Enantioselective Synthesis of Pyrrolizin-1-ones via Lewis Base Catalyzed N-Allylation of N-Silyl Pyrrole Latent Nucleophiles

Abstract

Pyrrolizidine alkaloids and their derivatives often feature interesting biological activities. A class of substituted 2,3-dihydro-1H-pyrrolizin-1-one derivatives has been explored as a potential treatment for Alzheimer’s disease, but enantioselective synthesis of these molecules is still elusive. We report that enantioselective N-allylation of N-silyl pyrrole latent nucleophiles with allylic fluorides followed by hydrogenation and diastereoselective Friedel–Crafts cyclization constitute an efficient synthetic route to access enantioenriched substituted 2,3-dihydro-1H-pyrrolizin-1-ones.

Catalytic asymmetric defluorinative allylation of silyl enol ethers

“…Compelled by the excellent regio- and diastereoselectivity of the reaction, we studied its mechanism. We initially focused our attention on the exquisite diastereocontrol, as none of the catalytic defluorinative AAA reported to date 13–15 generate more than one stereogenic carbon. First, we questioned whether the ammonium intermediate A could be detected (Fig.…”

“…The common feature of all these defluorinative transformations 13–15 is that the silylated nucleophilic moieties do not comprise a prochiral center. Consequently, the corresponding allylated products bear only one stereogenic carbon (Fig.…”

Latent Pronucleophiles in Lewis Base Catalysis: Enantioselective Allylation of Silyl Enol Ethers with Allylic Fluorides

“…Reaction scope for allylic fluoride reflected the scope of the previously reported allylic substitutions with similar substrates. [4][5][6]8] Both electron rich (3 b-3 d) and electron poor (3 e-3 h) allylic fluorides gave moderate to excellent yields. When halogenated allylic fluorides (3 i-3 p) were used, the corresponding products were also obtained in good yields.…”

Latent Pronucleophiles in Lewis Base Catalysis: Enantioselective Allylation of Silylated Stabilized Carbon Nucleophiles with Allylic Fluorides

“…Reaction scope for allylic fluoride reflected the scope of the previously reported allylic substitutions with similar substrates. [4][5][6]8] Both electron rich (3b -3d) and electron poor (3e -3h) allylic fluorides gave moderate to excellent yields. When halogenated allylic fluorides (3i -3p) were used, the corresponding products were also obtained in good yields.…”

“…Alkyl fluorides (3u -3v) were competent under the standard conditions even though the yields dropped to around 50% due to a competing fluoride elimination. [8] The methyl, ethyl, nbutyl, benzyl, and t-butyl esters within the MBH fluoride (3o -3r) were suitable substrates albeit yields declined with the increase of steric bulk at the ester. More importantly, the scope for the silyl enol ethers proved to be universal.…”