Diverse Synthesis of C-Glycosides by Stereoselective Ni-Catalyzed Carboboration of Glycals.

C-Glycosides are important structures that are common to natural products and pharmaceutical agents. Established methods for their synthesis involve the reaction of an activated anomeric carbon. In this study, we report a conceptually new approach that involves the stereoselective Ni-catalyzed carboboration of glycals. In these reactions, not only is a C-C bond formed at the anomeric carbon, but a synthetically useful C-B bond is also installed. Upon C-B oxidation, differentially protected C-glycosides to be formed. In addition, stereospecific manipulation of the C-B bond leads to diverse C-glycosides. Finally, we report the application of this method in the synthesis of established C-glycosides, such as C-glycosyl amino acids, as well as a strategy to make all possible diastereomers at C1 and C2.

Synthesis of Borylated Carbocycles by [2 + 2]-Cycloadditions and Photo-Ene Reactions.

Saturated bicyclic compounds make up a valuable class of building blocks in the development of agrochemicals and pharmaceuticals. Here, we present the synthesis of borylated bicyclo[2.1.1]hexanes via crossed [2 + 2]-cycloaddition. Due to the presence of the C-B bond, a variety of structures can be easily prepared that are not accessible by other methods. Moreover, a rare photo-ene reaction is also disclosed, allowing for the diastereoselective synthesis of trisubstituted borylated cyclopentanes.

Lewis Acid-Promoted [2 + 2] Cycloadditions of Allenes and Ketenes: Versatile Methods for Natural Product Synthesis.

ConspectusCycloaddition reactions are an effective method to quickly build molecular complexity. As predicted by the Woodward-Hoffmann rules, concerted cycloadditions with alkenes allow for the constructions of all possible stereoisomers of product by use of either the Z or E geometry. While this feature of cycloadditions is widely used in, for example, [4 + 2] cycloadditions, translation to [2 + 2] cycloadditions is challenging because of the often stepwise and therefore stereoconvergent nature of these processes. Over the past decade, our lab has explored Lewis acid-promoted [2 + 2] cycloadditions of electron-deficient allenes or ketenes with alkenes. The concerted, asynchronous cycloadditions allow for the synthesis of various cyclobutanes with control of stereochemistry.Our lab developed the first examples of Lewis acid-promoted ketene-alkene [2 + 2] cycloadditions. Compared with traditional thermal conditions, Lewis acid-promoted conditions have several advantages, such as increased reactivity, increased yield, improved diastereoselectivity, and, for certain cases, inverse diastereoselectivity. Detailed mechanistic studies revealed that the diastereoselectivity was controlled by the size of the substituent and the barrier of a deconjugation event. However, these reactions required the use of stoichiometric amounts of EtAlCl2 because of the product inhibition, which led us to investigate catalytic enantioselective [2 + 2] cycloadditions of allenoates with alkenes. Through the use of chiral oxazaborolidines, a broad range of cyclobutanes can be prepared with the control of enantioselectivity. Mechanistic experiments, including 2D-labled alkenes and Hammett analysis, illuminate likely transition state models for the cycloadditions. Additional studies led to the development of Lewis acid-catalyzed intramolecular stereoselective [2 + 2] cycloadditions of chiral allenic ketones/esters with alkenes.The methods we developed have been instrumental in the synthesis of several families of natural products. Specifically, one key lactone motif in (±)-gracilioether F was constructed by a ketene-alkene [2 + 2] cycloaddition and subsequent regioselective Baeyer-Villiger oxidation sequence. Enantioselective allenoate-alkene [2 + 2] cycloadditions allowed for the synthesis of (-)-hebelophyllene E. Another attempt of applying this method in the synthesis of (+)-[5]-ladderanoic acid failed to deliver the desired cyclobutane because of an unexpected rearrangement. The key cyclobutane was later assembled by a stepwise carboboration/Zweifel olefination process. Finally, the stereoselective [2 + 2] cycloadditions of allenic ketones and alkenes was applied in the syntheses of (-)-[3]-ladderanol, (+)-hippolide J, and (-)-cajanusine.

Photosensitized [2 + 2]-Cycloadditions of Dioxaborole: Reactivity Enabled by Boron Ring Constraint Strategy.

A strategy to achieve photosensitized [2 + 2] cycloadditions by means of temporary ring constraint is reported. Specifically, a dioxaborole is prepared that undergoes [2 + 2] cycloadditions with a wide variety of alkenes. This strategy overcomes some challenges with the cycloaddition of acyclic substrates. The products can be easily transformed into cyclobutyl diols or 1,4-dicarbonyl compounds; the latter represents a formal alkene vicinal diacylation. The synthetic utility of this method is shown in the synthesis of valuable heterocycles and biatriosporin D.

Ni-Catalyzed 1,1- and 1,3-Aminoboration of Unactivated Alkenes.

