Organocatalytic Asymmetric Assembly Reactions: Synthesis

20 Pages·2014·1.82 MB·English

Review
pubs.acs.org/acscatalysis
Organocatalytic Asymmetric Assembly Reactions: Synthesis of
Spirooxindoles via Organocascade Strategies
Daojuan Cheng,† Yoshihiro Ishihara,‡ Bin Tan,*,†,‡ and Carlos F. Barbas, III*,‡
†Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518055, People’s Republic of China
‡
The Skaggs Institute for Chemical Biology and Departments of Chemistry and Cell and Molecular Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
ABSTRACT: Spirooxindoles have become a privileged skeleton given their
broadandpromisingactivitiesinvarioustherapeuticareas.Thestrategiesand
catalyst systems described here highlight recent advances in the
enantioselective synthesis of spirooxindoles via organocascade strategies.
Variousorganocatalysts withdistinctactivationmodeshavefoundapplication
in constructing these sophisticated compounds. This review focuses on the
enantioselectivesynthesisofspirooxindolesviaorganocascadestrategiesandis
organized on the basis of three primary starting materials and then further
subdivided according to the types of organocatalyst. These methods are of
importance for the synthesis of complex natural products and the design of
new pharmaceutical compounds. We believe that compounds based on
spirooxindoleskeletonshavethepotentialtoprovidenoveltherapeuticagents
and useful biological tools.
KEYWORDS: spirooxindoles, asymmetric, catalysis, organocascade, strategies
1. INTRODUCTION mammaliantsFT210cells.4eMI-219isanorallyactiveinhibitor
Since our first report of an asymmetric organocatalytic of the interaction between the tumor suppressor p53 and the
Michael/aldol cascade reaction in the year 20001a and our E3 ubiquitin ligase MDM2.4h NITD609 is a very promising
drug candidate for the treatment of malaria; it shows
subsequent early studies in cascade, one-pot, and multi-
component organocatalytic reactions,1 therehas been dramatic pharmacokinetic properties compatible with once-daily oral
dosingandhassingle-doseefficacyinarodentmalariamodel.4i,j
growth in the development of organocatalytic synthesis of
complex molecules.2,3 A particular challenge comes with the The scope of biological modes of action and the therapeutic
promise of spirooxindole-containing molecules are exceptional
design of robust and operationally simple approaches to the
and have been a major driving force in the development of
synthesis of complex molecules containing multiple stereo-
centers. We have broadly classified reactions of these types as innovative approaches to their synthesis.
Several challenges are associated with the catalytic asym-
organocatalytic asymmetric assembly reactions because they
metric construction of spirooxindole structures. For example,
providefortheasymmetricassemblyofmultiplesubstratesinto
when starting from a 3-methyleneoxindole, control of the
higher-order products with stereochemical complexity. Herein,
regioselectivity at the double bond is difficult because the
we review progress toward the synthesis of just one class of
reactivity at the two carbon atoms can be influenced by
molecules,spirooxindoles,whichareparticularlyintriguingwith
substituents. Moreover, the chiral spirooxindole product
respect to both their structure and biological activities.
features an oxindole core with a spiro ring fused at the 3-
Organocatalysis has brought unprecedented progress to the
position (see oxindole numbering in Figure 2). The
catalytic asymmetric construction of stereochemically complex
spirooxindoles. Organocascade or domino stategies2 are substituents on this ring may result in multiple stereocenters,
and this steric congestion makes these reactions more
especially attractive because of the general availability and
stability of organocatalysts,3 the mild and simple reaction challenging than chiral auxiliary-induced cascade reactions. In
addition, the actual mechanism of the transformation is not
conditions used, and the powerful ability to construct
fully understood in many cases. For instance, it is unclear
enantiomerically enriched complex molecules via a cascade
whetherchiralorganocatalystsactivateonesubstratetocontrol
process. Spirooxindole motifs are found in many natural
products and biologically active molecules (Figure 1).4 For the stereochemistry or whether interactions with both
example, gelsemine is a complex alkaloid that is arguably the substrates are required to achieve high asymmetric induction.
most known spirooxindole natural product and one that has
been synthesized by numerous groups using various strat- Received: December 9,2013
egies.4a Spirotryprostatins A and B have been shown to Revised: January15, 2014
completely inhibit the G2/M progression of cell division in
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skeleton. Finally, oxindoles with a formal bis-nucleophilic
centeratthe3-positionmaybecoupledwithtwootherreaction
components or with a single reaction partner with two
electrophilic sites.
