Synthesis of Cycloheptatriene-Containing Azetidine Lactones

Abstract

We prepared a collection of complex cycloheptatriene-containing azetidine lactones by applying two key photochemical reactions: “aza-Yang” cyclization and Buchner carbene insertion into aromatic rings. While photolysis of phenacyl amines leads to a rapid charge transfer and elimination, we found that a simple protonation of the amine enables the formation of azetidinols as single diastereomers. We provide evidence, through ultrafast spectroscopy, for the electron transfer from free amines in the excited state. Further, we characterize the aza-Yang reaction by establishing the dependence of the initial reaction rates on the rates of photon absorption. An unanticipated change in reactivity in morpholine analogues is explained through interactions with the tosylate anion. The Buchner reaction proceeds with a slight preference for one diastereomer over the other, and successful reaction requires electron-donating carbene-stabilizing substituents. Overall, 16 compounds were prepared over seven steps. Guided by an increase in structural complexity, efforts such as this one extend the reach of chemists into unexplored chemical space and provide useful quantities of new compounds for studies focused on their properties.

Twisted Intramolecular Charge-Transfer State Addition to Electron-Poor Olefins

“…We were intrigued by this switch in reactivity that yields azetidines�a class of saturated heterocycles that we earlier accessed through an "aza-Yang" reaction. 4 Upon repeating their experiments, we isolated the compound and found that the NMR spectra matched those reported. However, the lower polarity of the compound compared to the starting material (as indicated by its greater mobility on a normal phase thin-layer chromatography plate), and several inconsistencies in chemical shifts, prompted us to reinvestigate this assignment.…”

“…This compound, referred to as an “abnormal photoadduct,” differs from the typical spirocyclic pyrrolidines that are usually formed under similar conditions with unsubstituted phenyl analogues. We were intrigued by this switch in reactivity that yields azetidinesa class of saturated heterocycles that we earlier accessed through an “aza-Yang” reaction . Upon repeating their experiments, we isolated the compound and found that the NMR spectra matched those reported.…”

Spacial Score – A Comprehensive Topological Indicator for Small Molecule Complexity

“…[14] It has generated significant interest, resulting in a rapid increase in its popularity since its introduction, notably by the organic synthesis community. [23][24][25][26][27][28][29] Considering the general interest in this scoring system and apparent improvement over the alternative complexity measures, we explored whether the Böttcher complexity score may also serve as a descriptor that could correlate compound complexity with biological activity and selectivity. In this case it might be employed to rationalize trends observed in the biological analysis of our in-house compound libraries.…”

Spacial Score─A Comprehensive Topological Indicator for Small-Molecule Complexity

“…The Böttcher score C m is inspired by the Shannon entropy and defines molecular complexity in an additive manner by the consideration of atomic connectivity, the number of valence electrons for atoms, heteroatom diversity, stereogenicity, and molecular symmetry. It has generated significant interest, resulting in a rapid increase in its popularity since its introduction, notably by the organic synthesis community. − Considering the general interest in this scoring system and apparent improvement over the alternative complexity measures, we explored whether the Böttcher complexity score may also serve as a descriptor that could correlate compound complexity with biological activity and selectivity. In this case, it might be employed to rationalize trends observed in the biological analysis of our in-house compound libraries.…”