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molecules Review

Non-Covalent Organocatalyzed Domino Reactions Involving Oxindoles: Recent Advances Tecla Gasperi 1, * ID , Martina Miceli 1 ID , Jean-Marc Campagne 2 and Renata Marcia de Figueiredo 2, * ID 1 2

*

ID

Dipartimento di Scienze, Sezione di Nanoscienze e Nanotecnologie, Università degli Studi Roma Tre, via della Vasca Navale 79, I-00146 Roma, Italy; [email protected] ICGM-Institut Charles Gerhardt Montpellier, UMR 5253 CNRS-UM-ENSCM, Ecole Nationale Supérieure de Chimie, 8, Rue de l’Ecole Normale, 34296 Montpellier CEDEX 5, France; [email protected] Correspondence: [email protected] (T.G.); [email protected] (R.M.d.F.); Tel.: +39-06-5733-3371 (T.G.); +33-467-147-224 (R.M.d.F.)

Received: 16 September 2017; Accepted: 26 September 2017; Published: 29 September 2017

Abstract: The ubiquitous presence of spirooxindole architectures with several functionalities and stereogenic centers in bioactive molecules has been appealing for the development of novel methodologies seeking their preparation in high yields and selectivities. Expansion and refinement in the field of asymmetric organocatalysis have made possible the development of straightforward strategies that address these two requisites. In this review, we illustrate the current state-of-the-art in the field of spirooxindole synthesis through the use of non-covalent organocatalysis. We aim to provide a concise overview of very recent methods that allow to the isolation of unique, densely and diversified spirocyclic oxindole derivatives with high structural diversity via the use of cascade, tandem and domino processes. Keywords: spirooxindole derivatives; non-covalent organocatalysis; hydrogen-bonding; cascade; tandem; domino; enantioselectivity; chiral building blocks

1. Introduction Heterocyclic compounds are found in a broad range of bioactive molecules, natural products, and drugs. Consequently, several novel efficient strategies based on catalytic methods have been validated to date for the direct assessment of such scaffolds in an enantiopure fashion [1–3]. In this context, spirocyclic oxindole derivatives have appeared as privileged structural motifs being part of a great number of synthetic and natural products displaying remarkable biological activities as well as useful biomedical applications (Figure 1) [4–6]. Asymmetric organocatalysis has appeared as an appealing tool in order to prepare such compounds with rich structural diversity and complexity through cascade, tandem, and domino processes [7–9]. Indeed, since the beginning of the 21st century, the golden-age of organocatalysis, several reports and substantial advances on the field of the synthesis of complex structural entities via the combination of organocatalysis and cascade transformations have been reported so far. The ability to reach for molecular complexity through the conscious choice of substrates and catalysts in a single transformation has inspired a growing number of research groups. Seminal reports that cover this subject have appeared before 2015 [10–13]. The aim of this review is to describe recent advances towards the stereocontrolled synthesis of strained spiro-quaternary stereocenters on the oxindole core through non-covalent organocatalysis [14–16] within the timeframe from 2015 to the middle of 2017. It is the authors’ aim to attract the reader’s attention to the potential of asymmetric non-covalent organocatalysis to mediate one-pot cascade, tandem, and domino processes that, employing an oxindole derivative as starting material, give a facile access to complex molecules featured by several functionalities and various stereogenic centers. Molecules 2017, 22, 1636; doi:10.3390/molecules22101636

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Figure 1. Examplesofofbioactive bioactivecompounds compounds built framework. Figure 1. Examples builtaround aroundthe theoxindole oxindole framework. Figure 1. Examples of bioactive compounds built around the oxindole framework. The observed high yields and remarkable stereoinduction, which resemble Nature’s outcomes, The and stereoinduction, which resemble Nature’s outcomes, Theobserved observed highyields yields and remarkable remarkable stereoinduction, Nature’s outcomes, mainly rely on high H-bond interactions, electrostatic effects, andwhich π–π resemble staking that are established mainly rely on H-bond interactions, electrostatic effects, and π–π π–π staking that established between mainly rely H-bond interactions, electrostatic effects, and staking that are cooperative established between theon oxindole core, the employed reagent, and the selected catalyst (i.e.,are dual and the oxindole core, the employed reagent, and the selected catalyst (i.e., dual and cooperative between the[17]. oxindole core,ofthe employed reagent, and the selected catalyst (i.e., dual and cooperative catalysis) Examples such connections are depicted in Figure 2.

catalysis) are depicted depictedininFigure Figure2.2. catalysis)[17]. [17].Examples Examplesof ofsuch such connections connections are Non Covalent Activation

Non Covalent Activation via Hydrogen Bond

via Brønsted Base

S

N H

NS H

N X H

S R* N H R*

N H

NS H

X

X

N XH

via Brønsted Acid

via Brønsted Base O O chiral backbone O O chiral N N backbone H H N N N X H H H

via Hydrogen Bond

N H

Nu N H

X

via Brønsted Acid chiral backbone chiral backbone H Nu

Nu

H

N

N

Nu

O O P O OHO O P HO H X O

H X

Nu

Nu

Nu

Nu

chiral backbone chiral O Obackbone O P O H O O O X P H H Y O X H Y

Examples with oxindole derivatives

Examples with oxindole derivatives chiral backbone chiral E Nbackbone EX NH O X H N PGO N PG

O

S NS N N H H H N N N Nu H H H O a PG N O

PG N

Figure 2. Examples of non-covalent

a

XNu b

O N H N H

b

O N N H H N N Nu H O aH

PG N O

(a) mostly when X = O, NR1 PG N (b) mostly when X = CR1R 2 (a) mostly when X = O, NR1 when X = CR1R 2 interactions (b) in amostly substrate/reagent/catalyst

X

O

aX

Nu b

X

b

system.

Figure 2.Examples Examplesofofnon-covalent non-covalent interactions interactions in system. in aa substrate/reagent/catalyst substrate/reagent/catalyst system. FarFigure to be 2. exhaustive and comprehensive, the current review is divided according to the most employed class of catalysts. Specifically, after a quick overview about the Cinchona alkaloids (Section 1), Far to be exhaustive and comprehensive, the current review is divided according to the most the synthetic elaborations of thesethe natural-occurring are going to be Farsubsequent to be exhaustive and comprehensive, current revieworganocatalysts is divided according to the most employed class of catalysts. Specifically, after a quick overview about the Cinchona alkaloids (Section 1), introduced (Sections 2–5); meanwhile, Section 6 will detail an example of non-covalent activation via employed class of synthetic catalysts. elaborations Specifically, after a quick overview about the Cinchona alkaloids (Section the subsequent of these natural-occurring organocatalysts are going to be 1), Brønsted acids. Finally, we apologize for any omissions. the subsequent synthetic elaborations of these natural-occurring organocatalysts are going to be introduced (Sections 2–5); meanwhile, Section 6 will detail an example of non-covalent activation via introduced (Sections 2–5); meanwhile, Section 6 will detail an example of non-covalent activation via Brønsted acids. Finally, we apologize for any omissions.

Brønsted acids. Finally, we apologize for any omissions.

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2. Cinchona Alkaloid Catalysts Discovered in 1820 for its antimalarial properties, Cinchona alkaloids have found several applications in various and quite different fields ranging from medicine to food and beverage industries, and in even including chemistry. Besides the initial uses as resolving Discovered 1820 for its organic antimalarial properties, Cinchona alkaloids have agents, found over several the last decades, Cinchona alkaloids havefields established a primary and outstanding role in asymmetric applications in various and quite different ranging from medicine to food and beverage industries, as highly efficient organocatalysts of uses promoting a wideagents, range of enantioselective andsynthesis even including organic chemistry. Besidescapable the initial as resolving over the last decades, transformations in both homogeneous and heterogeneous environments [18]. The impressive chiral Cinchona alkaloids have established a primary and outstanding role in asymmetric synthesis as highly induction mainly relies both on the accessibility of different chiral skeletons and on the facile adaptability efficient organocatalysts capable of promoting a wide range of enantioselective transformations in to various reaction processes (Figure 3). Specifically, the 1,2-aminoalcohol group summarizes in one both homogeneous and heterogeneous environments [18]. The impressive chiral induction mainly molecule:

2. Cinchona Alkaloid Catalysts

relies both on the accessibility of different chiral skeletons and on the facile adaptability to various (i) the basicity (Figure and bulkiness of quinuclidine moiety, apt to activate a nucleophile byin deprotonation reaction processes 3). Specifically, the 1,2-aminoalcohol group summarizes one molecule: as well as to stabilize the developing positive charge,

secondary group, which acts as bothapt an to acid and a H-bond donor, and is suitable (i) (ii)thethe basicity and 9-hydroxy bulkiness of quinuclidine moiety, activate a nucleophile by deprotonation for further chemical modification of the catalyst structure. Additionally, the overall catalytic as well as to stabilize the developing positive charge, action is also ascribed to the possible π–π interactions with the aromatic quinoline ring. (ii) the secondary 9-hydroxy group, which acts as both an acid and a H-bond donor, and is suitable forRepresentative further chemical modification of the catalyst structure. Additionally, the overall catalytic examples of widespread used Cinchona alkaloids are depicted in Figure 3. Notably, asalso fragments of to more (Sections the same structures play a action is ascribed the complex possible organocatalysts π–π interactions with the3–5) aromatic quinoline ring. crucial role to induce high levels of diastereo- and enantioselectivity.

Figure 3. Representative examples of Cinchona alkaloids.

Figure 3. Representative examples of Cinchona alkaloids.

Within this context, in 2015, Yuan and co-workers succeeded in the construction of a class of Representative examples of awidespread used Cinchona alkaloids depicted in Figure 3. Notably, spirocyclic oxindoles through domino Mannich-cyclization processare [19]. Specifically, employing as fragments of more complex organocatalysts (Sections 3–5) thethe same structures play a crucial role to various 3-isothiocyanate oxindoles 1 and imines 2 as substrates, simplest commercially available induce high and the enantioselectivity. quinine (I,levels 1 mol of %)diastereomade possible diastereo- (up to >99:1 d.r.) and enantioselective (up to 97% ee) synthesis spiro[imidazolidine-2-thione-4,3′-oxindole] derivatives 3 (Scheme Notably, the optimized Within of this context, in 2015, Yuan and co-workers succeeded in the1).construction of a class of conditions, i.e., using toluene aasdomino solvent at 0 °C with the addition of 4 Å [19]. molecular sieves (MS), led, spirocyclic oxindoles through Mannich-cyclization process Specifically, employing in just3-isothiocyanate 10 min, to the desired products isolated in2remarkable yields to 95%).commercially available various oxindoles 1 and imines as substrates, the(up simplest

quinine (I, 1 mol %) made possible the diastereo- (up to >99:1 d.r.) and enantioselective (up to 97% ee) synthesis of spiro[imidazolidine-2-thione-4,30 -oxindole] derivatives 3 (Scheme 1). Notably, the optimized conditions, i.e., using toluene as solvent at 0 ◦ C with the addition of 4 Å molecular sieves (MS), led, in just 10 min, to the desired products isolated in remarkable yields (up to 95%).

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Scheme 1. Synthesis of spiro[imidazolidine-2-thione-4,3′-oxindole] via domino Mannich/Cyclization

Scheme 1. Synthesis of spiro[imidazolidine-2-thione-4,30 -oxindole] via domino Mannich/Cyclization process and proposed of transition states where A and B are the suggested intermediates (Y = Yield). Scheme 1. Synthesis spiro[imidazolidine-2-thione-4,3′-oxindole] via domino Mannich/Cyclization process and proposed transition states where A and B are the suggested intermediates (Y = Yield). process and proposed transition states where A and B are the suggested intermediates (Y = Yield).

To explain the observed outstanding stereocontrol, the authors suggest that in the transition To explain the observed outstanding stereocontrol, the authors suggest that in the state state the simultaneously activates: (i) the tosyl-protected imine via a that H-bond interaction of the To quinine explain the observed outstanding stereocontrol, the authors suggest in transition the transition quinine simultaneously activates: (i) the tosyl-protected imine via a H-bond interaction of the C9-OH the C9-OH and (ii) the 3-isothiocyanate oxindole moiety via deprotonation and consequent state the quinine simultaneously activates: (i) the tosyl-protected imine via a H-bond interaction of and enolization performed by tertiary group. In such a way, imine Si-faceand is exposed to the (ii) thethe 3-isothiocyanate oxindole moiety amine via deprotonation and consequent enolization performed by the C9-OH and (ii) thethe 3-isothiocyanate oxindole moiety via the deprotonation consequent attack of the Si-face nucleophile counterpart (A, Scheme 1). The subsequent ring closure reaction enolization performed by the tertiary a way, Si-face exposednucleophile to the tertiary amine group. In such a way, theamine iminegroup. Si-faceInissuch exposed tothe theimine attack of theis Si-face involves the just formed N-nucleophile and the electron-poor carbon of the isocyanate oxindole attack of the Si-face nucleophile counterpart (A, Scheme 1). The subsequent ring closureN-nucleophile reaction counterpart (A, Scheme 1). The subsequent ring closure reaction involves the just formed involves the just formed N-nucleophile and the electron-poor carbon of the isocyanate oxindole framework (B, Scheme 1). and the electron-poor carbon of the isocyanate oxindole framework (B, Scheme 1). framework (B, Scheme More recently the 1). impressive stereoinduction properties of Cinchona alkaloids havevalidated been More recently the impressive stereoinduction properties of Cinchona alkaloids have been More recently the impressive stereoinduction properties of co-workers Cinchona alkaloids have been validated even in a kinetic resolution approach. Indeed, Tanaka and were engaged in the even in a kinetic resolution approach. Indeed, Tanaka and co-workers were engaged in the synthesis validatedofeven in a kinetic resolution Indeed, Tanaka and co-workers werewas engaged in the synthesis spirooxindole polycyclesapproach. 8 bearing a spiro[4,5]decane system that remarkably of spirooxindole 8 bearing a spiro[4,5]decane system that was remarkably by synthesis of polycycles spirooxindole 8 bearingaaformal spiro[4,5]decane system that and wasaccomplished accomplished by a two-steppolycycles strategy involving [4 + 1] cycloaddition aremarkably subsequent a two-step strategy involving a formal [4 + 1] cycloaddition and a subsequent Michael-Henry cascade accomplished cascade by a two-step strategy involving formal [4 + 1] cycloaddition and a subsequent Michael-Henry transformation (Scheme 2)a [20]. transformation (Scheme 2) transformation [20]. Michael-Henry cascade (Scheme 2) [20].

