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Cooperative Hydrogen-Bond-Donor Catalysis with Hydrogen Chloride Enables Highly Enantioselective Prins Cyclization Reactions

Dennis A. Kutateladze and Eric N. Jacobsen*

*Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States, Email:

D. A. Kutateladze, E. N. Jacobsen, J. Am. Chem. Soc., 2021, 143, 20077-20083.

DOI: 10.1021/jacs.1c10890

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Cooperative asymmetric catalysis with hydrogen chloride (HCl) and chiral dual-hydrogen-bond donors (HBDs) enables a highly enantioselective Prins cyclization of a wide variety of simple alkenyl aldehydes. The optimal chiral catalysts withstand the strongly acidic reaction conditions and induce rate accelerations of 2 orders of magnitude over reactions catalyzed by HCl alone.

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General procedure for enantioselective Prins reactions:

Hydrogen-bond donor catalyst (0.0111 g, 0.015 mmol, 5 mol%) and substrate (0.3 mmol, 1.0 eq.) were weighed directly into a flame-dried 20 mL scintillation vial charged with a magnetic stir bar. Anhydrous toluene (3 mL) was added, followed by a solution of anhydrous ethanol in anhydrous diethyl ether (45 L of a 2 M solution, 0.1 mmol, 0.3 eq.). Reactions were initiated by the addition of an ethereal solution of acetyl chloride (45 L of a 2 M solution, 0.1 mmol, 0.3 eq.) and were carried out at 23C. After completion of the reaction (as indicated by TLC analysis), a solution of KHMDS in THF (180 L of a 1 M solution, 0.180 mmol, 0.6 eq.) was added and a dark yellow color was seen to develop. After 10 minutes, the reaction mixture was passed through a plug of silica gel eluting with Et2O and concentrated in vacuo. The resulting residue was purified via flash column chromatography using Et2O and hexanes as the eluents to provide homoallylic alcohol products. Enantiomeric excess of cyclized products was evaluated following TMS derivatization.

Key Words

Prins reaction, chromans, organocatalysis

ID: J48-Y2021