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.

Synthesis of complex bicyclic scaffolds by intermolecular photosensitized dearomative cycloadditions of activated alkenes and naphthalenes.

The rapid buildup of molecular complexity from simple precursors is a key goal in organic chemistry. One strategy to achieve this is through a dearomative cycloaddition wherein a 2D arene and alkene is converted to a 3D structure. In many cases this type of reactivity has been achieved with photochemistry. Despite the prospect of such a reaction, most known variants are intramolecular, which greatly limits the scope of chemical space that can be accessed. Intermolecular variants are known but are generally limited to heterocyclic systems such as indoles or quinolines. Herein, a method for intermolecular dearomative cycloaddition of simple naphthalenes with alkenes is presented. The reactions operate by a photoinduced sensitization of the arene. The bridged bicyclic products are generated with control of regiochemistry and function for a range of alkenes. In addition, the products can serve as useful intermediates as demonstrated in the synthesis of a biologically active benzazapine analog. Mechanistic studies are also included, which support reaction via a triplet excited state and that the selectivity can be rationalized by spin-density calculations.

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.

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.

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.

Photochemical intermolecular dearomative cycloaddition of bicyclic azaarenes with alkenes.

Dearomative cycloaddition reactions represent an ideal means of converting flat arenes into three-dimensional architectures of increasing interest in medicinal chemistry. Quinolines, isoquinolines, and quinazolines, despite containing latent diene and alkene subunits, are scarcely applied in cycloaddition reactions because of the inherent low reactivity of aromatic systems and selectivity challenges. Here, we disclose an energy transfer-mediated, highly regio- and diastereoselective intermolecular [4 + 2] dearomative cycloaddition reaction of these bicyclic azaarenes with a plethora of electronically diverse alkenes. This approach bypasses the general reactivity and selectivity issues, thereby providing various bridged polycycles that previously have been inaccessible or required elaborate synthetic efforts. Computational studies with density functional theory elucidate the mechanism and origins of the observed regio- and diastereoselectivities.

Enantioselective Synthesis of (+)-Hippolide J and Reevaluation of Antifungal Activity.

A synthesis of the reported antifungal agent (+)-hippolide J is presented. The rapid assembly of the natural product was enabled through implementation of an enantioselective isomerization/[2 + 2]-cycloaddition sequence. Due to the simplicity of the route, >100 mg of the natural product were prepared in a single pass. Anitfungal assays of hippolide J, however, confirmed that it showed no activity against several fungal strains, contrary to the isolation report.

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.

Formal Total Synthesis of Hybocarpone Enabled by Visible-Light-Promoted Benzannulation.

The formal total synthesis of hybocarpone was achieved in eight steps from commercially available 1,2,4-trimethoxybenzene. Key transformations include a visible-light-promoted benzannulation to construct the key α-naphthol intermediate and a modified CAN-mediated dimerization/hydration cascade sequence to generate the vicinal all-carbon quaternary centers in a stereocontrolled manner. The total synthesis of boryquinone was also achieved in seven steps.