Asymmetric Organocatalytic Cyclization and Cycloaddition Reactions

130 Pages·2011·23.1 MB·English

REVIEW
pubs.acs.org/CR
Asymmetric Organocatalytic Cyclization and Cycloaddition Reactions
Albert Moyano*,† and Ramon Rios*,‡
†DepartamentdeQuímicaOrg(cid:1)anica,FacultatdeQuímica,UniversitatdeBarcelona,C.MartíiFranqu(cid:1)es1-11,08028-Barcelona,
Catalonia,Spain
‡
ICREAResearcheratUB,CatalanInstituteforResearchandAdvancedStudies(ICREA),Pg.LluísCompanys23,08018-Barcelona,
Catalonia,Spain
CONTENTS 4.8. OrganocatalyticAsymmetricPolycyclizations 4741
4.9. SynthesisofHeterocyclesviaAsymmetric
1. Introduction 4704
OrganocatalyticCyclizations 4742
2. OrganocatalyticModesofActivation 4704
4.9.1. Phosphine-CatalyzedCyclizationof
2.1. Introduction 4704
Hydroxyl-2-alkynoates 4744
2.2. CovalentCatalysis 4704
4.9.2. ReductiveCyclizationofN-Acylβ-Amino
2.2.1. EnamineActivationCatalysis 4704
Enones 4744
2.2.2. IminiumActivationCatalysis 4705
4.9.3. IntramolecularAllylicSubstitutionof
2.2.3. DienamineActivationCatalysis 4705
Morita(cid:1)Baylis(cid:1)HillmanAcetates 4745
2.2.4. SOMOActivationCatalysis 4706
4.9.4. OrganocatalyticAsymmetyric
2.2.5. CarbeneActivationCatalysis 4706
Halolactonization 4746
2.2.6. LewisBaseActivationCatalysis 4706
4.9.5. AsymmetricOrganocatalyticIntramole-
2.3. NoncovalentCatalysis 4707
cularTransacetalization 4747
2.3.1. Hydrogen-BondingandBrønstedAcid
4.9.6. OrganocatalyticAsymmetricSynthesisof
ActivationCatalysis 4707
PlanarChiralHeterocycles 4748
2.3.2. BrønstedBaseandBifunctionalActivation
5. OrganocatalyticAsymmetricCycloadditions 4749
Catalysis 4708
5.1. Diels(cid:1)AlderandRelated[4þ2]-Cycloadditions 4749
2.3.3. Phase-TransferCatalysis 4708
5.1.1. Introduction 4749
3. OrganocatalyticDesymmetrizingCyclizationsof
ProchiralSubstrates 4708 5.1.2. OrganocatalyticLewisBase-Catalyzed
Diels(cid:1)AlderReaction 4752
3.1. DesymmetrizingAldolCyclizations:The
Hajos(cid:1)Parrish(cid:1)Eder(cid:1)Sauer(cid:1)Wiechert 5.1.2.1. IminiumActivation 4752
ReactionandRelatedProcesses 4708 5.1.2.1. EnamineActivation 4756
5.1.3. OrganocatalyticAsymmetricDiels(cid:1)Alder
3.2. DesymmetrizingMichaelCyclizations 4714
ReactionsCatalyzedbyBrønstedBases 4759
3.3. DesymmetrizingCyclizationsviaStetterand
BenzoinReactions 4715 5.1.4. AsymmetricDiels(cid:1)AlderReactionsCata-
3.4. DesymmetrizingCyclizationsviaAza(cid:1)Wittig lyzedbyOrganicBifunctionalCatalysts 4761
Reactions 4715 5.1.5. AsymmetricDiels(cid:1)AlderReactionsCata-
4. OrganocatalyticAsymmetricRing-ClosingReactions lyzedbyOrganicBrønstedAcids 4763
ofAcyclicandMonocyclicAchiralSubstrates 4716 5.2.[3+2]-Cycloadditions 4766
4.1. IntramolecularAldolAdditions 4716 5.2.1. Introduction 4766
4.2. IntramolecularMichaelandRelatedAdditions 4719 5.2.2. OrganocatalyticAsymmetricDipolar
4.3. IntramolecularMorita(cid:1)Baylis(cid:1)Hillmanand CycloadditionsofNitrones 4766
Rauhut(cid:1)CurrierReactions 4728 5.2.3. OrganocatalyticAsymmetricDipolar
4.4. CyclizationsviaStetterandBenzoinReactions 4730 CycloadditionsofAzomethyneYlides 4768
4.5. Pictet(cid:1)SpenglerReactionsandRelated 5.2.4. MiscellaneousOrganocatalytic
Cyclizations 4731 AsymmetricDipolarCycloadditions 4771
4.6. OrganocatalyticIntramolecularR-Alkylation 5.3. [3þ3]-Cycloadditions 4772
