Enantioselective synthesis of substituted oxindoles

Current Opinion in Drug Discovery & Development 2010 13(6):758-776 © Thomson Reuters (Scientific) Ltd ISSN 2040-3437

REVIEW

Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery Joseph J Badillo, Nadine V Hanhan & Annaliese K Franz* Address University of California Davis, Department of Chemistry, 1 Shields Avenue, Davis, CA 95616, USA Email: [email protected] *To whom correspondence should be addressed

This review describes recent methods for the enantioselective synthesis of oxindoles and spirooxindoles, with a particular focus on scaffolds with applications in drug discovery. The synthetic challenge of the spiro-motif and the important biological activity of spirooxindoles continue to encourage the development of creative methods to access these important structures. Unique spirocycles often result from creative synthetic methods that would not typically be identified using classical synthetic disconnections. To establish the importance of asymmetric synthesis in the context of oxindole structures, recent examples are highlighted in which stereospecific binding and differential biological activity have been demonstrated based on the configuration at the 3-position. This review is organized by type of catalyst and synthetic strategy in order to compare traditional organometallic and Lewis acid methods with more recent organocatalytic methods. A section describing multicomponent and cascade reaction strategies is also included. Keywords Asymmetric synthesis, cascade organometallic, oxindole, spirooxindole

reaction,

enantioselective

Introduction As a result of their occurrence in diverse natural products and pharmaceutical lead compounds, considerable effort has been devoted to developing efficient and selective synthetic methods to access substituted oxindoles and spirooxindoles. Novel methodologies and chiral catalysts continue to be a focus of research in this field, with particular challenges including incorporating heterocycles, minimizing the use of protecting groups and obtaining high enantioselectivity. Oxindoles have been the topic of several reviews in the past 5 years [1-4]. Whereas previous reviews have focused on applications of oxindole and spirooxindole chemistry to natural product synthesis, this review highlights developments in the field within the past 2 years, with a focus on the synthesis of scaffolds related to pharmaceutically interesting compounds (Figure 1). Therefore, this review highlights synthetic methods to incorporate heterocycles, access spirooxindoles and employ multicomponent or cascade strategies. The sections of this review are organized by type of catalyst and mechanism or strategy of formation, enabling the comparison of traditional organometallic and Lewis acid methods with more recent organocatalytic methods.

The stereospecific biological activity of oxindoles Examples of stereospecific activity based on the configuration at the 3-position of oxindole have

catalysis,

multicomponent

reaction,

organocatalyst,

established the importance of asymmetric synthesis in the context of oxindole structures (Figure 1). The frequent use of resolution and chiral separation methods in oxindole synthesis, coupled with the substantial differential activity observed for many stereoisomers, indicates a continuing need for improved enantioselective synthetic methods. MI-63 (sanofi-aventis/Ascenta Pharmaceuticals), an inhibitor of the mouse double minute 2 protein (Mdm2)-/human Mdm2-p53 interaction, exhibited stereospecific binding to Mdm2 (Ki = 3 nM), with its enantiomer being 1000-fold less potent [5]. The stereospecific activity of SM-130686 has been demonstrated, with the (S)-enantiomer being 70-fold more potent than the (R)-enantiomer (EC50 = 3 versus 210 nM, respectively) [6,7]. A novel class of spirotetrahydro-β-carbolines (eg, compound 2) has been identified as providing promising therapeutic leads with antimalarial activity; the activities of all four stereoisomers of compound 2 were tested against the Plasmodium falciparum isolate NF54, and only the 1R,3S isomer demonstrated potent biological activity (NF54 IC50 = 9 nM) [8]. The limited availability of the chiral, substituted indoleamines required to synthesize the desired stereoisomer of compound 2 was noted as a particular limitation, and analogs had to be obtained using chiral resolution. Finally, differential potency between enantiomers has been observed for a novel class of spirocyclic oxindole thiazolindinone compounds (eg, compounds 3), which

Enantioselective synthesis of oxindoles and spirooxindoles Badillo et al 759

Figure 1. Selected synthetic oxindole-based pharmaceutical lead compounds. OCH3

CH3O O

H N

F3C

CH3

H3C

O

O

S

OCH3 F

NH

N 3

Cl

HN

O

O OCH

O NH

N

HO

O N

H

Cl

O

OEt

N(CH3)2

OEt

nelivaptan

flindokalner

(+)-AG-041R

O

O

t

N H

O

O

O

Cl

Bu

N

S OCH3

N

Et

Cl

O

F O

NH

EtO O

NH

N H

Cl

O

satavaptan

Bu

O

N

N H

Cl

O 1 (Hoffmann-La Roche)

t

MI-63 (sanofi-aventis/Ascenta Pharmaceuticals)

ent-MI-63

Mdm2 Ki = 3 nM

Mdm2 Ki = 4 µM

O O

O

NEt2.HCl

H3C

N

H2N

O Cl F3C

Cl

O2N HN

N H O

HO

O

F

N

S

O

F

N

N H F

SM-130686

3

2

(S)-enantiomer GHS-R EC50 = 3 nM

(1R,3S)-enantiomer NF54 IC50 = 9 nM

3 (racemic) MptpB IC50 = 1.2 ± 0.2 µM

(R)-enantiomer GHS-R EC50 = 210 nM

(1S,3R)-enantiomer NF54 IC50 > 5000 nM

(–)-3 ((R)-enantiomer) MptpB IC50 = 0.32 ± 0.05 µM (+)-3 ((S)-enantiomer) MptpB IC50 = 3.9 ± 0.6 µM

In several cases, stereospecific biological activity has been observed with these compounds. GHS-R Growth hormone secretagogues receptor, Mdm2 mouse double minute 2 protein, MptpB Mycobacterium tuberculosis protein tyrosine phosphatase B, NF54 Plasmodium falciparum isolate NF54

are potent and selective inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) [9]. The (−)-enantiomer was 7 to 20-fold more potent than the (+)-enantiomer in compounds from this

series [9]. These examples highlight the continuing need to develop asymmetric catalysis methods to enable access to single enantiomers of oxindole and spirooxindole compounds.

760 Current Opinion in Drug Discovery & Development 2010 Vol 13 No 6

Metal-catalyzed approaches to substituted oxindoles and spirooxindoles

additional activation of the isatin electrophile. Although several different arylboronic acid reagents were examined, there is no report of the range of isatins that can be used in this reaction [12]. In general, Rh(I)and Pd(I)-catalyzed methods for oxindole synthesis are limited to N-alkylated isatins and non-polar aryl and alkenyl boron reagents.