Scheme 2. Synthesis of spirooxindole polycycles bearing a spiro[4,5]decane system.

Scheme 2. Synthesis of spirooxindole polycycles bearing a spiro[4,5]decane system. Scheme 2. Synthesis of spirooxindole polycycles bearing a spiro[4,5]decane system.

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Moleculesthe 2017, 22, 1636reaction was carried under acidic catalysis, the Michael-Henry cascade steps 5 of 28 were While former performed under quinidine (II) catalysis at room temperature. In such conditions, the final polycyclic While the former reaction was carried under acidic catalysis, the Michael-Henry cascade steps derivatives 8 featuring seven stereogenic centers were isolated in high optical purity (80–92% ee) despite were performed under quinidine (II) catalysis at room temperature. In such conditions, the final modest yields (up to 28%)8 consequence the racemic mixture as starting materials. polycyclic derivatives featuring sevenofstereogenic centers wereused isolated in high optical purityHowever, (80–92% the unreacted enantiomer ent-6 was easily recovered in enantioenriched fashion (up to 43% yield, 92–98% ee). ee) despite modest yields (up to 28%) consequence of the racemic mixture used as starting materials. Although initially the simplest naturally available Cinchona have been widely However, the unreacted enantiomer ent-6 was easily recovered in alkaloids enantioenriched fashion (up toexploited, 43% over yield, the years, organic chemists have created more efficient and complex molecules bearing the 92–98% ee). Although the simplest with naturally Cinchona alkaloids have been widely exploited, same scaffold that initially was implemented the available introduction of further functionality capable of H-bond over the years, organic chemists have created more efficient and complex molecules bearing the same interactions. In the following sections, we are going to illustrate and compare other privileged organic scaffold that was implemented with be theadded introduction further functionality capable of H-bond chirality inducers, most of which could to the of realm of Cinchona alkaloid derivatives.

interactions. In the following sections, we are going to illustrate and compare other privileged organic chirality inducers, most of which could be added to the realm of Cinchona alkaloid derivatives. 3. (DHQD) 2 Based Catalysts

Joining together units of Cinchona derivatives/analogues in a single molecule, creating 3. (DHQD) 2 Based two Catalysts the so-called bis-Cinchona alkaloids, is the easiest way to enhance the H-bond network inside the Joining together two units of Cinchona derivatives/analogues in a single molecule, creating the catalyst/substrates system. Such structures haveway mainly shown the theirH-bond efficiency as chiral ligands so-called bis-Cinchona alkaloids, is the easiest to enhance network inside the in the Sharpless dihydroxylation. However, over the years, several research groups have highlighted catalyst/substrates system. Such structures have mainly shown their efficiency as chiral ligands in the their Sharpless potentialdihydroxylation. and effectiveness as simple introduction of further However, overorganocatalysts the years, severalwithout researchthe groups have highlighted theirmetal potential and effectiveness as Wu simple organocatalysts without thethe introduction further metal salt additives. Among others, and co-workers exploited ability ofof(DHQD) (IX) in 2 PYRsalt additives. Among cascade others, Wu and co-workers exploited the ability of (DHQD)oxindoles 2PYR (IX) instarting Michael/from Michael/cyclization reaction to synthesize different spirocyclic cyclization cascade reaction synthesize different spirocyclic oxindoles starting from isatilidene isatilidene malonitriles as initialtoelectrophile. Precisely, the employment of acyclic β,γ-unsaturated malonitriles as initial electrophile. Precisely, the employment of acyclic β,γ-unsaturated amides 10 as amides 10 as vinylogous enolates, smoothly provided the titled spirooxindoles 11 in good yields vinylogous enolates, smoothly provided the titled spirooxindoles 11 in good yields (87–95%) and (87–95%) and noteworthy enantioselectivity (77–96% ee) even though the overall outcomes were noteworthy enantioselectivity (77–96% ee) even though the overall outcomes were affected by the affected by the steric hindrance introduced on both donor and acceptor reagents (Scheme 3) [21]. steric hindrance introduced on both donor and acceptor reagents (Scheme 3) [21]. O

NC

CN

R1

O

O + R3

N N X

N R2 9

NC NC

IX (2 mol%)

R4

o-xylene −20 °C

R3

R1

O

10

11

N R2

N

R1

MeO CN

R2

H

CN

N

N a

Re-attack

O OMe

N Ph

N R4

O

b

O

N

* NR 3

N

Ph

O

N

(DHQD) 2PYR, IX

N X

R3

a vinylogous Michael Addition b cyclization O

O

O

NC NC

NC NC

Ph

Ph

O N Bn X = N, R 4 = -(CH)488 % Y (90% ee)

N Bn X = N, R 4 = -(CH)496 % Y (92% ee)

Br

O

N Bn

N Bn

X = N, R 4 = -(CH)489 % Y (97% ee)

O

X = N, R 4 = -(CH)494 % Y (92% ee)

O

NC NC

Ph

NC NC

Ph

O N Ph

Me

NC NC

Ph O

O Cl

O

NC NC

Ph Ph

X = N, R 4 = -(CH)4traces (n.d.% ee)

O N Bn X = C, R 4 = 3,5-(CH3)2 traces (n.d.% ee)

Scheme 3. Michael/cyclization cascade reaction to spirociclyc oxindoles catalyzed by (DHQD)2PYR (IX).

Scheme 3. Michael/cyclization cascade reaction to spirociclyc oxindoles catalyzed by (DHQD)2 PYR (IX).

Likewise, the replacement of the Michael donor with suitable pyrazolone 12 furnished the expected spiro[indoline-3,40 -pyrano[2,3-c]pyrazole] derivatives 13 by performing the reaction in

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Molecules 2017, 22,replacement 1636 28 Likewise, the of the Michael donor with suitable pyrazolone 12 furnished the6 of expected spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives 13 by performing the reaction in analogous Likewise, the replacement of◦ the Michael donor with suitable pyrazolone 12 furnished the expected analogous conditions −20 C, AcOEt solvent) and mol adding 1 mol % of the chosen conditions (i.e., −20 °C,(i.e., AcOEt as solvent) andasadding % ofonly the chosen spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives 13only by 1 performing the reaction organocatalyst in analogous IX organocatalyst IX (Scheme 4) [22]. The whole process was completed in a shorter reaction (Scheme 4) [22]. The whole process was completed in a shorter reaction time (from 10 min to 9 IX h) time with conditions (i.e., −20 °C, AcOEt as solvent) and adding only 1 mol % of the chosen organocatalyst (from 10 min to 9 h) with respect the previous vinylogous Michael/cyclization sequence (from 60 respect the previous vinylogous Michael/cyclization sequence (from 60 min to 7 days) and provided (Scheme 4) [22]. The whole process was completed in a shorter reaction time (from 10 min to 9 h) with min to 7 days) and the products in notable yields (96–99%) and60good-to-moderate optical purity the products inprovided notable vinylogous yields (96–99%) and good-to-moderate optical purity (47–91% respect the previous Michael/cyclization sequence (from min to 7 days) andee). provided (47–91% ee). the products in notable yields (96–99%) and good-to-moderate optical purity (47–91% ee). NC

CN

NC

R

1

R

CN

O

1

N N R2

H2N

R3 +

O

N

+

O +

O

N Tr 14

N Tr

+

CNCN CN

+ +

15

15

NC

N

1

R1

R

N

R2

R2

13

Ph Ph

H2NH2N O

NN N N Ph Ph

3 O R

R3 O N

13 Y (47 96 96 99%99% Y (47 91% 91% ee) ee)

MeMe

CN

14

AcOEt, 20 °C

1212

9

O

O

NC

AcOEt, 20 °C

O NN N R4 4 R

R2

9

(DHQD)2PYR, IX (1 mol%)

O

O

H2N

(DHQD)2PYR, IX (1 mol%)

R3

R4 O R4 N N N

IX (1 mol%) (DHQD)2PYR, (DHQD) 2PYR, IX (1 mol%)

OO

AcOEt,

AcOEt,

ON

N

NCNC

20 °C

20 °C

N N

O Me Me

O

N Tr

N

Tr 13 Me, R4 = Ph R1 = H, R2 = Tr, R3 =13 3 R2Y=(28% Tr, Ree) = Me, R4 = Ph R1 = H, 41%

12 12 R4 = Ph R3 = Me,

R3 = Me, R4 = Ph

41% Y (28% ee)

Scheme 4. Michael/cyclization cascade reaction catalysed by (DHQD)2PYR (IX) when pyrazolone 12 Scheme 4. Michael/cyclization cascade reaction catalysed by (DHQD)2 PYR (IX) when pyrazolone 12 Scheme Michael/cyclization cascade reaction catalysed by (DHQD)2PYR (IX) when pyrazolone 12 was 4. employed as Michael donor. was employed as Michael donor. was employed as Michael donor. Unfortunately, the optimized protocol failed when the one-pot three component reaction of 4 = Ph) was Unfortunately, the optimized failed when three component reaction N-trityl isatin (14), malonitrile (15),protocol and pyrazolone (R3 = the Me, one-pot R attempted affording the of Unfortunately, the optimized protocol failed 12 when the one-pot three component reaction of 3 4 in 1 2 3 4 hypothesized spirocompound 13 (R = H, R = Tr, R = Me, R = Ph) low yield (41%) and poor 3 4 N-trityl isatin (14), malonitrile (15), and pyrazolone 12 (R = Me, R = Ph) was attempted affording N-trityl isatin (14), malonitrile (15), and pyrazolone 12 (R = Me, R = Ph) was attempted affording the 1 = H,2 R2 = Tr, 3R3 = Me, R 4 enantioselectivity (28% ee). 13 13 the hypothesized spirocompound Ph)ininlow lowyield yield (41%) (41%) and poor hypothesized spirocompound (R1(R = H, R = Tr, R = Me, R4 = =Ph) Almost simultaneously, Enders and co-workers designed and realized an organocatalytic enantioselectivity enantioselectivity (28% (28% ee). ee). Mannich/Boc-deprotection/aza-Michael sequence of N-Boc ketimine 16 and 3-substituted oxindoles Almost simultaneously, Enders and co-workers co-workers designed and realized realized an an organocatalytic organocatalytic 17 that straightforwardly afforded the functionalized 3,3′-pyrrolidinyl derivatives 18 bearing three Mannich/Boc-deprotection/aza-Michael sequenceof ofN-Boc N-Boc ketimine ketimine 16 16 and 3-substituted oxindoles Mannich/Boc-deprotection/aza-Michael sequence stereocenters, two of which were contiguous spiro-stereocenters [23]. Therefore, the devised and validated 0 -pyrrolidinyl derivatives 18 bearing three 17 straightforwardly afforded the 3,3 17 that that straightforwardly affordedMTBE the functionalized functionalized 3,3′-pyrrolidinyl 18 2PHAL protocol (i.e., room temperature, as solvent), which relied on the efficiency of (DHQD) stereocenters, two of which were contiguous spiro-stereocenters [23]. Therefore, the devised and stereocenters, ofcatalyst, which were spiro-stereocenters [23]. Therefore, devised and validated X (10 moltwo %) as gavecontiguous access in moderate-to-good yields (41–84%) and the high stereoselectivity validated protocol (i.e., room MTBE as solvent), which relied onofthe efficiency of (up to >20:1 d.r., temperature, 90–98% ee) totemperature, complex spirocyclic systems 18 (Scheme 5). efficiency protocol (i.e., room MTBE as solvent), which relied on the (DHQD) 2PHAL

(DHQD) X (10 mol %)access as catalyst, gave access inyields moderate-to-good yieldsstereoselectivity (41–84%) and X (10 mol2 PHAL %) as catalyst, gave in moderate-to-good (41–84%) and high NBoc high stereoselectivity (up to >20:1 d.r., 90–98% ee) to complex spirocyclic systems 18 (Scheme 5). (up to >20:1 d.r., 90–98% ee) to complex spirocyclic systems 18 (Scheme 5). R2

O N R1

NBoc 16

R2

N R1

O CO2Et

+

2.TFA, DCM

16 R3

+

O

N CO 2Et H 17

R3

1. X (10 mol%), MTBE, rt R2

O

R3

1. X (10 mol%), MTBE, rt R2 2.TFA, DCM

R1 N O N H

R1 CO 2Et N OO N H N H

18 CO 2Et 41-84% Y R3 O (up to >20:1Nd.r.; 90−98% ee)

N N

N H MeO

O

O

H

H

MeO

H OMe

N N

N H

N

N

O

NO

H

H

(DHQD) 2PHAL X

N

N H OMe N

H

Scheme 5. Organocatalytic Mannich/Boc-deprotection/aza-Michael sequence (DHQD) developed by X Enders N 2PHAL 18 H and co-workers. 41-84% Y 17

(up to >20:1 d.r.; 90−98% ee)

Scheme 5. 5. Organocatalytic OrganocatalyticMannich/Boc-deprotection/aza-Michael Mannich/Boc-deprotection/aza-Michael sequence Enders Scheme sequence developed developed by by Enders and co-workers. and co-workers.