andR-ArylationofAldehydes 4736
4.7. OrganocatalyticAsymmetricNazarovand Received: October18,2010
OtherElectrocyclicReactions 4738 Published: May26,2011
r2011AmericanChemicalSociety 4703 dx.doi.org/10.1021/cr100348t|Chem.Rev.2011,111,4703–4832
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5.4. [2þ2]-Cycloadditions 4772 Theaimofthisreviewistocoverasymmetricorganocatalytic
6. OrganocatalyticTwo-ComponentCyclization methodsleadingtotheenantioselectivesynthesisofcarbocyclic
Reactions 4773 and heterocyclic compounds, focusing on synthetically useful
protocols. Wherever possible, working mechanistic models are
6.1. SynthesisofCarbocycles 4773
presented. Reactions requiring a stoichiometric amount of an
6.1.1. OrganocatalyticAsymmetricSynthesisof
organicpromoterarenotdiscussedindetail,exceptwhenthey
Cyclopropanes 4774 bear a direct relationship with truly catalytic methods or when
6.1.2. SynthesisofFive-MemberedCarbocycles 4783 thereisnootheralternative(cf.section3.4).Itmustbebornin
6.1.3. SynthesisofSix-MemberedCarbocycles 4786 mind,however,thatinmanyinstances,especiallysoforamino-
catalyzedprocesses,relativelylargeamountsoftheorganocata-
6.2. SynthesisofHeterocycles 4792
lyst(20(cid:1)30mol%orevenmore)arerequired.
6.2.1. OrganocatalyticAsymmetricSynthesisof This review is organized according to the different types of
Azacycles 4792 syntheticproceduresaffordingcyclicframeworks:Afteranover-
6.2.2. OrganocatalyticAsymmetricSynthesisof view of organocatalytic modes of activation (section 2), we
Oxacycles 4800 discussinthefirstplaceorganocatalyticdesymmetrizingcycliza-
6.2.3. OrganocatalyticAsymmetricSynthesisof tionsofprochiralsubstrates,inwhichatleastoneofthenewly
created stereogenic centers arises as a result of the desymme-
Thiacycles 4808
trization (section 3). Organocatalytic asymmetric ring-closing
6.2.4. OrganocatalyticAsymmetricSynthesisof
reactionsofacyclicandmonocyclicachiralsubstrates,inwhich
OtherHeterocycles 4812 the stereogenic centers are the result of the newly created
7. OrganocatalyticAsymmetricMulticomponent carbon(cid:1)carbon or carbon(cid:1)heteroatom bonds, are dealt with
Cyclizations 4814 insection4.Asymmetricorganocatalyticreactionscorrespond-
8. Conclusions 4822 ing (at least formally) to classical cycloaddition processes are
discussed insection5, irrespectivelyofthe concerted ormulti-
AuthorInformation 4822
step nature of their mechanism. Finally, two-component and
Biographies 4822
multicomponentcyclizationreactions(includingorganocatalytic
Acknowledgment 4823 cascadeprocesses),takingplacethroughwell-definedintermedi-
Abbreviations 4823 ates,areconsideredinsections6and7,respectively.
References 4823 Severalreviewsdealingwithspecificaspects(processes,reac-
tionconditions,catalystandreagenttypes,andmechanisms)of
organocatalysishavebeenpublishedinthepastfewyears,11but
1.INTRODUCTION
with very scarce exceptions,5,12 none of them is devoted to
Thestereocontrolledconstructionofchiralcarbo-andhetero- asymmetricorganocatalyticcycloadditionsandcyclizations.The
cycles is a topic of paramount importance in modern organic coverageofthepresentreviewextendsgenerallyuntilJuly2010,
synthesis, driven by the predominance of chiral mono- and poly- althoughselectedmorerecentreferenceshavebeenincluded.
