esermethole and 2-oxindole

The first enantioselective total syntheses of architecturally interesting prenylated pyrroloindole alkaloids, (-)-pseudophrynamines 272A (3d) and 270 (3b), have been achieved starting from enantioenriched 2-oxindoles having all-carbon quaternary stereocenters. A common strategy involving a thio-urea catalyzed aldol reaction is employed for the total synthesis of both spiro(pyrrolidinyl-oxindole) and hexahydropyrrolo[2,3-b]indole alkaloids.

Topics: Aldehydes; Aniline Compounds; Catalysis; Indole Alkaloids; Indoles; Molecular Structure; Oxindoles; Physostigmine; Prenylation; Spiro Compounds; Stereoisomerism

The first phosphine-catalyzed enantioselective γ-addition with prochiral nucleophiles and 2,3-butadienoates as the reaction partners has been developed. Both 3-alkyl- and 3-aryl-substituted oxindoles could be employed in this process, which is catalyzed by a chiral phosphine that is derived from an amino acid, thus affording oxindoles that bear an all-carbon quaternary center at the 3-position in high yields and excellent enantioselectivity. The synthetic value of these γ-addition products was demonstrated by the formal total synthesis of two natural products and by the preparation of biologically relevant molecules and structural scaffolds.

Topics: Allyl Compounds; Biological Products; Catalysis; Fatty Acids, Unsaturated; Indoles; Iridium; Oxindoles; Phosphines; Physostigmine; Stereoisomerism

Oxindoles and their indoline derivatives are common structural motifs found in a wide array of natural and biologically active molecules. Most catalytic methods for the asymmetric syntheses of these compounds rely heavily on the use of transition-metal catalysts. In contrast, alternative catalytic procedures involving organocatalysis are scarce. Herein we disclose a conceptually novel organocatalytic approach to the syntheses of these materials using thiourea-catalyzed asymmetric 1,4-additions of oxindole derivatives to nitroolefins as a key step. These addition reactions create up to two stereogenic centers, one of which is a quaternary center. These reactions are broad in scope with respect to both the oxindole and nitroolefin substrates and provide the desired products in good yields with enantioselectivities of up to 99% and diastereoselectivities of up to >20:1. To demonstrate the utility of this approach, (+)-esermethole was synthesized in good overall yield over 3 steps starting from the 1,4-addition product, thereby providing a formal synthesis of (+)-physostigmine.

Topics: Alkenes; Catalysis; Cholinesterase Inhibitors; Indoles; Molecular Structure; Nitro Compounds; Oxindoles; Physostigmine; Stereoisomerism; Thiourea