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4. Thiourea-Based Thiourea-Based Catalysts Catalysts 4. Thiourea-based organocatalysts organocatalysts [24–27] [24–27] have have been intensively intensively considered considered for promoting Thiourea-based multiple C-C and C-heteroatom bonds formation via domino reactions multiple C-C and C-heteroatom bonds formation via domino reactions throughthrough H-bondH-bond network network between between substrates andIncatalysts. In this section, recent selected cascade reactions such substrates and catalysts. this section, recent selected cascade reactions involving such involving organocatalysts organocatalysts (Figure 4) allowing to highlychiral functionalized chiral spirooxindole-bearing (Figure 4) allowing to highly functionalized spirooxindole-bearing compounds are compounds going to be are going to be discussed. discussed. CF3 H

Ph

S

N H

N

CF3 Ph

N H

CF3

Ph N

CF3

S

S

N H

N H

XI

CF3

N H

F 3C

XII

N H

N

XIII

Ph Ph

TsHN HN

OMe S

N

N

OMe S N H

H

N N H

XVII

H N

MeO

S

XVIII

S

CF3 F3C

S

CF3

XIX CF3 S

NH N

NH

O

N H

CF3

MeO

CF3 XX

CF3

N H

N

H N

N

N NH

N

OTBS

N

N

N XVI

CF3

F3C

S

MeO

CF3

XV

Ph Ph NHMs H NH N

N

S

N H

S

N XIV

N

C8F17

NH

MeO

H H N

H N

F3C

N

HN

CF3

XXI

N

XXII

Figure 4. Thiourea and thiocarbamate organocatalysts used in this section. Figure 4. Thiourea and thiocarbamate organocatalysts used in this section.

4.1. Michael Addition/Cyclization Sequence 4.1. Michael Addition/Cyclization Sequence Electrophilic isatilydene malonitrile derivatives 9 are substrates of choice to promote Michael Electrophilic isatilydene malonitrile derivatives 9 are substrates of choice to promote Michael addition/cyclization transformations through reaction with nucleophiles. In 2015, Kesavan and addition/cyclization transformations through reaction with nucleophiles. In 2015, Kesavan and co-workers have indeed devised a sequential vinylogous Michael addition/cyclization in the presence co-workers have indeed devised a sequential vinylogous Michael addition/cyclization in the presence of vinyl malononitriles 19 and 20 as vinylogous nucleophiles [28]. The reaction, conducted in the of vinyl malononitriles 19 and 20 as vinylogous nucleophiles [28]. The reaction, conducted in presence of L-proline derived bifunctional thiourea catalyst XI (10 mol %) in toluene at 0 °C, the presence of L-proline derived bifunctional thiourea catalyst XI (10 mol %) in toluene at 0 ◦ C, demonstrated a wide scope with both substrates (Scheme 6, compounds 21 and 22). In addition, an demonstrated a wide scope with both substrates (Scheme 6, compounds 21 and 22). In addition, enantioselective three-component reaction could also be proposed via in situ formation of isatylidene an enantioselective three-component reaction could also be proposed via in situ formation of malonitrile derivatives. The authors have also highlighted the ability of XI to afford high levels of isatylidene malonitrile derivatives. The authors have also highlighted the ability of XI to afford enantioselectivity without the need for N-protected oxindoles. Indeed, enantioselective transformations high levels of enantioselectivity without the need for N-protected oxindoles. Indeed, enantioselective involving oxindoles usually require the prior N-protection in order to avoid unsought substrate transformations involving oxindoles usually require the prior N-protection in order to avoid unsought interactions with the catalyst. substrate interactions with the catalyst.

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Scheme 6. Recent 9 Scheme 6. Recent examples examplesof ofspirooxindoles spirooxindolessynthesized synthesizedfrom fromisatylidene isatylidenemalonitrile malonitrilederivatives derivatives a Three-component through cascade processes involving Michael addition/cyclization sequence. a 9 through cascade processes involving Michael addition/cyclization sequence. Three-component reaction performed during during 36 36 h. h. bb Three-component reaction performed Three-component reaction reaction performed performed during during 48 48 h. h.

Herrera and co-workers reported the combination of enamines 23 and isatylidene malonitrile 9 Herrera and co-workers reported the combination of enamines 23 and isatylidene malonitrile 9 to propose a promising asymmetric synthesis of few 2-oxospiro-[indole-3,4′-(1′,4′-dihydropyridine)] to propose a promising asymmetric synthesis of few 2-oxospiro-[indole-3,40 -(10 ,40 -dihydropyridine)] 24 in moderate yields and enantioselectivities (Scheme 6, compound 24) [29]. The domino process is 24 in moderate yields and enantioselectivities (Scheme 6, compound 24) [29]. The domino process is believed to follow a mechanism that involves a Michael addition, an intramolecular cyclization and believed to follow a mechanism that involves a Michael addition, an intramolecular cyclization and then, then, a tautomerization and is catalyzed by Takemoto’s catalyst [30] XIII (30 mol %) in acetonitrile at a tautomerization and is catalyzed by Takemoto’s catalyst [30] XIII (30 mol %) in acetonitrile at 15 ◦ C. 15 °C. The synthesis of several spiro[4H-pyran-oxindole] derivatives 26 was proposed by Wu and The synthesis of several spiro[4H-pyran-oxindole] derivatives 26 was proposed by Wu and co-workers by using α-cyano ketones 25 as nucleophiles (Scheme 6) [31]. In the presence of very co-workers by using α-cyano ketones 25 as nucleophiles (Scheme 6) [31]. In the presence of very low low loadings of quinidine-derived thiourea organocatalyst XVII (2 mol %) and morpholine (1 mol %) loadings of quinidine-derived thiourea organocatalyst XVII (2 mol %) and morpholine (1 mol %) in in dichloromethane at 0 or −10 ◦ C, the cascade process takes place within less than two hours and dichloromethane at 0 or −10 °C, the cascade process takes place within less than two hours and accommodates a broad range of substrates affording the expected products in excellent yields and accommodates a broad range of substrates affording the expected products in excellent yields and high enantioselectivities. The authors have shown that the chiral tertiary amine moiety in catalyst high enantioselectivities. The authors have shown that the chiral tertiary amine moiety in catalyst XVII is crucial to afford enantioenriched spiro compounds 26 as in its absence, the expected products XVII is crucial to afford enantioenriched spiro compounds 26 as in its absence, the expected products were obtained in a racemic manner. were obtained in a racemic manner. Novel thiazole-fuzed spirooxindoles 28 were synthesized in high yields and enantioselectivities by Novel thiazole-fuzed spirooxindoles 28 were synthesized in high yields and enantioselectivities using (1R,2R)-1,2-diphenylethane-1,2-diamine derived thiourea catalyst XII (2 mol %) (Scheme 6) [32]. by using (1R,2R)-1,2-diphenylethane-1,2-diamine derived thiourea catalyst XII (2 mol %) (Scheme 6) [32]. In this case, the domino transformation also takes place in shorter reaction times and the catalytic In this case, the domino transformation also takes place in shorter reaction times and the catalytic system proved to be suitable to a series of 2-substituted thiazol-4-ones 27 as nucleophiles and system proved to be suitable to a series of 2-substituted thiazol-4-ones 27 as nucleophiles and 2-(12-(1-methyl-2-oxoindolin-3-ylidene)malonitrile as electrophile. Concerning the mechanism, the authors methyl-2-oxoindolin-3-ylidene)malonitrile as electrophile. Concerning the mechanism, the authors reasoned that the observed stereochemistry of this domino reaction can be explained via a first reasoned that the observed stereochemistry of this domino reaction can be explained via a first Michael addition of thiazolones 27 to 9 to afford the Michael addition intermediate followed by its Michael addition of thiazolones 27 to 9 to afford the Michael addition intermediate followed by its subsequent intramolecular Thorpe-Ziegler-type cyclization. Both steps operate through dual activation of substrates in the presence of the bifunctional thiourea catalyst XII.

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subsequent Thorpe-Ziegler-type cyclization. Molecules 2017,intramolecular 22, 1636

Both steps operate through dual activation 9 of 28 of substrates in the presence of the bifunctional thiourea catalyst XII. combination of ofnaphthoquinone naphthoquinoneand andchromenone chromenonederivatives derivatives with oxindole ketoesters The combination with oxindole ketoesters as as Michael acceptors paved waytotothe thepreparation preparationofof versatile versatile heterocyclic heterocyclic compounds. compounds. Michael acceptors hashas paved thetheway The group groupofofKesavan Kesavan has, again, underscored proline-based XI %) (5 as mol %) as has, onceonce again, underscored proline-based catalystcatalyst XI (5 mol powerful powerfulto catalyst carry on tandem Michael addition/hemiketalization ketoester 29 with catalyst carry ontotandem Michael addition/hemiketalization of ketoester 29ofwith 2-hydroxy-1,42-hydroxy-1,4-naphthoquinone 30 in dichloromethane at room temperature (Scheme [33]. naphthoquinone 30 in dichloromethane at room temperature (Scheme 7) [33]. The expected 7) hybrid The expected hybrid spirooxindole-naphthoquinone compounds 31 were obtained in excellent yields spirooxindole-naphthoquinone compounds 31 were obtained in excellent yields and enantioselectivities and displayed goodconcerning functional tolerance concerning the scaffold oxindoleincluding ketoester and enantioselectivities displayed good functional tolerance the oxindole ketoester scaffold including different N-protecting groups. However, unprotected (i.e., N-H) oxindole substrates different N-protecting groups. However, unprotected (i.e., N-H) oxindole substrates gave lower gave lower yields and enantioselectivities probably due to theH-bond additional H-bond sitebe that yields and enantioselectivities probably due to the additional binding site binding that might in might be in competition either with the organocatalyst or with theIndependently substrates. Independently and competition either with the organocatalyst or with the substrates. and shortly after, shortly after, the group of Wang proposed a similar transformation in the presenceXX of (10 catalyst XX the group of Wang proposed a similar transformation in the presence of catalyst mol %). (10this molwork, %). In this work, a broader scope has been of both [34]. In a broader scope has been proposed withproposed respect ofwith bothrespect substrates [34].substrates Additionally, Additionally, the synthesis of several optically active spiro[oxindole-benzo[g]chromene-dione] the synthesis of several optically active spiro[oxindole-benzo[g]chromene-dione] derivates was also derivates via wascascade also described via cascade reaction between 2-hydroxy-1,4-naphthoquinone as described reaction between 2-hydroxy-1,4-naphthoquinone as nucleophile and oxindole nucleophile and oxindole ketoesters. ketoesters.

Scheme Scheme 7. 7. Synthesis Synthesis of of hybrid hybrid spirooxindole-naphthoquinones spirooxindole-naphthoquinones through through catalysis catalysis with with proline-based proline-based a a ◦ catalyst catalyst XI. XI. Reaction Reaction was was carried carried out out at at 55 °C. C.