cyclic systems in natural products and in chiral pharmaceuticals.1
The historical development of enantioselective versions of the
Diels(cid:1)Alder reaction can serve as a paradigm for the evolution 2.ORGANOCATALYTICMODESOFACTIVATION
experiencedbyotherwell-establishedcycloadditionandcyclization
2.1.Introduction
methods:thefirstpracticalenantioselectiveversionswereachieved
Asymmetricorganocatalysisstandsoutbothforthevarietyof
in the decade of the 1980s by using chiral auxiliaries covalently
itsmodesofactivationandforthestructuralsimplicityofmost
bondedtothediene2or,morecommonly,tothedienophile;3the
organocatalysts,afeaturethathasoftenallowedthegenerationof
decade of the 1990s witnessed the development of asymmetric
mechanisticworkingmodelsthatcanrationalizeorevenpredict
metal-catalyzed Diels(cid:1)Alder reactions;4 and in the past 10 years, thestereochemicaloutcomeoforganocatalyzedreactions.11v
asymmetric organocatalyzed Diels(cid:1)Alder cycloadditions have at-
From a mechanistic point of view, organocatalytic modes of
tainedexcellentdegreesofefficiencyandstereoselectivity.5 activation can be classified according to the covalent or non-
The use of small chiral organic molecules as enantioselective covalent character of the substrate(cid:1)catalyst interaction and to
catalysts,withtheassociatedadvantagesoftheireasyavailabilityand the chemical nature (Lewis base, Lewis acid, Brønsted base,
ofcarryingoutasymmetrictransformationsinametalfree-environ- Brønstedacid)ofthecatalyst.7bItisimportanttobearinmind,
ment and under mild and simple reaction conditions, has lately however,thatmanyorganocatalysts(cf.aminoacids,phosphoric
experienced an impressive growth;6,7 therefore, asymmetric orga- acids) act through both covalent and noncovalent interactions
nocatalysisisnowconsideredthe“thirdpillar”ofenantioselective and/ordisplayadualacid/basecharacter(“bifunctionalcatalysts”).
catalysis,togetherwithbiocatalysisandmetalcatalysis,andisbeing All of the known organocatalytic modes of activation are
increasinglyusedinthekeystepsinthetotalsynthesisofcomplex operative in the reactions covered in this review. We will
naturalproducts.8,9Amongthegreatvarietyoforganictransforma- presently discuss the basic features of each activation mode
tionsthatareamenableto asymmetric organocatalysis,cycloaddi- and present the structures of the most representative catalysts,
tionandcyclizationreactionsoccupyapreeminentposition,andin whose numbering (in Roman numerals) follows their order of
fact, two of the widely recognized milestones in its historical appearanceinthemainbodyofthereview(sections3(cid:1)8).
development, the Hajos(cid:1)Parrish(cid:1)Eder(cid:1)Wiechert(cid:1)Sauer reac-
tion (1971, discussed in section 3.1) and the chiral imidazolidi- 2.2.CovalentCatalysis
none-catalyzed Diels(cid:1)Alder cycloaddition (2000, dealt with in 2.2.1. Enamine Activation Catalysis. After the initial
section5.1),belongtothiscathegory.10 reportsonproline-catalyzedintermolecularaldol13andMannich14
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Scheme 1. GeneralMechanismfortheAmine-Catalyzed electrophile with purely steric effects, leading to the opposite
r-FunctionalizationofCarbonyls facialstereoselectivity(Figure1B).Seebachetal.haveproposed
analternativemechanismforthefirstcase,inwhichtheelectro-
philicattackisdirectedbyanchimericassistanceofthedeproto-
natedaminesubstituentX(Figure1C).16Althoughthemech-
anisticdebateopenedbythisproposalisstilllively,itisworth
noting that some features of the catalytic cycle proposed by
Seebach et al. for the proline-catalyzed aldol reaction, espe-
ciallyinaproticsolvents,haverecentlyreceivedstrongexperi-
mentalsupport.17
Intramolecularaldolreactionsdiscussedinsections3.1and4.1
arerepresentativeexamplesofthismodeofactivation,andtheir
stereochemical outcome can be generally rationalized by an
intramolecularversionoftheHouk(cid:1)Listmodel.18
Representative chiral amines with hydrogen-bond-directing
groupsusedinenaminecatalysisandappearinginthisrevieware
depicted in Figure 2, and examples of chiral secondary amines
withnonacidicsubstituentscanbefoundinFigure3.Itmustbe
born in mind, however, that compounds shown in Figure 3
havingbothaprimaryorsecondaryamineandatertiaryamine
(cf. VII, IX, X, XI...), when used in conjunction with an acid
cocatalyst,canactfromthemechanisticpointofviewlikethose
with hydrogen-bond-directing groups by means of the tertiary
ammonium cation; on the other hand, achiral amines like
CXXXVI can act as chiral catalysts when used in conjunction
withachiralacidsuchasVIII(asymmetriccounterion-directed
catalysis,discussedinsection6.2.2).