ThethreereactionpatternsdepictedinFigure2canthenbe
furthersubdividedaccordingtothetypesofcatalysisemployed,
includingenamineandiminiumcatalysis,nucleophiliccatalysis,
N-heterocyclic carbene (NHC) catalysis, and hydrogen
bonding catalysis. All the organocatalysts that are described in
thisreviewforthepurposeofspirooxindoleformationarelisted
inFigure3.Thislistcontainsproline-derived catalysts1,chiral
phosphine catalysts 2, cinchona alkaloid-derived primary (1°)
amine catalysts 3, cinchona alkaloid-derived hydrogen-bonding
catalysts 4, cinchona alkaloid-derived tertiary (3°) amine
catalysts 5, chiral carboxylic acid 6, thiourea-based catalysts 7,
urea-orthiocarbamate-basedcatalysts8,bifunctionalthiourea/
phosphine catalyst 9, binaphthyl phosphate-based catalyst 10,
binaphthyl phosphoric acid-based catalysts 11, squaramide-
basedcatalysts12,andN-heterocycliccarbene(NHC)catalysts
13.
2. USE OF UNSATURATED OXINDOLE DERIVATIVES
Various organocatalysts promote cascade reactions between
methyleneoxindole, isatin, or isatinimine and reacting partners
toyieldchiralspirooxindoleswithdifferentringsystems.These
Figure 1. Representative examples of natural products and reactions can be classified on the basis ofactivation mode, and
pharmaceutical molecules containing a spirooxindole corestructure. relevant reports on this topic are collected in this section.
2.1.EnamineandIminiumCatalysis.Chiralprimaryand
secondary amine catalysts have been used extensively to
activate carbonyl groups. The ability of these catalysts to
participate in various enamine- and iminium-mediated
processes also makes them ideal for the sequential addition
of nucleophiles and electrophiles in a cascade manner. Such
reactions can readily access products with multiple stereo-
centers. Recently, organocascade reactions that proceed
through enamine or iminium activation modes have been
reviewed.6Althoughavarietyofpyrrolidinecatalysts,including
pyrrolidine ether catalysts, have been described in the early
organocatalysis literature, the Hayashi−Jørgensen pyrrolidine
organocatalysts 1 (Figure 3) have proven to be versatile and
effective in several synthetic strategies to create spirooxindoles
with high enantioselectivities.7
In 2009, Melchiorre’s group developed a triple Michael/
Michael/intramolecular aldolanddehydration cascadereaction
(Scheme1).8Usingchiralaminecatalyst(S)-1b,methyleneox-
indoles 14a, aliphatic aldehydes 15, and α,β-unsaturated
aldehydes 16 were combined to generate spirooxindoles 17a
in moderate yields, excellent diastereoselectivities (dr) and
Figure 2. Three types of starting materials for the enantioselective enantioselectivities (ee). In a related triple cascade strategy, an
synthesis of spirooxindoles via organocascade strategies. efficient one-pot, three-componenttandemannulation hasalso
been successfully developed by the Chen group to construct
Inthepastseveralyears,creativeandefficientorganocascade various six-membered spirooxindoles 17b.9
strategieshavebeenusedtobuildthesesophisticatedscaffolds.5 Onthebasisofthisstrategy,propanal(15a)wasreactedwith
This review focuses on the enantioselective synthesis of electron-deficientmethyleneoxindole14cinthepresenceof2°
spirooxindoles via organocascade strategies and is organized amine (S)-1b to give bifunctional intermediate 18, which was
onthebasisofthreetypesofstartingmaterials(Figure2):First, further combined with diverse electrophiles (activated olefins
one can start from unsaturated oxindole derivatives, such as 19aor20aorimine21a)eitherin1,4-or1,2-fashion(Scheme
methyleneoxindole, isatin, or isatinimine. These unsaturated 2). The final intramolecular cyclization process yielded the
derivativesreactwithdesignedreactionpartnersthathaveboth expected six-membered spirooxindole skeleton with molecular
electrophilic and nucleophilic sites through an addition- diversity, complexity and excellent stereocontrol.
cyclization sequence to produce spirooxindole motifs. Second, Recently, Ghosh et al. harnessed the reaction between
one can couple 3-substituted oxindoles with reaction partners methyleneoxindoles14andpentane-1,5-dial(15b)toconstruct
viaanaddition-annulationprocesstoprovidethespirooxindole substituted spirocyclohexane oxindoles 17 (Scheme 3).10 This
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Figure 3. Organocatalysts described in thisreview for the purpose of spirooxindole formation.
