes intramolecular proton transfer to generate a more stable S-aryl sulfur ylide. This can react in various manners, including engaging weak acids (HA) in the reaction medium. This can produce transient ion pairs ArSR2(+)A(-) that proceed to the products ArSR + RA. When cyclic sulfides are used, A(-) opens the ring and is incorporated into the product, an outcome that constitutes a versatile, three-component coupling process.

Reactions of thermally generated benzynes with diaziridines are reported. These trapping reactions follow the same pathway as reported earlier by Heine and co-workers with electron-deficient alkynes. The resulting N-arylhydrazones were obtained efficiently in a single step. The preference for the mode of addition of the nucleophilic diaziridine nitrogen atom to the more electrophilic benzyne carbon was consistent with what is predicted on the basis of distortion analysis. The feasibility of converting the hydrazone into a Fisher-indole adduct was demonstrated.

Thioamides bearing electron-withdrawing groups on the thiocarbonyl carbon atom react with benzynes [generated by the hexadehydro-Diels–Alder (HDDA) cycloisomerization] in an unprecedented fashion. Namely, the dihydrobenzothiazole products are consistent with a pathway involving initial formation of a stabilized ammonium ylide by a rare type of [3+2]-cycloaddition reaction. The fate of this species depends upon the nature of the R group(s) attached to the ylide nitrogen atom. The demonstration of new modes of reactivity represents the major advance arising from this study.

Access to a new class of oxazaborinines using an efficient transition-metal-catalyzed rearrangement is demonstrated. The method overcomes the synthetic challenge of achieving an aza-Claisen rearrangement of vinylogous N-allylic amide substrates, giving rise to a variety of highly modifiable oxazaborinine products. An investigation of the unique reactivity of these boron-based heterocycles has unveiled their underexplored potential as valuable building blocks and intermediates for organic synthesis.

We report here reactions of alkyl sulfides with benzynes thermally generated by the hexadehydro-Diels–Alder (HDDA) cycloisomerization. The initially produced 1,3-betaine (o-sulfonium/aryl carbanion) undergoes intramolecular proton transfer to generate a more stable S-aryl sulfur ylide. This can react in various manners, including engaging weak acids (HA) in the reaction medium. This can produce transient ion pairs ArSR2+A– that proceed to the products ArSR + RA. When cyclic sulfides are used, A– opens the ring and is incorporated into the product, an outcome that constitutes a versatile, three-component coupling process.