Metal-catalyzed additions to isatins

Traditional approaches to the asymmetric synthesis of substituted oxindoles and spirooxindoles have used organometallic and Lewis acid reagents and catalysts. The enantioselective addition of nucleophiles to isatin reagents has remained an important route for direct access to 3-hydroxy-3-aryl-oxindoles; for example, the metal-catalyzed arylation of isatins (compound 4; Scheme 1) with arylboronic acids was first reported in 2006 by Hayashi and colleagues [10], and has been reported subsequently by other research groups [11,12]. Hayashi and colleagues have reported the highest enantioselectivity (93% enantiomeric excess [ee]) in forming 3-hydroxy-3-aryl-oxindoles, using Rh(I)catalyzed addition with the axially chiral monophosphine (R)-MeO-mop ligand 6 (Scheme 1) [10]. This method is less tolerant of NH isatins, which proceed with reduced efficiency (< 50% yield) compared with N-alkylated analogs. Qin and colleagues have recently achieved moderate yields and ≤ 73% ee for the first reported Pd(II)-catalyzed arylation of N-benzylisatins, using a novel class of sulfinyl imine P,N-ligands (Scheme 1) [12]. This method also uses boron trifluoride diethyl etherate (BF3·OEt2) as a Lewis acid for

Shibasaki and colleagues described an enantioselective Cu-catalyzed addition of silicon-based reagents to isatins with zinc difluoride as a catalytic co-activator (Scheme 1) [13]. Excellent yields and ≤ 97% ee were observed with this method. It was proposed that the silane reagents were activated via transmetalation to form a reactive copper species, which was the active nucleophile. The Cu-catalyzed route required a triarylmethyl-N-protected isatin (eg, use of a dimethoxytrityl [DMTr]-protecting group) to obtain high enantioselectivity; however, the DMTr group could be removed without racemization of the product. In an effort to synthesize SM-130686, addition to an isatin with the necessary trifluoromethyl substituent at the 4-position was attempted, resulting in a significantly decreased yield (26%) and poor enantioselectivity (44% ee), even after additional optimization. Shibaski and colleagues note that this trifluoromethyl substituent at the C(4) position creates a particular challenge for the

Scheme 1. Rh-, Pd- and Cu-catalyzed additions of boronic acid or silane nucleophiles to isatins. 5

4

3

R1 6

O 2

R2 B(OH)2 O

Conditions A or B

7

Condition C

R2 = Ph, Ar, alkenyl

N1

HO

R2 Si(OMe)3

or

R2 O

R1

N R

R 4

5

Condition A [10]: [RhCl(C2H4)2]2 (5 mol%) / 6 (10 mol%) / KOH (15 mol%) / THF:H2O (20:1) / 50°C / 24 h

Condition B [12]: Pd(OAc)2 (5 mol%) / 7 (10 mol%) / t-BuOK (0.5 eq) / BF3.Et2O (4 eq) / THF / rt / 48 h

Condition C [13]: (i) CuF.3P(4-F-Ph)3.2EtOH (5 to 10 mol%) / 8 (14 mol%) / ZnF2 (30 mol%) / toluene / rt or 80°C (ii) TBAF

R = H, PMB, CH3, Bn R1 = Cl, CH3O, CH3

R = Bn R1 = H

R = PMB, DMTr R1 = H, Cl, OCH3, CH3, CF3

O OCH3

H3C

N

PPh2

H3C

PPh2

S

H3C

O

Ar2P

N

CH3

t

Bu Ar2P

Fe

6 (R)-MeO-mop

7

8 Ar = 3,5-xylyl

78 to 98% yield 72 to 93% ee

30 to 78% yield 38 to 73% ee

90 to 99% yield 80 to 97% ee

DMTr Dimethoxytrityl, ee enantiomeric excess, eq equivalent, PMB 4-methoxybenzyl, rt room temperature, TBAF tetra-n-butylammonium fluoride, THF tetrahydrofuran

Enantioselective synthesis of oxindoles and spirooxindoles Badillo et al 761 enantioselective construction of the C(3)-tetrasubstituted carbon. Although both siliconand boron-based nucleophiles provided high enantioselectivity, the use of silicon-based reagents was generally more facile [13].

of a broad range of heteroaromatic and electron-rich π-nucleophiles to isatins under mild conditions using a Sc(III)-pybox complex with as little as 1 mol% catalyst loading has been reported (Scheme 2A) [14]. High yields and excellent enantioselectivities were achieved with both NH isatins and N-alkylated isatins. Less reactive isatin electrophiles required up to 10 mol% catalyst loading, but the reaction continued to exhibit high enantioselectivity, even at room temperature. As part of this investigation, the reactivity and selectivity

Several recent reports have included advances that broadened the scope of metal-catalyzed addition to isatins to enable the use of NH isatins and to include the addition of indoles and heteroaromatic nucleophiles. For example, the first direct enantioselective addition

Scheme 2. The addition of indole and diverse π-nucleophiles to isatins. A O

CH3

N

CH3

OTf OTf

N

10 (1 to 10 mol%)

N

+

O

R1

N

Sc

TfO O

O

N N

OH

4Å MS / CH2Cl2 or CH3CN / rt or -20°C / 0.08 to 48 h

R1

R

O N R

4

9

11

R = H, CH3, Ph R1 = H, Br, Cl, F, OCH3, CH3, OCF3

73 to 98% 87 to 99% ee

Other nucleophiles OCH3

O

CH3O

R2 N H

N(CH3)2 94% ee

OTMS

97% ee

H2C

R2 = H, OCH3

SnBu3

H2C

Ph

95% ee

80% ee

88 to 99% ee

B

H N

O

R2 O

R1

N

+

Conditions A or B

R2 N H

R

4

Condition A [15]: 14a (20 mol%) / PhCO2H (20 mol%) / 1,4-dioxane / rt / 4.5 days 68 to 97% (76 to 91% ee)

OH O

R1

R = H, CH3, Bn R1 = H, F, Cl, NO2, CH3, OCH3 R2 = H, Br, CH3, OCH3, CO2CH3

N R

12

Condition B [16]: 14b (15 mol%) / THF / rt / 4Å MS / 4 days 88 to 99% (80 to 97% ee)

13

H2C OH H

N OR

N 14a (R = H) 14b (R = Bn)

(A) The direct addition of heteroaromatic and electron-rich π-nucleophiles to isatins under mild conditions using a Sc(III)-pybox complex, and (B) the use of bifunctional Cinchona alkaloid catalysts to access 3-indolyl-3-hydroxy-2-oxindole products. ee Enantiomeric excess, MS molecular sieves, rt room temperature, THF tetrahydrofuran, TMS trimethylsilyl


of Sc(III)-inda-pybox and In(III)-inda-pybox complexes were compared. For indoles and other aromatic nucleophiles, In(III) complexes catalyzed the Friedel-Crafts reaction with comparable results to those obtained with the Sc(III) catalyst. Although both catalysts were suitable for Friedel-Crafts reactions of aromatic nucleophiles, it was notable that Sc(III)inda-pybox was also successful for aldol and allylation reactions of silylenolethers and allylstannanes. In contrast to the Rhand Pd-catalyzed arylation methodology, this method retains high yields and enantioselectivity (94% ee) even with 4-substituted isatins, which have been noted as being particularly challenging, as well as being important for the synthesis of natural products and bioactive structures such as SM-130686 [14]. In two subsequent reports, enantioselective indole additions were demonstrated using bifunctional Cinchona alkaloid catalysts to access 3-indolyl-3-hydroxy-2-oxindole

products 13 under mild conditions, providing good yields and up to 99% ee (Scheme 2B). Li and colleagues first reported the Friedel-Crafts reaction of indoles with isatins, employing the cupreine catalyst 14a (R = H) with a moderately high catalyst loading (20 mol%) and using benzoic acid as a co-catalyst [15]. A similar approach was reported by Chimni and Chauhan, in which the cupreine catalyst 14b (R = Bn) with a slightly lower catalyst loading (5 to 15 mol%) and no additive was used [16]. The Cinchona alkaloid was proposed as a bifunctional catalyst that could activate both the nucleophile and the electrophile components of the reaction simultaneously through hydrogen-bonding. Because these two reactions likely proceed via the same mechanism, the co-catalyst and C(9) hydroxyl group may not be essential for the reaction. The mild reaction conditions, high enantioselectivity and ability to use NH isatin reagents are advantages of this methodology, but the scope of the isatin electrophiles and the requirement for using NH indoles may be limiting.

