Rapid Synthesis of the Spiroketal Subunit of Neaumycin B: Stereochemical Aspects of Singly Anomeric Spiroketals and Proposal for a Stereocenter Reassignment.

Neaumycin B is a complex polyketide that shows phenomenal cytotoxicity against U87 glioblastoma cells. The singly anomeric spiroketal core is a notable subunit in the natural product's structure. We report a rapid and convergent approach to the spiroketal group, resulting in the formation of two isomeric singly anomeric spiroketals.

Potent and Selective Oxidatively Labile Ether-Based Prodrugs through Late-Stage Boronate Incorporation.

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols.

Nitrogen Heterocycle Synthesis through Hydride Abstraction of Acyclic Carbamates and Related Species: Scope, Mechanism, Stereoselectivity, and Product Conformation Studies.

Acyliminium ions and related species are potent electrophiles that can be quite valuable in the synthesis of nitrogen-containing molecules. This manuscript describes a protocol to form these intermediates through hydride abstractions of easily accessible allylic carbamates, amides, and sulfonamides that avoids the reversibility that is possible in classical condensation-based routes. These intermediates are used in the preparation of a range of nitrogen-containing heterocycles, and in many cases high levels of stereocontrol are observed.

Peroxide-Mediated Release of Organophosphates from Boron-Containing Phosphotriesters: A New Class of Organophosphate Prodrugs.

Phosphate mono- and diesters can be liberated efficiently from boryl allyloxy (BAO) and related phosphotriesters by HO. This protocol was applied to the release of a phosphorylated serine derivative and the nucleotide analogue AZT monophosphate. Nucleotide release in the presence of ATP and a kinase provides a diphosphate, demonstrating that this method can be applied to biological processes.

Synthetic applications of hydride abstraction reactions by organic oxidants.

Carbon-hydrogen bond functionalizations provide an attractive method for streamlining organic synthesis, and many strategies have been developed for conducting these transformations. Hydride-abstracting reactions have emerged as extremely effective methods for oxidative bond-forming processes due to their mild reaction conditions and high chemoselectivity. This review will predominantly focus on the mechanism, reaction development, natural product synthesis applications, approaches to catalysis, and use in enantioselective processes for hydride abstractions by quinone, oxoammonium ion, and carbocation oxidants.

Kinetics-Based Approach to Developing Electrocatalytic Variants of Slow Oxidations: Application to Hydride Abstraction-Initiated Cyclization Reactions.

Electrochemical oxidant regeneration is challenging in reactions that have a slow redox step because the steady-state concentration of the reduced oxidant is low, causing difficulties in maintaining sufficient current or preventing potential spikes. This work shows that applying an understanding of the relationship between intermediate cation stability, oxidant strength, overpotential, and concentration on reaction kinetics delivers a method for electrochemical oxoammonium ion regeneration in hydride abstraction-initiated cyclization reactions, resulting in the development of an electrocatalytic variant of a process that has a high oxidation transition state free energy. This approach should be applicable to expanding the scope of electrocatalysis to include additional slow redox processes.

Solvent Effects and Mechanistic Studies for ReO-Catalyzed Allylative Annulation Reactions.

The sequence of allylic alcohol transposition, carbonyl group trapping, oxocarbenium ion formation, and nucleophilic addition results in the formation of a ring while serving as a fragment-coupling and stereocenter-generating reaction. Successful applications of these processes require a balancing of the kinetics of numerous productive and unproductive steps. This work describes the manner in which solvent changes can be used to expand the scope and change the stereochemical outcomes of these processes.

Mechanism-Based Approach to Reagent Selection for Oxidative Carbon-Hydrogen Bond Cleavage Reactions.

Numerous hydride-abstracting agents generate the same cationic intermediate, but substrate features such as intermediate cation stability, oxidation potential, and steric environment can influence reaction rates in an oxidant-dependent manner. This manuscript provides experimental data to illustrate the role that structural features play in the kinetics of hydride abstraction reactions with commonly used quinone-, oxoammonium ion-, and carbocation- based oxidants. Computational studies of the transition state structures and energies explain these results and energy decomposition analysis calculations reveal unique sensitivities to electrostatic attraction and steric repulsions.

Synthesis of Nitrogen-Containing Heterocycles through Catalytic Dehydrative Cyclization Reactions.

ReO in hexafluoroisopropyl alcohol provides access to cationic intermediates from alcohols through the intermediacy of perrhenate esters. This manuscript describes the application of the system to the formation of a number of weakly basic heterocyclic systems through dehydration reactions and intramolecular nucleophilic addition. The influence of the substrate structure on the reaction rates and stereocontrol is discussed with respect to intermediate ion pairs.

Dehydrative ReO-Catalyzed Approach to Dihydropyran Synthesis.

Monoallylic 1,3- and 1,5-diols undergo ReO-mediated ionization to form allylic cations that engage in cyclization reactions to form dihydropyran products. The reactions give the 2,6--stereoisomer as the major products as a result of minimizing steric interactions in a boat-like transition state. The results of these studies are consistent with cationic intermediates, with an intriguing observation of stereochemical retention in one example.

Dictating Thermodynamic Control through Tethering: Applications to Stereoselective Bis-Spiroketal Synthesis.

Approaches to stereocontrol that invoke thermodynamic control fail when two or more potential products are energetically similar, but rational structural perturbations can be employed to break the energetic degeneracy and provide selective transformations. This manuscript illustrates that tethering is an effective approach for the stereoselective construction of bis-spiroketals with thermodynamically similar stereoisomers, providing a new approach to set remote stereocenters and prepare complex structures that have not previously been accessed stereoselectively.

ReO-Catalyzed Approach to Spirocyclic Ether Formation from Acyclic Precursors: Observation of Remote Stereoinduction.

