Skeletal Alteration of Bioactive Polycyclic Molecules by Catalytic Ring-Opening/Cross-Metathesis

Informazioni relative al progetto

METEDIT

ID dell’accordo di sovvenzione: 101150431

DOI

10.3030/101150431

Progetto concluso il 12 Febbraio 2025

Data della firma CE 19 Marzo 2024

Data di avvio 1 Maggio 2024

Data di completamento 30 Aprile 2026

Finanziato da

• Marie Skłodowska-Curie Actions (MSCA)

Costo totale

Nessun dato

Contributo UE

€ 211 754,88

Coordinato da

UNIVERSITE DE STRASBOURG
France

Periodic Reporting for period 1 - METEDIT (Skeletal Alteration of Bioactive Polycyclic Molecules by Catalytic Ring-Opening/Cross-Metathesis)

Periodo di rendicontazione: 2024-05-01 al 2026-04-30

Sintesi del contesto e degli obiettivi generali del progetto

The aim of the project was to develop an efficient and stereoselective ring-opening cross-metathesis (ROCM) method between small-ring cyclic alkenes and dihalogenated ethylenes, which could then serve as a platform for framework editing of complex bioactive molecules. Specific objectives included:
1) Development of ROCM between 5- to 8-membered cyclic alkenes and Z-1,2-dichloroethylene (Z-DCE), leading to formation of various stereodefined (bis)alkenyl chloride products.
2) Expansion of the above strategy to other Z- or E-dihalogenated ethylenes.
3) Application to late-stage skeletal modification of androstadiene and vindoline as representative polycyclic bioactive compounds.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

WP1 focused on the identification of optimal catalysts and conditions for stereoretentive ROCM between cyclohexene and dihalogenated ethylenes. Key achievements include:
• Preparation of a series of Mo-based cyclic alkylidene complexes.
• Optimization of ROCM between cyclohexene and Z-dichloroethylene (Z-DCE).
• Investigation on ROCM with E-DCE and discovery of primary side-reaction pathway attributed to low stereo- and chemoselectivity.

WP2 involved investigations on ROCM with other cyclic olefins. The researcher started with ROCM of 1-methylcyclohexene. Typically, in the presence of 5.0 mol % of a seven-membered pentafluorophenylimido cyclic MAP, ROCM with 1-methylcyclopentene was efficient (>98% conv), allowing us to isolate the diene in 82% yield with high stereoretentivity (91:9 and 90:10 Z:E for di- and trisubstituted alkenyl chloride, respectively). Whereas the catalyst derived from adamantylimido-bearing cyclic MAP was less effective (31% conv), there was >98% conv to (bis)alkenyl chloride with previous acyclic MAP, the Z:E selectivity of which was diminished. ROCM was more efficient with methyl-cyclopentene compared to when cyclohexene served as the substrate. This counter-intuitive finding may be attributed to greater ring strain of the smaller ring (5.0 kcal/mol vs 2.5 kcal/mol for cyclohexene).

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

Scientific Impact: The project addressed a long-standing challenge in the field of olefin metathesis, namely the lack of broadly applicable and stereoselective methods for ROCM of low-strain cyclic alkenes. The present work successfully demonstrated the feasibility of applying newly developed cyclic molybdenum-based alkylidene complexes to enable Z-retentive transformations. The outcomes of WP1 as well as WP2 lay the groundwork for further exploration of late-stage skeletal editing of bioactive molecules, a direction that holds significant promise for organic synthesis and drug discovery.