Total Synthesis of Lissodendoric Acid A.

We describe a full account of our synthetic strategy leading to the first total synthesis of the manzamine alkaloid lissodendoric acid A . These efforts demonstrate that strained cyclic allenes are valuable synthetic building blocks and can be employed efficiently in total synthesis.

Generation and reactivity of unsymmetrical strained heterocyclic allenes.

Strained cyclic allenes are short-lived intermediates that confine a functional group with a preferred linear geometry, an allene, into a small ring, inducing strain-driven reactivity. Nitrogen-containing variants, or azacyclic allenes, have proved valuable for the assembly of complex nitrogen-containing compounds. Whereas 3,4-azacyclic allenes, which bear a symmetrical core, have been the focus of multiple studies, their unsymmetrical 2,3-azacyclic counterparts have remained underexplored. In the present study, we report density functional theory studies investigating the structure of such unsymmetrical azacyclic allenes and experimental efforts to access and engage them in strain-promoted cycloadditions under mild conditions. Control experiments support either concerted or stepwise diradical mechanisms for these reactions, depending on the type of cycloaddition examined. Moreover, we generate the corresponding 2,3-oxacyclic allene and demonstrate its reactivity in cycloadditions and a metal-catalysed process. Given the scaffolds accessed, coupled with the observed selectivity trends, these results are expected to encourage the application of unsymmetrical heterocyclic allenes for the synthesis of heterocycles that bear a high fraction of sp3-hybridized atoms.

Facile synthesis of 2-aza-9,10-diphenylanthracene and the effect of precise nitrogen atom incorporation on OLED emitters performance.

Polycyclic aromatic hydrocarbons (PAHs) are important compounds in materials chemistry, particularly for optoelectronic applications. One strategy for tuning PAH properties involves the net exchange of carbon atoms for heteroatoms, such as nitrogen. We report a comparative study of the well-known fluorophore 9,10-diphenylanthracene with an aza analog. The latter compound is accessed using a short sequence involving the use of two strained cyclic alkynes, benzyne and a 3,4-piperidyne, in Diels-Alder cycloaddition sequences. Comparative studies of 9,10-diphenylanthracene and the aza-analog show how the addition of a single nitrogen atom impacts electrochemical and optical properties. Organic light-emitting diode (OLED) devices were prepared using both compounds, which showed that nitrogen substitution leads to an unexpected red shift in electroluminescence, likely due to exciplex formation between the active layer and the 4,4'-N,N'-bis[N-(1-naphthyl)-N-phenylamino]biphenyl (NPB) hole-transport layer. These studies highlight a unique approach to accessing heteroatom-containing PAHs, while underscoring the impact of heteroatoms on OLED device performance.

Strain-promoted reactions of 1,2,3-cyclohexatriene and its derivatives.

Since 18251, compounds with the molecular formula C6H6-most notably benzene-have been the subject of rigorous scientific investigation2-7. Of these compounds, 1,2,3-cyclohexatriene has been largely overlooked. This strained isomer is substantially (approximately 100 kcal mol-1) higher in energy compared with benzene and, similar to its relatives benzyne and 1,2-cyclohexadiene, should undergo strain-promoted reactions. However, few experimental studies of 1,2,3-cyclohexatriene are known8-12. Here we demonstrate that 1,2,3-cyclohexatriene and its derivatives participate in a host of reaction modes, including diverse cycloadditions, nucleophilic additions and σ-bond insertions. Experimental and computational studies of an unsymmetrical derivative of 1,2,3-cyclohexatriene demonstrate the potential for highly selective reactions of strained trienes despite their high reactivity and short lifetimes. Finally, the integration of 1,2,3-cyclohexatrienes into multistep syntheses demonstrates their use in rapidly assembling topologically and stereochemically complex molecules. Collectively, these efforts should enable further investigation of the strained C6H6 isomer 1,2,3-cyclohexatriene and its derivatives, as well as their application in the synthesis of important compounds.

Palladium-Catalyzed Annulations of Strained Cyclic Allenes.