Alkene borylfunctionalization reactions have emerged as useful methods for chemical synthesis. While much progress has been made on 1,2-borylamination reactions, the related 1,1- and 1,3-borylaminations have not been reported. Herein, a Ni-catalyzed 1,1-borylamination of 1,1-disubstituted and monosubstituted alkenes and a 1,3-borylamination of cyclic alkenes are presented. Key to development of these reactions was the identification of an alkyllithium activator in combination with Mg salts. The utility of the products and the mechanistic details are discussed.

Single-Source Precursors for the Controlled Aqueous Synthesis of Bismuth Oxyhalides.

Bismuth oxyhalides are a promising class of photocatalysts for harvesting solar energy. These materials are often synthesized in aqueous media with poor synthetic control resulting from the extremely fast nucleation and growth rates of the particles. These fast rates are caused by the rapid precipitation of bismuth salts with free halide ions. We have developed water-soluble precursors combining bismuth with either chlorine or bromine atoms in the same metal-organic complex. With the application of heat, halide ions are released, which then precipitate with bismuth ions as BiOX (X = Cl, Br). By controlling the halide ion formation rate, the nucleation and growth rates of BiOX materials can be tuned to provide synthetic control. The diverse potential of these precursors is demonstrated by synthesizing BiOX in three ways: aqueous colloidal synthesis, solid-state decomposition, and fabrication of films of BiOX via spray pyrolysis of the aqueous precursor solutions. These broadly applicable single-source precursors will enhance the ability to synthesize future BiOX materials with controlled morphologies.

Photosensitized [4+2]- and [2+2]-Cycloaddition Reactions of N-Sulfonylimines.

The synthesis of polycyclic compounds is of high interest due to the prevalence of these motifs in drugs and natural products. Herein, we report on the stereoselective construction of 3D bicyclic scaffolds and azetidine derivatives by modulation of N-sulfonylimines to achieve either [4+2]- or [2+2]-cycloaddition reactions. The utility of the method was established by further modulation of the product. Mechanistic studies are also included, which support reaction via Dexter energy transfer.

Synthesis of 2-Azanorbornanes via Strain-Release Formal Cycloadditions Initiated by Energy Transfer.

Rigid bicycles are becoming more popular in the pharmaceutical industry because they allow for expansion to new and unique chemical spaces. This work describes a new strategy to construct 2-azanorbornanes, which can act as rigid piperidine/pyrrolidine scaffolds with well-defined exit vectors. To achieve the synthesis of 2-azanorbornanes, new strain-release reagent, azahousane, is introduced along with its photosensitized strain-release formal cycloaddition with alkenes. Furthermore, new reactivity between a housane and an imine is disclosed. Both strategies lead to various substituted 2-azanorbornanes with good selectivities.

Boronic Ester Enabled [2 + 2]-Cycloadditions by Temporary Coordination: Synthesis of Artochamin J and Piperarborenine B.

A strategy for the photosensitized cycloaddition of alkenylboronates and allylic alcohols by a temporary coordination is presented. The process allows for the synthesis of a diverse range of cyclobutylboronates. Key to development of these reactions is the temporary coordination of the allylic alcohol to the Bpin unit. This not only allows for the reaction to proceed in an intramolecular manner but also allows for high levels of stereo and regiocontrol. A key aspect of these studies is the utility of the cycloadducts in the synthesis of complex natural products artochamin J and piperarborenine B.

Strain-Release [2π + 2σ] Cycloadditions for the Synthesis of Bicyclo[2.1.1]hexanes Initiated by Energy Transfer.

Saturated bicycles are becoming ever more important in the design and development of new pharmaceuticals. Here a new strategy for the synthesis of bicyclo[2.1.1]hexanes is described. These bicycles are significant because they have defined exit vectors, yet many substitution patterns are underexplored as building blocks. The process involves sensitization of a bicyclo[1.1.0]butane followed by cycloaddition with an alkene. The scope and mechanistic details of the method are discussed.

Photochemical Dearomative Cycloadditions of Quinolines and Alkenes: Scope and Mechanism Studies.

Photochemical dearomative cycloaddition has emerged as a useful strategy to rapidly generate molecular complexity. Within this context, stereo- and regiocontrolled intermolecular para-cycloadditions are rare. Herein, a method to achieve photochemical cycloaddition of quinolines and alkenes is shown. Emphasis is placed on generating sterically congested products and reaction of highly substituted alkenes and allenes. In addition, the mechanistic details of the process are studied, which revealed a reversible radical addition and a selectivity-determining radical recombination. The regio- and stereochemical outcome of the reaction is also rationalized.

Stereoselective [2+2]-Cycloadditions of chiral allenic ketones and alkenes: Applications towards the synthesis of benzocyclobutenes and endiandric acids.