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Scheme 1. Cascade Reaction of Methyleneoxindoles 14, withdrawinggrouptoanelectron-donatinggroup,theabsolute
Aliphatic Aldehydes 15 and α,β-Unsaturated Aldehydes 16 configuration of the hydroxyl center also changed to give 17f
and17g,respectively,indicatingthattheN-protectinggroupon
theoxindolehasacriticaleffectonthestereochemistryofaldol
ring closure.
In 2010, Chen’s group reported a three-component domino
reaction of rationally designed methyleneoxindoles 14d with
two molecules of α,β-unsaturated aldehyde 16 and 16′ under
quadruple iminium/enamine/iminium/enamine catalysis
(Scheme 4).11 Employing chiral amine (S)-1b as catalyst, a
Scheme 4. A Three-Component Reaction of
Methyleneoxindole14withTwoDifferentMoleculesofα,β-
Unsaturated Aldehyde 16
Scheme 2. Coupling of Chiral Bifunctional Intermediate 18
with Other Electrophiles
spectrum of complex spirooxindoles (17h) bearing six
contiguous stereocenters were obtained via this unique triple-
Michael/aldol process. Remarkably, the Michael/Michael
intermediate can be trapped by other electrophiles, such as
nitroolefins 19b, further expanding the synthetic utility of this
type of reaction.
A trienamine activation method was used by two groups to
construct chiral spirooxindoles. In 2011, Chen, Jørgensen, and
co-workers found that exposure of polyenals 22 to chiral 2°
amines 1 generates reactive trienamine intermediates 23a that
Scheme 3. (R)-1b-Catalyzed Michael/Aldol Cascade readily undergo Diels−Alder reactions with various classes of
Reaction between Methyleneoxindoles 14 and Pentane-1,5- dienophiles (Scheme 5).12 This method offers a facile entry to
dial (15b) highly complex molecular frameworks with excellent stereo-
control. For the Diels−Alder reactions between 14 and 24a,
spirooxindoles 17j were formed in high yields and with
excellent enantioselectivities. This activation strategy allowed
for excellent chirality “relay” over a distance of up to eight
bonds.Examplesoftrienamine/enaminetandemreactionswere
also shown. By using NMR spectroscopic studies and
calculations of the reactive trienamine intermediates, a
mechanistic hypothesis was proposed to rationalize the origin
ofstereochemistryandthepreferredreactionpathway.12Inthe
sameyear,Melchiorre’sgroupdocumentedthefirstasymmetric
catalytic Diels−Alder reaction of heterocyclic ortho-quinodi-
methanes 23b.13 In the presence of chiral amine catalyst (S)-
1b, reactive diene species were generated in situ from simple
starting materials and cyclizations with nitroolefins (19)
occurred with high stereocontrol (up to >20:1 dr, >99% ee).
procedure proceeded through a Michael/aldol sequence in the For Diels−Alder reactions with methyleneoxindoles 14, a
presence of (R)-1b to afford products with multiple stereo- structurally diverse range of complex spirooxindole-containing
centers in high yields and excellent enantioselectivities. tetrahydrocarbazoles 17k was obtained with high chemical
Interestingly, the authors noted that when the N-protecting yields and excellent stereoselectivities. This strategy could be
group on the oxindole was modified from an electron- extended to pyrrole- and furan-based ortho-quinodimethanes,
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Scheme 5. Trienamine Activation Modes and Their Scheme 7. Double Michael Cascade Reactions between
Application to the Synthesis of Chiral Spirooxindoles Methyleneoxindoles14aandα,β-UnsaturatedKetones28via
Dienamine Intermediates
anticipated that condensation of catalyst 3a with 28 would
generate dienamine intermediate 29, which could undergo a
doubleMichael addition with methyleneoxindole 14a actingas
both an acceptor and a latent donor to accomplish the
sequence.Amongthecatalystsexamined,hydroquinine-derived
primary amine 3a in conjunction with ortho-fluorobenzoic acid
which would be beneficial for the application of this (OFBA) was found to be most efficacious, giving the desired
methodology in medicinal arenas.
products17linmoderateyields,gooddiastereoselectivities,and
Melchiorreandco-workershavealsomadeuseofdienamine excellentenantioselectivities. Thisisthefirstexampleofaone-
activation to synthesize chiral spirooxindoles (Scheme 6).14
step synthesis of multistereogenic spirocyclohexane oxindole
derivatives via a tandem iminium and enamine catalytic
Scheme 6. Dienamine Activation in the Synthesis of Chiral
sequence.