In 2016, Enders and co-workers developed a highly selective domino oxa-Michael/1,6-addition In 2016, Enders and co-workers developed a highly selective domino oxa-Michael/1,6-addition sequence to synthesize functionalized chromans with an oxindole moiety [35]. The success of the sequence to synthesize functionalized chromans with an oxindole moiety [35]. The success of the transformation relies on the use of unprecedented ortho-hydroxyphenyl-substituted para-quinone transformation relies on the use of unprecedented ortho-hydroxyphenyl-substituted para-quinone methide 33 as donor-Michael acceptor substrates in combination with isatin-derived enoate 32 methide 33 as donor-Michael acceptor substrates in combination with isatin-derived enoate 32 (Scheme 8). The mild reaction conditions [i.e., catalyst XVIII (5 mol %) in toluene at room (Scheme 8). The mild reaction conditions [i.e., catalyst XVIII (5 mol %) in toluene at room temperature] temperature] showed significantly wide substrate scope and functional group tolerance. showed significantly wide substrate scope and functional group tolerance. Other interesting substrates used in cascade transformations to afford highly substituted and Other interesting substrates used in cascade transformations to afford highly substituted and poly-functionalized spirooxindoles through Michael addition/cyclization process are 3-isothiocyanate poly-functionalized spirooxindoles through Michael addition/cyclization process are 3-isothiocyanate oxindoles (Scheme 9, compound 35). Indeed, their ambiphilic character (e.g., bearing both electrophilic oxindoles (Scheme 9, compound 35). Indeed, their ambiphilic character (e.g., bearing both electrophilic and nucleophilic sites) allows for the synthesis of several functionalized spirooxindoles via reaction with and nucleophilic sites) allows for the synthesis of several functionalized spirooxindoles via reaction diversified suitable substrates such as electron-poor olefins. Chowdhury, Ghosh, and co-workers with diversified suitable substrates such as electron-poor olefins. Chowdhury, Ghosh, and co-workers proposed the use of quinine-derived thiourea catalyst XIX (20 mol %) in toluene at 0 °C◦in order to proposed the use of quinine-derived thiourea catalyst XIX (20 mol %) in toluene at 0 C in order synthesize a broad range of 3,2′-pyrrolidinyl spirooxindoles 37 in high yields and excellent diastereoand enantioselectivities by using quite unreactive π-electrophiles such as diethyl benzylidene malonate 36 [36]. Moreover, Jing, Qin, and co-workers reported an asymmetric synthesis of transconfigured trispirooxindoles by combining 35 and cyclic methyleneindolinones 38 in the presence of Takemoto’s catalyst XIII (15 mol %) [37]. Interestingly, less than 60 min is enough to the cascade

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to synthesize a broad range of 3,20 -pyrrolidinyl spirooxindoles 37 in high yields and excellent diastereo- and enantioselectivities by using quite unreactive π-electrophiles such as diethyl benzylidene malonate 36 [36]. Moreover, Jing, Qin, and co-workers reported an asymmetric synthesis of trans-configured by combining 35 and cyclic methyleneindolinones 38 in the presence Molecules 2017, 22,trispirooxindoles 1636 10 of 28 of Takemoto’s catalyst XIII (15 mol %) [37]. Interestingly, less than 60 min is enough to the cascade Molecules 2017, 22, 1636 10 of 28 reaction to reach completion and the expected spiro compounds bears three quaternary reaction to reach completion and the expected spiro compounds that bearsthat three quaternary stereocenters Molecules 2017, 22, 1636 10 of 28 stereocenters are isolated in good yield and selectivities. arereaction isolatedto in reach good yield and selectivities. completion and the expected spiro compounds that bears three quaternary reaction to reach completion and theand expected spiro compounds that bears three quaternary stereocenters are isolated in good yield selectivities. stereocenters are isolated in good yield and selectivities.

Scheme 8. Synthesis of chromans 34 with an oxindole moiety catalyzed by XVIII. Scheme 8. Synthesis of chromans 34 with an oxindole moiety catalyzed by XVIII. Scheme 8. Synthesis of chromans 34 with an oxindole moiety catalyzed by XVIII. Scheme 8. Synthesis of chromans 34 with an oxindole moiety catalyzed by XVIII. Ph S HNS S

CO 2Et CO 2Et CO 2Et

CO OCO 2Et 2Et N CO 2Et HN Me O N O 37 Me N 78% Y (97:3 d.r., 97% ee) Me 37 78%9. Y (97:3 d.r., 97% ee) Scheme 3-Isothiocyanate 37 HN

CO 2Et

CO22Et Et CO 36CO Et Ph 2 CO 2Et XIX (20 mol%) 36CO 2Et toluene, 0 °C XIX (20 36mol%) 10 h XIX (20 mol%) toluene, 0 °C 10 h toluene, 0 °C 10 h

Ph

S C NS CS NC O N N Me O N 35 Me O N 35

Me

O N 38 BocO N O XIII (15 mol%) 38NBoc DCE, 30Boc °C 38 XIII 40 (15 mol%) min

S

O

Boc N Boc N Boc

O HN S N O S O HN N XIII (1530 mol%) DCE, °C HN Me 40 min O DCE, 30 °C N39 40 min O Me 84% Y (88:12 d.r., 93% ee) N 39 Me Y (88:12 93% ee) for the synthesis84% of densely functionalized 39d.r.,

oxindoles as versatile 35substrates 84% Y (88:12 d.r., 93% ee) 78% Y (97:3 d.r., 97% ee) spirooxindoles. Scheme9.9. 3-Isothiocyanate oxindoles as versatile substratessubstrates for the synthesis of densely functionalized Scheme 3-Isothiocyanate oxindoles as versatile for the synthesis of densely Scheme 9. 3-Isothiocyanate oxindoles as versatile substrates for the synthesis of densely functionalized spirooxindoles. functionalized Remarkably,spirooxindoles. the use of chiral amino-thiocarbamate catalyst XXII (10 mol %) gave rise to several spirooxindoles.

polycyclic spirooxindoles 41 containing three contiguous chiral centers, with two of them having Remarkably, the use of chiral amino-thiocarbamate catalyst XXII (10 mol %) gave rise to several quaternary stereocenters, the presence of 35 and 3-nitroindoles 40 (Scheme 10) [38]. Excellent yields Remarkably, the use chiral amino-thiocarbamate catalyst XXII (10mol mol %) gave rise several Remarkably, the useofin of chiral amino-thiocarbamate catalyst (10 %) gave to to several polycyclic spirooxindoles 41 containing three contiguous chiral XXII centers, with two of rise them having and selectivitivites were obtained when the N1-position of 35 was blocked with a methyl group while polycyclic spirooxindoles 41 containing three contiguous chiral centers, with two of them having polycyclic spirooxindoles containing three contiguous chiral40centers, with two Excellent of them having quaternary stereocenters, in41the presence of 35 and 3-nitroindoles (Scheme 10) [38]. yields slight erosion of the diastereoand enantioselectivities were observed for more hindered N1-protecting quaternary stereocenters, in the thepresence presence 3-nitroindoles 40 (Scheme 10) [38]. quaternary stereocenters, ofof 35 35 andand 3-nitroindoles (Scheme 10)a [38]. Excellent yields and selectivitivites were obtained when the N1-position of 35 was 40 blocked with methyl groupExcellent while groups. yields and selectivitivites were obtained when the N1-position of 35 was blocked with a methyl and selectivitivites were obtained when the N1-position of 35 was blocked with a methyl group while slight erosion of the diastereo- and enantioselectivities were observed for more hindered N1-protecting group while slight erosion of the diastereoand enantioselectivities were observed for more hindered slight erosion of the diastereoand enantioselectivities were observed for more hindered N1-protecting groups. groups. N1-protecting groups.

Scheme 10. Asymmetric synthesis of polycyclic spirooxindoles in the presence of amino-thiocarbamate catalyst XXII. Scheme 10. Asymmetric synthesis of polycyclic spirooxindoles in the presence of amino-thiocarbamate Scheme XXII. 10. Asymmetricsynthesis synthesisof ofpolycyclic polycyclic spirooxindoles spirooxindoles in catalyst Asymmetric inthe thepresence presenceofofamino-thiocarbamate amino-thiocarbamate 4.2.Scheme Michael10. Addition/Mannich/Cyclization Sequence catalyst XXII. catalyst XXII.

4.2. Michael Addition/Mannich/Cyclization Sequence Recyclable fluorous bifunctional Cinchona alkaloid catalyst XV [39] has proved its efficiency to 4.2. Michael Addition/Mannich/Cyclization catalyze cascade reaction in the presenceSequence of electron-deficient olefinic oxindole 42 and nucleophiles. Recyclable fluorous bifunctional Cinchona alkaloid catalyst XV [39] has proved its efficiency to The syntheses of spirooxindoles containing 2-piperidinone 44 and 46efficiency rings were Recyclable Cinchona alkaloid catalyst XVtetrahydropyridine [39] has proved to catalyze cascadefluorous reaction bifunctional in the presence of electron-deficient olefinic oxindole 42 anditsnucleophiles. successfully accomplished in 2015 by Zhang and co-workers through a four-component cascade catalyze cascade reaction in the presence of 2-piperidinone electron-deficient olefinic oxindole 42 and 46 nucleophiles. The syntheses of spirooxindoles containing 44 and tetrahydropyridine rings were transformation in spirooxindoles the presence of containing diethyl malonate 43 or 1,3-diketone 45 respectively (Scheme 11)were [40]. The syntheses of 2-piperidinone 44 and tetrahydropyridine 46 rings successfully accomplished in 2015 by Zhang and co-workers through a four-component cascade

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4.2. Michael Addition/Mannich/Cyclization Sequence Recyclable fluorous bifunctional Cinchona alkaloid catalyst XV [39] has proved its efficiency to catalyze cascade reaction in the presence of electron-deficient olefinic oxindole 42 and nucleophiles. syntheses MoleculesThe 2017, 22, 1636 of spirooxindoles containing 2-piperidinone 44 and tetrahydropyridine 46 rings were 11 of 28 successfully accomplished in 2015 by Zhang and co-workers through a four-component cascade the presence of diethyl malonate 43 or 1,3-diketone 45 respectively 11) [40]. Under transformation the optimal in conditions [i.e., catalyst XV (10 mol %) in toluene] high (Scheme yields and levels of Under the optimal conditions [i.e., catalyst XV (10 mol %) in toluene] high yields and levels of selectivity were reached affording polycyclic molecules densely functionalized that were prone to selectivity were reached affording polycyclic molecules densely functionalized that were prone to either either further derivatization or scale-up. Although the authors have mainly proposed the use of further derivatization or scale-up. Although the authors have mainly proposed the use of oxindoles bearing a methyl group atatthe onesingle single example using free-N1 has been oxindoles bearing a methyl group theN1-position, N1-position, one example using free-N1 has been described affording slightly lower yields selectivities. described affording slightly lower yieldsand and comparable comparable selectivities. O EtO

EtO 2C

O

XV (10 mol%) O N R1

EtO

OEt

43

O

EtO 2C

toluene, −20 °C 3h

O O

OEt

N R1

NH 4OAc PhCHO

O

EtO 2C

NH

EtO 2C

Ph O

piperidine, 25 °C toluene/EtOH 1:2 12 h

N R1 44

42

R1 = Me; 80% Y (6:1 d.r., 98% ee) R1 = H; 60% Y (6:1 d.r., 98% ee) O

O O

O

EtO 2C

45 XV (10 mol%) O

N R1

EtO 2C

toluene, −30 °C 3h

O O

N R1

NH 4OAc PhCHO

NH

EtO 2C

Ph O

piperidine, 25 °C toluene/EtOH 1:2 8h

N R1 46

42

R1 = Me; 84% Y (5:1 d.r., 96% ee) R1 = H; 59% Y (4:1 d.r., 94% ee)

Scheme 11. Synthesis of piperidone andtetrahydropyridine tetrahydropyridine rings bearing spirooxindoles in the in the Scheme 11. Synthesis of piperidone and rings bearing spirooxindoles presence of recyclable catalyst XV. presence of recyclable catalyst XV.

Shortly same grouphas hasused used catalyst XV (10(10 molmol %) during a similar cascade cascade reaction for Shortly after,after, the the same group catalyst XV %) during a similar reaction the synthesis of spiro-γ-lactam oxindoles via a thiol-Michael/Mannich/lactamization cascade reaction for the synthesis of spiro-γ-lactam oxindoles via a thiol-Michael/Mannich/lactamization cascade in good yields and enantioselectivities and moderate diastereoselectivities [41]. The method goes reaction in good yields and enantioselectivities and moderate diastereoselectivities [41]. The method through a four-component/one-pot synthesis and paves the way to novel compounds 48 containing goes through a four-component/one-pot synthesis and paves the way to novel compounds 48 three contiguous stereocenters including a quaternary one (Scheme 12). As for the previous example, containing stereocenters including quaternary one (Scheme As for the N-Me three indolescontiguous were exclusively used as substrates and aonly one example with N-H was12). reported. previous example, N-Me indoles exclusively used as one silica example In both cases, catalyst recovery were has been realized through firstsubstrates (i) loading and onto only a fluorous gel with cartridge for solid-phase extraction (F-SPE) [42] followed by (ii) elution with 80:20 MeOH/H O N-H was reported. In both cases, catalyst recovery has been realized through first (i) loading 2 for onto a products other non-fluorous components and 100%(F-SPE) MeOH for thefollowed catalyst XV. catalyst is 80:20 fluorous silica and gel cartridge for solid-phase extraction [42] byOverall, (ii) elution with recovered in more than 91% yield and >97% of optical purity. MeOH/H2O for products and other non-fluorous components and 100% MeOH for the catalyst XV. Overall, catalyst is recovered in more than 91% yield and >97% of optical purity. SH EtO 2C

47 XV (10 mol%) O

N R1 42

EtO 2C

toluene, −20 °C 3h

S O

N R1

NH 4OAc PhCHO piperidine, 25 °C toluene/EtOH 1:1.5 12 h

O NH

S

Ph O N R1 48

containing three contiguous stereocenters including a quaternary one (Scheme 12). As for the previous example, N-Me indoles were exclusively used as substrates and only one example with N-H was reported. In both cases, catalyst recovery has been realized through first (i) loading onto a fluorous silica gel cartridge for solid-phase extraction (F-SPE) [42] followed by (ii) elution with 80:20 MeOH/H 2O 22, for1636 products and other non-fluorous components and 100% MeOH for the catalyst Molecules 2017, 12 XV. of 30 Overall, catalyst is recovered in more than 91% yield and >97% of optical purity. SH EtO 2C