Scheme 3. Asymmetric allylation and prenylation of isatins. A

O

R1

O N

+

H3C C

CH2

[Ir(cod)Cl]2 (2.5 mol%) / 17 (5 mol%) i-PrOH (200 mol%) / Cs2CO3 (7.5 mol%) / 3-NO2-BzOH (7.5 mol%) / toluene / 60°C / 40 h

H3C

R

N R

OCH3

15

CH2

O

R1

R1 = CH3, OCH3, Br, Cl, F 4 (R = Bn)

CH3

H3C HO

16 70 to 90% 90 to 96% ee

N CH3O

PPh2

CH3O

PPh2 N OCH3 17

B

CH2

O O

R1

N

+

H2C

OH R2

R 4

18

HO

Et3B (3 eq) / Pd(OAc)2 (5 mol%) / 20 (10 mol%)

R2 O

R1

THF / 30°C R = H, CH3, Bn, Ph, Ts, CH2(t-Bu) R1 = H, Cl, CH3, OCH3 R2 = H, CH3, Ar, Bn

N R 19 74 to 99% 46 to 71% ee

O O

P

N

CH3 Ph

20

(A) The novel Ir-catalyzed transfer hydrogenation approach that is applicable to allylation, crotylation and reverse prenylation reactions, and (B) the Pd-catalyzed asymmetric allylation of isatins. cod Cyclooctadiene, ee enantiomeric excess, eq equivalent, THF tetrahydrofuran, Ts tosyl

Enantioselective synthesis of oxindoles and spirooxindoles Badillo et al 763 Several metal-catalyzed routes have also been reported for the direct allylation of isatin reagents. For example, Krische and colleagues have described a novel Ir-catalyzed transfer hydrogenation approach that is applicable to allylation, crotylation and reverse prenylation reactions (Scheme 3A) [17]. This approach uses allyl acetate reagents or 1,1-dimethylallene (compound 15) as precursors for in situ-generated, transient allyl-metal intermediates. While this method avoids the requirement for stoichiometric quantities of allyl-metal reagents, the reaction involves a complex mixture of additives that may need to be optimized for use with different substrates [17]. In addition, Zhou and colleagues have developed a new class of phosphoramidite ligands, such as compound 20, for the Pd-catalyzed asymmetric allylation of isatins (Scheme 3B); however, the enantioselectivity of this reaction is not yet synthetically useful [18].

Metal-catalyzed carbon-carbon and carbonheteroatom bond-forming reactions of oxindoles Various metal-catalyzed asymmetric reactions of substituted 2-oxindoles (ie, compounds 21; Scheme 4) have been reported, including amination [19,20], fluorination [21,22], arylation [23] and Michael reactions [21,22,24]. Two recent metal-catalyzed amination reactions are highlighted in this section (Scheme 4). First, Shibasaki and colleagues reported the amination of oxindoles with chiral bimetallic Ni Schiff base complexes (ie, compound 26) using azodicarboxylate derivatives 22 as electrophiles [19]. Interestingly, the related monometallic complexes led to a reversal of enantiofacial selectivity that conveniently provided the other enantiomer of the product without requiring alteration of the chiral ligand. The use of the tert-butylsubstituted azodicarboxylate allowed the 3-aminooxindole products to be generated readily, and transformations

Scheme 4. The amination of oxindoles catalyzed by Sc and Ni complexes HN R2 R1

+

O N

N R3O2C

R2

CO2R3

Conditions A or B

N

R1

N

CO2R3 (i) HCl (3M) (ii) Rh/C / H2

CO2R3 O

[19]

N

R3 = t-Bu

R

R 21

22

23

O

R1

R2

NH2 O N H

24

(i) NaOH (2M) / CH3OH / rt / 2 h

NH

(ii) MsCl / NaHCO3 / CH3CN / 80ºC / 18 h

O N H

R2 = CH2CO2CH3 and R1 = H 25

74%

Condition A [19]: 26 (1 to 2 mol%) / toluene / 50°C / 18h R = Boc R1 = H, OCH3, F, Cl, Br R2 = CH3, allyl, Bn, CH2CN, CH2CO2CH3, (E)-cinnamyl R3 = t-Bu

HN N

O

Ni O

R = H, CH3, Bn R1 = H, Br R2 = alkyl, Bn, CH2Ar, Ar R3 = Et

O

O Ni

Condition B [20]: Sc(OTf)3 (0.5 to 5 mol%) / 27 (0.75 to 7.5 mol%) / 4Å MS / CH2Cl2 / -20 or 30°C / 2 to 4 days

O

Ar

+

N

H

O

+

N

N

O

O

H

N

26

27 (Ar = 2,6-di-isopropylphenyl)

86 to 99% yield 87 to 99% ee

71 to 98% yield 92 to 96% ee

Ar

Boc Tert-butyloxycarbonyl, ee enantiomeric excess, Ms mesyl, MS molecular sieves, rt room temperature, Tf triflate


Metal-catalyzed approaches for spirooxindoles

for the synthesis of the spiro-β-lactam 25 and for the formal synthesis of (+)-AG-041R were demonstrated. Second, the most recent example of an amination reaction involved a chiral N,N'-dioxide-Sc(III) complex with catalyst loading as low as 0.5 mol%, and a wide range of alkylated oxindoles (Scheme 4) [20]. The same Sc complex has also been reported for direct asymmetric aldol reactions with glyoxal derivatives [25].