2.2.2. Iminium Activation Catalysis. Iminium activation
catalysis is another key catalytic concept in organocatalysis.8,19
Initialworkwascenteredoncycloadditions,20butitwasrapidly
extended to Michael additions21 and is now established as a
general strategy for the asymmetric conjugate addition of nu-
cleophilestoR,β-unsaturatedcarbonylcompounds.Thecataly-
ticcycleforachiralpyrrolidine-catalyzedβ-functionalizationof
Figure 1. Stereochemical models for enamine reactivity: (A) an R,β-unsaturated carbonyl compound is shown in Scheme 2
List(cid:1)Houkmodel,(B)stericmodel,and(C)Seebachmodel. andbeginswiththeacid-promotedcondensationofthecarbonyl
withtheaminetoformanunsaturatediminiumion.Thisreactive
reactions,enamineactivationcatalysishasbecomeoneofthemost intermediatesuffersthentheadditionofthenucleophileatthe
intensively used organocatalytic modes of activation,15 allowing β-position, leading to a β-functionalized enamine that upon
the enantioselective R-functionalization of enolizable aldehydes protonation gives a saturated iminium ion. Hydrolysis of this
andketoneswithahugevarietyofelectrophiles. intermediatereleasesboththeproductandthecatalyst.
The catalytic cycle for a chiral pyrrolidine-catalyzed R-func- Althoughchiralamineswithhydrogen-bond-directinggroups
tionalization of a carbonyl compound is depicted in Scheme 1 likethoseshowninFigure2canbeusediniminiumactivation
and involves the initial acid-promoted condensation of the catalysis,usuallybestresultsareobtainedwithaminessubstituted
carbonyl with the amine to form an iminium ion. One of the with bulky nonacidic groups. In this case, the stereochemical
R-acidicprotonsoftheiminiumionisthenremovedbythebasic outcomeoftheadditiontoenalscanbeusuallypredictedbythe
counterion and the key nucleophilic enamine intermediate is transitionstatedepictedinFigure4,whichimpliestheattackof
formed. Reaction with the electrophile E (generally in its theelectrophilebythefaceoppositetothebulkyaminesubstituent
protonated form EHþ; the protonation can take place before inthe energetically favored s-transconformer of the (E)-config-
orafterthisstep)regeneratesaniminiumion,whosehydrolysis ured unsaturated iminium ion.22 An alternative mechanistic ex-
liberatestheproduct,theacid,andtheaminecatalyst,whichcan planation, based on stereoelectronic effects, has been recently
re-enter the catalytic cycle. The acid cocatalyst can be a protic proposedbySeebachandco-workers.23
solvent (water, alcohols), an added external acid, or an acidic Representativeexamplesofiminiumactivationcatalysisarefound
moietyofthechiralaminecatalyst. forinstanceinasymmetricorganocatalyticDiels(cid:1)Aldercycloaddi-
Theenantioselectivestep,thereactionoftheenaminewiththe tions(discussed in section 5.1),inintramolecular Michael addi-
electrophile, can take place via two different pathways. If the tionstounsaturatedcarbonylcompounds(section4.2),andinthe
chiral amine substituent contains a hydrogen-bond-directing epoxidationofenals(section6.2).Themostcommonchiralamines
group (a carboxylic acid, an amide or thioamide, a protonated usediniminiumactivationcatalysisarethoseshowninFigure3and
amine),theattackoftheelectrophiletakesplaceinanintramo- MacMillan’simidazolidinones(SeeFigure5forexamples).
lecular fashion,viaacyclictransitionstate (List(cid:1)Houk model; 2.2.3.DienamineActivationCatalysis.Initiallydiscovered
Figure1A);ontheotherhand,iftheaminesubstituentisbulky in 2006,24 dienamine activation catalysis is finding increasing
and devoid of acidic protons, it directs the attack of the applications in asymmetric organocatalysis. Examples of its use
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Figure2. Chiralamineswithhydrogen-bond-directinggroupsusedinasymmetricenamineandiminiumactivationcatalysis.