Cyclobutanes are important motifs that have found utility in many contexts. Prior work has demonstrated an enantioselective isomerization/stereoselective [2 + 2] as a means to access bicyclo [4.2.0] octanes. Herein, the utility of this method is demonstrated towards the synthesis of benzocyclobutenes and a key intermediate towards the endiandric acids.

Arylboration of Enecarbamates for the Synthesis of Borylated Saturated N-Heterocycles.

Two catalytic systems have been developed for the arylboration of endocyclic enecarbamates to deliver synthetically versatile borylated saturated N-heterocycles in good regio- and diastereoselectivities. A Cu/Pd dual catalytic reaction enables the synthesis of borylated, α-arylated azetidines, while a Ni-catalysed arylboration reaction efficiently functionalizes 5-, 6-, and 7-membered enecarbamates. In the case of the Cu/Pd-system, a remarkable additive effect was identified that allowed for broader scope. The products are synthetically useful, as demonstrated by manipulations of the boronic ester to access biologically active compounds.

Photosensitized [2+2]-Cycloadditions of Alkenylboronates and Alkenes.

A new strategy for the synthesis of highly versatile cyclobutylboronates via the photosensitized [2+2]-cycloaddition of alkenylboronates and alkenes is presented. The process is mechanistically different from other processes in that energy transfer occurs with the alkenylboronate as opposed to the other alkene. This strategy allows for the synthesis of an array of diverse cyclobutylboronates. The conversion of these adducts to other compounds as well as their utility in the synthesis of melicodenine C is demonstrated.

Nickel-Catalyzed Dearomative Arylboration of Indoles: Regioselective Synthesis of C2- and C3-Borylated Indolines.

Indole dearomatization is an important strategy to access indolines: a motif present in a variety of natural products and biologically active molecules. Herein, a method for transition-metal catalyzed regioselective dearomative arylboration of indoles to generate diverse indolines is presented. The method accomplishes intermolecular dearomatization of simple indoles through a migratory insertion pathway on substrates that lack activating or directing groups on the C2- or C3-positions. Synthetically useful C2- and C3-borylated indolines can be accessed through a simple change in N-protecting group in high regio- and diastereoselectivities (up to >40:1 rr and >40:1 dr) from readily available starting materials. Additionally, the origin of regioselectivity was explored experimentally and computationally to uncover the remarkable interplay between carbonyl orientation of the N-protecting group on indole, electronics of the C2-C3 π-bond, and sterics. The method enabled the first enantioselective synthesis of (-)-azamedicarpin.

Ladderane Natural Products: From the Ground Up.

The ladderane family of natural products are well known for their linearly concatenated cyclobutane skeletal structure. Owing to their unique carbocyclic framework, several chemical syntheses have been reported since their discovery in 2002. The focus of this review is to showcase the novel tactics that have been used to generate the ladderane core and the challenges that are associated with the synthesis of these unusual and complex natural products.

Allenylidene Induced 1,2-Metalate Rearrangement of Indole-Boronates: Diastereoselective Access to Highly Substituted Indolines.

A process to achieve 1,2-metalate rearrangements of indole boronate as a way to access substituted indolines in high diastereoselectivities is presented. The reaction involves the generation of a Cu-allenylidene, which is sufficiently electrophilic to induce the 1,2-metalate rearrangement. The scope of the reaction is evaluated as well as further transformations of the product.

Modular Synthesis of a Versatile Double-Allylation Reagent for Complex Diol Synthesis.

Double-allylation reagents allow for the construction of highly complex molecules in an expedient fashion. We have developed an efficient, modular, and enantioselective approach towards accessing novel variants of these reagents through Cu/Pd-catalyzed alkenylboration of alkenylboron derivatives. Importantly, we demonstrate novel use of an allylBdan reagent directly in a stereocontrolled allylation without initial deprotection to the boronic ester. These allylation products are employed in a second intermolecular allylation to access complex diol motifs, which has yet to be shown with these types of double-allylation reagents. Overall, the modularity of this approach and the ease in which complex structural motifs can be accessed in a rapid manner signify the importance and utility of this method.

Evolution of a Strategy for the Enantioselective Synthesis of (-)-Cajanusine.

The first enantioselective synthesis of (-)-cajanusine is presented. Key features of the route include a rapid synthesis of the [4.2.0]bicyclooctane core by an enantioselective isomerization/stereoselective [2+2]-cycloaddition strategy as well as prominent use of catalytic methods for bond construction. The evolution of the approach is also presented that highlights unexpected roadblocks and how novel solutions were developed.

Regioselective Arylboration of 1,3-Butadiene.

A method for the regioselective 1,2-arylboration of 1,3-butadiene, a feedstock chemical, is reported. The reactions result in the formation of products that can be easily elaborated to other structures. The mechanistic details of this process are also discussed.