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

This review collects the recent developments in the synthesis of chiral 3-substituted 3-amino-2-oxindoles based on enantioselective catalytic nucleophilic additions to isatin imines published since the beginning of 2015.


Introduction
Chiral oxindoles represent an important class of products widely present in nature and exhibiting many biological activities. Among them, chiral 3-substituted 3-amino-2-oxindoles constitute privileged candidates in medicinal chemistry [1][2][3][4][5][6][7][8]. Consequently, the development of novel catalytic routes to produce these compounds is highly desired [9][10][11][12][13][14][15][16][17][18][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. This is not only because of the easy access to isatin imines, but also by the possibility of using a wide range of nucleophiles, thus increasing the structural diversity of the resulting products. The first asymmetric catalytic versions were reported only in the 2010s despite tremendous achievements in catalytic asymmetric imine addition reactions [20][21][22]. Ever since, a number of catalytic asymmetric nucleo-philic additions to isatin imines have been developed, including Mannich reactions, aza-Morita-Baylis-Hillman reactions, Friedel-Crafts reactions, aza-Henry reactions, additions of heteronucleophiles, Strecker reactions, among others. The goal of this review is to update the catalytic asymmetric synthesis of chiral 3-substituted 3-amino-2-oxindoles based on enantioselective nucleophilic additions to isatin imines reported since 2015, since this field was recently reviewed by Chimni et al. [16]. It is divided into six parts, dealing successively with enantioselective Mannich reactions, aza-Morita-Baylis-Hillman reactions, Friedel-Crafts reactions, aza-Henry reactions, domino reactions initiated by nucleophilic additions to isatin imines, and miscellaneous reactions. Most of the reactions depicted in this review have been promoted by a wide variety of chiral organocatalysts but chiral metal catalysts have also proved to be highly efficient for a range of transformations. Scheme 1: Mannich reaction of N-Boc-isatin imines with ethyl nitroacetate (2) catalyzed by a cinchona alkaloid followed by denitration and synthesis of AG-041R.
An extensively used two-component variant of this reaction consists in using a preformed imine. Among chiral metal complexes, a wide variety of organocatalysts [26][27][28][29][30][31][32][33][34] has been used to promote asymmetric Mannich reactions. Among them, cinchona alkaloid 1 was employed in 2015 by Enders et al. at a remarkably low catalyst loading (0.0225 mol %) to promote the enantioselective Mannich reaction of ethyl nitroacetate (2) with N-Boc-isatin imines 3 [35]. The process afforded, after a subsequent denitration, the corresponding chiral 3-amino-2-oxindoles 4 in moderate to high yields (51-91%) and uniformly high enantioselectivities (92-99% ee), as shown in Scheme 1. Common protecting groups (R 1 ), such as methyl, ethyl, 4-methoxybenzyl, methoxymethyl, phenyl and benzyl, were tolerated as well as various substituents (R 2 ) on the aromatic ring of the isatins, including electron-donating and electron-withdrawing groups. The lowest yield (51%) was obtained in the reaction of a fluorinated isatin imine (R 1 = Me, R 2 = 7-F). The utility of this methodology was demonstrated by its application in the formal synthesis of the anticancer agent AG-041R. Furthermore, several of the formed products were converted into useful intermediates for the synthesis of pyrroloindoline alkaloids and related drugs, such as psychotrimine and (+)-folicanthine.
In 2018, Tanyeli et al. reinvestigated this type of reactions in the presence of related cinchona alkaloid-derived squaramide catalyst 8 [37]. Indeed, the reaction of acetylacetone (5a) with various N-alkoxycarbonylisatin imines 3 and 9 in the presence of only 1 mol % of catalyst 8 in diethyl ether as solvent afforded at room temperature the corresponding chiral Mannich products 7 and 10 in low to nearly quantitative yields (29-98%) combined with moderate to excellent enantioselectivities (41 to >99% ee) as shown in Scheme 3. The lowest yields (29-42%) were obtained for the ketimines having acetyl and ethyl substituents (R 1 = Ac or Et) at the amide nitrogen while better yields (70-98%) were generally achieved for other (un)substituted isatin imines (R 1 = Me, Bn, H). Moreover, a range of electronwithdrawing and electron-donating groups on the aryl moiety (R 2 ) as well as different N-carbamoyl protecting groups (R 3 = t-Bu, Et, Bn) were compatible, providing generally high enantioselectivities (85 to >99% ee), except for the 5-bromosubstituted derivative (R 2 = 5-Br) which afforded the corresponding product in only 41% ee. An advantage of this methodology was the use of a very low catalyst loading (1 mol %).
In 2017, Shao et al. investigated the use of simple chiral primary amines to promote the enantioselective Mannich reaction of N-Boc-isatin imines 3 with aldehydes, such as acetaldehyde (15a) [39]. When these reactions were catalyzed by simple chiral primary amine 16 in aqueous THF at 0 °C, they led to the corresponding chiral Mannich products 17 in good yields (74-81%) and uniformly excellent enantioselectivities (90-94% ee), as shown in Scheme 5. The synthetic utility of this novel methodology was demonstrated through the total synthesis of the natural product (−)-psychotriasine (Scheme 5) and the biologically active compound AG-041R (Scheme 1).

