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
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.
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.
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).
• 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).
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.