47 XV (10 mol%) O

N R1

EtO 2C

S

toluene, −20 °C 3h

O N R1

O

NH 4OAc PhCHO

NH

S

piperidine, 25 °C toluene/EtOH 1:1.5 12 h

Ph O N R1

42

48 R1 = Me; 78% Y (6:1 d.r., 93% ee) R1 = H; 57% Y (1.5:1 d.r., 95% ee)

Scheme catalyzed by by catalyst catalyst XV. XV. Scheme 12. 12. Synthesis Synthesis of of spiro-γ-lactam spiro-γ-lactam oxindoles oxindoles via via cascade cascade reaction reaction catalyzed

Recently, co-workers have described the the asymmetric asymmetric preparation preparation of of Recently, Enders Enders and and co-workers have described trifluoromethylated 3,3′-pyrrolidinyl-dispirooxindole derivatives bearing four contiguous stereogenic 0 trifluoromethylated 3,3 -pyrrolidinyl-dispirooxindole derivatives bearing four contiguous stereogenic centers cycloaddition takes place in centers among among which which two two are arevicinal vicinal[43]. [43].The TheMichael-Mannich Michael-Mannich[3[3+ 2] + 2] cycloaddition takes place the presence of oxindoles 42 and 49 through thiourea-based derivative XXI catalysis (Scheme 13). Molecules 2017, 22, 1636 12 of 28 in the presence of oxindoles 42 and 49 through thiourea-based derivative XXI catalysis (Scheme 13). Concerning electron-neutral, electron-donating or Concerning the the scope, scope,several severalolefinic olefinicoxindoles oxindoles4242(containing (containing electron-neutral, electron-donating electron-withdrawing groups in in the ketimines 49 49 or electron-withdrawing groups thebenzene benzenering) ring)asaswell well as as trifluoroethyl trifluoroethyl isatin isatin ketimines (bearing electron-donating or a 5-F groups in the benzene moiety) are well tolerated. To replace the (bearing electron-donating or a 5-F groups in the benzene moiety) are well tolerated. To replace Boc Boc protecting group by by a Me group hamper the the the protecting group a Me groupononthe thenitrogen nitrogenofof substrate substrate 42 42 did did not not hamper enantioselectivities. Under the optimized conditions (i.e., XXI (10 mol %) in CCl 4 at 4 °C ◦ for 12 h) enantioselectivities. Under the optimized conditions (i.e., XXI (10 mol %) in CCl4 at 4 C for 12the h) authors described 17 novel 3,3′-pyrrolidinlyl-dispirooxindoles 50 in good (60–92%), the authors described 17 novel 3,30 -pyrrolidinlyl-dispirooxindoles 50 yields in good yields moderate(60–92%), to-good diastereoselectivities (4:1 to >20:1(4:1 d.r.)to and enantioselectivities (72–93% ee). In addition, moderate-to-good diastereoselectivities >20:1 d.r.) and enantioselectivities (72–93%scale ee). up on a gram scale of the reaction was realized conserving high yields and keeping the same levels In addition, scale up on a gram scale of the reaction was realized conserving high yields and keeping of selectivities. the same levels of selectivities.

Scheme 13. 13. Domino cycloaddition for for the the asymmetric synthesis of 3,3′Scheme DominoMichael-Mannich Michael-Mannich[3 [3+ 2] + 2] cycloaddition asymmetric synthesis of pyrrolidinlyl-dispirooxindoles 50. 0 3,3 -pyrrolidinlyl-dispirooxindoles 50.

4.3. Double Double Michael Michael Addition Addition Sequence Sequence 4.3. A double double Michael Michael cascade cascade reaction reaction sequence, sequence, that thatallowed allowedfor foraastereoselective stereoselective[3+2] [3+2] and and[4+2] [4+2] A spiroannulation process, gave rise to both fiveand six-membered β-nitro spirocarbocyclic oxindoles spiroannulation process, gave rise to both five- and six-membered β-nitro spirocarbocyclic oxindoles respectively [44]. [44]. After the screening screening of of several several thiourea-based thiourea-based organocatalysts, organocatalysts, Quintavalla Quintavalla and and respectively After the co-workers have identified Takemoto’s catalyst XIII (10 mol %) as the most effective in terms of yields co-workers have identified Takemoto’s catalyst XIII (10 mol %) as the most effective in terms of and selectivities. By combining 2-(2-oxoindolin-3-ylidene)-acetic esters 32 and nitroenoates 51 51 as yields and selectivities. By combining 2-(2-oxoindolin-3-ylidene)-acetic esters 32 and nitroenoates donor/acceptor compounds, novel spirooxindoles this as donor/acceptor compounds, novel spirooxindolesdensely denselyfunctionalized functionalizedwere were isolated isolated via via this Michael-Michael cascade process (Schemes 14 and 15). Noteworthy to mention, the authors Michael-Michael cascade process (Schemes 14 and 15). Noteworthy to mention, the authors foreground foreground that upon varyingbond the double bond (E or Z) of51, nitroesters 51, the configuration that upon varying the double geometry (Egeometry or Z) of nitroesters the configuration of the spiro of the spiro quaternary stereocenter is inverted affording C3-epimers. This observation is valid for quaternary stereocenter is inverted affording C3-epimers. This observation is valid for both five-(52) both five-(52) and six-membered (53) spirooxindoles. If the absolute configuration of the spiro center and six-membered (53) spirooxindoles. If the absolute configuration of the spiro center was determined was determined accordingly E/Z geometry of nitroesters double-bonds, thewere remaining accordingly to the E/Z geometrytoof the nitroesters double-bonds, the remaining stereocenters forged stereocenters were forged under the catalyst XIII control. under the catalyst XIII control. CO 2Et

O2N (E)-51a

XIII (10 mol%) CH 2Cl 2, rt 5h

O2N H EtO 2C

CO2Et

3

O N Boc

Michael-Michael cascade process (Schemes 14 and 15). Noteworthy to mention, the authors foreground that upon varying the double bond geometry (E or Z) of nitroesters 51, the configuration of the spiro quaternary stereocenter is inverted affording C3-epimers. This observation is valid for both five-(52) and six-membered (53) spirooxindoles. If the absolute configuration of the spiro center was determined Molecules 2017, 22, 1636accordingly to the E/Z geometry of nitroesters double-bonds, the remaining 13 of 30 stereocenters were forged under the catalyst XIII control. CO 2Et

O2N (E)-51a

O2N H EtO 2C

XIII (10 mol%) CH 2Cl 2, rt 5h

EtO 2C

CO2Et

3

O N Boc 52a 73% Y (85:15 d.r., 98% ee)

[3+2] annulation 5-membered spirooxindoles

O N Boc O2N

32

O2N (Z)-51b

CO 2Et

H EtO 2C

XIII (10 mol%) CH 2Cl 2, rt 6h

CO2Et

3

O N Boc 52b 52% Y (90:10 d.r., 99% ee)

Scheme 14. 14. Synthesis Synthesis of of β-nitro β-nitro spirocyclopentane spirocyclopentane indolinones indolinones 52 via double double Michael Michael cascade cascade in in the the Scheme 52 via presence of of Takemoto’s Takemoto’scatalyst catalystXIII. XIII. presence Molecules 2017, 22, 1636 13 of 28 O2N

CO 2Et (E)-51c XIII (10 mol%) CH 2Cl 2, rt 3 days

EtO 2C

O2N H EtO 2C

3

CO 2Et

O N Boc 53a 73% Y (98% ee)

[4+2] annulation 6-membered spirooxindoles

O N Boc

O 2N

32

CO 2Et

(Z)-51d

XIII (10 mol%) CH 2Cl2, rt 1 day

O2N H EtO 2C

3

CO 2Et

O N Boc 53b 79% Y (97% ee)

Scheme 15. 15. Synthesis Synthesis of of β-nitro β-nitro spirocyclohexane spirocyclohexane indolinones double Michael Michael cascade cascade in the Scheme indolinones 53 53 via via double in the presence of of Takemoto’s Takemoto’s catalyst catalyst XIII. XIII. presence

4.4. Aldol/Lactonization/Elimination Sequence 4.4. Aldol/Lactonization/Elimination Sequence An enantioselective domino reaction reaction involving an unprecedented aldol/lactonization/ An enantioselective domino involving an one-pot unprecedented one-pot elimination sequence has been developed, in 2016, yielding a broad range of 3-spiro-α-alkylidene-γaldol/lactonization/elimination sequence has been developed, in 2016, yielding a broad range of butyrolactone oxindoles 58 (Scheme oxindoles 16) [45]. The reaction 16) is performed in the presence of β-nitro 3-spiro-α-alkylidene-γ-butyrolactone 58 (Scheme [45]. The reaction is performed in the indolin-2-ones 54 and paraformaldehyde 55 as starting materials and it ismaterials catalysed byitbifunctional presence of β-nitro indolin-2-ones 54 and paraformaldehyde 55 as starting and is catalysed Cinchona-derived thiourea XVI (10 thiourea mol %) inXVI dichloromethane 0 °C or room temperature. by bifunctional Cinchona-derived (10 mol %) inatdichloromethane at 0 ◦ C or While room 54 was used as a 1:1 mixture of C3 epimers, where both the Cα and Cβ absolute configuration were temperature. While 54 was used as a 1:1 mixture of C3 epimers, where both the Cα and Cβ absolute fixed and known [46], the expected products were isolated with well-established C3 quaternary configuration were fixed and known [46], the expected products were isolated with well-established spirocenter. Even though theEven two well defined Cα and stereocenters during domino C3 quaternary spirocenter. though the two wellCβ defined Cα andare Cβdestroyed stereocenters arethe destroyed process,the it is domino interesting to mention the only stereolabile center 54 became the unique controlled during process, it isthat interesting to mentionC3 that the of only stereolabile C3 center of 54 and defined one present on the final products. It was postulated that the reaction might became the unique controlled and defined one present on the final products. It was postulatedproceed that the through might an aldol reaction between 54 and 55 to afford the54 acyclic whichintermediate bears three reaction proceed through an aldol reaction between and 55intermediate to afford the56 acyclic stereodefined including thecenters fixed C3 quaternary one.C3 Then, lactonization affords the cyclic 56 which bearscenters three stereodefined including the fixed quaternary one. Then, lactonization lactone 57 which in turn loses its nitro group through HNO 2 extrusion to afford the expected affords the cyclic lactone 57 which in turn loses its nitro group through HNO2 extrusion to afford the compounds 58 (Scheme expected compounds 58 16). (Scheme 16). Aldol EtO 2C

β α

H 3

N Boc

NO 2 O

(CH 2O) n 55 XVI (10 mol%) CH 2Cl 2, 0 °C or rt 6 days

NO 2

EtO 2C 3

N Boc

Lactonization

O2N

O

O O

OH O

Elimination

O

O N Boc

O HNO 2

N Boc

process, it is interesting to mention that the only stereolabile C3 center of 54 became the unique controlled and defined one present on the final products. It was postulated that the reaction might proceed through an aldol reaction between 54 and 55 to afford the acyclic intermediate 56 which bears three stereodefined centers including the fixed C3 quaternary one. Then, lactonization affords the cyclic lactone 57 which Molecules 2017, 22, 1636 in turn loses its nitro group through HNO2 extrusion to afford the expected 14 of 30 compounds 58 (Scheme 16). Aldol EtO 2C

β α

H 3

N Boc 54

NO 2 O

(CH 2O) n 55 XVI (10 mol%)

NO 2

EtO 2C 3

CH 2Cl 2, 0 °C or rt 6 days

N Boc 56

Lactonization

O2N

O

O O

OH O

O

Elimination O

N Boc 57

O HNO 2

N Boc 58

Scheme 16. Synthesis Synthesis of of 3-spiro-α-alkylidene-γ-butyromactone 3-spiro-α-alkylidene-γ-butyromactone oxindoles oxindoles 58 58 in in the the presence of Cinchona-derived thiourea catalyst XVI.

4.5. 4.5. Friedel-Crafts/Hemiketalization Friedel-Crafts/Hemiketalization Sequence Sequence The Kesavan group group has has published published aa straightforward straightforward synthesis synthesis of of several several oxindole-fused oxindole-fused The Kesavan naphthopyran a naphthopyran derivatives derivatives60 60by bycombining combiningoxindole oxindoleα-ketoester α-ketoester2929and and2-naphthol 2-naphthol5959and andusing using sequence of Friedel-Crafts-hemiketalization reactions [47]. Under the optimized conditions (i.e., XI a sequence of Friedel-Crafts-hemiketalization reactions [47]. Under the optimized conditions (i.e., XI (5 mol mol %), %), in in 1,1,1-trifluoromethyl 1,1,1-trifluoromethyl benzene benzene at at room room temperature) temperature) N1-protected N1-protected oxindoles oxindoles afforded afforded (5 the expected products in good yields and enantioselectivities. However, unprotected N-H oxindoles the expected products in good yields and enantioselectivities. However, unprotected N-H oxindoles conducted to lower due to to competitive competitive binding binding of of the the N-H N-H site conducted to lower yields yields and and selectivities selectivities probably probably due site with with the catalyst that might partially hamper the catalytic activity (Scheme 17). the catalyst that might partially hamper the catalytic activity (Scheme 17). Molecules 2017, 22, 1636 14 of 28

Scheme 60 60 in the presence of catalyst XI. aXI. 86%a ee after Scheme 17. 17. Synthesis Synthesisofofspirooxindole-naphthopyrans spirooxindole-naphthopyrans in the presence of catalyst 86% ee recrystallization. after recrystallization.

