Highly Stereoselective [4+2] and [3+2] Spiroannulations of 2‐(2‐Oxoindolin‐3‐ylidene)acetic Esters Catalyzed by Bifunctional Thioureas

Abstract

A new Michael-Michael cascade reaction between 2-(2-oxoindolin-3-ylidene)acetic esters 1 and nitroenoates 2, catalyzed by bifunctional thioureas, is investigated. The combination of the two Michael reactions results in a novel and facile [4+2] or [3+2] spiroannulation process, which is characterized by the following features: 1) two carbon-carbon bonds and four stereocenters, including a quaternary spiro carbon, are formed under mild conditions; 2) an unprecedented and stereochemically defined substitution pattern on the spirocarbocyclic unit is obtained; 3) the double-bond configuration of the donor-acceptor nitroenoate 2 determines the absolute configuration of the spiro center, whereas the remaining stereocenters are formed under control of the catalyst. The effect on the final stereochemical outcome of structural variations of each starting material, catalyst, and experimental conditions is analyzed in detail. In particular, the use of specifically designed chiral nitroenoates enables diverse polyfunctional spirocyclohexane derivatives containing six consecutive stereogenic centers to be constructed. To our knowledge, this is the first asymmetric organocatalytic strategy enabling both five- and six-membered β-nitro spirocarbocyclic oxindoles.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[255] Quintavalla and co-workers reported as ynthesis of spirocarbocyclico xindole derivatives based on as imilar domino Michael/Michaelr eaction. [256] As shown in Scheme 173, using oxindole derivatives 655 and wnitro-substituted alkenes 656 as the substrates andt he cyclohexanediamine-derived thiourea 581 as the catalyst, the domino reaction producede ither diastereomers 657a or 657b depending on the configurationo f the nitroalkenes( 656), with (E)-configured 656a giving diastereomers 657a,a nd (Z)-configured 656b giving diastereomers 657b.B oth diastereomers were obtained as single diastereomersi nm oderate to good yields ande xcellent stereoselectivities.S imilar reactions between 655 and 658 catalyzed by the quinidinederivedt hiourea 660 gave the corresponding spirocyclopentane oxindole derivatives 659a or 659b in moderate to good yields and excellent stereoselectivities, again depending on the configuration of the nitroalkenes 658 (Scheme 173). [256] Wang and co-workers realized an asymmetric domino Michael/cyclization/tautomerization reaction between isatylidenemalononitriles 615 and a,a-dicyanoalkenes 662 or 535,u sing the quinine-derived thiourea 664 as the catalyst (Scheme174).…”

“…[256] As shown in Scheme 173, using oxindole derivatives 655 and wnitro-substituted alkenes 656 as the substrates andt he cyclohexanediamine-derived thiourea 581 as the catalyst, the domino reaction producede ither diastereomers 657a or 657b depending on the configurationo f the nitroalkenes( 656), with (E)-configured 656a giving diastereomers 657a,a nd (Z)-configured 656b giving diastereomers 657b.B oth diastereomers were obtained as single diastereomersi nm oderate to good yields ande xcellent stereoselectivities.S imilar reactions between 655 and 658 catalyzed by the quinidinederivedt hiourea 660 gave the corresponding spirocyclopentane oxindole derivatives 659a or 659b in moderate to good yields and excellent stereoselectivities, again depending on the configuration of the nitroalkenes 658 (Scheme 173). [256] Wang and co-workers realized an asymmetric domino Michael/cyclization/tautomerization reaction between isatylidenemalononitriles 615 and a,a-dicyanoalkenes 662 or 535,u sing the quinine-derived thiourea 664 as the catalyst (Scheme174). [257] Ther eactions offered spirooxindoled erivatives 661 and 663 in good enantioselectivities, respectively.H owever, in the case of 661,t he diastereoselectivities obtained were generally low.Aone-pot three-componentv ariant of this domino reactioni nvolving N-acetylisatin (302a), malononitrile (407a), and 662 under the conditions optimized for the two-component reaction produced 661 with as atisfactory yield and stereoselectivity.…”

“…Quintavalla and co‐workers reported a synthesis of spirocarbocyclic oxindole derivatives based on a similar domino Michael/Michael reaction . As shown in Scheme , using oxindole derivatives 655 and ω‐nitro‐substituted alkenes 656 as the substrates and the cyclohexanediamine‐derived thiourea 581 as the catalyst, the domino reaction produced either diastereomers 657a or 657b depending on the configuration of the nitroalkenes ( 656 ), with ( E )‐configured 656a giving diastereomers 657a , and ( Z )‐configured 656b giving diastereomers 657b .…”

Non-Covalent Organocatalyzed Domino Reactions Involving Oxindoles: Recent Advances

“…A double Michael cascade reaction sequence, that allowed for a stereoselective [3+2] and [4+2] spiroannulation process, gave rise to both five- and six-membered β-nitro spirocarbocyclic oxindoles respectively [ 44 ]. After the screening of several thiourea-based organocatalysts, Quintavalla and co-workers have identified Takemoto’s catalyst XIII (10 mol %) as the most effective in terms of yields and selectivities.…”

tert-Butyl (2S,3R,4R)-7′-bromo-4-methyl-2′,5-dioxo-4,5-dihydro-3H-spiro[furan-2,3′-indoline]-3-carboxylate

“…The key structural characteristic of these compounds is the spiro ring fused at the 3-position of the oxindole core (Cerisoli et al, 2016) with varying degrees of substitution around it (Trost & Brennan, 2009;Wang et al, 2013;Monari et al, 2015). However, it is a challenge to synthesize chiral spirocyclic oxindoles with spiro quaternary centers and multiple chiral centers.…”