Ketones that are flanked by an allylic alcohol and an alkene isomerize to spirocyclic ethers in the presence of ReO through allylic alcohol transposition, oxocarbenium ion formation, and Prins cyclization. These processes provide significant increases in molecular complexity, with multiple stereocenters being set relative to a stereocenter in the substrate. Stereoselectivity arises from the initial reversible steps being more rapid than the final step, thereby allowing for thermodynamically controlled stereochemical equilibration prior to product formation.

Diaphorin, a polyketide synthesized by an intracellular symbiont of the Asian citrus psyllid, is potentially harmful for biological control agents.

The Asian citrus psyllid Diaphorina citri Kuwayama (Hemiptera: Sternorrhyncha: Psylloidea: Liviidae) is an important pest of citrus species worldwide because it transmits Candidatus Liberibacter spp. (Alphaproteobacteria), the causative agents of an incurable citrus disease known as huanglongbing or greening disease. Diaphorina citri possesses a vertically-transmitted intracellular symbiont, Candidatus Profftella armatura (Betaproteobacteria), which produces diaphorin, a polyketide that is significantly toxic to mammalian cells.

Diarylmethane synthesis through ReO-catalyzed bimolecular dehydrative Friedel-Crafts reactions.

This manuscript describes the application of ReO to the syntheses of diarylmethanes from benzylic alcohols through solvolysis followed by Friedel-Crafts alkylation. The reactions are characterized by broad substrate scope, low catalyst loadings, high chemical yields, and minimal waste generation. The intermediate perrhenate esters are superior leaving groups to chlorides and bromides in these reactions.

Total Synthesis of Divergolides E and H.

This manuscript describes the first total syntheses of divergolides E and H. The route employs a telescoped hetero-Diels-Alder and oxidative carbon-hydrogen bond cleavage as an entry into the central bridged bicyclic acetal unit. Additional key steps of the highly convergent route include a desymmetrizing epoxidation, a chelation-controlled alkenylzinc addition, an amide formation between a hindered aniline and an acylating agent that is prone to ketene formation, and a challenging macrolactonization.

Potent and Readily Accessible Bistramide A Analogues through Diverted Total Synthesis.

A diverted total synthesis effort is described that is designed to prepare potent cytotoxins based on the actin-binding natural product bistramide A. The major focus of this study is the preparation of analogues that contain oxygenation at the C29 position, which is necessary for a key reaction in the sequence but is not present in the natural product. This process showed that C29 ketone analogues are accessed more readily and show similar potency compared to the natural product.

Copper-catalyzed oxidative cross-dehydrogenative coupling of 2H-chromenes and terminal alkynes.

An efficient copper-catalyzed cross-dehydrogenative coupling of 2H-chromenes and terminal alkynes mediated by DDQ has been established. A protic additive, EtOH, proved to be crucial for harmonizing the oxidation with a subsequent alkynylation step by retaining the oxidation state of an oxocarbenium ion in the form of acetal. The CDC reaction exhibits a good substrate scope, with a range of terminal aryl- and alkyl alkynes being well tolerated.

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.

Re O -Mediated Dehydrative Cyclization Reactions: Total Synthesis of Herboxidiene and Its 12-Desmethyl Analogue.

Re O catalysis effects efficient and stereoselective dehydrative cyclization reactions from monoallylic diols, with stereocontrol arising from thermodynamic equilibration. This method was applied to a rapid synthesis of the spliceosome inhibitor herboxidiene. The route was also utilized for the synthesis of an analogue that highlights the importance of a single methyl group in biasing the conformation in the acyclic region of the molecule.

Alcohol, Aldehyde, and Ketone Liberation and Intracellular Cargo Release through Peroxide-Mediated α-Boryl Ether Fragmentation.

α-Boryl ethers, carbonates, and acetals, readily prepared from the corresponding alcohols that are accessed through ketone diboration, react rapidly with hydrogen peroxide to release alcohols, aldehydes, and ketones through the collapse of hemiacetal intermediates. Experiments with α-boryl acetals containing a latent fluorophore clearly demonstrate that cargo can be released inside cells in the presence of exogenous or endogenous hydrogen peroxide. These experiments show that this protocol can be used for drug activation in an oxidative environment without generating toxic byproducts.

Convergent One-Pot Oxidative [n + 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.

Highly enantioselective catalytic cross-dehydrogenative coupling of N-carbamoyl tetrahydroisoquinolines and terminal alkynes.

The first catalytic asymmetric cross-dehydrogenative coupling of cyclic carbamates and terminal alkynes has been established. The reaction features high enantiocontrol and excellent functional group tolerance and displays a wide range of structurally and electronically diverse carbamates as well as terminal alkynes. N-Acyl hemiaminals were identified as the reactive intermediates through preliminary control experiments.

Spiroacetal formation through telescoped cycloaddition and carbon-hydrogen bond functionalization: total synthesis of bistramide A.

Spiroacetals can be formed through a one-pot sequence of a hetero-Diels-Alder reaction, an oxidative carbon-hydrogen bond cleavage, and an acid treatment. This convergent approach expedites access to a complex molecular subunit which is present in numerous biologically active structures. The utility of the protocol is demonstrated through its application to a brief synthesis of the actin-binding cytotoxin bistramide A.

Heterocycle synthesis based on allylic alcohol transposition using traceless trapping groups.

Allylic alcohols undergo transposition reactions in the presence of Re2 O7 whereby the equilibrium can be dictated by trapping one isomer with a pendent electrophile. Additional ionization can occur when the trapping group is an aldehyde or ketone, thus leading to cyclic oxocarbenium ion formation. Terminating the process through bimolecular nucleophilic addition into the intermediate provides a versatile method for the synthesis of diverse oxygen-containing heterocycles.

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.