4.6. 4.6. Miscellaneous Miscellaneous The The synthesis synthesis of of spiro-3,4-dihydropyrans spiro-3,4-dihydropyrans 62 62 bearing bearing three three stereocenters stereocenters with with vicinal vicinal quaternary quaternary ones has been reported by Kesavan and co-workers through the use of catalyst XI (5 %)mol in toluene ones has been reported by Kesavan and co-workers through the use of catalystmol XI (5 %) in at room temperature (Scheme 18a) [48]. Supported by the obtained syn configuration of the secondary toluene at room temperature (Scheme 18a) [48]. Supported by the obtained syn configuration of the alcohol andalcohol the cyclopentanone moiety, the authors an inverse-electron-demand hetero-Dielssecondary and the cyclopentanone moiety, defend the authors defend an inverse-electron-demand Alder reaction pathway of oxindole α-ketoester 29 with cyclic β-oxoaldehyde 61 rather than cascade hetero-Diels-Alder reaction pathway of oxindole α-ketoester 29 with cyclic β-oxoaldehyde a61 rather transformation via Micheal addition/hemiketalization. An efficient enantioselective [3+2] cyclization than a cascade transformation via Micheal addition/hemiketalization. An efficient enantioselective of 3-isothiocyanate oxindoles 63 andoxindoles trifluoromethylated 2-butenedioic acid diester 64 or 65 diester paved [3+2] cyclization of 3-isothiocyanate 63 and trifluoromethylated 2-butenedioic acid the way to the synthesis of spirooxindoles with a CF 3-containing all-carbon stereogenic center 66 64 or 65 paved the way to the synthesis of spirooxindoles with a CF3 -containing all-carbon stereogenic (Scheme [49]. 18b) Interestingly, the authors the possibility to obtaintoeither isomers center 66 18b) (Scheme [49]. Interestingly, thehighlighted authors highlighted the possibility obtain either (i.e., epimers at C4 position) in the presence of the same catalyst XIV (20 mol %) at different temperatures. isomers (i.e., epimers at C4 position) in the presence of the same catalyst XIV (20 mol %) at different This observation relies on the ability of isomerization maleate into dimethyl fumarate temperatures. This observation relies on the ability of ofdimethyl isomerization of 64 dimethyl maleate 64 into 65 through azomethine ylide intermediate the intermediate presence of the amine moietyofofthe aminals dimethyl fumarate 65 through azomethine in ylide in the presence amine[50]. moiety of aminals [50].

of 3-isothiocyanate oxindoles 63 and trifluoromethylated 2-butenedioic acid diester 64 or 65 paved the way to the synthesis of spirooxindoles with a CF3-containing all-carbon stereogenic center 66 (Scheme 18b) [49]. Interestingly, the authors highlighted the possibility to obtain either isomers (i.e., epimers at C4 position) in the presence of the same catalyst XIV (20 mol %) at different temperatures. This observation relies on the ability of isomerization of dimethyl maleate 64 into dimethyl fumarate Molecules 2017, 22, 1636 15 of 30 65 through azomethine ylide intermediate in the presence of the amine moiety of aminals [50].

Scheme 18. 18. (a) spiro-3,4-dihydropyrans 62 and (b) (b) synthesis synthesis of of trifluoromethylated trifluoromethylated Scheme (a) Synthesis Synthesis of of spiro-3,4-dihydropyrans 62 and spirooxindoles derivatives 66. spirooxindoles derivatives 66.

5. Squaramide Catalysts Inspired by the ability of urea/thiourea derivatives to promote high stereoselective organocatalytic reactions, several research groups have been engaged in the construction of alternative and complementary catalysts that involve in their architecture less explored H-bond donor motifs. Among others, in 2008 Rawal and co-workers postulated the potential of squaramide catalophores [51]. Specifically, over the years, several thorough studies have recognized that secondary squaramides featured by two H-bond donors (NH) and two H-bond carbonyl acceptors (C=O) should easily establish a strong hydrogen bond network with acceptors and donors as well as with mixed acceptor-donor systems (Figure 5a). Additionally: (i) the conformational restriction due to the aromaticity enhancement of the cyclobutendione core upon the delocalization of nitrogen lone pairs, which make the two N-H bonds coplanar with the rigid “squara structure” and (ii) the distance between the two N-H that is of 0.6 Å broader than in thioureas, make squaramide derivatives not only a valuable alternative to the urea/thiourea counterpart but also a class of more wide-range applicable organocatalysts (Figure 5b). Herein we are going to depict selected recent examples that demonstrate their remarkable ability in various cascade reactions involving an oxindole derivative as substrate and the catalophores depicted below (Figure 6).

broader than in thioureas, make squaramide derivatives not only a valuable alternative to the urea/thiourea counterpart but also a class of more wide-range applicable organocatalysts (Figure 5b). Herein we are going to depict selected recent examples that demonstrate their remarkable ability in various cascade reactions involving an oxindole derivative as substrate and the catalophores Molecules 2017, 22, 1636 16 of 30 depicted below (Figure 6).

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Figure 5. (a) donor ability and thiourea; thiourea;(b) (b)Lone Lone pairs conjugation Figure 5. H-Bond (a) H-Bond donor abilityofofsquaramide squaramide and pairs conjugation and and to aresonance broad substrate scope achieving the desired products 67 in high yields with excellent diastereoforms of the aromatic resonance forms of the aromaticsystem. system.

(up to >99:1 d.r.) and enantioselectivities (from 93% ee to >99% ee in almost all cases). 5.1. Double Michael Addition Sequence As stated before, oxindole derivatives have been a privileged substrate in organocatalysis. Specifically, as consequence of its unique electron-demand, α-alkylidene oxindoles have been often involved in cascade reactions mainly relying on Michael addition promoted by both C-nucleophiles and hetero atoms. In such a scenario, squaramide derivatives clearly have ever played a predominant role since their undiscussed ability as bifunctional catalysts [52]. Notably in this field Zhao and Du devoted their efforts not only to the design and synthesis of novel more efficient squaramide organocatalysts but also to the preparation of uncommon cascade reagents that should be suitable to build quite complex and densely functionalized carbocycles. Thus, in 2015, their group reported the first squaramide asymmetric protocol for the synthesis of chiral spiro[pyrrolidine-3,3′-oxindole]s 67 (Scheme 19). The optimized cascade aza-Michael/Michael addition sequence, distinguished for its mild conditions (i.e., −10 °C in CH2Cl2) and quite low catalyst loading (5 mol %), was easily applied

Figure organocatalysts reported in the present section. Figure6.6.Squaramide Squaramide based based organocatalysts reported in the present section.

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5.1. Double Michael Addition Sequence As stated before, oxindole derivatives have been a privileged substrate in organocatalysis. Specifically, as consequence of its unique electron-demand, α-alkylidene oxindoles have been often involved in cascade reactions mainly relying on Michael addition promoted by both C-nucleophiles and hetero atoms. In such a scenario, squaramide derivatives clearly have ever played a predominant role since their undiscussed ability as bifunctional catalysts [52]. Notably in this field Zhao and Du devoted their efforts not only to the design and synthesis of novel more efficient squaramide organocatalysts but also to the preparation of uncommon cascade reagents that should be suitable to build quite complex and densely functionalized carbocycles. Thus, in 2015, their group reported the first squaramide asymmetric protocol for the synthesis of chiral spiro[pyrrolidine-3,30 -oxindole]s 67 (Scheme 19). The optimized cascade aza-Michael/Michael addition sequence, distinguished for its mild conditions (i.e., −10 ◦ C in CH2 Cl2 ) and quite low catalyst loading (5 mol %), was easily applied to a broad substrate scope achieving the desired products 67 in high yields with excellent diastereo(up to >99:1 d.r.) and (from 93% ee to >99% ee ininalmost all cases). Figure 6. enantioselectivities Squaramide based organocatalysts reported the present section.

0 -oxindoles]s 67. Scheme 19. Asymmetric cascade addition spiro[pyrrolidine-3,3′-oxindoles]s Scheme 19. Asymmetric cascadeaza-Michael/Michael aza-Michael/Michael addition forfor spiro[pyrrolidine-3,3 a Thereaction reaction was was carried scale. carriedout outonongram gram scale. 67. a The

Remarkably, the the reaction could be be repeated even onon gram scale Remarkably, reaction could repeated even gram scalewithout withoutany anyloss lossininboth bothyield yield or stereoselectivity. Thereasoned authors reasoned such an outstanding stereocontrol should or stereoselectivity. The authors that suchthat an outstanding stereocontrol should be ascribed be ascribed to the squaramide moiety that contemporarily activates and orients the (E)-tert-butyl to the squaramide moiety that contemporarily activates and orients the (E)-tert-butyl 3-(2-ethoxy-23-(2-ethoxy-2-oxoethylidene)-2-oxoindoline-1-carboxylate 32 as well as the hydroquinine oxoethylidene)-2-oxoindoline-1-carboxylate 32 as well as the hydroquinine frameworkframework and enhances and enhances the nucleophilicity of the tosylaminomethyl enone 68 (Scheme 20). In the aza-Michael the nucleophilicity of the tosylaminomethyl enone 68 (Scheme 20). In the aza-Michael addition, the addition, the settled H-bond network (A) drives the nitrogen attack only from the Si face of the settled H-bond network (A) drives the nitrogen attack only from the Si face of the substrate to furnish substrate to furnish the intermediate B where the enone group undergoes an intramolecular Michael the intermediate B where the enone group undergoes an intramolecular Michael addition on the Si addition on the Si face via the transition state C, which rapidly provides the product 67 and restores face via the transition the catalyst XXIII. state C, which rapidly provides the product 67 and restores the catalyst XXIII. The The justjust disclosed reaction mechanism consequentstereochemical stereochemical outcomes prompted disclosed reaction mechanismand and the the consequent outcomes prompted the authors to toreplace α,β-unsaturated esters α-alkylidene succinimides 69 structurally the authors replace the the α,β-unsaturated esters withwith α-alkylidene succinimides 69 structurally similar similar to the oxindole counterpart [53]. The previously developed squaramide-catalysed to the oxindole counterpart [53]. The previously developed squaramide-catalysed approach inapproach even milder conditions (i.e., room temperature and THF as solvent) the formation highly of in even milder conditions (i.e., room temperature and THF as guaranteed solvent) guaranteed the of formation functionalized spirooxindoles 70 in yield andand stereocontrol (up (up to 97:3 d.r., d.r., up to ee). ee). highly functionalized spirooxindoles 70elevated in elevated yield stereocontrol to 97:3 up98% to 98% In Scheme is reported mostrepresentative representative examples examples ofofthe library, which was was also also In Scheme 21 it21isitreported thethe most theproduced produced library, which synthesized in gram scale without any loss in term of stereoinduction. synthesized in gram scale without any loss in term of stereoinduction.

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17 of 28

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Scheme 20. Proposed reaction forthe theaza-Michael/Michael aza-Michael/Michael cascade reaction developed Scheme 20. Proposed reactionmechanism mechanism for cascade reaction developed by Zhaoand and20. Du. A–D are hypothesized intermediates on the proposed cycle by Zhao Du. A–D arereaction hypothesized intermediates on catalytic the catalytic proposed cycle developed Scheme Proposed mechanism for the aza-Michael/Michael cascade reaction by Zhao and Du. A–D are hypothesized intermediates on the catalytic proposed cycle

Scheme 21. Organocatalytic Organocatalytic cascade cascade Michael/Michael Michael/Michael addition containing five Scheme addition for spirooxindoles containing five five Scheme 21. 21. Organocatalytic cascade Michael/Michael additionfor forspirooxindoles spirooxindoles containing a The reaction was carried out on gram scale. a contiguous stereocenter. contiguous stereocenter. The reaction was carried out on gram scale. a contiguous stereocenter. The reaction was carried out on gram scale.