Scheme 5:
Mannich reaction of N-Boc-isatin imines with acetaldehyde catalyzed by a primary amine.
By using another type of organocatalyst, such as L-diphenylprolinol trimethylsilyl ether 18, these authors showed that a range of N-Cbz-isatin imines 19 reacted with α-substituted acetaldehydes 20 to give the corresponding chiral Mannich products 21 as major syn-diastereomers [39]. The latter were generally obtained with high syn/anti ratios (89:11 to 93:7) along with good yields (62-83%) and uniformly excellent enantioselectivities (92-99% ee), as shown in Scheme 6. Along with enolates employed as nucleophilic partners in Mannich reactions, related reactions involving enamines have been developed. For example in 2018, Lu, Zhang and Shi reported the first catalytic asymmetric construction of the cyclic enaminone-based 3-substituted 3-amino-2-oxindole scaffold with potential bioactivity on the basis of enantioselective additions of cyclic enaminones to N-Boc-isatin imines [40]. As shown in Scheme 7, the addition of dimedone-derived enaminones 22 to a variety of N-Boc-isatin imines 3 was optimally promoted by chiral phosphoric acid 23 exhibiting a bulky 2,4,6-(iPr) 3 C 6 H 2 group, which provided at 50 °C in 1,4-dioxane as solvent the corresponding chiral cyclic enaminone-based 3-substituted 3-amino-2-oxindoles 24 in moderate to quantitative yields (54-99%) and good to high enantioselectivities (84-96% ee). The process was compatible with a wide range of N-Boc-isatin imines bearing various substituents, the electronic nature and position of which having no obvious effect on the enantioselectivity. Moreover, a variety of dimedone-derived enaminones bearing electronically different substituents at the ortho, meta and para-positions of the aniline moieties was compatible.
The scope of this methodology could be extended to another type of enaminones, such as hydroxyfuran-2-one-derived ones 25, which afforded by reaction with N-Boc-isatin imines 3 the corresponding chiral products 26 in moderate to excellent yields (58-99%) and good to high enantioselectivities (81-97% ee), as illustrated in Scheme 8 [40]. A preliminary evaluation on the cytotoxicity of some selected products revealed that two of them exhibited moderate to strong cytotoxicity to A549, 786-0, ECA109 and BT474 cancer cell lines.

