Thiourea-Catalyzed Enantioselective Addition of Indoles to Pyrones: Alkaloid Cores with Quaternary Carbons

Abstract

We report the development of a catalytic method for the enantioselective addition of indoles to pyrone-derived electrophiles. Arylpyrrolidino-derived thioureas catalyze the addition with high stereoselectivity in the presence of catalytic quantities of an achiral Brønsted acid. The indole–pyrone adducts feature a quaternary stereocenter and represent an unusual class of indolines bearing structural resemblance to the hybrid natural product pleiocarpamine.

Catalytic Asymmetric Addition of Meldrum’s Acid, Malononitrile, and 1,3‐Dicarbonyls to ortho‐Quinone Methides Generated In Situ Under Basic Conditions

“…[26] In conclusion, we have developed the first example of acatalytic asymmetric reactionw ith o-QMs which exploits basic conditions for the in situ generation of these challengingi ntermediates. [27] This approach gives full complementarity to previous methodologies, [6][7][8][9][10][11][12][13][14] and allows to perform the enantioselective additions of different nucleophilesw ith good results and broad substrate scope, giving an ew and general access to valuable3 ,4-dihydrocoumarin and 4H-chromene scaffolds.…”

“…[5] This challenging task has been recently met by exploiting different strategies for the transient generation of an o-QM intermediate. Available examples involve palladium catalysed oxidative additions to ortho-hydroxy styrenes, [6,7] desilylation-halidee limination of O-silyl 2-haloalkyl phenols [8] and pyrones, [9] alcohol elimination of 2-alkoxyalkyl phenols, [10] and dehydration of the corresponding benzylic alcohols. [11] The latter approach, wherein chiral Brønsted acid catalysts promote both dehydration and addition to the thus formed o-QM, has provent ob ep articularly flexible, and has been very recently applied to electron-rich aromatics, [12] enamides, [13] and 1,3-dicarbonyl compounds (mostly diketones) [14] as nucleophilic reactionpartners.Herein, we report an ew approach to the utilization of o-QMs in asymmetricc atalysis, by demonstrating that enantioselective additions of 1,3-dicarbonyls promoted by Cinchona-derived organocatalysts 3 [15] can be combined with the in situ generation of sensitive o-QM from 2-(arylsulfonyl)alkyl phenols [16] 1-2 (Scheme 1).…”

Organocatalysts for enantioselective synthesis of fine chemicals: definitions, trends and developments

“…This transformation, catalysed by a thiourea catalyst (54) under mild conditions, leads to spirocyclopentaneoxindoles (53) with quite good diastereoselectivity and enantioselectivity (up to >30:1 dr; up to >99% ee) ( Figure 13) [52]. The great potential of chiral thioureas has been recently employed in other asymmetric transformations [53,54]. Another significant organocatalyst is the S-2-diphenylhydroxymethylpyrrolidine 33, which has been thoroughly exploited in organocatalysis.…”

Condensations based on 5‐(indol‐3‐yl)‐pyrrolidin‐2‐thiones

“…In recent years, demand for modification of these biologically significant molecules has increased. [5][6][7] Previously, we found a convenient method of preparative synthesis of 5-(indolyl-3)-pyrrolidones [8] and showed reduced reactivity of the carbonyl group of these compounds in organic synthesis. [9] Synthesized derivatives of indole were of interest in terms of pharmacology, by analogy with the known structures.…”