Spirooxindoles represent a departure from the flat heterocyclic compounds encountered in many drug discovery programs, and may provide improved physiochemical properties. Unique spirocycles are often generated using synthetic methods that would not be identified based on classical approaches to disconnections and retrosynthesis. Several examples

Scheme 5. Selected examples of metal-catalyzed synthetic routes to access spirocycles from isatins. A O R1

O N

PdCp(η3-C3H5) (5 mol%) / 29a (10 mol%)

Ar

+

R2O2C O

R

4

R2O2C R1

N

O

R1

O N

R

OCH3 O

O

THF / 0°C to rt

O

R = CH3, CH2OCH3 R1 = H, CH3, OCH3, Br, Cl R2 = CH3, t-Bu Ar = Ph, 3-thienyl

28

Ar

LiAlH4

O

THF / 0°C / 3 h

O

CH2

CH2

Ar

CH2

R

30

31 (R = CH3, Ar = Ph)

85 to 94% 73 to 87% ee 88:12 to 95:5 dr

91%

CH3 P

N CH3 OCH3

29a B O C R1

O N

+

C

R2

H

R

R2 O O

CH2Cl2 / rt / 18 h

O

R = H, CH3, Ph R1 = H R2 = n-Bu, Cy, Ar, Cl(CH2)3

O

4

[Rh(34-(R,R))]BF4 (5 to 10 mol%)

32

N R 33

Ph2P Fe

73 to 97% 89 to 99% ee

PAr2 CH3

34-(R,R) [Ar = 3,5-(F3C)2C6H3] C

O R1

O N

+

O

R2 N

R3

R 4

OCH3

35

CH3O2C TiCl4 (10 to 20 mol%) CH2Cl2 / rt R = H, CH3, Bn, Ph, PMB R1 = H, halogen R2 = Ar R3 = H, CH3, i-Pr

R2

N

R3

O

R1

O N

or

R1

O

CO2CH3 O

N R

R 36a

R3

N R2

77 to 99% 81:19 to 99:1 dr 99:1 regioselectivity

36b

(A) The asymmetric Pd-catalyzed decarboxylative cyclization of methylidene-δ-valerolactones with isatins using the chiral P,N-ligands. (B) The cationic Rh-catalyzed intermolecular [4+2] annulation reaction between 2-alkynylbenzaldehydes and isatins. (C) The Lewis acid activation of isatin reagents to enable the highly regio- and stereoselective cyclization of oxazoles. dr Diastereomeric ratio, ee enantiomeric excess, PMB 4-methoxybenzyl, rt room temperature, THF tetrahydrofuran

Enantioselective synthesis of oxindoles and spirooxindoles Badillo et al 765 of novel spirooxindole syntheses are highlighted in this section. Hayashi and colleagues have developed an asymmetric Pd-catalyzed decarboxylative cyclization of methylidene-δ-valerolactones with isatins using the chiral P,N-ligands 29 to access spirocyclic oxindole pyrans, such as compounds 30 (Scheme 5A) [26]. The presence of the ester substituent on the methylidene-δ-valerolactone enables further functional group manipulations, and the transformation of the products with lithium aluminum hydride provides access to complex tetracycles (eg, compounds 31) containing an N,O-acetal functionality [26]. In addition, Tanaka and colleagues have developed a cationic Rh-catalyzed intermolecular [4+2] annulation reaction between 2-alkynylbenzaldehydes and isatins that provides access to the corresponding spirocyclic benzopyranones 33 with excellent yields and enantioselectivities up to 99% ee (Scheme 5B) [27]. The Rh-catalyzed reaction tolerates the use of NH isatins; however, the scope of the reaction for use with both substituted isatins and benzaldehydes (prepared by a one-step Sonogashira coupling of commercially available terminal alkynes with bromobenzaldehyde) remains unexplored. The Lewis acid activation of isatin reagents has been developed to enable the highly regio- and stereoselective cyclization of oxazoles to provide unique spirooxindole oxazolines, such as compounds 36a and 36b (Scheme 5C) [Badillo JJ, Franz AK: unpublished data].

The substitution of the oxazole ring can be used to manipulate the regiochemistry of the reaction to obtain either of the regioisomers 36a or 36b. Porco and colleagues have developed a stereoselective synthesis of spirocyclic oxindole pyrans and oxepenes 39 using a trimethylsilyl trifluoromethanesulfonate (TMSOTf)-catalyzed Prins cyclization of enantiopure homoallylic alcohols 38 with isatin ketals 37 (Scheme 6) [28]. Although the occurrence of racemization during Prins cyclizations is well documented [29], no reduction in enantiopurity was observed in this reaction, and products retained up to 99% ee [28]. This reaction also proceeded successfully with NH functionality on the isatin. In a complementary transformation of isatin ketals, Zhang and Panek have developed a stereocontrolled synthesis of spirooxindole oxepenes, such as compounds 41, via a Lewis acid-promoted [5+2] annulation of enantio-enriched silyl alcohols (Scheme 6) [30]. Using TMSOTf-catalyzed conditions, mixtures of cis and trans products were observed, with the cis:trans ratio depending on the solvent used and the reaction time; however, the use of BF3∙Et2O eliminated epimerization and provided the kinetic cis product with > 20:1 diastereoselectivity. The use of 4-bromoisatin or bromo-silyl alcohol derivatives yielded products capable of further transformation through

Scheme 6. Stereoselective syntheses of spirocyclic oxindole pyrans and oxepenes. H3C

Condition A [28]: TMSOTf (0.3 eq) / -40°C to rt / CH2Cl2 CH2 H3C

n

R 39 H

43 to 88% 10:1 to > 20:1 dr 2.6:1 to 20:1 rr > 99% ee

OCH3

R1

N

R2

n 38

CH3O

O

R1

OH

R2 O

O N

(ii) H2 / Pd/C

R2 = CH3, CH2OPh, CH2OBn n = 1, 2

R

O O

R2 = 2-Br-Bn

37 R = H, CH3 R1 = H, Br, OCH3

H

H3C

N

OH SiMe2Ph 40

R2 = CH3, 2-Br-Bn, propargyl

86% dr > 20:1

O

R1

R2

42

(i) Pd(OAc)2 / Et3N / 120oC

H3C O

H3C

CH3

R2

Condition B [30]: BF3·OEt2 / CH2Cl2 / reflux

N

CH3

R O

41 50 to 76% 4:1 to > 20:1 dr

O N

R1 = Br R2 = H

CH3 43 82% dr > 20:1

BF3·OEt2 Boron trifluoride diethyl etherate, dr diastereomeric ratio, ee enantiomeric excess, eq equivalent, rr regiomeric ratio, rt room

temperature, TMSOTf trimethylsilyl trifluoromethanesulfonate


Scheme 7. Rh-catalyzed aza-spiroannulation and asymmetric synthesis of (+)-AG-041R. O

D

D

NH2

O

NBoc

D

48 (7 mol%) / PhI(OAc)2 / MgO

D O NH

CH2Cl2 / reflux

CH3

Cl

Cl

NBoc

t

Bu

Rh

65% (2 steps)

D

D O O

6 steps

NBoc O NBoc 46

45

Cl

N

70% 96% ee

O O

(ii) Boc2O / Et3N / DMAP / CH2Cl2

CH2

Cl

O

44

(i) O3 / CH2Cl2 / CH3OH / -78°C / (CH3)2S

O

O Rh

48 Rh2(S-TCPTTL)4 CH3

CH3

H3C

O

NH

N O NH O

(i) KOH / EtOH / H2O

O NH

(ii) 4-toluidine / EDC·HCl / CH2Cl2 81% (2 steps)

