Organocatalytic Enantioselective Conia‐Ene‐Type Carbocyclization of Ynamide Cyclohexanones: Regiodivergent Synthesis of Morphans and Normorphans

Abstract

Described herein is an organocatalytic enantioselective desymmetrizing cycloisomerization of arylsulfonyl‐protected ynamide cyclohexanones, representing the first metal‐free asymmetric Conia‐ene‐type carbocyclization. This method allows the highly efficient and atom‐economical construction of a range of valuable morphans with wide substrate scope and excellent enantioselectivity (up to 97 % ee). In addition, such a cycloisomerization of alkylsulfonyl‐protected ynamide cyclohexanones can lead to the divergent synthesis of normorphans as the main products with high enantioselectivity (up to 90 % ee). Moreover, theoretical calculations are employed to elucidate the origins of regioselectivity and enantioselectivity.

Recent advances towards organocatalytic enantioselective desymmetrizing reactions

“…Density functional theory (DFT) calculations identified (S)-configured enamines (1-A) as the key intermediates and 4-substituents imposed an enantiodetermining effect to some degree in the oxidation step. Subsequently, in 2019, the Ye group described an unprecedented metal-free Conia-ene-type carbocyclization of cyclohexanone-ynamides (3), promoting the regiodivergent construction of chiral morphans (4) and normorphans (5) with excellent enantioselectivities and diastereoselectivities, respectively (Figure 2B) [24][25][26]. In addition, theoretical studies rationalized that the regioselectivity was governed by the protecting group on the nitrogen atom as well as solvent.…”

“…(H) CPA-catalyzed asymmetric condensation of cyclic and acyclic 1,3-diketones. See[23,24,27,31,32,[34][35][36].…”

Catalytic asymmetric Nakamura reaction by gold(I)/chiral N,Nʹ-dioxide-indium(III) or nickel(II) synergistic catalysis

“…The addition of carbonyl compounds without prior enolate formation to unactivated alkynes is an attractive and atom economical method for carbon–carbon bond formation 1 . It results in the introduction of a vinyl substituent to vicinal position of carbonyl groups, possessing an important role in organic synthesis of natural products and drugs 2 – 5 . The intramolecular type, which is known as the Conia-ene reaction, generating cycloalkene derivatives, has achieved significant progress.…”