Nature-inspired catalytic asymmetric rearrangement of cyclopropylcarbinyl cation

Sci Adv. 2023 May 10;9(19):eadg1237. doi: 10.1126/sciadv.adg1237. Epub 2023 May 10.


In nature, cyclopropylcarbinyl cation is often involved in cationic cascade reactions catalyzed by natural enzymes to produce a great number of structurally diverse natural substances. However, mimicking this natural process with artificial organic catalysts remains a daunting challenge in synthetic chemistry. We report a small molecule-catalyzed asymmetric rearrangement of cyclopropylcarbinyl cations, leading to a series of chiral homoallylic sulfide products with good to excellent yields and enantioselectivities (up to 99% enantiomeric excess). In the presence of a chiral SPINOL-derived N-triflyl phosphoramide catalyst, the dehydration of prochiral cyclopropylcarbinols occurs rapidly to generate symmetrical cyclopropylcarbinyl cations, which are subsequently trapped by thione-containing nucleophiles. A subgram-scale experiment and multiple downstream transformations of the sulfide products are further pursued to demonstrate the synthetic utility. Notably, a few heteroaromatic sulfone derivatives could serve as “covalent warhead” in the enzymatic inhibition of severe acute respiratory syndrome coronavirus 2 main protease.

PMID:37163601 | DOI:10.1126/sciadv.adg1237


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