Once validated the efficiency of their squaramide XXIV as catalyst, in 2016 Zhao and Du designed

Once validated the efficiency theirsquaramide squaramide XXIV as inin 2016 Zhao andand Du designed Once validated efficiency ofoftheir XXIV ascatalyst, catalyst, 2016 Du designed the new cascade the reagent 72 featured by both an active nucleophile center and Zhao an electrophile site the new cascade reagent 72 featuredby byboth both an an active nucleophile center and an an electrophile site the new cascade reagent 72 featured active nucleophile center and electrophile (Scheme 22) [54]. The authors demonstrated their hypothesis fruitfully employing the developed site (Scheme 22) [54]. The authors demonstrated their hypothesis fruitfully employing the developed donor (Scheme [54]. acceptor The authors demonstrated hypothesis reaction fruitfully employing developed donor22) Michael reagent 72 in a tandemtheir Michael/Michael which smoothlythe furnished Michael acceptor reagent 72 in a tandem Michael/Michael reaction which smoothly furnished highly donor Michael acceptor reagent 72 in a tandem Michael/Michael reaction which four smoothly furnished highly functionalized bispirooxindole-tetrahydrofurane scaffolds 73 bearing contiguous functionalized bispirooxindole-tetrahydrofurane scaffolds 73 bearing four contiguous stereocenters. stereocenters. Despitebispirooxindole-tetrahydrofurane the number of different substituents introduced oxindole framework, highly functionalized scaffolds on 73each bearing four contiguous Despite the number of different substituents introduced on each oxindole framework, the overall the overallDespite process never failed toofgive the expected products 73 in very high levels of opticalframework, purity stereocenters. the number different substituents introduced on each oxindole (>20:1 d.r., up to >99% ee) and moderate-to-high yields (58–96% yield). the overall process never failed to give the expected products 73 in very high levels of optical purity (>20:1 d.r., up to >99% ee) and moderate-to-high yields (58–96% yield).

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process never failed to give the expected products 73 in very high levels of optical purity (>20:1 d.r., up to >99% ee)1636 and moderate-to-high yields (58–96% yield). Molecules 2017, 22, 18 of 28 electrophilic site

nucleophilic center EWG R1

O

CO 2Et

O

R2

+

R2

XXIV (2.5 mol%) EtO 2C O

THF, −10 °C 30-72 h

N PG

N PG 71

N PG 73

O

O

N H

N H

O 2N

O

N

O

N Bn

chiral backbone

R" N ' R H

EtO 2C O

el Micha

EWG

EtO 2C

N R O EWG O

R1

72

PG

O

EtO 2C

O

Michael

O

O CO 2Et O

N

N Bn

R

EtO 2C

N Bn O CO 2Et O

O CO2Et O

N Boc

O

N Bn

N H

75% Y

89% Y

96% Y

(> 20:1 d.r., 95% ee)

(> 20:1 d.r., 98% ee)

(> 20:1 d.r., 99% ee)

EtO 2C

N

O

EtO 2C

O

O CO 2Et O N Bn

N Bn O CO 2Et O

N Bn

91% Y

93% Y

(> 20:1 d.r., 99% ee)

(> 20:1 d.r., 99% ee)

Scheme Scheme 22. 22. Asymmetric Asymmetric enantioselective enantioselective tandem tandem Michael/Michael Michael/Michaelreaction reactiontotobispirooxindoles bispirooxindoles73. 73.

5.2. 5.2.Michael MichaelAddition/Cyclization Addition/CyclizationReaction ReactionSequence Sequence A A second second highly highly exploited exploited reaction reaction sequence sequence that that straightforwardly straightforwardly furnishes furnishes complex complex spiro spiro compounds involves a Michael addition followed by a fast cyclization reaction (see also compounds involves a Michael addition followed by a fast cyclization reaction (see alsoSection Section2.1). 4.1). Among Among all all the thepossible possiblesubstrate/reagent substrate/reagentsystems systemslargely largelyreported reportedin inliterature, literature,Yuan Yuanand andco-workers co-workers chose chosethe thepreviously previouslyinvestigated investigated3-hydroxyoxindoles 3-hydroxyoxindoles 75 75and and3-aminooxindoles 3-aminooxindoles76 76as asinitial initialMichael Michael donor and the α,β-unsaturated acylphosphonates as Michael acceptor [55]. Such an donor and the α,β-unsaturated acylphosphonates as Michael acceptor [55]. Such an uncommon uncommon electron due to to thethe lability of the C-PC-P bond thatthat simplifies the electronpoor poorcounterpart counterpartwas wasmainly mainlyselected selected due lability of the bond simplifies phosphonate group removal. Relying on the efficiency of squaramide organocatalyst XXV together the phosphonate group removal. Relying on the efficiency of squaramide organocatalyst XXV with the designed starting molecules, the authors developed a highly stereoselective Michael/ cyclization cascade sequence able to afford a broad spectrum of spirocyclic oxindoles 78 and 79. Indeed, applying the initial optimized conditions (i.e., CH3CN or CH2Cl2 as solvent, room temperature), the overall reaction proceeded without any loss in stereoslectivity (up to >99:1 d.r.; 71–97% ee) and yield (up to 98%) when (i) the Michael donor was either a 3-hydroxy or a 3-aminooxindoles (75 and

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together with the designed starting molecules, the authors developed a highly stereoselective Michael/cyclization cascade sequence able to afford a broad spectrum of spirocyclic oxindoles 78 and 79. Indeed, applying the initial optimized conditions (i.e., CH3 CN or CH2 Cl2 as solvent, room temperature), the overall reaction proceeded without any loss in stereoslectivity (up to19>99:1 Molecules 2017, 22, 1636 of 28 d.r.; 71–97% ee) and yield (up to 98%) when (i) the Michael donor was either a 3-hydroxy or a 3-aminooxindoles (75 and 76 to respectively), which afford toXthe spiro 76 respectively), which afford the spiro γ-lactones (78 for = O) andγ-lactones γ-lactames(78 (79for forXX==O) N),and as γ-lactames (79 for X = N), as well as (ii) substituents quite different in terms of electron demand and well as (ii) substituents quite different in terms of electron demand and steric hindrance were steric hindrance were introduced on both nitrogen and aromatic ring. introduced on both nitrogen and aromatic ring. A slight drop in the stereoinduction was observed when the the β β position position of of the the α,β-unsaturated α,β-unsaturated A slight drop in the stereoinduction was observed when acylphosphonate 74 was decorated with excessively bulky groups (Scheme 23). The observed observed acylphosphonate 74 was decorated with excessively bulky groups (Scheme 23). The efficiency should should be be due due to to the the dual dualactivation activation of of the thecatalyst catalystthat that(i) (i)promotes promotes the the enolyzation enolyzationof ofthe the efficiency 3-hydroxyoxindoles and (ii) exposes the Re face of the α,β-unsaturated acyl phosphonate to the attack 3-hydroxyoxindoles and (ii) exposes the Re face of the α,β-unsaturated acyl phosphonate to the attack from the the Si-face Si-face of of the the just just generated generated nucleophile. nucleophile. from

Scheme Scheme23. 23. Organocatalysed Organocatalysed Michael/cyclization Michael/cyclizationcascade cascadereaction reactionfor forthe theconstruction constructionof ofspirocyclic spirocyclic oxindole-γ-lactones/lactams. oxindole-γ-lactones/lactams.

More recently, the similar squaramide-quinine based catalyst XXVI (10 mol %) was effective More recently, the similar squaramide-quinine based catalyst XXVI (10 mol %) was effective when α,β-unsaturated N-acylated succinimides 80 were chosen as the initial Michael acceptor and when α,β-unsaturated N-acylated succinimides 80 were chosen as the initial Michael acceptor and 3-hydroxyoxindoles 75 as the nucleophilic counterpart (Scheme 24). [56] Specifically, after having 3-hydroxyoxindoles 75 as the nucleophilic counterpart (Scheme 24). [56] Specifically, after having carefully optimized the reaction conditions (i.e., CH2Cl2 as solvent, −10 °C as best temperature), Du carefully optimized the reaction conditions (i.e., CH2 Cl2 as solvent, −10 ◦ C as best temperature), and co-workers validated their protocol by performing the proposed asymmetric cascade Du and co-workers validated their protocol by performing the proposed asymmetric cascade Michael/cyclization reaction on various Michael donor/acceptor systems obtaining the corresponding Michael/cyclization reaction on various Michael donor/acceptor systems obtaining the corresponding spirooxindoles lactones 78 in good yields (75–89%). Although the stereochemical outcomes were spirooxindoles lactones 78 in good yields (75–89%). Although the stereochemical outcomes were always excellent in term of enantioselectivity (96–99% ee), the diastereomeric ratios seemed to be always excellent in term of enantioselectivity (96–99% ee), the diastereomeric ratios seemed to be more more easily affected by various substituents introduced both on the enone system and on the oxindole easily affected by various substituents introduced both on the enone system and on the oxindole moiety (from 75:25 to >95:25 d.r.). Afterwards, once assigned the correct configuration to the moiety (from 75:25 to >95:25 d.r.). Afterwards, once assigned the correct configuration to the generated generated stereocenter, the authors provided a mechanistic study that pointed out how the quininestereocenter, the authors provided a mechanistic study that pointed out how the quinine-derived derived squaramide XXVI should act as bifunctional catalyst. As depicted in Scheme 24, the tertiary squaramide XXVI should act as bifunctional catalyst. As depicted in Scheme 24, the tertiary amine amine unit deprotonates the 3-hydroxyoxindole while the squaramide moiety binds the resulting unit deprotonates the 3-hydroxyoxindole while the squaramide moiety binds the resulting nucleophile nucleophile (A) which in turn, attacks the electrophile already activated by the protonated amine (B). (A) which in turn, attacks the electrophile already activated by the protonated amine (B). The Michael The Michael adduct C undergoes an intramolecular cyclization which removes the succinimide auxiliary and generates the expected spirooxindole 78. Exploiting the well-known reactivity of 3-isothiocyano oxindoles conferred by the strongly electron withdrawing NCS group, Du and co-workers reported also the preparation of more complex pyrrolidinyl spirooxindoles employing either chalcones 82 [57] or maleimides 84 [58] as acceptor counterpart (Scheme 25). In both cases the extremely similar quinine-derived squaramide XXVII (10

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adduct C undergoes an intramolecular cyclization which removes the succinimide auxiliary and generates the expected spirooxindole 78. Exploiting the well-known reactivity of 3-isothiocyano oxindoles conferred by the strongly electron withdrawing NCS group, Du and co-workers reported also the preparation of more complex pyrrolidinyl spirooxindoles employing either chalcones 82 [57] or maleimides 84 [58] as acceptor counterpart (Scheme 25). In both cases the extremely similar quinine-derived squaramide XXVII (10 mol %) and Molecules 2017, 1636 of 28 XXVIII (522, mol %) resulted to be the best catalysts in the same reaction condition (i.e., CH2 Cl2 , 020◦ C). The desired spirocyclic products 83 and 85 were achieved in high yields (87-99%) and excellent diastereoexcellent diastereo(up to >99:1 d.r.) and (upa complex to 99% ee) triggered by where a complex (up to >99:1 d.r.) and enantioselectivities (upenantioselectivities to 99% ee) triggered by H-bond network the H-bond network enable wherethe thestereocontrolled organocatalystattack enable attackeither of thethe oxindole donors organocatalyst of the the stereocontrolled oxindole donors toward electron-poor toward either82the electron-poor chalcones or maleimides 84. chalcones 82 or maleimides 84.

Scheme 24. Asymmetric cascade Michael/cyclization reaction performedreaction on 3-hydroxyoxindoles/NScheme 24. Asymmetric cascade Michael/cyclization performed on acylated succinimides as donor/acceptor system. A–C are hypothesized intermediates the catalytic 3-hydroxyoxindoles/N-acylated succinimides as donor/acceptor system. A–C are on hypothesized cycle proposed. on the catalytic cycle proposed. intermediates

The substitution of quinine moiety with a tertiary ethylenediamine framework decorated with naphthyl groups opened the door to the synthesis of pharmacologically interesting dihydropyranoindole derivatives. Indeed, Zhao and co-workers performed a Michael addition/cyclization sequence at relatively low temperature (−20 °C) in CH2Cl2 employing the

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and stereocontrol Molecules 2017, 22, 1636 (85–98% ee) were accomplished only when the squaramide catalyst XXIX 22 was of 30 substituted with the (1R, 2R)-diphenyl-1,2-diamine derived bifunctional thiourea XII.

Scheme 83 and Scheme 25. 25. Du’s Du’s research research toward toward the the preparation preparation of of pyrrolidinyl pyrrolidinyl spirooxindoles spirooxindoles 83 and 85 85 employing employing respectively chalcones 82 and maleimides 84. respectively chalcones 82 and maleimides 84. CF 3 CN The substitution of quinine moiety with ethylenediamine framework decorated NC CN EtO 2a C tertiary CF 3 15 the door to the synthesis with naphthyl groups opened of pharmacologically interesting NH 2 H NH N 1 O and co-workers performed R dihydropyranoindole derivatives. Indeed, Zhao a Michael XXIX (5 mol%) N N ◦ CH Cl , −20 °C 2 2 addition/cyclization sequence at relatively low temperature (−20 C) in CH2 Cl2 employing the R2 O O CF 3 squaramide derivative XXIX as organocatalyst able to join together the isatine-based trifluoroacrylates 87 EtO 2C XXVIII CF 3 - 99% Y 86 and the malonitrile 15 (Scheme 26) [59]. 91 The hypothesized products 87, bearing a novel (86 - 99 % ee) trifluoromethylated all-carbon-substituted stereocenter, were almost always isolated with excellent 1 O R N and high level of optical purity (86–99% ee). Unfortunately, the optimized protocol yields (91–99%) R2 failed not only when less hindered substituents (R2 = Me, Ac) were introduced as protecting groups 86 NC when CO 2Et the malonitrile CO 2Et CF 3 15 in the oxindole unit, but also was replaced with the less reactive ethyl EtO 2C cyanoacetate 88. Noteworthy, in88the latter case, nearly analogous outcomes in term S of yields CF 3 (38–79%) NH 2 N HN 1 mol%) accomplished O R and stereocontrol (85–98%XIIee)(10were only when the squaramide catalyst XXIX was HN N CH 2Cl2, 0 °C substituted with the (1R, 2R)-diphenyl-1,2-diamine derived bifunctional thiourea XII. R2 XII CF 3 The just depicted results, one more time, confirm 89 the complementary use of thiourea-based and 38 79% Y squarate derived organocatalyst for the stereoselective preparation of complex bioactive products. (85 - 98% ee)

Scheme 26. Synthesis of dihydropyranoindole derivatives, a comparison between squaramide-based and thiourea catalyst.