N

HN

O

O N

OEt OEt

OEt OEt (+)-AG-041R

47

Boc Tert-butyloxycarbonyl, DMAP 4-dimethylaminopyridine, EDC 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, ee enantiomeric excess, TCPTTL dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate]

Pd-catalyzed intramolecular Heck reactions, providing polycyclic oxindoles such as compounds 42 and 43. Iwabuchi and colleagues have developed an expedient route to the potent gastrin/CCK-B receptor antagonist (+)-AG-041R using an asymmetric oxidative azaspiroannulation (Scheme 7) [31]. Chiral spiro-β-lactam 45 is efficiently accessed with high enantioselectivity from indole 44 using a chiral Rh(II)-catalyzed intramolecular spiroannulation. This reaction proceeds through a metal nitrenoid pathway, and both the tert-butyloxycarbonyl (Boc) group and the incorporation of two deuterium atoms into the nitrenoid precursor 44 were essential for the efficient promotion of the spirocyclization. The oxindole structure 46 was generated by ozonolysis of the exomethylene and further transformations provided additional oxindole structures of interest, eventually leading to the desired (+)-AG-041R. Several structures obtained in this concise route could provide access to other synthetically relevant 3-aminooxindole-containing biologically active compounds.

Metal-catalyzed cyclizations of arylamides An alternative 3,3-disubstituted enantioselective

strategy for the synthesis of oxindoles involves the use of an metal-catalyzed intramolecular aryl

amide cyclization inspired by methods published by the research groups of Buchwald and Hartwig [32,33]. For example, as an alternative approach to the direct arylation of isatins, Shibasaki and colleagues reported a Cu-catalyzed cyclization of the α-keto amide arylboronate 49; this strategy was applied to an enantioselective synthesis of SM-130686 [13]. More recently, a Pd-catalyzed cyanoamidation strategy has been reported to provide chiral 3,3-substituted oxindoles; the products from this reaction can be cyclized to generate either 5- or 6-membered ring N-heterocycle spirocycles, such as 54 (Scheme 8) [34-37]. Takemoto and colleagues first reported this enantioselective catalytic cyanoamidation reaction, albeit with enantioselectivities typically in the lower range (≤ 86% ee) and a description only of the N-benzyl tertiary amides [35]. Reddy and Douglas subsequently reported improved conditions that demonstrated the use of free NH groups and proceeded with excellent enantioselectivity (up to 99% ee) [36,37]. Disadvantages of the cyanoamidation strategy include the high reaction temperatures and the formation of HCN during the preparation of starting materials. Both studies demonstrated the utility of the cyano-substituted oxindole products by transforming the products to spirolactams, including several biologically relevant natural products.


Scheme 8. Pd- and Cu-catalyzed amide cyclization strategies. CH3

H3C F3C

F3C

CH3

O B

O O

Ar O

toluene

Ar

N

HO

CuF·3PPh3·2EtOH (10 mol%) / 50-(R,R) (14 mol%)

CH3

N

Ph

BOM

Ph

BOM O P

P

49 Ph

51a (Ar = 2-CH3-C6H4; 90%; 87% ee) 51b (Ar = 2-Cl-C6H4; 70%; 77% ee) 51c (Ar = Ph; 82%; 84% ee)

Ph 50-(R,R)

O

R2 CH2

R N O

R2

Conditions A or B

CN

R

R

H N

[35]

O N

O

when R2 = CH2CH2OTBS

N

R

CN

CH3

52

53

54

Condition A [34,35]: Pd(dba)2 (2 to 5 mol%) / 29b (8 to 20 mol%) / DMPU (1 eq) / decalin / 100°C / 24h

Condition B [36,37]: Pd2dba3 (2 mol%) / 29c (16 mol%) / DMPU (1 eq) / THF / 100°C

R = Bn R1 = H, CH3, OCH3, Cl R2 = CH3, propyl, CH2OTBS, Ph

R = H, CH3, Bn R1 = H, OCH3 R2 = CH3, CH2Cy, Ph, t-Bu, CH2OTBS

Ph O

P

N

O Ph

CH3 CH3

O

i

Pr

P

O

29b

29c

44 to 99% 69 to 88% ee

48 to 88% 82 to 99% ee

N

i

Pr

BOM benzyloxymethyl, dba dibenzylideneacetone, DMPU 1,3-dimethylhexahydropyrimidin-2-one, ee enantiomeric excess, eq equivalent, TBS tert-butyldimethylsilyl, THF tetrahydrofuran

Organocatalyzed approaches to substituted oxindoles and spirooxindoles In the past 2 years there has been a particular increase in the application of chiral organocatalysts for the enantioselective synthesis of various oxindoles and spirooxindoles. These novel catalysts include chiral amino catalysts, Cinchona alkaloids, chiral phosphoric acid catalysts and (thio)urea catalysts. Compared with organometallic and Lewis acid-catalyzed methods, organocatalysts frequently require higher catalyst loading; however, the metal-free methods generally are considered to be more environmentally friendly, and can often be used in aqueous solvent. Examples of common organocatalysts that have been used for the

enantioselective synthesis of substituted oxindoles are shown in Figure 2. Although there is still some debate regarding the exact mechanistic details for each catalyst variation, there are often common features of activation based on non-covalent interactions, such as hydrogen-bonding and π-π stacking [38,39]. In the case of chiral amino catalysts, reactions with these agents proceed via a common activation mechanism involving covalent enamine formation [40].

Organocatalyzed carbon-carbon and carbonheteroatom bond-forming reactions of oxindoles Organocatalysts enable the use of a broad range of electrophiles capable of undergoing enantioselective bond formation at the 3-position for the synthesis of


Figure 2. Examples of organocatalysts used for the synthesis of oxindoles and spirooxindoles

OH

H2C H

H2C

H

H H2C

N

N

OH H

OR

H N

HO

H3C

N

N

14a R = H 14b R = Bn

N H

N H

CH3

55

N

N H

56

Ar

NO2

O

NO2

S

N

N

H3C

Ph

H

O

O

Ph

O N H

O

CH3

O P

Ph OH

N H

Ph OTMS

Ar 57

58a Ar = 2,4,6-tri-isopropylphenyl 58b Ar = 2-naphthyl

59

TMS Trimethylsilyl

substituted oxindoles. Oxindoles 21 have been used in organocatalyzed variants of aldol, Mannich, Michael, alkylation, amination, hydroxylation and fluorination reactions. A recent example of a reaction of substituted oxindoles involved a thiourea-catalyzed Michael addition, demonstrating the first oxindole addition to maleimides (Scheme 9) [41]. The use of thiourea catalyst 56 was important to obtain high yields, as well as the desired diastereo- and enantioselectivity (≤ 99% ee). The N-Boc group was crucial for reactivity and stereocontrol. Also reported was an efficient enantioselective hydroxymethylation of N-Boc-protected oxindoles using catalyst 56 at 5 mol% loading and a polymeric

form of formaldehyde [42]. To extend the scope of carbon-oxygen bond-forming reactions for oxindoles, Barbas and colleagues developed a method for the enantioselective aminooxygenation of 2-oxindoles 21 using nitrosobenzene (compound 62) [43]. A series of quinidine-based catalysts was investigated and the dimeric quinidine 55 was identified as the optimal catalyst for the aminooxygenation reaction, providing oxindole 63 with up to 96% ee (Scheme 9) [43]. Although this method is limited to N-benzyl and 4-methoxybenzyl (PMB)-protected oxindoles, the substrates used for the reaction may include sterically demanding methyl and dimethyl-allyl chains, and allyl substitution provides