Spirooxindoles 26 from Isatins 25a and Enals 16b In2011,Wang’sgroupdemonstratedthatthecombinationof
a cinchona-based chiral 1° amine 3e and BINOL-phosphoric
acid (R)-11a is a powerful and synergistic catalyst system for
the double Michael addition of isatylidene malononitriles 31
with α,β-unsaturated ketones (28a), delivering chiral spiro-
[cyclohexane-1,3′-indoline]-2′,3-diones (17m) in excellent
yields and stereocontrol (Scheme 8).16 This reaction showed
Scheme8.ReactionbetweenIsatylideneMalononitriles(31)
and α,β-Unsaturated Ketones (28a) or Ynones (33)
Catalyzed by Cinchona-Based Chiral Primary Amine
Catalysts 3
Exposureofenal16btotheaminocatalyst(S)-1bresultsinthe
formation of dienamine intermediate 27, which reacts with
isatin 25a to generate spirocyclic oxindole scaffold 26. Their
experimental observations were in agreement with a hetero-
Diels−Alder (HDA) process for the reaction.
Although aldehyde substrates are often activated using 2°
amine catalysts, ketone substrates are typically activated by 1°
amine catalysts. Cinchona-based chiral primary amines 3 are
recognized as some of the most common catalysts for
dienamine intermediate formation (see Figure 3).15
In 2009, the Melchiorre group reported Michael/Michael
cascade reactions between methyleneoxindoles 14a and α,β-
unsaturated ketones 28 for the synthesis of spiro-4-cyclo-
hexanone oxindole derivatives 17l (Scheme 7).8 The authors
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an interesting temperature effect: elevation of the temperature Scheme 10. Chiral Phosphine-Catalyzed [3 + 2] Cyclization
to 100 °C improves reaction efficiency without significant loss between Methyleneoxindoles (14) and Allenes (35)
of stereoselectivity. It is noteworthy that the regioselectivity of
this reaction differs from that of monosubstituted methyl-
eneoxindoles (14). This difference might stem from the more
electron-withdrawing dicyano groups, making the nucleophilic
dienamine intermediate prone to attack the 3-position of the
isatylidenemoietytogive32.Theenoneisactivated bythe1°
amine catalyst, and similarly, ynones also have the ability to
react with this catalyst to form a reactive intermediate. Thus,
Ramachary et al. presented a strategy based on the use of
catalytic amino enyne 34 to construct functionalized six-
membered spirooxindoles (17n) from 2-(2-oxoindolin-3-
ylidene) malononitriles (31) and ynones (33).17
In a similar manner, enones (28a) can react with isatins
(25b) through enamine activation of enones (Scheme 9). In
Scheme9.HDAReactionbetweenIsatins(25b)andEnones
(28a)
Scheme 11. [4 + 2] Annulation between 31a and Allenoates
35c Catalyzed by Bifunctional Phosphine 2c
2013, Cui and Tanaka evaluated the feasibility of this kind of
HDA reaction.18 Notably, an amine (3c)/acid (6)/thiourea
(7a) combination catalyst system proved optimal. The
interaction between thiourea and the two oxygens of isatin MBH carbonates 37 are readily available and versatile C
was essential for an efficient reaction. Under the published synthons (Scheme 12).22 The Barbas23 and Lu24 groups3
conditions, spirooxindole tetrahydropyranones (26c) were independently reported the synthesis of related spirocyclopen-
synthesized with up to 94% ee. Moreover, the reactions were taneoxindolesfromMBHcarbonatesby[3+2]cycloaddition.
efficient on gram scale, and various transformations of the The Barbas group found that C -symmetric phosphine catalyst
2
product demonstrated the utility of this formal HDA reaction. (+)-Ph-BPE 2d efficiently catalyzed the [3 + 2] cycloaddition
2.2. Nucleophilic (Phosphine and Amine) Catalysis.
Nucleophilic catalysis remains an active and dynamic area of
Scheme 12. Chiral Phosphine-Catalyzed [3 + 2]
interest for synthetic chemists. Small-molecule electron-pair
Cycloaddition between MBH Carbonates (37) and
donors (Lewis bases) are effective catalysts for a range of
Methyleneoxindoles
synthetic transformations. Nucleophilic phosphine catalysis is
firmly established as a reliable platform for a variety of
transformations that include activated allenes and Morita−
Baylis−Hillman (MBH) carbonates as starting materials.19
In 2010, Marinetti’s group realized a [3 + 2] cyclization
strategy between methyleneoxindoles (14) and allenes (35)
catalyzedbyBINOL-derivedphosphinecatalyst2a,resultingin
theformation of“γ-adduct”spirocyclopentane oxindoles(36a)
in excellent yields, regioselectivities, and enantioselectivities
(Scheme10).20Tofurtherexpandthisstrategy,thegroupused
tricyclic oxindole 14f as a substrate and obtained the desired
product 36b with 94% ee. Notably, under the catalysis of a
ferrocene-derived phosphine catalyst 2b, allenylphosphonate
35b also worked well in this spirocyclization to give 36c with
high enantioselectivity.