within the scope of this review are found in intramolecular process.Avariantofthiscyclerelyingonthecombinationofan
Rauhut(cid:1)Currierreactions(section4.3)andin[4þ2]-cycload- imidazolidinone with a photoredox catalyst in which a photo-
ditions(section5.1).Themechanisticcycleisverysimilartothat chemically generated radical reagent couples with the classical
depictedinScheme2,butthepresenceofacidicγ-hydrogensin enamine intermediate has been also reported by MacMillan.26
theinitiallyformediminiumintermediateleadstotheformation Examples of organo-SOMO activation catalysis of asymmetric
of an electron-rich dienamine intermediate whose s-cis confor- cyclizationsarediscussedinsections4.6and4.8.
mer undergoes a highly stereoselective [4þ2]-cycloaddition. 2.2.5.CarbeneActivationCatalysis.ChiralN-heterocyclic
Release of the catalyst is then achieved by hydrolysis (giving carbenes(NHC’s)areaparticularclassofLewisbasic(nucleo-
γ-functionalized carbonyls) or by E1cb-elimination, affording philic)catalyststhatareplayinganimportantroleinthediscovery
cyclic compounds (Scheme 3). Prolinol derivatives such as of new asymmetric organocatalytic processes.27 The two funda-
XLVIII(Figure3)aretypicalcatalystsforthesetransformations. mentalreactiontypescatalyzedbythesecompoundsaretheipso-
2.2.4.SOMOActivationCatalysis.Organo-SOMOactiva- functionalization of saturated carbonyls and the enantioselective
tion catalysis is an alternative pathway for the asymmetric R-functionalizationofunsaturatedcarbonyls(Scheme5).
organocatalyticR-functionalizationofcarbonylsthatwasuncov- ExamplesoftheuseofchiralNHC’sinthisreviewarefoundin
ered by MacMillan and co-workers in 2007.25 The mecha- sections3.1,3.3,4.4,and5.1.Thesecatalystsareusuallygenerated
nistic cycle is outlined in Scheme 4. Condensation between insitubytreatmentofchiraltriazolium(seeFigure6)orimidazo-
the secondaryaminecatalyst(uptonowonly chiral imidazoli- liumsaltsbyasuitablebase.
dinones have been employed successfully in this process; see 2.2.6. Lewis Base Activation Catalysis. Lewis base or
Figure5)leadsfirsttoaniminiumionandthentotheenamine. nucleophiliccatalysisbychiralaminesandphosphineshasbeen
Inthepresenceofamildoxidant(usuallyatransitionmetalion), intensivelyexploitedinasymmetricorganocatalysis.28Amongits
theenamineisconvertedintoacationradical,whichthenreacts numerous applications, several reactions leading to cyclic pro-
with a radicophile to form a new cation radical intermediate. ductsarecoveredinthisreview(cf.,sections3.4,4.1,and4.3).
Oxidation of this intermediate followed by hydrolysis liberates RepresentativecatalystsareshowninFigure7.Notethatsomeof
theR-functionalizedcarbonylandthecatalyst.Twoequivalents thesecompounds(cf.XLVIandXLVII,usedinintramolecular
ofaone-electronoxidantand2equivofbaseareconsumedinthe Morita(cid:1)Baylis(cid:1)Hillman cyclizations) are in fact bifunctional
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Figure3. Chiralamineswithnonacidicsubstituentsusedinenamineandiminiumcatalysis.