Scheme 9. Selected oxindole additions to electrophiles. R3 O

R3 N

O

N

O

O

R2

O

61

R2 R1

O N R 60

56 (5 to 20 mol%) / CH2Cl2 / rt / 10 h R = Boc R1 = H, CH3, F R2 = Ar, Bn, allyl, n-Bu, i-Pr R3 = Ar, allyl, cyclohexyl, i-Pr

R1

O N R

21

N 62

55 (5 to 10mol%) / THF / -20 °C / 48 h R = Bn, 4-CH3OBn R1 = H R2 = CH3, Bn, allyl, alkyl

R2 R1

65 to 92% 87:13 to 99:1 dr 85 to 99% ee

Boc Tert-butyloxycarbonyl, dr diastereomeric ratio, ee enantiomeric excess, rt room temperature, THF tetrahydrofuran

O

N H O

N R 63 65 to 86% 73 to 96% ee

Enantioselective synthesis of oxindoles and spirooxindoles Badillo et al 769 a functional handle for further functional group manipulations. Cinchona-catalyzed amination reactions have also been reported to provide aminooxindoles such as compound 23, as described in Scheme 4 [44,45].

cyclohexane derivatives 68 with three new chiral centers in high yields and selectivity (Scheme 10) [47]. The bifunctional thiourea catalyst 57 was proposed to activate both components through hydrogen-bonding interactions. In preliminary catalyst screening, minor structural features of the thioureas demonstrated a significant effect on the yields (from 6 to 91%) and enantioselectivities (from 49 to 91% ee), but the dr was consistently high. Overall, the more acidic thiourea catalyst rendered the reaction more selective and provided higher conversions. Further modification of products 68 provided the free NH oxindole, and the synthesis of spirocycle 1 was demonstrated in three steps (71% yield) with 95% ee [47].

Organocatalyzed approaches to spirooxindoles The research groups of both Melchiorre [46] and Gong [47] have described tandem double Michael addition strategies with alkylidene oxindoles 64 for the synthesis of spirooxindole derivatives such as compounds 66 and 68 (Scheme 10). Both of these methods have been applied to the synthesis of spirooxindole 1, which has been identified as a potent inhibitor of the Mdm2-p53 interaction [48]. Melchiorre and colleagues used the catalytic ability of chiral amine 59 in an enamine-iminium activation strategy that provided spirooxindole cyclohexane derivatives 66 with four new chiral centers in good yield and variable diastereomeric ratio (dr), with up to 98% ee [46]. This method tolerates free NH oxindoles and demonstrates the formation of the challenging all-carbon quaternary spirocenter. As an example of this methodology, spirooxindole 1 was prepared in one step with 70% yield and 84% ee; in addition, the complex bicyclo[2.2.2]octane scaffold 67, containing two adjacent all-carbon stereocenters, could be prepared with this methodology, albeit in lower yields (24%) [46]. This strategy has been extended further in a multicomponent/cascade reaction, as described in the next section of this review. Wei and Gong subsequently reported that chiral thiourea 57 catalyzes a similar tandem double Michael addition reaction to provide access to the spirooxindole

While investigating the enantioselective synthesis of antihypertensive benzo(thia)diazine pharmaceuticals (such as (R)-thiabutazide), List and colleagues developed a Brönsted acid-catalyzed model reaction between 2-aminobenzamide 69 and various carbonyls, including isatin (Scheme 11) [49]. Several substituted phosphoric acid catalysts were investigated for this reaction, and the catalyst 58a was optimal for the isatin reaction, providing spirocycle 70 in 84% ee. Different phosphoric catalysts had to be evaluated to optimize the reaction for different carbonyl substrates, and further improvement in the enantioselectivity of this method would be desirable. Although only one example of a reaction of a spirocyclic oxindole was demonstrated by List and colleagues [49], this route would presumably be useful with a variety of isatin reagents, as well as for a variety of aminobenzamides and sulfonamides relevant for drug synthesis and discovery.

Scheme 10. Synthesis of spirooxindole cyclohexane derivatives via organocascade reactions. O R4

O

R1

O R3

65a

R4

59 (20 mol%) / 2-F-C6H4CO2H (30 mol%) / toluene / 60°C / 72 h R2

O

R3

N

CO2Et

O

O

R1

R=H R1= H, Cl R2 = Ph, Et, i-Bu, CO2Et R3 = H, CH3 R4 = Ar

H3C

R2

N H

N H 66

67

59 to 82% 89 to 98% ee 80:20 to 95:5 dr

24% 97% ee > 95:5 dr

R O

64

OH CO2R3

R4

CO2R3 R4

65b 57 (10 mol%) / 4Å MS / CH2Cl2 / 10°C R = Ac R1= Br, Cl R2 = Ar, alkyl, CO2Et R3 = Et, Bn R4 = Ar, alkyl

R1

O

(i) LiOH / THF / H2O (ii) Pd/C (10%) / H2 (iii) Et3N / EtOAc

R2 O N Ac

Cl Et

R3 = Bn

O Cl

N H

68

1

29 to 98% 88 to 98% ee 89:11 to 99:1 dr

71% (over 3 steps) 95% ee

dr Diastereomeric ratio, ee enantiomeric excess, MS molecular sieves, THF tetrahydrofuran


Scheme 11. Enantioselective synthesis of spirooxindole dihydroquinazolinones.

O R1

+

O N

HN

toluene / 5Å MS / -45°C / 24h NH2

R

O

58a (10 mol%)

O

4 (R = R1 = H)

NH2

R1

69

NH O N H

70 85% 84% ee

ee Enantiomeric excess, MS molecular sieves

Viswambharan et al developed a diastereoselective method to access 3-spirodihydroindolizine oxindoles, such as compounds 74, via the 1,5-electrocyclization of vinyl pyridinium ylides (eg, compounds 73), which were generated from bromo-isomerized Morita-BaylisHillman adducts of isatin and pyridine (Scheme 12) [50]. Spiroindolizines occur as core structural features in many yohimbane alkaloid natural products [1,50], and may also provide attractive scaffolds for pharmaceutical leads. Broad substrate scope was demonstrated for the isatin component of the reaction; however, substitution of the pyridine was limited because electron-withdrawing groups reduce nucleophilicity, and the 2- and 4-hydroxyl pyridines failed to react as a result of keto-enol tautomerization. Although this method is limited because no catalytic variant has been reported, it is possible that an organocatalytic variant may be developed.

