The propargyl Claisen rearrangement is a known protocol to gain access to functionalized allenes through the [3,3]-sigmatropic transformation of propargyl vinyl ethers. The correct use of appropriate propargyl vinyl ethers as starting materials coupled with suitable reaction conditions can aid in the development of new domino methodologies in which the allenes are valuable intermediates in route to a wide range of important classes of organic compounds.

Generative chemical language models (CLMs) can be used for de novo molecular structure generation by learning from a textual representation of molecules. Here, we show that hybrid CLMs can additionally leverage the bioactivity information available for the training compounds. To computationally design ligands of phosphoinositide 3-kinase gamma (PI3Kγ), a collection of virtual molecules was created with a generative CLM. This virtual compound library was refined using a CLM-based classifier for bioactivity prediction. This second hybrid CLM was pretrained with patented molecular structures and fine-tuned with known PI3Kγ ligands. Several of the computer-generated molecular designs were commercially available, enabling fast prescreening and preliminary experimental validation. A new PI3Kγ ligand with sub-micromolar activity was identified, highlighting the method’s scaffold-hopping potential. Chemical synthesis and biochemical testing of two of the top-ranked de novo designed molecules and their derivatives corroborated the model’s ability to generate PI3Kγ ligands with medium to low nanomolar activity for hit-to-lead expansion. The most potent compounds led to pronounced inhibition of PI3K-dependent Akt phosphorylation in a medulloblastoma cell model, demonstrating efficacy of PI3Kγ ligands in PI3K/Akt pathway repression in human tumor cells. The results positively advocate hybrid CLMs for virtual compound screening and activity-focused molecular design.

In memory of Professor Rafael SuauPropargyl vinyl ethers (PVEs) 1 constitute a privileged group of small size, structurally simple, readily available, and densely functionalized scaffolds. [1][2][3][4] Efforts from our group, [2] and others, [3] have revealed the synthetic potential of these platforms in accessing important heterocyclic cores. The key to the chemical reactivity encoded in these structures is the [3,3] propargylic sigmatropic rearrangement [5] shown in Scheme 1. The allenyl compounds 2, thus obtained, are reactive units and well suited to participate in a wide array of chemical transformations. Thus, in the presence of metallic catalysts, they have been selectively transformed into furans, [3a-d] 2H-pyrans, [3e] dihydropyrans, [3f] 1,2-dihydropyridines, [3g] or pyrroles.[3h] Recently, we have described a metal-free, microwave-assisted domino synthesis of substituted 1,2-dihydropyridines [2c] and pyridines, [2d] from PVEs 1 and primary amines, via the thermally-assisted formation of a homoallenyl ester intermediate 2. During the course of these studies, we discovered a new chemical reactivity of these platforms when a solution of PVE 3 a in toluene was submitted to microwave (MW) irradiation in a sealed vial (Scheme 2). The reaction cleanly afforded the unexpected mixture of compounds 4 a and 5 a in 91 % overall yield. These structures featured an unprecedented chemical outcome for this domino process, which is enabled by the presence of a hydrogen atom at the homopropargylic position. Fascinated by these unexpected results, we undertook the study and scope of this novel domino reaction. Overall, this reaction should provide an expedient route to useful multifunctionalized phenolic platforms, [6] such as 4, which constitute key structural motifs for the preparation of numerous pharmacologically important natural products (e.g., coumarins, [7a] flavones, [7b] and several mycotoxins [7c] ) and catalysts.[8]In addition, PVEs 3 are easily accessible starting materials, spanning a wide substitution pattern. They are conveniently assembled from commercial sources (aldehydes, alkynes, and alkyl propiolates) in one or two straightforward synthetic steps.[2]We hypothesized that the formation of products 4 a and 5 a should result from a domino process triggered by the expected microwave-assisted rearrangement of PVE 3 a to the corresponding dienic ester 7 a, via the formation of a transi-

Malaria is a tropical parasitic disease threatening populations in tropical and sub-tropical areas. Resistance to antimalarial drugs has spread all over the world in the past 50 years, thus new drugs are urgently needed. Plasmodione (benzylmenadione series) has been identified as a potent antimalarial early lead drug, acting through a redox bioactivation on asexual and young sexual blood stages. To investigate its metabolism, a series of plasmodione-based tools, including a fully 13C-labelled lead drug and putative metabolites, have been designed and synthesized for drug metabolism investigation. Furthermore, with the help of UHPLC-MS/MS, two of the drug metabolites have been identified from urine of drug-treated mice.