The Lu group successfully used allenes in a [4 + 2]
annulation strategy with activated alkenes and α-substituted
allenoates (35c) catalyzed by amino acid-based bifunctional
phosphine 2c (Scheme 11).21 Using isatin-derived alkenes
(31a), the cycloaddition afforded biologically important 3-
spirocyclohexene-2-oxindoles (17o) with up to 93% ee.
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reactiontogive“γ-adduct”spirocyclopentane oxindoles(36d) Scheme 13. Chiral Phosphine-Catalyzed, One-Pot MBH/
in excellent yields, regioselectivities, and enantioselectivities.23a Bromination/[3 + 2] Cyclization Sequence To Give
Theauthorsconductedcontrolexperimentsthatindicatedthat Spirooxindoles 40
boththesecondphosphineofthe catalyst2dandthe carbonyl
of methyleneoxindole 14 had a major impact on the
stereoselectivity. This reaction likely begins with the activation
ofMBHcarbonate37byoneofthephosphines,followedbyan
addition−eliminationprocessinwhichmethyleneoxindole14is
activated by the second phosphine. Recently, Barbas and co-
workers further extended this type of [3 + 2] cycloaddition
reaction to 3-substituted methylenebenzofuranone deriva-
tives.23b Using (−)-Ph-BPE (ent-2d) as catalyst, the desired
polysubstitutedspirocyclopentenebenzofuranonescaffoldswere
obtained with excellent enantioselectivities. In contrast, the Lu
group used a threonine-derived phosphine thiourea 9 to
catalyze the stereoselective [3 + 2] cycloaddition process
between the MBH carbonates (37) and isatin-derived
tetrasubstitutedalkenes(31b),whichallowedfacilepreparation
of the “γ-adduct”, in this case biologically important 3-
spirocyclopentene-2-oxindoles (36e), in excellent diastereose-
lectivities and enantioselectivities.24 A plausible reaction
mechanism was proposed in which the MBH carbonate 37
was activated by the phosphine to generate ylide intermediate
38, which then underwent γ-addition (or conjugate addition),
intramolecular cyclization, and final elimination to give the
reportedtheuseofNHC13ainaformal[2+2]cycloaddition
desired product. Hydrogen-bonding interactions between the
of disubstituted ketenes 41a and isatins 25 to provide the
thioureamoietyofthecatalystandtheisatinmayplayacrucial
correspondingspirocyclicoxindole-β-lactones42ingoodyields
role in asymmetric induction (Figure 4).
with good diastereoselectivities and excellent enantioselectiv-
ities (Scheme 14).27 The same group also disclosed the first
example of NHC-catalyzed [3 + 2] annulation of enals 16 and
Scheme 14. NHC-Catalyzed Cycloaddition Reaction of
Isatins (25) with Ketenes (41a), Enals (16), and α,β-
Unsaturated β-Methylacyl Chloride 44
Figure4.Hydrogen-bondinginteractionsbetweenthethioureamoiety
of the catalystand the isatin unit, resultingin asymmetric induction.
TheMBH reactioncanalsobeemployedinthe synthesisof
spirooxindoles without using MBH carbonates (such as 37 in
Scheme 12). Very recently, Zhou and co-workers reported the
asymmetric synthesis of spirooxindoles starting from bromo-
methylated oxindole starting materials, such as 14h (Scheme
13).25Withnucleophilic 3°amine catalyst 5a, 14hwasreacted
withketone39ina[3+2]cyclizationtogivespirooxindole40,
whichbearsanadditionalall-carbonquaternarycenteradjacent
to the quaternary center at C3. In an impressive three-step,
one-pottransformation,isatin25ccanbetreatedwithenal16c
with catalyst 5a, then HBr, then ketone 39 and base, to yield
40a in moderate to good yields and excellent ee. Thisreaction
first undergoes an MBH reaction on enal 16c, then an allylic
alcoholdisplacementwithbromidetogive14h,followedby[3
+ 2] cyclization.
