Access to Complex Scaffolds Through [2 + 2] Cycloadditions of Strained Cyclic Allenes.

We report the strain-induced [2 + 2] cycloadditions of cyclic allenes for the assembly of highly substituted cyclobutanes. By judicious choice of trapping agent, complex scaffolds bearing heteroatoms, fused rings, contiguous stereocenters, spirocycles, and quaternary centers are ultimately accessible. Moreover, we show that the resulting cycloadducts can undergo thermal isomerization. This study provides an alternative strategy to photochemical [2 + 2] cycloadditions for accessing highly functionalized cyclobutanes, while validating the use of underexplored strained intermediates for the assembly of complex architectures.

Determination of Enantiomeric Excess and Diastereomeric Excess via Optical Methods. Application to α-methyl-ß-hydroxy-carboxylic acids.

Characterization of chiral molecules in solution is paramount for measuring reaction success. However, techniques to distinguish between chiral molecules containing more than one stereocenter through the use of optical techniques remains a challenge. Herein, we report a techique using a series of circular dichroism spectra to train multivariate regression models that are capable of predicting the complete speciation of 3-hydroxy-2-methylbutanoic acid stereoisomers. From this, it is possible to rapidly and accurately determine the enantiomeric excess and diastereomeric excess of the solution without the need for chiral chromatography.

Catalyst-Controlled Annulations of Strained Cyclic Allenes with π-Allylpalladium Complexes.

Strained cyclic allenes are a class of in situ-generated fleeting intermediates that, despite being discovered more than 50 years ago, has received significantly less attention from the synthetic community compared to related strained intermediates. Examples of trapping strained cyclic allenes that involve transition metal catalysis are especially rare. We report the first annulations of highly reactive cyclic allenes with in situ-generated π-allylpalladium species. By varying the ligand employed, either of two isomeric polycyclic scaffolds can be obtained with high selectivity. The products are heterocyclic and sp3-rich and bear two or three new stereocenters. This study should encourage the further development of fragment couplings that rely on transition metal catalysis and strained cyclic allenes for the rapid assembly of complex scaffolds.

Interception of 1,2-cyclohexadiene with TEMPO radical.

Transient strained cyclic intermediates, such as strained cyclic allenes, are useful building blocks for the synthesis of structurally and stereochemically complex scaffolds. Trappings of strained cyclic allenes are thought to occur primarily through either two or one electron processes. Regarding the latter, diradical intermediates have been invoked in (2 + 2) cycloadditions and (3 + 2) nitrone cycloadditions. The present study questions if a monoradical pathway could exist for strained cyclic allene reactivity, as examined in the reaction of 1,2-cyclohexadiene and TEMPO radical. Our findings suggest the viability of this monoradical pathway.

Leveraging Fleeting Strained Intermediates to Access Complex Scaffolds.

Arynes, strained cyclic alkynes, and strained cyclic allenes were validated as plausible intermediates in the 1950s and 1960s. Despite initially being considered mere scientific curiosities, these transient and highly reactive species have now become valuable synthetic building blocks. This Perspective highlights recent advances in the field that have allowed access to structural and stereochemical complexity, including recent breakthroughs in asymmetric catalysis.

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.

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.