Enantioselective Potassium-Catalyzed Wittig Olefinations
Jake Z. Essman, Eric N. Jacobsen*
*Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States,
Email: jacobsen
chemistry.harvard.edu
J. Z. Essman, E. N. Jacobsen, J. Am. Chem. Soc., 2024, 146, 7165-7172.
DOI: 10.1021/jacs.4c00564
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Abstract
A chiral potassium isothiourea boronate catalyzes Wittig olefinations of 4-substituted cyclohexanones with non-stabilized phosphorus ylides to afford highly enantioenriched axially chiral alkenes. A Lewis acid mediated olefination results in the formation of the oxaphosphetane adduct under cryogenic conditions. Thermal fragmentation of the oxaphosphetane provides the alkene product.
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proposed catalytic cycle
Details
The document discusses a study on enantioselective potassium-catalyzed Wittig olefinations of 4-substituted cyclohexanones using a novel potassium-isothiourea-boronate complex. The Wittig reaction, a key method for stereoselective alkene synthesis, typically involves a carbonyl compound and a phosphorus ylide forming oxaphosphetane intermediates. This study introduces a highly enantioselective catalytic system, achieving up to 92% enantiomeric excess (ee) with the optimal catalyst featuring a macrocyclic amide-potassium-boronate chelate. The mechanism involves a stepwise cycloaddition forming a potassium betaine complex, followed by cycloreversion to yield the alkene. The study highlights the superior performance of potassium-based catalysts over lithium and sodium analogues. Structural and kinetic analyses reveal that the catalyst's unique chelation mode and moderate Lewis acidity are crucial for its high enantioselectivity. The scope of the reaction includes various cyclohexanone and ylide derivatives, with high yields and enantioselectivities. Computational studies support the proposed mechanism and enantioinduction model. The findings suggest potential applications in other alkali-metal-mediated transformations, emphasizing the importance of catalyst structure in achieving high enantioselectivity.
General procedures for enantioselective catalytic Wittig olefinations
Preparation of 0.5 M phosphorus ylide stock solution: An oven-dried 2-dram septum-top vial with a magnetic stir bar was charged with dry phosphonium salt (1.2 mmol, 1.2 equiv). The vial threads were wrapped with Teflon tape, the vial was sealed with a septum-top screw cap, and the vial was put through three vacuum-N2 cycles to provide an inert atmosphere. A solution of potassium hexamethyldisilazide (KHMDS) (2000 μL, 0.5 M in PhMe, 1.0 mmol, 1 equiv) was added via syringe with rapid stirring. The inert gas needle was removed; the top of the vial was wrapped with Parafilm; and the mixture was stirred rapidly at RT for 1 hour. The resulting orange suspension was centrifuged at 3000 rpm for 10 minutes. The resulting air-sensitive clear red-orange supernatant solution of phosphorus ylide was measured via N2-flushed 1-mL syringe for addition to the reaction mixture, assuming a roughly 0.5 M titer.
Preparation of 16.7 mM catalyst stock solution: An oven-dried 2-dram septum-top vial was charged with isothiourea-boronate precatalyst 3f (32.0 mg, 0.04 mmol, 1 equiv). The vial threads were wrapped with Teflon tape, the vial was sealed with a septum-top screw cap, and the vial was put through three vacuum-N2 cycles to provide an inert atmosphere. Dry PhMe (2300 μL) was added via syringe, swirling to dissolve the solid. A solution of KHMDS (88 μL, 0.5 M in PhMe, 0.044 mmol, 1.1 equiv) was added via micro-syringe, and the mixture was homogenized briefly on a vortex mixer. The resulting air-sensitive light-yellow solution of K-3f was measured via N2-flushed 1-mL syringe for addition to the reaction mixture.
Running the reaction: An oven-dried 1.5-dram septum-top vial with a magnetic stir bar was charged with solid ketone substrate (0.1 mmol, 1 equiv). The vial threads were wrapped with Teflon tape, the vial was sealed with a septum-top screw cap, and the vial was put through three vacuum-N2 cycles to provide an inert atmosphere. Volatile liquid ketone substrates were added via micro-syringe to the inert-gas-filled vial. The vial was charged with dry PhMe (700 μL) and a stock solution of catalyst K-3f (600 μL, 16.7 mM in PhMe, 0.01 mmol, 10 mol%). The reaction mixture was stirred at RT for 2 minutes, then cooled to -78 °C and stirred for 5 minutes. A solution of phosphorus ylide (300 μL, 0.5 M in PhMe, 0.15 mmol, 1.5 equiv) was added dropwise at a rate of 1 drop per second. The reaction vial was transferred to a -80 °C freezer and stirred for 24 hours. The reaction mixture was removed from the freezer and stirred at RT for 20 minutes to convert the intermediate oxaphosphetane to the axially chiral alkene product. The reaction mixture was diluted with Et2O (2 mL), loaded onto a plug of SiO2 in a pipette, eluted with Et2O (4 CV), and concentrated under reduced pressure to afford a colorless oil. Purification by flash column chromatography (0 to 10% Et2O in hexanes) afforded the alkene product as a colorless oil.
Analysis of enantiomeric excess: Purified alkene products were subjected to chiral SFC analysis or chiral GC analysis to determine their enantiomeric excess (ee). Racemic standards were obtained using the procedure described above, in the absence of chiral catalyst K-3f. In cases where the alkene enantiomers could not be separated on a chiral column, epoxidation with mCPBA was carried out as described below; at least one of the resulting epoxide diastereomers could typically afford baseline enantiomer separation by chiral SFC to obtain the ee of the axially chiral alkene product, assuming stereospecific epoxidation by mCPBA. Alkene product epoxidation: A 1-dram vial with a magnetic stir bar was charged with purified axially chiral alkene product (5) (~ 0.1 mmol, 1 equiv) and CH2Cl2 (500 μL). The reaction mixture was cooled to 0 °C with rapid stirring, and a solution of mCPBA (23 mg, ~ 77% pure, ~ 0.1 mmol, 1 equiv) in CH2Cl2 (200 μL) was added dropwise. The mixture was stirred at 0 °C for 1 hour, then quenched with 1:1 water:saturated aqueous K2CO3 (1 mL). The organic layer was separated, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Flash column chromatography (0 to 25% Et2O in hexanes) afforded the epoxide product as a mixture of diastereomers.
Key Words
ID: J48-Y2024