Enantioselective aza-Morita-Baylis-Hillman reactions
The Morita-Baylis-Hillman reaction is a carbon-carbon bondforming reaction occurring between the α-position of an activated alkene and a carbon electrophile such as an aldehyde. Employing a nucleophilic organocatalyst [26], such as a tertiary amine or a phosphine, this simple reaction provides densely functionalized products, such as α-methylene-β-hydroxycarbonyl compounds [50][51][52][53][54][55][56]. The aza-variant of this process consists in using an activated imine instead of an aldehyde, thus affording α-methylene-β-aminocarbonyl derivatives. In 2015, Takizawa et al. developed enantioselective aza-Morita-Baylis-Hillman reactions of N-Boc-isatin imines 3 with acrolein (35) promoted by 15 mol % of β-isocupreidine at −40 °C in a 1:1 mixture of toluene and CPME as solvent [57]. As shown in Scheme 11, the corresponding chiral 3-amino-2oxindoles 36 were synthesized with uniformly excellent enantioselectivities (95-98% ee) and moderate to good yields (48-83%). Generally, the highest yields (68-83%) were achieved in the reactions of N-benzylisatin imines (R 2 = Bn) while N-allyl, N-phenyl and N-prenyl-substituted ones led to the corresponding products in 48-70% yields. Interestingly, the authors found that using 20 mol % of α-isocupreine as organocatalyst instead of 15 mol % of β-isocupreidine (Scheme 11) in this reaction resulted in the formation of the corresponding (R)-configured products ent-36 with good to high enantioselectivities (83-95% ee) and moderate to good yields (37-79%), as shown in Scheme 12. The stereoselectivity of these processes (Scheme 11 and Scheme 12) can be explained by the favored transition states proposed in Scheme 12 based on the fact that the proton transfer constitutes the rate-determining step in the aza-Morita-Baylis-Hillman reaction [58][59][60]. Indeed, in these favored transition states, the proton shift mediated by the organocatalyst occurred with the least steric hindrance between the quinuclidine moiety of the catalyst and the aromatic ring of the isatin imine.

Enantioselective Friedel-Crafts reactions
The Friedel-Crafts reaction is widely employed in total synthesis [63][64][65]. In 2015, Pedro et al. reported the first asymmetric Friedel-Crafts reaction of N-Boc-isatin imines 3 with naphthols performed in the presence of cinchona alkaloid-derived thiourea 40 [66]. As shown in Scheme 15, the reaction of 1-naph-Scheme 12: Aza-Morita-Baylis-Hillman reaction of N-Boc-isatin imines with acrolein (35) catalyzed by α-isocupreine. thols 42 promoted by 2 mol % of this bifunctional catalyst in toluene at room temperature led to the corresponding chiral 3-substituted 3-amino-2-oxindoles 43 in good to high yields (78-99%) and uniformly excellent enantioselectivities (94-99% ee) regardless of the electronic character of the aromatic rings of the isatin and 1-naphthol and the position of their substituent (R 1 and R 2 ). Moreover, comparable excellent yields (90-97%) and enantioselectivities (96-99% ee) were achieved with variously N-alkyl substituted isatin imines (R 3 = Bn, allyl, Me, MOM). The scope of this unprecedented methodology was extended to 2-naphthols 44 which required 10 mol % of catalyst loading to provide the optimal results. In these conditions, the reaction with a range of variously substituted N-Boc-isatin imines 3 provided the corresponding products 45 in comparable yields (85-99%) and moderate to excellent enantioselectivities (75-99% ee), as illustrated in Scheme 15. A variety of 2-naphthols substituted with electron-donating or electron-withdrawing groups were tolerated, giving good results in most cases. The best enantioselectivity (99% ee) was achieved in the reaction of 3-methoxy-substituted 2-naphthol whereas the lowest one (75% ee) was obtained in the reaction of an N-methylisatin imine (R 2 = H, R 3 = Me) with unsubstituted 2-naphthol (R 1 = H). It must be noted that these transformat-ions represented the first highly enantioselective additions of naphthols to ketimines.
In 2017, similar reactions were reinvestigated by Tanyeli and Karahan by using the closely related catalyst 8 at −20 °C in dichloromethane as the solvent [67]. The products 43 and 46 arisen from the reaction of 1-naphthols 42 with a range of vari- ously substituted N-alkoxycarbonylisatin imines 3 and 9 were obtained in moderate to quantitative yields (61-99%) and excellent enantioselectivities (92 to >99% ee) in most cases. Only two substrates, such as a disubstituted N-Boc-isatin imine (R 1 = 5,7-Me 2 , R 2 = H) and an N-acetylated one (R 1 = H, R 2 = Ac), afforded the products in much lower enantioselectivities of 37% and 3% ee, respectively. On the other hand, products 45 and 47 arisen from the reaction of 2-naphthols 44 with N-alkoxycarbonylisatin imines 3 and 9 were formed in moderate to excellent enantioselectivities (54-97% ee) combined with good to quantitative yields (76-99%), as shown in Scheme 16. It must be noted that both reactions involving 1 and 2-naphthols employed only 2 mol % of catalyst loading.