The just depicted results, one more time, confirm the complementary use of thiourea-based and squarate derived organocatalyst for the stereoselective preparation of complex bioactive products.

Scheme 25.1636 Du’s research toward the preparation of pyrrolidinyl spirooxindoles 83 and 85 employing Molecules 2017, 22, 23 of 30 respectively chalcones 82 and maleimides 84.

NC

CN

EtO 2C

CF 3 CN

15 XXIX (5 mol%) CH 2Cl 2, −20 °C

NH 2 O

R1 N R2

CF 3

R1

O

O

CF 3

CF 3

XXVIII

91 - 99% Y (86 - 99 % ee)

O

H N

N

87

EtO 2C

NH

N R2 86 NC

CO 2Et

EtO 2C

88 XII (10 mol%) CH 2Cl2, 0 °C

CF 3 CO 2Et NH 2 O

R1 N R2

89 38 - 79% Y (85 - 98% ee)

S N

HN

CF 3

HN XII

CF 3

Scheme 26. 26. Synthesis of dihydropyranoindole derivatives, a comparison between squaramide-based Scheme and thiourea catalyst.

The just depicted results, one more time, confirm the complementary use of thiourea-based and 5.3. Miscellaneous squarate derived organocatalyst for the stereoselective preparation of complex bioactive products. In 2012 Casiraghi and co-workers illustrated how 3-alkylidene oxindoles could also react as vinylogous nucleophile in order to functionalize the γ-position in the presence of a suitable electrophile [60,61]. Inspired by this evidence as well as by subsequent Casiraghi’s researches concerning the Mukaiyama type aldol reactions [62], Han and Chang postulated the creation of biologically relevant 3-hydroxyoxindole framework relying on the nucleophilicity of 3-alkylidenes 90 and the undeniable electrophilicity of isatins 91 [63]. Surprisingly, instead of obtaining the expected aldol adduct, the spirooxindole dihydropyranones 93 were isolated by using the chiral Cinchona alkaloid-squaramide bifunctional organocatalyst system XXVIII (Scheme 27). The stereochemical outcome of the overall reaction was not influenced by the introduction of different substituents (i.e., in terms of either electron demand or steric hindrance) on both substrates (87–99% ee). A slight drop down was observed in the yield only when a NO2 group decorated the electrophilic aromatic ring (R3 = NO2 ). Without going in fine details, the authors suggested two models for explaining the dual activation of both nucleophile and electrophile (Scheme 27, B and C) which could account for the Si face addition of the s cis-enolate in the initial aldol reaction. Once obtained the intermediate A, the surprising replacement of the lactam C-N bond with a lactone C-O bond occurs delivering the product 93 after protonation and catalyst regeneration. Such an uncommon behaviour of amide C-N bond was also recently detected by Zhao and co-workers during their studies concerning the organocatalytic Friedel-Crafts/lactonization domino reaction (Scheme 28) [64]. Actually, the authors reported a remarkable example of the employment of squaramide catalophore XXX in the asymmetric synthesis of dihydrocoumarins, a ubiquitous scaffold in bioactive natural products. Specifically, the formal [3+3] protocol involved an initial Friedel-Crafts alkylation of naphthols at the Cβ position of the 3-ylidene oxindoles 94 (A, Scheme 28) followed by an unexpected intramolecular cyclization with a C-N bond cleavage of the lactam moiety by the phenolic hydroxyl group (B, Scheme 28).

co-workers during their studies concerning the organocatalytic Friedel-Crafts/lactonization domino reaction (Scheme 28) [64]. Actually, the authors reported a remarkable example of the employment of squaramide catalophore XXX in the asymmetric synthesis of dihydrocoumarins, a ubiquitous scaffold in bioactive natural products. Specifically, the formal [3+3] protocol involved an initial Friedel-Crafts alkylation of naphthols at the Cβ position of the 3-ylidene oxindoles 94 (A, Scheme 28) Molecules 2017, 22, followed by1636 an unexpected intramolecular cyclization with a C-N bond cleavage of the lactam moiety24 of 30 by the phenolic hydroxyl group (B, Scheme 28).

Scheme 27. Asymmetric aldol/lactonization sequence for the synthesis of spirooxindole dihydropyranones

Scheme 27. Asymmetric aldol/lactonization sequence for the synthesis of spirooxindole 93. A is the hypothesized intermediate on the reaction pathway, while B and C are proposed dihydropyranones 93. A is the hypothesized intermediate on the reaction pathway, while B and alternative models for explaining the dual activation of nucleophile and electrophile. C are proposed alternative models for explaining the dual activation of nucleophile and electrophile. Molecules 2017, 22, 1636 23 of 28

Scheme 28. Friedel-Crafts/lactonization domino reaction developed by Zhao and co-workers and

Scheme 28. Friedel-Crafts/lactonization domino reaction developed by Zhao and co-workers and suggested reaction pathway. suggested reaction pathway.

Although the lactonization occurred to disadvantage of the chemically inert oxindole unit, the overall process proceeded under very mild conditions (i.e., CH2Cl2 at low temperature) and affording attractive outcomes in term of yields (60–99%) and stereoselectivity (>20:1 d.r., 80–98% ee) when both α- and β-naphthols (95 and 97) were alternatively used as nucleophiles (Scheme 28). Cinchona-derived squaramides have shown their potential as organocatalysts even when they are involved in more complex domino reactions. An interesting example was reported by Lu and co-workers in 2015 who initially optimize a simple Diels-Alder/aromatization sequence and then, by

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Although the lactonization occurred to disadvantage of the chemically inert oxindole unit, the overall process proceeded under very mild conditions (i.e., CH2 Cl2 at low temperature) and affording attractive outcomes in term of yields (60–99%) and stereoselectivity (>20:1 d.r., 80–98% ee) when both α- and β-naphthols (95 and 97) were alternatively used as nucleophiles (Scheme 28). Cinchona-derived squaramides have shown their potential as organocatalysts even when they are involved in more complex domino reactions. An interesting example was reported by Lu and co-workers in 2015 who initially optimize a simple Diels-Alder/aromatization sequence and then, by adding an excess of oxindole moiety, observed a Diels-Alder/Michael/aromatization domino process (Scheme 29) [65]. The reactions always proceeded smoothly under very mild conditions (i.e., CH2 Cl2 at room temperature) and with quite low catalyst loading (10 mol % of XXVI) providing the expected carbazolespirooxindole derivatives 101 in moderate-to-good yields (48–90%) and interesting stereoinduction (from 4:1 to >20:1 d.r., 60–99% ee). Unfortunately, for the product 102 with six contiguous stereocenters furnished by the triple domino reaction, it was not possible to define the stereochemical outcome mainly due to the arduous separation of the complex diastereomeric mixture. Molecules 2017, 22, 1636 24 of 28

Scheme (DA)/aromatization sequence and triple domino Scheme 29. 29. Diels-Alder Diels-Alder (DA)/aromatization sequence and DA/Michael/aromatization triple DA/Michael/aromatization process. domino process.

6. Miscellaneous 6. Miscellaneous The derivatives hashas found several notable applications even The impressive impressive reactivity reactivityofofoxindole oxindole derivatives found several notable applications when phosphoric acids, a less explored class of catalophores are employed as Brønsted acid even when phosphoric acids, a less explored class of catalophores are employed as Brønsted organocatalyst. Among the very few reported examples, Shi and co-workers rationally designed a acid organocatalyst. Among the very few reported examples, Shi and co-workers rationally chiral phosphoric acid (CPA)-catalyzed Michael addition/intramolecular Friedel-Crafts cascade designed a chiral phosphoric acid (CPA)-catalyzed Michael addition/intramolecular Friedel-Crafts reaction toward the construction of cyclopenta[b]indole and spirooxindole frameworks [66]. cascade reaction toward the construction of cyclopenta[b]indole and spirooxindole frameworks [66]. Specifically, the authors supposed that, in order to promote the initial vinylogous Michael addition, Specifically, the authors supposed that, in order to promote the initial vinylogous Michael addition, the CPA XXXI could simultaneously activate throughout a complex H-bond network both the 7the CPA XXXI could simultaneously activate throughout a complex H-bond network both the vinylindoles 103 as nucleophile and the electrophilic vinyliminium C, which should be generated in 7-vinylindoles 103 as nucleophile and the electrophilic vinyliminium C, which should be generated in situ form the 3-indolylmethanols 104. Subsequently the transient adduct B should undergo, always situ form the 3-indolylmethanols 104. Subsequently the transient adduct B should undergo, always assisted by the dual H-bond activation of CPA XXXI, the intramolecular Friedel-Crafts reaction to assisted by the dual H-bond activation of CPA XXXI, the intramolecular Friedel-Crafts reaction to restore the initial aromatic indolic structure and furnish the expected complex spirooxindole systems 105 (Scheme 30). The authors demonstrated their hypothesis successfully performing the diastereo- and enantioselective synthesis of several cyclopenta[b]indole derivatives 105 starting from a series of 7-vinylindoles 103 and various isatin-derived 3-indolylmethanols 104. Comparing the obtained results, it was clear that the stereoinduction was essentially not affected by the different nature of the substituents on both acceptor and donor partners. Conversely, they dramatically influenced the

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restore the initial aromatic indolic structure and furnish the expected complex spirooxindole systems 105 (Scheme 30). Molecules 2017, 22, 1636 25 of 28

2-N ap

hth y

2-N ap l

hth y

l

Scheme 30. 30. (CPA)-catalyzed Michael addition/intramolecular addition/intramolecular Friedel-Crafts Scheme Friedel-Crafts cascade reaction toward the construction of cyclopenta[b]indole and spirooxindole scaffold. A–C are postulated intermediates on the mechanism of the reaction.

7. Conclusions The authors demonstrated their hypothesis successfully performing the diastereo- and enantioselective of several cyclopenta[b]indole derivativesorganocatalysts 105 starting from a oxindole series of As shown bysynthesis the examples depicted here, when newly developed meet 7-vinylindoles andmost various isatin-derived 3-indolylmethanols Comparing theimpressive obtained derivatives, one103 of the widespread frameworks in Nature, it is 104. possible to achieve results, was clear that the stereoinduction affected stereogenic by the different nature of levels ofit molecular complexity featured by was the essentially formation not of multiple centers upon the substituents both acceptor and donor partners. Conversely, they dramatically influenced not the multiple cascadeon reactions. Such outstanding results and all the future predictable improvements overall Particularly, electron-donating groups onto C7-functionalised gave much only arereactivity. going to constantly provide easier and easier access a broad spectrumindoles of highly valuable higher yields than the electron-withdrawing while it was less the electronic complex compounds, but also to furnish a groups, better understanding of explainable Nature’s modes of actioneffect and due to substituents onan thealmost isatin units. ultimately even reach similar degree of perfection. 7. Conclusions Acknowledgments: Tecla Gasperi and Martina Miceli gratefully acknowledge Dipartimento di Scienze and Sezione di Nanoscienze e Nanotecnologie (Università si Roma Tre, Roma, Italy) for the financial support. As shown by the examples depicted here, when newly developed organocatalysts meet oxindole Jean-Marc Campagne and Renata Marcia de Figueiredo are grateful to the support from ENSCM and CNRS.

derivatives, one of the most widespread frameworks in Nature, it is possible to achieve impressive AuthorofContributions: Tecla Gasperi, Martina Miceli, Jean-Marc Campagne, and Renata Marciaupon de Figueiredo levels molecular complexity featured by the formation of multiple stereogenic centers multiple conceived, wrote and revised the review. cascade reactions. Such outstanding results and all the future predictable improvements not only are going to constantly provide easier andno easier access to a broad spectrum of highly valuable complex Conflicts of Interest: The authors declare conflict of interest.

References 1.

Wang, Y.; Lu, H.; Xu, P.F. Asymmetric catalytic cascade reactions for constructing diverse scaffolds and complex molecules. Acc. Chem. Res. 2015, 48, 1832–1844.

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compounds, but also to furnish a better understanding of Nature’s modes of action and ultimately even reach an almost similar degree of perfection. Acknowledgments: Tecla Gasperi and Martina Miceli gratefully acknowledge Dipartimento di Scienze and Sezione di Nanoscienze e Nanotecnologie (Università si Roma Tre, Roma, Italy) for the financial support. Jean-Marc Campagne and Renata Marcia de Figueiredo are grateful to the support from ENSCM and CNRS. Author Contributions: Tecla Gasperi, Martina Miceli, Jean-Marc Campagne, and Renata Marcia de Figueiredo conceived, wrote and revised the review. Conflicts of Interest: The authors declare no conflict of interest.

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