Organocatalyzed Enantioselective Synthesis of Quaternary Carbon‐Containing Isoindolin‐1‐ones

Abstract

Keywords: Synthetic methods / Asymmetric catalysis / Enantioselectivity / Nitrogen heterocycles / Alkylation 3,3Ј-Triphenylsilyl-substituted (S)-BINOL-based (1,1Ј-bi-2-naphthol) phosphoric acid has proven to be an effective organocatalyst for the asymmetric Friedel-Crafts alkylation of indoles with 3-substituted 3-hydroxyisoindolin-1-ones, affording the corresponding quaternary carbon-containing 3,3-disubstituted isoindolin-1-ones in good yields (up to 99 %)

Solvent‐Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII‐Catalyzed C−H Activation

“…Despite the moderate enantiocontrol for the formation of the chiral allene,t he Z-monofluoroalkenyl isoindolinones and alkynyl isoindolinones were obtained in good enantiopurities by one or two sequential kinetic resolution processes.The skeleton of 3,3-disubstituted isoindolin-1-ones bearing atetrasubstituted stereogenic carbon center at the 3-position is common in natural products and drug candidates,f or example,i na ni nhibitor for the microsomal triglyceride transfer protein (MTP) and apolipoprotein B( Apo B) secretion, [1] in ap otential drug for the treatment of cardiac arrhythmias, [2] and in ar enin inhibitor [3] for regulating blood pressure ( Figure 1). As to the enantioselective construction of chiral 3,3disubstituted isoindolin-1-ones,m any elegant methods have been developed based on either organocatalysis [4] or transition-metal catalysis. [5] However,t he substrates were mainly limited to 3-hydroxyisoindolinones,a lkenyl benzamides,a nd N-halobenzoyl indoles.W hereas transition-metal-catalyzed CÀHa ctivation has shown great potential [6] in terms of expanding the structural diversity of available isoindolinone motifs,asymmetric variants remain extremely rare and highly challenging.…”

“…As to the enantioselective construction of chiral 3,3disubstituted isoindolin-1-ones,m any elegant methods have been developed based on either organocatalysis [4] or transition-metal catalysis. [5] However,t he substrates were mainly limited to 3-hydroxyisoindolinones,a lkenyl benzamides,a nd N-halobenzoyl indoles.W hereas transition-metal-catalyzed CÀHa ctivation has shown great potential [6] in terms of expanding the structural diversity of available isoindolinone motifs,asymmetric variants remain extremely rare and highly challenging.…”

Enantioselective Reactions of N‐Acyliminium Ions Using Chiral Organocatalysts

“…The expected quaternary carbon-containing 3,3-disubstitutent isoindolin-1-one 63 was obtained in excellent yield (up to 99 %) with good to excellent enantioselectivities (up to 99 %), thereby indicating that the choice of catalyst is very important to for the enantioselectivity. [85] The substitution of the indole ring with either electron-donating or electron-withdrawing groups was well tolerated, and this led to the formation of the desired product in good to excellent yield. However, the conversion and enantioselectivity were dependent on the temperature, solvent, indole substituents, and the concentration of the reaction mixture.…”

Imine and iminium precursors as versatile intermediates in enantioselective organocatalysis

“…Having received poor results with a 3-alkyl-3-hydroxyisoindolin-1-one in the first study, they later tackled the synthesis of quaternary stereocenters with slight changes in methodology, again obtaining the products in good yields and good to excellent enantioselectivities (Scheme 13). 29 Scheme 10. Chiral BINOL-phosphoramide-catalyzed FriedeleCrafts reaction.…”