Multicomponent and cascade approaches to spirooxindoles Multicomponent reactions (MCRs) provide a powerful method to access complex structures, and MCRs have been particularly successful in enabling access to highly

functionalized oxindoles and spirooxindoles that may be important for drug discovery [51-54]. As an extension of the enamine-iminium activation strategy described in the previous section of this review, Melchiorre and colleagues developed a three-component asymmetric organocascade reaction that exploited amine catalyst 59 in an enamine-iminium-enamine sequential activation of aldehydes and α,β-unsaturated aldehydes with alkylidine oxindoles 64 (Scheme 13) [46]. This one-step Michael/Michael/aldol condensation sequence provided complex spirooxindole derivatives, such as compound 80, in good yield and excellent selectivity. Chen and colleagues have also developed a tandem organocatalytic [2+2+2] annulation reaction using catalyst 59 to form various 6-membered spirocyclic oxindoles, such as compounds 81 to 83 [55]. Using N-Boc-imine, nitroolefin, and α,β-unsaturated aldehyde components, this route provides access to spirocycles containing both carbocycle and piperidine structures. However, nitroolefins bearing β-alkyl groups proceeded with reduced reactivity and failed to cyclize. Although many organocatalyzed reactions require up to 20 mol% of catalyst, this threecomponent domino reaction proceeded with 5 mol% catalyst under optimized conditions. A disadvantage

Scheme 12. The synthesis of 3-spirodihydroindolizines via adducts of isatin and pyridine.

Br

H3CO2C

N

R2 72

R1 O N R

71

K2CO3 / CH3CN / reflux

+

CH3O2C

N

R1

R2

O

N

R2

H3CO2C

R1

O

N

N

R

R

73

74

R = CH3, allyl, Bn, propargyl, ethyl R1 = H, F, Br, CH3, CHO R2 = H, CH3, OH, Br

72 to 92%


Scheme 13. Organocatalytic three-component domino strategies to generate carbocycle and piperidine spirooxindoles.

O

R1

R3

O

R2

+

N

O R3

H

Michael addition

R4

R2

H

59

X

N

R

OH R5

77

R2 O

R1

N

R 75

64

R3

X

R4

tandem 1,4or 1,2-additionannulation

O

R1

R5

R 78

76

O

O

H

H 77a

R3

Ph

CH3

from condition A

CO Et O 2

R = H, R2 = Et, R3 = Ph N H 80 60% 99% ee O2N

O2N 77b

OH

Ph

Ph

CH3 t

DIPEA (20 mol%) / CH2Cl2 / 1 to 4 h O

R2O2C

O N

+

O

59 CH3

H

64a

O N

Condition A [46]: 59 (15 mol%) / 2-FC6H4CO2H (15 mol%) / toluene / 40°C / 48 h Condition B [55]: 59 (5 mol %) / PhCO2H (10 mol%) / CH3CN / rt / 2 h

79

85% 95% ee 88:12 dr

Boc N

R 75

Boc 81

CO2R2

H

from condition B

N

R = Boc, R2 = t-Bu

CH3

Conditions A or B

R

O

CO2 Bu

77c

Ph

Boc

(i) DIPEA (20 mol%) / CH2Cl2 / 1 to 4 h

Ph

N CH3 t

CO2 Bu O

(ii) Et3SiH / BF3·OEt2 / CH2Cl2 / 0°C

from condition B

N

R = Boc, R2 = t-Bu

H 82 41% 93% ee 99:1 dr

O Bn

N O

61

DBU (40 mol%) / CH2Cl2 / 4 h R = Boc, R2 = t-Bu

Bn

O OH

N

CH3

O

t

O

from condition B

CO2 Bu

N Boc 83 50% 90% ee dr > 99:1

Boc Tert-butyloxycarbonyl, DBU 1,8-diazabicyclo[5.4.0]undec-7-ene, DIPEA N,N-diisopropylethylamine, dr diastereomeric ratio, ee enantiomeric excess, rt room temperature


of this method is that only N-Boc-protected olefinic oxindoles were used [55]. In addition to the chiral amine 59, the methods described by both research groups require an acid co-catalyst to promote the reaction. In another cascade process, Chen and colleagues synthesized enantio-enriched spirooxindole hydroindanes 86 and 87 using (E)-4-(1-methyl-2-oxindolin-3-ylidene)3-oxobutanoates 84 (Scheme 14) [56]. This reaction also used amine catalyst 59, and proceeded via quadruple iminium-enamine-iminium-enamine catalysis, to produce spirocycles containing six to eight contiguous stereocenters with consistently excellent enantioselectivity (96 to 99% ee). Although this one-pot process is a powerful method to access complex structures, the moderate-to-low yields that are observed in this reaction (as a result of unidentified side products) remain a distinct disadvantage [56]. Gong and colleagues used a chiral phosphoric acid-catalyzed three-component reaction to access densely functionalized spiro[pyrrolidine-3,3'-oxindole] derivatives 90 [57], which are similar to core structures that occur in various alkaloid natural products, such as spirotrypostatin A, and other bioactive compounds (Scheme 15) [1,3]. This is the sole report of an asymmetric catalytic synthesis of spiro[pyrrolidine-3,3'-oxindole] derivatives. The reaction proceeds via a 1,3-dipolar addition between azomethine ylides (derived from aldehydes and amino ester 89) and alkylidine oxindoles 64. In contrast to the NH isatin derivatives that are typically used as dipolarophiles for auxialiary-induced

reactions, the N-acetate was essential for high yields and regioselectivity. Isatins with chlorine and/or fluorine substituents on the C(5) or C(6) position were selected as a result of their occurrence in important lead compounds for pharmacological activity. The regiochemistry of the reaction was observed to be independent of the electronic effect, and provided regioselectivity opposite to that directed by the electronic effect. To account for the high enantio- and regioselectivity of the reaction, theoretical studies for the mechanism were also reported and a transition structure was proposed (eg, transitionstate structures 91), in which both the azomethine ylide and the methyleneindolinone were hydrogen-bonded to the chiral phosphoric acid catalyst. It was proposed that the unusual regiochemistry results from stabilizing π-π stacking interactions between the oxindole ring and the conjugated esters [57]. A series of MCRs using isatin with dicarbonyl and nitrile reagents to access spirooxindole pyran scaffolds such as compounds 94 (Scheme 16) have been reported. For example, Yuan and colleagues developed a method to access spirocyclic oxindole pyrans in high yields and enantiopurities, using a three-component domino Knövenagel/Micheal/cyclization sequence catalyzed by the Cinchona alkaloid 14a [58]. Using a high-throughput reaction screening process, Stephenson and colleagues had previously reported a similar, albeit not enantioselective, three-component reaction to form related spirooxindole pyranochromenediones [59]. The variation described by Stephenson and colleagues is notable in

Scheme 14. Amine-catalyzed synthesis of spirooxindole hydroindanes. R3

O

R3

H

H H 77a

R3

HO

59 (20 mol%)

