Synthesis of Bridged Inside–Outside Bicyclic Ethers through Oxidative Transannular Cyclization Reactions

The classical geometry of the 6-<i>endo</i> transition state for nucleophilic additions into oxocarbenium ions can be perturbed by incorporating the reactive groups into medium-sized rings, leading to the formation of 2,6-<i>trans</i>-dialkyl tetrahydropyrans. The bicyclic products exhibit inside–outside stereoisomerism, as seen in numerous macrolide natural products

Synthesis of Sulfur-Containing Heterocycles through Oxidative Carbon–Hydrogen Bond Functionalization

Vinyl sulfides react rapidly and efficiently with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form α,β-unsaturated thiocarbenium ions through oxidative carbon–hydrogen bond cleavage. These electrophiles couple with appended π-nucleophiles to yield sulfur-containing heterocycles through carbon–carbon bond formation. Several nucleophiles are compatible with the procedure, and the reactions generally proceed through readily predictable transition states

Cyclopropane Compatibility with Oxidative Carbocation Formation: Total Synthesis of Clavosolide A

Cyclopropane-substituted allylic ethers react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form oxocarbenium ions with no competitive ring cleavage. This reaction can be used for the preparation of cyclopropane-substituted tetrahydropyrans. The protocol was used as a key step in the total synthesis of the sponge-derived macrolide clavosolide A

Synthesis of Bridged Inside–Outside Bicyclic Ethers through Oxidative Transannular Cyclization Reactions

The classical geometry of the 6-<i>endo</i> transition state for nucleophilic additions into oxocarbenium ions can be perturbed by incorporating the reactive groups into medium-sized rings, leading to the formation of 2,6-<i>trans</i>-dialkyl tetrahydropyrans. The bicyclic products exhibit inside–outside stereoisomerism, as seen in numerous macrolide natural products

Convergent One-Pot Oxidative [<i>n</i> + 1] Approaches to Spiroacetal Synthesis

Two one-pot oxidative annulative approaches to spiroacetal synthesis are described. One approach uses a Lewis acid mediated Ferrier reaction in the fragment-coupling stage followed by DDQ-promoted oxidative carbon–hydrogen bond cleavage and cyclization. An alternative approach employs a Heck reaction for fragment coupling followed by DDQ-mediated enone formation and cyclization. These strategies provide convergent routes to common subunits in natural products, medicinal agents, and chemical libraries under mild reaction conditions

Aromatic Cations from Oxidative Carbon–Hydrogen Bond Cleavage in Bimolecular Carbon–Carbon Bond Forming Reactions

Chromenes and isochromenes react quickly with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form persistent aromatic oxocarbenium ions through oxidative carbon–hydrogen cleavage. This process is tolerant of electron-donating and electron-withdrawing groups on the benzene ring and additional substitution on the pyran ring. A variety of nucleophiles can be added to these cations to generate a diverse set of structures

Stereocontrolled Cyanohydrin Ether Synthesis through Chiral Brønsted Acid-Mediated Vinyl Ether Hydrocyanation

Vinyl ethers can be protonated to generate oxocarbenium ions that react with Me₃SiCN to form cyanohydrin alkyl ethers. Reactions that form racemic products proceed efficiently upon conversion of the vinyl ether to an α-chloro ether prior to cyanide addition in a pathway that proceeds through Brønsted acid-mediated chloride ionization. Enantiomerically enriched products can be accessed by directly protonating the vinyl ether with a chiral Brønsted acid to form a chiral ion pair. Me₃SiCN acts as the nucleophile and PhOH serves as a stoichiometric proton source in a rare example of asymmetric bimolecular nucleophilic addition into an oxocarbenium ion. Computational studies have provided a model for the interaction between the catalyst and the oxocarbenium ion

Predictive Model for Oxidative C–H Bond Functionalization Reactivity with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a highly effective reagent for promoting C–H bond functionalization. The oxidative cleavage of benzylic and allylic C–H bonds using DDQ can be coupled with an intra- or intermolecular nucleophilic addition to generate new carbon–carbon or carbon–heteroatom bonds in a wide range of substrates. The factors that control the reactivity of these reactions are well-defined experimentally, but the mechanistic details and the role of substituents in promoting the transformations have not been firmly established. Herein, we report a detailed computational study on the mechanism and substituent effects for DDQ-mediated oxidative C–H cleavage reactions in a variety of substrates. DFT calculations show that these reactions proceed through a hydride transfer within a charge transfer complex. Reactivity is dictated by the stability of the carbocation intermediate, the degree of charge transfer in the transition states, and, in certain cases, secondary orbital interactions between the π orbital of the forming cation and the LUMO of DDQ. A linear free energy relationship was established to offer a predictive model for reactivity of different types of C–H bonds based on the electronic properties of the substrate

Synthesis and Biological Evaluation of Neopeltolide and Analogs

The synthesis of neopeltolide analogues that contain variations in the oxazole-containing side chain and in the macrolide core are reported along with the GI₅₀ values for these compounds against MCF-7, HCT-116, and p53 knockout HCT-116 cell lines. Although biological activity is sensitive to changes in the macrocycle and the side chain, several analogues displayed GI₅₀ values of <25 nM. Neopeltolide and several of the more potent analogues were significantly less potent against p53 knockout cells, suggesting that p53 plays an auxiliary role in the activity of these compounds

Studies toward the Unique Pederin Family Member Psymberin: Structure–Activity Relationships, Biochemical Studies, and Genetics Identify the Mode-of-Action of Psymberin

Psymberin is the only member of the pederin natural product family that contains a dihydroisocoumarin side chain. Structural modifications of psymberin uncoupled inhibition of protein translation from cytotoxicity, suggesting that psymberin has more than one bioactivity. A forward genetic screen in Caenorhabditis elegans was conducted to identify the molecular target(s) of psymberin. Multiple independent psymberin-resistant mutants were isolated, each containing the same point mutation in a gene encoding a ribosomal protein. However, a psymberin-resistant mutant strain bearing this mutation was not cross-resistant to the pederin family member mycalamide A, which binds to the archaeal form of the same protein. Thus, two pederin family members likely differ in how they bind the same molecular target. The accumulation of psymberin in cells was sensitive to the stereochemistry of the amide side chain at C4 or C8 and the presence of the dihydroisocoumarin side chain. The observation that psymberin diastereomers or dihydroisocoumarin-truncated analogs lose all cytotoxic activity while retaining the ability to inhibit protein translation in a cell-free in vitro assay can be explained in the context of these differential cell uptake issues. Finally, we also demonstrate that the blistering activity associated with pederin and other members of the family is not due to their protein synthesis inhibiting activity. Unlike pederin and mycalamide, psymberin does not display irritant or blistering activity