Palladium-Catalyzed, Enantioselective (3 + 2)-Cycloannulation of β-Keto Esters with Alkylidene 2H-Indoles toward Complex Indole-Based Heterocycles

Abstract

A cooperative approach toward biologically important N-fused polycyclic indoles with synthetically challenging tetracyclic [6–5–5–6] and [6–5–5–5] core structures has been developed. The concept is based on a highly stereoselective (3 + 2)-cycloannulation of chiral metal enolates with a reactive vinylogous iminium ion, both generated in situ via dual activation with a single chiral Pd catalyst (5 mol %). Densely functionalized pyrrolo­[1,2-a]­indoles with three contiguous chiral centers were constructed with high stereoselectivities (>95:5 d.r. and up to >99% ee) and excellent yields (up to 99%). ESI-MS studies and additional control experiments provided a clear mechanistic picture of the cycloannulation event. The products were readily transformed into an array of valuable, indole-based, highly complex heterocycles.

Asymmetric Brønsted Acid Catalyzed Cycloadditions of ortho-Quinone Methides and Related Compounds

“…56 Densely substituted and highly functionalized pyrrolo[1,2-a]indoles 82 were obtained with excellent yields and enantioselectivities. Scheme 25 Pd[BINAP]/HSbF 6 -co-catalyzed [3+2]-cycloaddition of indole-2-carbinols 64 with -keto esters 36 56 Notably, during the course of this reaction, three new stereogenic centers were formed with perfect diastereoselectivity, two of which were quaternary. Control experiments established, that the in situ released hexafluoroantimonic acid effects dehydration of the indole-2-carbinol to the indolyl-2-methide.…”

“…Thus, indole-2-carbinols 64 were treated with keto esters 36 in the presence of 5 mol% of [(R)-BINAP]-Pd(SbF 6 ) 2 in toluene at -20 °C, followed by treatment with Et 3 N to effect ring closure (Scheme 25). 56 Densely substituted and highly functionalized pyrrolo[1,2-a]indoles 82 were obtained with excellent yields and enantioselectivities. Scheme 25 Pd[BINAP]/HSbF 6 -co-catalyzed [3+2]-cycloaddition of indole-2-carbinols 64 with -keto esters 36 56 Notably, during the course of this reaction, three new stereogenic centers were formed with perfect diastereoselectivity, two of which were quaternary.…”

Organocatalytic Discrimination of Non-Directing Aryl and Heteroaryl Groups: Enantioselective Synthesis of Bioactive Indole-Containing Triarylmethanes

“…In this context, here we describe an organocatalytic discrimination of non-directing aryl and heteroaryl groups with excellent enantioselectivity.Indole imine methides (IIMs) have recently emerged as versatile intermediates for the asymmetric synthesis of enantioenriched indole derivatives, a family of useful units in medicinal chemistry. [22][23][24][25][26][27][28][29][30][31] In particular, those with the methide motif adorned in the 2-position of indole are particularly useful to construct indole-fused polyheterocycles via asymmetric annulation processes, as pioneered by Shi and co-workers. [22][23][24][25][26][27][28] However, the majority of these examples either involve straightforward discrimination (e.g., aryl vs. H) or do not involve asymmetric control in the 2-benzylic position (e.g, with two same substituents).…”

“…[22][23][24][25][26][27][28][29][30][31] In particular, those with the methide motif adorned in the 2-position of indole are particularly useful to construct indole-fused polyheterocycles via asymmetric annulation processes, as pioneered by Shi and co-workers. [22][23][24][25][26][27][28] However, the majority of these examples either involve straightforward discrimination (e.g., aryl vs. H) or do not involve asymmetric control in the 2-benzylic position (e.g, with two same substituents). [22][23][24][25][26][27][28][29][30][31] In continuation of our efforts in this area, 14,[29][30][31] we envisioned that this type of intermediates would be a good platform to study the power of organocatalysis for the challenging discrimination between aryl and heteroaryl groups lacking a directing group (Scheme 1c).…”

“…[22][23][24][25][26][27][28] However, the majority of these examples either involve straightforward discrimination (e.g., aryl vs. H) or do not involve asymmetric control in the 2-benzylic position (e.g, with two same substituents). [22][23][24][25][26][27][28][29][30][31] In continuation of our efforts in this area, 14,[29][30][31] we envisioned that this type of intermediates would be a good platform to study the power of organocatalysis for the challenging discrimination between aryl and heteroaryl groups lacking a directing group (Scheme 1c). However, additional challenges should be expected since this intermediate II is likely generated as a Z/E mixture, typically in equilibrium with carbocation I.…”