+

R1 O N

H

O

CH3 84

77a

PhCO2H (20 mol%) / DCE / rt to 35°C R1 = H, CH3, OCH3 R2 = Et, t-Bu R3 = Ar, CH3, propenyl, thienyl

R1

t

O

CO2R2

H

O

R1

OO CH3 86 30 to 97% 99% ee

O

NO2

N CH3 85

CO2 Bu

R3

N

R3

R2O2C

O

OH O2N

Ph 77b DIPEA (40 mol%) / rt / 15 h

R1

H

Ph CO2Et

Ph OO N CH3 87 50% 99% ee 99% de

DCE Dichloroethane, de diastereomeric excess, DIPEA N,N-diisopropylethylamine, ee enantiomeric excess, rt room temperature


Scheme 15. A catalytic asymmetric route to spiro[pyrrolidine-3,3'-oxindole] derivatives. R3

R2

+

O

R1

O R3

N

+

H

CO2Et

H2N

3Å MS / CH2Cl2 / rt / 48 h

88

89

R1

O N Ac 90 73 to 97% 99:1 regioselectivity 81 to 98% ee

R = Ac R3

+ N

-

R2 R1

CO2Et CO2Et

R1= CH3, F, Cl R2 = Ar, naphthyl, furanyl, alkyl R3 = Ar, alkyl

R 64

R2

58b (10 mol%)

CO2Et

H N

H O

CO2Et CO2Et O

P H

O

OR* OR*

N Ac 91

ee Enantiomeric excess, MS molecular sieves, rt room temperature

Scheme 16. Multicomponent reactions of isatins with dicarbonyls.

O

R1

N

+

NC

CN

+

O

O R2

CH2Cl2 / 4Å MS / 0°C / 14 h

R 4

92

O R1

H3C O

N R 4

+

N

NH2

95

R 94 87 to 99% 5 to 97% ee

R2 N N

CAN (10 mol%) / H2O / 80°C / 6 to 12 h

+ O

R2

N

H N

O

N

O

R1

R = CH3, Bn, allyl, MOM R1 = H, CH3, F, Cl, Br, OCH3 R2 = CH3, Ph R3 = CH3, OCH3, OEt

93a

COR3

NC

14a (10 mol%)

R3

R2

O

H2N

O

R = H, CH3 R1 = H, CH3, F, Cl, Br R2 = CH3, Ph

93b

O R1

O

CH3

N R 96 57 to 90%

CAN Ceric ammonium nitrate, ee enantiomeric excess, MOM methoxymethyl, MS molecular sieves

the use of SnCl4-hydrate as a catalyst with microwave conditions. Li and colleagues have also described a similar MCR catalyzed by l-proline, but no enantioselectivity was observed in this reaction [60]. Chen and Shi developed a one-pot synthesis of spirooxindole derivatives 96 using a cerium-catalyzed threecomponent reaction of isatins, 5-amino-3-methylpyrazole (compound 95), and 1,3-dicarbonyl compounds [61]. Although organic solvents were explored for these reactions, the optimal conditions used environmentally friendly aqueous solvent. The reports from both Li [60]

and Chen [61] discuss mechanistic details to confirm the order of nucleophile addition and propose a reaction pathway proceeding via a 3-hydroxyoxindole intermediate. Notably, the methods described by Chen and Shi allowed the use of unprotected NH isatins [61]. Shi and colleagues have also reported two examples of three-component 1,3-dipolar cycloaddition methodology to synthesize spiro[pyrrolidine-3,3'-oxindole] derivatives. The general strategy for these reactions involves the generation of azomethine ylides in situ from isatin and


Scheme 17. Three-component dipolar cycloaddition approaches to synthesize spiropyrrolidines. R2

R2 R CN

N

R

R1

CN CN

O

N

R1

CN

O

O

N

99 O

H2C

N 4

R

N R

EtOH / reflux +

N

CH3

100

R = H, CH3 R2 = H, Br

R1

CH3 O

82 to 93%

O N

+ H3C

H N

R CO2H

97

98

CH3

O

O

EtOH / reflux O

H3C O

R = H or CH3 R1 = H, CH3, F, Cl, Br

OH

Ar

O

N

R1

HO O

Ar

CH O 3

N R

101

102 87 to 97% > 99:1 regioselectivity

an amino acid such as N-methylglycine (ie, compound 97; Scheme 17). In the first report, a three-component reaction of 2-(2-oxoindolin-3-ylidene)malononitrile (compound 99), isatin and N-methylglycine was described in which two equivalents of isatin were incorporated (ie, a pseudo four-component reaction) to provide dispiropyrrolidine bisoxindole derivatives 100 [62]. In a second report, a three-component reaction was described using acryloyl-pyran-2-ones 101 as the dipolarophile [63]. To expand the scope of the reaction, N-methylglycine was replaced by thiaproline to obtain spirothiapyrrolizidines. The high regioselectivity of these reactions was explained by considering secondary orbital interactions between the carbonyl of the dipolarophile and the ylide [63]. Although these processes were not enantioselective, the advantages of this methodology include mild reaction conditions, high yields, high regio- and stereoselectivity, the one-pot procedure and operational simplicity.

Conclusion Substituted oxindoles continue to be recognized as important compounds of interest for drug discovery. For example, a recent report described an organocatalyzed enantioselective synthesis of spiro[thiocarbamate-3,3'oxindoles], which were evaluated in preliminary biological studies and identified as promising antipyretic agents [64]. As more examples of the enantiospecific biological activity of such compounds are identified, efficient and reliable asymmetric syntheses of oxindoles will become ever more valuable. Challenges remain in the design

and development of efficient catalysts with low catalyst loading,

the

achieve

high

identification

of

synthetic

enantioselectivity,

the

methods

incorporation

that of

polar groups and heterocycles, and in determining the effects of additives and co-catalysts for both metaland

organocatalyzed

enantioselectivities

of

reactions. novel

In

many

syntheses

cases,

are

the

modest;

however, new methods and improvements continue to push the boundaries of synthesis forward in order to access more complex structures with greater efficiency and higher selectivity. As more examples of asymmetric syntheses are reported, interesting trends may emerge that

improve

the

understanding

of

the

mechanisms

and scope of organocatalyzed reactions. As continued emphasis

is

placed

on

multicomponent

and

tandem

reactions, improvements in yields and novel enantioselective variants will certainly be forthcoming.

References •• •

of outstanding interest of special interest

1.

Trost BM, Brennan MK: Asymmetric syntheses of oxindole and indole spirocyclic alkaloid natural products. Synthesis (2009) (18):3003-3025.

2.

Zhou F, Liu YL, Zhou J: Catalytic asymmetric synthesis of oxindoles bearing a tetrasubstituted stereocenter at the C-3 position. Adv Synth Catal (2010) 352(9):1381-1407.

3.

Galliford CV, Scheidt KA: Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents. Angew Chem Int Ed Engl (2007) 46(46): 8748-8758.

Enantioselective synthesis of oxindoles and spirooxindoles Badillo et al 775 4.

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