(Lewis base/hydrogen-bond donor) catalysts and that those catalystsofthistype(seeFigure8forchiralhydrogen-bonding
havingtertiaryaminogroups(cf.LXXI,LXXII,XC,CXXXII...) catalystsappearinginthisreview).30
canalsoactasBrønstedbasecatalysts. On the other hand, the field of Brønsted acid activation
organocatalysis31isclearlydominatedbychiralBINOL-derived
2.3.NoncovalentCatalysis phosphoric acids, which after the seminal reports of Akiyama
2.3.1. Hydrogen-Bonding and Brønsted Acid Activa- et al.32 and of Uraguchi and Terada33 have become one of the
tion Catalysis. Chiral organic compounds with acidic hydro- mostpowerfultypesoforganiccatalysts.34Figure9showsseveral
gens that interact with substrates contaning basic functional BINOL-derived phosphoric acids and amides that efficiently
groupsareabletocatalyzeagreatvarietyofprocessesandhave catalyze cyclization or cycloaddition reactions covered in this
becomeextremelyusefultoolsinasymmetricorganocatalysis.29 review(cf.sections3.1,3.2,4.2,4.5,and5.1).Therelationship
Depending on the degree of proton transfer in the transition betweenhydrogen-bondingandBrønstedacidcatalysishaslately
state,onemaydistinguishbetweenhydrogen-bondingactivation beenemphasizedbyJacobsenthroughtheprincipleofhydrogen-
catalysis(whenthehydrogenisstillboundtothecatalyst)and bond-donorcatalysisbyanion-binding.35Figure10summarizes
Brønstedacidactivationcatalysis(completeprotontransferfrom themaintypesofcatalysisbyorganicmoleculescontainingacidic
thecatalysttothesubstrate),butobviouslyseveralintermediate hydrogens. In Brønsted acid activation catalysis (Figure 10a,b)
situations are possible. Chiral thioureas, chiral amidinium ions, the catalyst (exemplified by a chiral phosphoric acid) transfers
chiral squaramides, and chiral diols are the most widely used a proton to a basic center in the substrate, making it more
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Scheme 2. GeneralMechanismfortheAmine-Catalyzed basicmoiety(Figure11),foreshadowedbytheseminalpaperof
β-Functionalizationofr,β-UnsaturatedCarbonyls RiantandKagan38onquinidine-catalyzedDiels(cid:1)Alderreactions
(see section 5.1) and first developed by Takemoto and co-
workers,39hasevolvedintoageneralandreliablestrategy.11p,29a,30e
Although initially applied to intermolecular Michael reactions,40
bifunctionalactivationorganocatalysishasbeenshowntobeuseful
in intramolecular Michael additions (section 4.2), in Nazarov
cyclizations(section4.7),inhalolactonizationreactions(section
4.9), as well as in a variety of cycloaddition (section 5) and
multicomponentcyclizations(sections6and7).
Somebifunctionalhydrogen-bond-donor/Brønstedbasecat-
alysts appearing in this review (including Takemoto’s thiourea
XLI)39areshowninFigure12.
2.3.3.Phase-TransferCatalysis.Sincethesuccessfulappli-
cation of Cinchona-alkaloid-based quaternary amonium salts as
chiral phase-transfer catalysts in 1984,41 the use of chiral qua-
ternaryammoniumsaltsinasymmetriccatalysishasexperienced
anotablegrowth.11p,42Inparticular,theasymmetricalkylationof
glycine-derivedSchiffbasesbymeansofphase-transferorgano-
catalysis,pioneeredbyO’Donnelletal.43andfurtherimproved
by Lygo and co-workers44 and Maruoka and co-workers,45
amongothers,hasbecomeoneofthemostreliableprocedures
fortheenantioselectivepreparationofR-aminoacids.46
Thegenerallyaccepted(butsimplified)mechanismforasym-
metric phase-transfer catalysis, depicted in Figure 13, assumes
that the quaternary ammonium cation forms a tight ionic
complexwiththenucleophileanion,generatedbydeprotonation
oftheneutralpronucleophileattheinterphaseoftheorganicand
aqueous phases by an alkaline hydroxide. This ionic complex
reacts with the electrophile, liberating the product and the
quaternaryammoniumsalt,whichreturnstotheinterphasefor
catalyst recycling. The asymmetric induction originates on the
chiralenvironmentofthecomplexednucleophileanionprovided
bythechiraltetrahedralammoniumcation.47
Asymmetricphase-transfercatalysishasbeenemployed,with-
in the scope of this review, for 6π electrocyclizations (section
4.7), for the synthesis of planar chiral heterocycles (section
4.9.6),andforthesynthesisofsomecyclicR-alkyl-R-aminoacid
derivatives and of epoxides (section 6.2). Structures of the
Figure 4. Stereochemical outcome of the amine-catalyzed Michael correspondingcatalystscanbefoundinFigure14.
additiontoenals.
