Recent Catalytic Asymmetric Syntheses of 3,3‐Disubstituted Indolin‐2‐ones and 2,2‐Disubstituted Indolin‐3‐ones

Abstract

Disubstituted oxindoles represent an important family of bioactive compounds and synthetic derivatives that mimic natural products. The construction of the asymmetric quaternary carbon at C‐3 or C‐2 is therefore a challenging problem for organic chemists. In the last years, many papers have appeared on asymmetric catalytic methods for the synthesis of these compounds, in particular about spirocyclic derivatives and this literature has been largely reviewed, as well as the literature on 3‐substituted‐3‐hydroxyoxindoles and 3‐substituted‐3‐aminooxindoles. On the other hand, the literature on non‐spirocyclic 3,3‐dialkyloxindoles as well as on 2,2‐disubstituted 3‐indolinones has not fully reviewed since our previous review on this topic. This review aims to fill this gap covering the literature on these topics.Abbreviations: Alloc=allyloxycarbonyl; Ant=anthracenyl; BINOL=1,1′‐binaphthalene‐2,2′‐diol; Boc=t‐butoxycarbonyl; Bz=benzoyl; Cbz=benzyloxycarbonyl; CSA=camphorsulfonic acid; Cy=cyclohexyl; DABCO=1,4‐diazabicyclo[2.2.2]octane; dba=bis(dibenzylideneacetone); DBU=1,8‐diazabicyclo[5.4.0]undec‐7‐ene; DDQ=2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone; (DHQD)2AQN=hydroquinidine (anthraquinone‐1,4‐diyl) diether; (DHQD)2PHAL=hydroquinidine 1,4‐phthalazinediyl diether; (DHQD)2PYR=hydroquinidine 2,5‐diphenyl‐4,6‐pyrimidinediyl diether; DIPEA=N,N‐diisopropylethylamine; esp=α,α,α′,α′‐tetramethyl‐1,3‐benzenedipropionic acid; HFIP=1,1,1,3,3,3‐hexafluoro‐2‐propanol; HMDS=hexamethyldisilazane; β‐ICD=β‐isocupreidine; LG=leaving group; Mes=2,4,6‐trimethylphenyl; Moc=methoxycarbonyl; MOM=methoxymethyl; MS=molecular sieves; MsOH=methanesulfonic acid; NHC=N‐heterocyclic carbene; Npt=naphthyl; PG=protecting group; Phg=phenylglycine; Phth=phthalimidyl; Piv=2,2‐dimethylpropanoyl; PMB=4‐methoxybenzyl; Red‐Al=sodium bis(2‐methoxyethoxy)aluminium hydride; Suc=succinimidyl; TBDPS=tert‐butyldiphenylsilyl; TBS=tert‐butyldimethylsilyl; TES=triethylsilyl; TIPS=triisopropylsilyl; TMEDA=N,N,N′,N′‐tetramethylethylenediamine; TMG=1,1,3,3‐tetramethylguanidine; TMS=trimethylsilyl; Ts=4‐toluenesulfonyl.magnified image

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

“…After analysing the binding modes of known MDM2 inhibitors and CDK4 inhibitors, we speculated that fusion of the planar tetrahydronaphthalene (THN) ring at the C3-position of oxindole might generate a scaffold that could bind at the P53-binding site in MDM2 as well as at the allosteric site in CDK4. We started with THN 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 and spirooxindole derivatives 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 because they are privileged drug-like architectures, so the resulting THN-fused C3-spirooxindoles should possess good druglikeness ( Fig. 2 C).…”

Palladium-catalyzed Conia-ene Reaction of 1-alkynylindolin-3-ones: a strategy for the construction of Pyrrolo[1,2-a]indoles

“…Therefore, the development of efficient and easy approaches for the construction of pyrrolo[1,2-a]indole scaffolds is highly desired. Over the past decade, much efforts was focused on the nucleophilic indole-3-ones for the construction of C2-quaternary indolin-3-one and indole-polycyclic-skeletons (such as indole-fused cyclic at the N1 and C2 positions, 2,2'-spirocyclic indoles and indole-fused cyclic at the C2 and C3 positions) [16][17][18][19][20]. Unlike the significant progress of 2-oxindole chemistry in the synthesis of indole-polycyclic-skeletons, indolin-3-ones have received very little attention [16][17]21].…”

“…Over the past decade, much efforts was focused on the nucleophilic indole-3-ones for the construction of C2-quaternary indolin-3-one and indole-polycyclic-skeletons (such as indole-fused cyclic at the N1 and C2 positions, 2,2'-spirocyclic indoles and indole-fused cyclic at the C2 and C3 positions) [16][17][18][19][20]. Unlike the significant progress of 2-oxindole chemistry in the synthesis of indole-polycyclic-skeletons, indolin-3-ones have received very little attention [16][17]21]. In 2014, we have developed a bifunctional thiourea-catalyzed asymmetric Michael-Micheal cascade reaction for the construction of highly functionalized N-fused piperidinoindoline derivatives via employing less explored indolin-3-ones 1 (Scheme 1a) [20].…”

Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines

“…Among them, chiral 3-substituted 3-amino-2-oxindoles constitute privileged candidates in medicinal chemistry [1–8]. Consequently, the development of novel catalytic routes to produce these compounds is highly desired [9–19] with a special mention for organocatalyzed methodologies [10,13]. The simplest method to prepare chiral quaternary 3-amino-2-oxindoles is based on enantioselective catalytic nucleophilic additions to isatin imines.…”