2.3.N-Heterocyclic Carbene(NHC)Catalysis.Chiral N-
heterocyclic carbenes (NHCs) are a class of Lewis basic
(nucleophilic) catalysts used in a number of asymmetric
organocatalytic processes. In the past decade, NHC-catalyzed
annulation reactions have become powerful methods for the
synthesis of various heterocycles.26 In 2010, the Ye group
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isatins25togeneratespirocyclicoxindolo-γ-butyrolactones43a cooperative catalysis strategy to carry out the annulation
in good yields with good diastereo- and enantioselectivities.28 reaction between enals 16d and isatins 25.34 The addition of
(Thereafter, other examples followed, such as the work of lithium chloride asaLewis acid toβ-aryl substituted enals16d
Coquerel in 2013.29) Among the catalysts evaluated, 13b was generated lactone products with good enantioselectivity,
foundtobemostefficacious;noreactionoccurredwhenNHCs whereas lithium chloride was detrimental to the reaction of
with a silyl substituent were used. On the basis of the strong enals bearing β-alkyl substituents. The authors proposed that
influence of the free hydroxyl group on the activity of the the enantioselectivity for β-aryl substituted enals 16d might
catalyst and the stereochemical outcome of the reaction, the stem from the generation of an organized transition state by
authors hypothesized a transition state in which hydrogen lithium cations through coordination of the enol oxygen atom
bonding between the catalyst 13b and isatin 25 enhance the oftheNHC-boundhomoenolate andthe1,2-dicarbonyl ofthe
reactivity and direct the addition of the dienolate 45b to the isatin 25. The utility of this method was highlighted by a
carbonyl group of isatin 25. Ye’s laboratory further extended concise total synthesis of maremycin B.
this strategy to α,β-unsaturated β-methylacyl chloride 44 and 2.4. Hydrogen Bonding Catalysis. Hydrogen bonding
foundthatthesilylatedNHCcatalyst13awasoptimalinterms (H-bonding) catalysts are designed on the basis of the
of reactivity.30 The additive triethylamine is essential to assumption that small organic molecules are able to increase
generate a ketene intermediate. Under the established the electrophilic character of a substrate via H-bonding
conditions, the reaction between α,β-unsaturated β-methylacyl interactions with oxygen or nitrogen lone pair electrons in
chloride 44 and isatins 25 proceeded smoothly, providing
the reagent, making the reaction more likely to take place and
spirocyclic oxindole-dihydropyranones 26din good yields with under stereocontrol.35 Recently, H-bond donors such as ureas
good to high enantioselectivities. The authors further andthioureashavebeenrecognizedasefficientorganocatalysts.
demonstrated that the spirocyclic lactones 26d could be
Novel urea and thiourea derivatives act as general Brønsted
subjected to aminolysis with pyrrolidine to afford the
acids in various transformations that yield chiral spiroox-
corresponding 3-hydroxyoxindoles while maintaining its ee. It indoles.36 The most common bifunctional catalysts contain a
is noteworthy that unprotected (N−H) isatins are not used in
ureaorathioureaandatertiaryaminegroup,whichalsoserves
the NHC catalysis literature.
as an H-bonding catalyst.
N-Aryl isatinimines (46) also serve as substrates in NHC-
In 2011, Barbas and co-workers utilized a C -symmetric
catalyzed conjugate umpolung reactions (Scheme 15).31 The bisthiourea organocatalyst 7e to promote the D2iels−Alder
reaction of 3-vinylindoles 24b and methyleneoxindoles 14b to
Scheme15.NHC-CatalyzedCycloadditionReactionofEnals
yield optically active and structurally diverse carbazolespiroox-
16d with Isatinimines 46, Vinyligous Isatinimines 14i, or
indole derivatives 17p in almost quantitative yield and with
Isatins 25 high enantiopurity (Scheme 16).37 Mild reaction conditions,
simple starting materials, scalability, and ability to recycle the
catalyst andsolvent makethisstrategyappealing. Althoughthe
mechanismofthisreactionhasnotbeencompletelyelucidated,
itwasshownthatboththeN−Hgroupofvinylindole24band
the protecting group in methyleneoxindole 14b had a
Scheme16.Diels−AlderReactionand[3+2]Cycloaddition
Catalyzed by Bisthiourea Organocatalyst 7e
NHC-catalyzed addition of enals (16d) to isatinimines (46)
proceeds efficiently in one pot to yield spirocyclic γ-lactam
oxindoles(47).Anenantioselectivevariantofthismethodology
using13casthecatalystresultedinmoderateenantioselectivity.