We report Pd-catalyzed annulations of in situ generated strained cyclic allenes. This methodology employs aryl halides and cyclic allene precursors as the reaction partners in order to generate fused heterocyclic products. The annulation proceeds via the formation of two new bonds and an sp3 center. Moreover, both diastereo- and enantioselective variants of this methodology are validated, with the latter ultimately enabling the rapid enantioselective synthesis of a complex hexacyclic product. Studies leveraging transition metal catalysis to intercept cyclic allenes represent a departure from the more common, historical modes of cyclic allene trapping that rely on nucleophiles or cycloaddition partners. As such, this study is expected to fuel the development of reactions that strategically merge transition metal catalysis and transient strained intermediate chemistry for the synthesis of complex scaffolds.

Intercepting fleeting cyclic allenes with asymmetric nickel catalysis.

Strained cyclic organic molecules, such as arynes, cyclic alkynes and cyclic allenes, have intrigued chemists for more than a century with their unusual structures and high chemical reactivity1. The considerable ring strain (30-50 kilocalories per mole)2,3 that characterizes these transient intermediates imparts high reactivity in many reactions, including cycloadditions and nucleophilic trappings, often generating structurally complex products4. Although strategies to control absolute stereochemistry in these reactions have been reported using stoichiometric chiral reagents5,6, catalytic asymmetric variants to generate enantioenriched products have remained difficult to achieve. Here we report the interception of racemic cyclic allene intermediates in a catalytic asymmetric reaction and provide evidence for two distinct mechanisms that control absolute stereochemistry in such transformations: kinetic differentiation of allene enantiomers and desymmetrization of intermediate π-allylnickel complexes. Computational studies implicate a catalytic mechanism involving initial kinetic differentiation of the cyclic allene enantiomers through stereoselective olefin insertion, loss of the resultant stereochemical information, and subsequent introduction of absolute stereochemistry through desymmetrization of an intermediate π-allylnickel complex. These results reveal reactivity that is available to cyclic allenes beyond the traditional cycloadditions and nucleophilic trappings previously reported, thus expanding the types of product accessible from this class of intermediates. Additionally, our computational studies suggest two potential strategies for stereocontrol in reactions of cyclic allenes. Combined, these results lay the foundation for the development of catalytic asymmetric reactions involving these classically avoided strained intermediates.

Silyl Tosylate Precursors to Cyclohexyne, 1,2-Cyclohexadiene, and 1,2-Cycloheptadiene.

Transient strained cyclic intermediates have become valuable intermediates in modern synthetic chemistry. Although silyl triflate precursors to strained intermediates are most often employed, the instability of some silyl triflates warrants the development of alternative precursors. We report the syntheses of silyl tosylate precursors to cyclohexyne, 1,2-cyclohexadiene, and 1,2-cycloheptadiene. The resultant strained intermediates undergo trapping in situ to give cycloaddition products. Additionally, the results of competition experiments between silyl triflates and silyl tosylates are reported.

Safety Assessment of Benzyne Generation from a Silyl Triflate Precursor.

Silyl triflate precursors to benzyne and related intermediates have emerged as valuable synthetic building blocks. However, data addressing the safety of employing these silyl triflate precursors are lacking. We report the calorimetric analysis of a typical Kobayashi procedure for forming and trapping benzyne using a silyl triflate precursor. Our findings suggest that, unlike benzenediazonium carboxylate precursors to benzyne, silyl triflates may be employed under mild conditions without severe concern for runaway reaction.

Bioinspired Design Provides High-Strength Benzoxazine Structural Adhesives.

A synthetic strategy to incorporate catechol functional groups into benzoxazine thermoset monomers was developed, leading to a family of bioinspired small-molecule resins and main-chain polybenzoxazines derived from biologically available phenols. Lap-shear adhesive testing revealed a polybenzoxazine derivative with greater than 5 times improved shear strength on aluminum substrates compared to a widely studied commercial benzoxazine resin. Derivative synthesis identified the catechol moiety as an important design feature in the adhesive performance and curing behavior of this bioinspired thermoset. Favorable mechanical properties comparable to commercial resin were maintained, and glass transition temperature and char yield under nitrogen were improved. Blending of monomers with bioinspired main-chain polybenzoxazine derivatives provided formulations with enhanced shear adhesive strengths up to 16 MPa, while alloying with commercial core-shell particle-toughened epoxy resins led to shear strengths exceeding 20 MPa. These results highlight the utility of bioinspired design and the use of biomolecules in the preparation of high-performance thermoset resins and adhesives with potential utility in transportation and aerospace industries and applications in advanced composites synthesis.