Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols

Abstract

Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93−98% ee). The obtained products are important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as octahydrobenzo[h]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16 representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique profile and a clear morphological change.

Horizons in Asymmetric Organocatalysis: En Route to the Sustainability and New Applications

“…We would like to comment on a pivotal recent example, since sometimes it is difficult to separate a multicomponent reaction from a cascade process, and the complexity of both processes together can be of extraordinary elegance [73]. Recently, Jørgensen and co-workers reported an amazing example of an organocatalytic multicomponent cascade process via dienamine catalysis, involving at the same time a cycloaddition, a nucleophilic addition, and a ring-opening reaction between uncommon isobenzopyrylium precursors, α,β-unsaturated aldehydes, and H 2 O [74]. The process was successfully developed to prepare chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield (up to 95%), high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93−98% ee) (Scheme 4).…”

Brønsted Acid Catalyzed Oxocarbenium-Olefin Metathesis/Rearrangements of 1H-Isochromene Acetals with Vinyl Diazo Compounds

“…These intriguing transformations are initiated by concerted [5 + 4]- or [4 + 2]-cycloadditions of vinyl diazo compounds with gold complex-stabilized isobenzopyrylium intermediates, followed by ring opening and rearrangement. Instead of gold catalysis with ortho-alkynylbenzaldehydes, we surmised that the reaction of 1 H -isochromene acetal with Brønsted acid catalysts would give ionic isobenzopyrylium salts that could also undergo vinylogous addition to vinyl diazo compounds with overall [4 + 3]-cycloaddition like that of Scheme b through vinyl diazonium and vinyl carbocation intermediates. Instead, we discovered a metathesis transformation that forms tunable rearranged products in high yields and diastereoselectivities.…”

A simple iodine–DMSO-promoted multicomponent reaction for the synthesis of 2,4-disubstituted dihydrotriazole-3-ones

“…Multicomponent reactions (MCRs) have the advantages of simpler procedures, atom economy and product complexity. They have attracted increasing interest in synthetic, [17][18][19] materials 20 and pharmaceutical chemistry. [21][22][23] In recent years, we have focused on the development of efficient MCRs for the synthesis of novel heterocycles [24][25][26][27][28][29] as well as their bioactivities, [30][31][32][33] optical properties and applications.…”

“…3 ) (entries 14 and 15) but increased by the addition of Brønsted acids, such as hydrochloric acid (HCl), sulfuric acid (H 2 SO 4 ), trifluoroacetic acid (TFA) and acetic acid (AcOH) (entries[16][17][18][19], with H 2 SO 4 being the best one (entry 17) which caused the yield of 4a to increase to 51%. The screening of the amount of H 2 SO 4 (entries 17, 20-21) indicated that 0.5 equivalent of H 2 SO 4 is suitable (entry 17).…”