The Chi group carried out an NHC-catalyzed annulation
reaction of 16d and 46b for the rapid construction of
spirooxindole-γ-lactams 47b with excellent diastereo- and
enantioselectivities.32 In 2012, another NHC-catalyzed cascade
reactionbetweenchallengingβ,β-disubstituted,α,β-unsaturated
imines14handenals16dwasdisclosedbyChiandco-workers,
providingdiastereoselectiveaccesstoβ-lactam-fusedspirocyclic
oxindoles36f.33Inthegroup’sattempttorealizeanasymmetric
version of this reaction using NHC catalysts 13d or 13e, only
moderateenantioselectivitieswereobtained.Inaddition,inthe
same year, Scheidt’s group employed an NHC/Lewis acid
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significant effect on stereoselectivity. No evidence of catalyst Scheme 18. Cupreine (4a)-Catalyzed One-Pot Reaction of
interactions with 3-vinylindole 24b alone was found by 1H or Isatin 25, Malononitrile (50), and 1,3-Diketone 51
13C NMR experiments, but strong interactions with the
methyleneoxindole 14b were observed in the 13C NMR
spectra. The H-bonding induced a downfield shift of up to
0.98 ppm. The authors hypothesized that, prior to C−C bond
formation, the bisthiourea 7eactivated methyleneoxindole 14b
through H-bonding interactions and that the vinylindole 24b
was oriented by interactions between the N−H group of the
dieneandtheBocgroupofthedienophileviaπ−πstackingand
weak H-bonding interactions. The effects of the N-protecting oxindoles] (52a) in excellent yields with good to excellent
group of methyleneoxindole 14 on the enantioselectivity are enantioselectivities. In this one-pot procedure, no loss of yield
striking. A bulky electron-acceptor group at the 3-position is or selectivity for the organocatalytic reaction is observed.
necessary; N-Boc-protected 3-methyleneoxindole derivatives An alternative strategy for the construction of chiral
14k, but not the unprotected derivative or the Bn-protected spiropyranooxindoles52wasdevelopedthroughanasymmetric
derivative (14l), provided stereocontrolled product. Michael/cyclization sequence by the Wang group (Scheme
Using the same bisthiourea 7e as a multiple H-bonding 19).41Thegroupemployedarosin-derivedbifunctionalcatalyst
donorcatalyst,anovel[3+2]annulationofmethyleneoxindole
14jwithnitrones48wasdisclosedbytheChenggroup.38Their Scheme 19. Michael/Cyclization Sequence of Isatylidene
protocol provides a convenient approach to enantioenriched Malononitriles 31 with α-Keto Esters 53, 4-
spiro[isoxazolidine-3,3′-oxindole] derivatives (49) in good Hydroxycoumarin (51a) or Naphthol (54)
yields with excellent enantio- and diastereoselectivities. Again,
the N-protecting group plays a significant role in the
stereocontrol. On the basis of NMR and mass spectrometry
experiments, this process is directed by multiple H-bonding
interactions between the bisthiourea catalyst and the two
substrates.
Using urea catalyst 8a, which has Brønsted acidic and Lewis
basic functionalities, sequential double Michael addition
reactions of Nazarov substrates 28b with methyleneoxindoles
14m proceeded smoothly, providing spirocyclohexanoneox-
indole derivatives 17s with excellent enantioselectivities
(Scheme 17).39 The high level of stereocontrol results from
Scheme 17. [4 + 2] Cycloaddition Reaction of Nazarov
Substrates (28b) and Methyleneoxindoles (14m)
7i.Theyextendedthereactiontoisatylidenemalononitriles31
with α-ketoesters 53,4-hydroxycoumarin (51a),andnaphthol
(54) to afford spiropyranoxindoles 52b, 52c, and 52d with
excellent results. It is noteworthy that several of these novel
spirocyclic alkaloids significantly inhibit the proliferation of
cancer cells in a preliminary biological evaluation, showing
promise as chemotherapeutic agents.