Miscellaneous reactions
In 2015, Arai et al. applied a chiral metal complex to promote the enantioselective addition of methanol to N-Boc-isatin imines 3 [79]. As shown in Scheme 20, the use of a chiral nickel catalyst in situ generated from NiCl 2 and the chiral bis(imidazolidine)pyridine ligand 56 promoted this reaction in toluene at room temperature in the presence of a base, such as DIPEA, and led to chiral isatin-derived N,O-acetals 57 in good to quantitative yields (69-99%) and good to high enantioselectivities (78-90% ee). Notably, generally excellent yields (93-99%) were obtained in the reactions of variously substituted substrates while the lowest yield of 69% was observed for the 5-fluorinated isatin imine (R = F). Comparable reaction conditions were applied to the addition of cumene hydroperoxide 58 to N-Boc-isatin imines 3 providing the corresponding chiral oxindoles 59 in even higher yields (99%) and enantioselectivities (88-94% ee), as shown in Scheme 20.

Conclusion
This review demonstrates that much progress has been achieved in the past three years in the field of asymmetric synthesis of 3-substituted 3-amino-2-oxindoles through enantioselective nucleophilic additions to isatin imines, involving both chiral metal and organocatalysts. Indeed, a variety of novel methodologies, including enantioselective Mannich reactions, aza-Morita-Baylis-Hilman reactions, Friedel-Crafts reactions, aza-Henry reactions, domino reactions, among others have allowed a wide range of these biologically important chiral products to be achieved in generally excellent enantioselectivities and high yields by using different types of metal ligands and organocatalysts. For example, remarkable enantioselectivities of up to 94 to >99% ee have been reported in recent examples of Mannich reactions promoted by organocatalysts, as varied as cinchonaalkaloids, squaramides, phosphoric acids, simple primary amines and L-diphenylprolinol trimethylsilyl ether. However, also metal complexes (Zn, Sn) derived from N,N'-dioxide and BINOL-derived ligands have been employed affording the products with enantioselectivities of up to 90-99% ee. Moreover, comparable enantioselectivities of up to 99% ee were reported in aza-Morita-Baylis-Hilman reactions organocatalyzed by cinchona-alkaloids, and unprecedented Friedel-Crafts reactions of isatin imines with naphthols and hydroxyquinolines promoted by cinchona-alkaloid-derived thioureas and cinchonaalkaloid-derived squaramides. Slightly lower enantioselectivity levels of up to 94% ee were described in aza-Henry reactions performed with bifunctional guanidines. In addition, excellent results (97% ee) were reported in unprecedented domino reactions promoted by squaramides recently. Miscellaneous transformations, including additions of methanol, hydroperoxides and arylboronic acids, were also developed with high enantioselectivities (up to 94% ee) by using chiral nickel and palladium complexes with imidazoline and pyridine-oxazoline ligands while the first additions of enaminones to isatin imines catalyzed by chiral phosphoric acids provided even higher enantioselectivities (up to 97% ee). In spite of these significant advances, the involvement of other types of organocatalysts and Scheme 21: Palladium-catalyzed addition of arylboronic acids to N-tert-butylsulfonylisatin imines. metal ligands will have to be investigated in these transformations along with the use of other nucleophiles to even more extend the library of chiral 3-substituted 3-amino-2-oxindoles available for drug discovery.