Concise and Convergent Enantioselective Total Syntheses of (+)- and (−)-Fumimycin

Abstract

The concise and convergent total syntheses of (+)-and (−)-Fumimycin have been achieved by taking advantage of strategies for the asymmetric aza-Friedel−Crafts reaction of a highly substituted hydroquinone and N-fumaryl ketimine generated from the corresponding dehydroalanine. The enantiomerically pure natural product and its enantiomer were prepared in seven steps and 22% overall yield by employing both enantiomers of a BINOL-derived chiral phosphoric acid (CPA) catalyst.

In the Pursuit of (Ald)Imine Surrogates for the Direct Asymmetric Synthesis of Non-Proteinogenic α-Amino Acids

“…Soon thereafter, Piersanti reported a more successful enantioselective version of the aza-Friedel-Crafts alkylation with CPA catalyst C12 (up to 30% e.e., Scheme 17B). 27 This reaction proceeded with concomitant lactonization to obtain the (-)fumimycin core structure in a single step. Both of these studies further demonstrate that the asymmetric synthesis of quaternary α-alkyl α,α-disubstituted NPAAs remains challenging and that Nacyl enamines (enecarbamates and enamides) can serve as valuable surrogates of reactive ketimine by tautomerization.…”

“…Soon thereafter, Piersanti reported a more successful enantioselective version of the aza-Friedel-Crafts alkylation with CPA catalyst C12 (up to 30% e.e., Scheme 17B). 27 This reaction proceeded with concomitant lactonization to generate the (-)-fumimycin core structure in a single step. Both of these…”

Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis

“…In 2019, Piersanti and co‐workers reported an enantioselective total synthesis of (‐)‐fumimycin ( 450 ) and its enantiomer (+)‐fumimycin via an organocatalytic asymmetric aza‐Friedel‐Crafts reaction (Scheme 48). [95] Using the BINOL‐derived chiral phosphoric acid 447 as the catalyst, an asymmetric aza‐Friedel‐Crafts reaction between highly substituted hydroquinone 445 and dehydroalanine derivative 446 led to the formation of the desired optically active lactone 448 regioselectively. Removing the methyl protecting group in 448 yielded (−)‐fumimycin methyl ester ( 449 ).…”

“…Cleavage of the methyl ester of 449 gave (−)‐fumimycin ( 450 ) (Scheme 48). Use the enantiomer of 447 as the catalyst, (+)‐fumimycin was obtained with the same yield and almost opposite enantioselectivity [95] …”

“…Use the enantiomer of 447 as the catalyst, (+)-fumimycin was obtained with the same yield and almost opposite enantioselectivity. [95] In 2020, Uria, Merino, Vicario, and co-workers reported an enantioselective total synthesis of (À )-α-tropanol (455) and (+)-ferruginine (460, Scheme 49). [96] They first realized an asymmetric pseudotransannular ring-opening of epoxycycloheptylamines using a chiral phosphoric acid 452 as the catalyst.…”