α-Isothiocyanato derivatives were recently used as nucleo-
philes for organocatalytic asymmetric aldol and Mannich
reactions, proving to be useful synthons for the synthesis of
chiral spirooxindoles.42 In 2010, Wang’s group reported an
thesimultaneousactivationofeachreactioncomponentbythe aldol/cyclization reaction of isatins (25) with α-isothiocyanato
catalyst. Remarkably, use of urea 8a rather than thioureas for imides (55a; Scheme 20).43 By screening various catalysts, the
the catalyst enhanced stereoselectivity. This protocol has the authors found that bifunctional thiourea catalyst 7f promoted
pot′e-nintidaloltinoe]sy-2n′t,h4e-sdiizoenebiodloegriicvaaltliyveascti(vee.gs.,pir1o7[cuy)cloinhexhaingeh-1,3 the reaction efficiently, leading to optically active spiro-
enantiomeric purity. [thiocarbamate-3,3′-oxindole]s (56a) in excellent yields,
Cupreine (4a) is also an efficient catalyst for organocatalytic diastereoselectivities, and enantioselectivities. The products
reactionsbetweenisatylidenemalononitrilederivatives(formed were readily t5ra6nbs.foItrmiseldikeilnytothabtiothloegeicleacltlyrona-cdteivfiecienchtiNra-lspirooxazolines
from 25 and 50) and 1,3-diones (51), as shown by Yuan’s protectedisatin(25)isactivatedbythetwothioureahydrogen
group(Scheme18). atoms, while the α-isothiocyanato imide (55a) is enolized by
40Thiscatalyticprocessinvolvesadomino thetertiaryamineofthecatalyst.Usingthioureaorganocatalyst
Knoevenagel/Michael/cyclization sequence with 4a serving as 7l derived from a cinchona alkaloid, Zhao and co-workers
the catalyst, leading to optically active spiro[4H-pyran-3,3′-
751 dx.doi.org/10.1021/cs401172r|ACSCatal.2014,4,743−762
ACS Catalysis Review
Scheme20.Aldol/CyclizationReactionofIsatins25withα- featureofthisstrategyisthatthepyrazolemoietycanbeeasily
Isothiocyanato Imides 55a Catalyzed by Bifunctional converted into other functional groups, such as alcohols. In
Thiourea Catalysts 7 contrast,Wangandco-workers employedrosin-derived bifunc-
tional catalyst 7g with oxazolidinone isothiocyanatoimides 55c
to access thiopyrrolidonyl spirooxindoles 57b, which bears
three contiguous stereocenters.46 In this procedure, both
substrates are activated by the bifunctional catalyst (Figure
5). Barbas and co-workers proposed a [3 + 2] cycloaddition
described a similar process that results in the desired products
in high yields with excellent stereocontrol.44
TheBarbas45andWang46groupsindependentlydevelopeda
Figure5.Proposedactivationmodesforthesynthesisofpyrrolidonyl
highly enantioselective synthesis of thiopyrrolidonyl spiroox- spirooxindole derivatives from methyleneoxindoles and α-isothiocya-
indole derivatives 57 from methyleneoxindoles 14 and α- natoimides.
isothiocyanatoimides 55 (Scheme 21). The [3 + 2] cyclo-
process for the reaction in which the methyleneoxindole is
Scheme 21. Michael/Cyclization Reaction of activated bythe tertiary amine, andthe α-isothiocyanato imide
Methyleneoxindoles 14 and α-Isothiocyanatoimides 55 isenolizedbydeprotonationatitsα-carbonatombydoubleH-
bonding.Wang’sgroupproposedthatthemethyleneoxindoleis
activated by double H-bonding and that the α-isothiocyanato
imide is enolized by the tertiary amine of the catalyst.
Isocyanidesareirreplaceablebuildingblocksforthesynthesis
ofanumberofimportantclassesofnitrogenheterocycles. The
unique divalent features of the isocyano group enable
isocyanides to react with both electrophiles and nucleophiles.
Isocyanoacetates(58)possessseveralpotentialreactioncenters
(anisocyanogroup,anacidicC−H,andaprotectedcarboxylic
acid) and show exceptional reaction diversity. The following
examples in Scheme 22 describe elegant work utilizing
isocyanoacetates to construct chiral spirooxindoles via cascade
strategies.
A novel [3 + 2] cycloaddition of isocyanoesters 58 and
methyleneoxindoles 14 in the presence of quinine-based
thiourea tertiary amine catalyst 7m was adopted by Wang et
al. in 2012 to access optically active 3,3′-pyrrolidinyl
spirooxindoles 57d with multiple contiguous stereocenters.48
It is noteworthy that the N-protecting groups of the
Scheme 22. Catalytic Asymmetric Synthesis of
Spirooxindoles from Isocyanoesters (58)
addition reaction of rationally designed dimethylpyrazole
isothiocyanato amides 55b with methyleneoxindoles 14 led to
the formation of 3,3′-thiopyrrolidonyl spirooxindoles 57a.45
Initial studies of this reaction using oxazolidinone DGc as the
directing group gave poor diastereoselectivities. Inspired by a
report by Sibi and Itoh,47 the Barbas group utilized
dimethylpyrazole directing group DGb, expecting that such
substrates would have an extra H-bond acceptor site for the
thiourea catalyst. Experimental results showed that, in the
presence of catalyst 7j, this new methodology provides access
to multisubstituted spirooxindole derivatives 57a in excellent
enantioselectivities (up to 98% ee) and almost complete
diastereoselectivities (>25:1 dr in all cases), regardless of the
stereoelectronic nature of the substituents. One important
752 dx.doi.org/10.1021/cs401172r|ACSCatal.2014,4,743−762