3.ORGANOCATALYTICDESYMMETRIZINGCYCLIZA-
electrophilic.Inhydrogen-bondingactivationcatalysis(Figure10c),
TIONSOFPROCHIRALSUBSTRATES
thecatalyst(exemplifiedbyachiralthiourea)alsoenhancesthe
electrophilicity of the substrate, in this case by hydrogen- 3.1. Desymmetrizing Aldol Cyclizations: The Hajos(cid:1)
bonding to an heteroatom. Finally, in hydrogen-bond-donor Parrish(cid:1)Eder(cid:1)Sauer(cid:1)Wiechert Reaction and Related
activation catalysis by anion-binding, the chiral catalyst en- Processes
hancestheacidityofanachiralBrønstedacid(Figure10d)or AsmentionedintheIntroduction,thesimultaneousdiscovery
makesthesubstratemorepronetoanucleophilicsubstitution in 1971 by Hajos and Parrish at Hoffmann-La Roche48 and by
process(Figure10e). Eder,Sauer,andWiechertatSchering49oftheproline-catalyzed
2.3.2. Brønsted Base and Bifunctional Activation Cat- intramolecular aldol reaction of 2,2-disubstituted cyclic 1,3-
alysis.Withafewexceptions,mosttheminvolvingtheCinchona diketones,whichaffordedsyntheticallyusefulbicyclicdiketones
alkaloidcompoundsshowninFigure7andrelatedcompounds,36 ingoodyieldandenantioselectivities,canberegardedasthefirst
catalystsactingsolelyasBrønstedbasesarenothighlyenantiose- practicalasymmetricorganocatalyticcyclization.50
lective, probably due to the rather loose nature of nonbonded Hajos and Parrish48 found that, using N,N-dimethylforma-
interactions between extended organic anions and quaternary mide(DMF)asthesolventinthepresenceof3mol%of(S)-
ammoniumsalts. proline (I), the intramolecular enol/endo-aldolization of
On the other hand, the concept of bifunctional asymmetric 2-methyl-2-(3-oxobutyl)-1,3-cyclopentanedione (1) afforded
catalysis, involving the synergistic activation of both acidic and the bicyclic diketone 2 in 99% yield and with 93% ee. Acid-
basicsitesinthesubstrate,37hasreceivedconsiderableattention. promoted dehydration of 2 provided the unsaturated diketone
Asymmetric activation organocatalysis by bifunctional species (S)-3(theHajos(cid:1)Parrishdiketone),averyusefulbuilding-block
containing a hydrogen-bond donor in addition to a Brønsted insteroidsynthesis.AsshownbyEderetal.,493canbeobtained
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Figure5. MacMillan’simidazolidinoniumsaltcatalysts.
Scheme 3. GeneralizedMechanismfortheAmine-Catalized directly from 1, albeit with somewhat lower yield and enantio-
γ-Functionalizationofr,β-UnsaturatedAldehydes mericpurity,byusingperchloricacidasacocatalystinrefluxing
acetonitrile(Scheme6).51
The proline-catalyzed reactions of substrates related to 1
generally take place with useful yields and enantioselectivities
(Figure15).48,49,52(cid:1)54
Itisworthnotingherethattheuseofprimaryaminoacidsas
catalysts can be sometimes advantageous, especially so for
sterically hindered substrates. Thus, in the case of compound
7,boththeyield(upto82%)andtheenantioselectivity(upto
86%ee)couldbeimprovedbyusing(S)-phenylalanine(II)
insteadof(S)-proline(I).53
The(S)-proline-catalyzedcyclizationof2-methyl-2-(3-oxobutyl)-
1,3-cyclohexanedione (9), under the conditions reported by
Hajos and Parrish,48 takes place both with moderate yield
(52%) and enantioselectivity (74% ee), and after dehydration
oftheintermediateketol10,arecrystallizationstepisnecessary
to obtain highly enantiopure Wieland(cid:1)Miescher ketone (S)-
11.55 The direct cyclization(cid:1)dehydration conditions of Eder
et al.49 do not give much better results (Scheme 7). While the
synthesisof9isconvenientlyeffectedbyheating2-methylcyclo-
hexane-1,3-dione(12)withmethylvinylketone(13)inaqueous
aceticacidat75(cid:1)Cfor1h,51bin2000BuiandBarbasfoundthatthe
entireRobinsonannulationsequencecanbeperformedbyreaction
of12and13(slowaddition,1.5molequiv)inDMSOat35(cid:1)Cin
thepresenceof(S)-proline(I)(35mol%).Afterpurification,(S)-
11wasobtainedin49%yieldand76%ee(Scheme8).56
Given theimportance ofopticallyactiveWieland(cid:1)Miescher
ketone(andoftheHajos(cid:1)Parrishketone3)innaturalproduct
synthesis,53(cid:1)57 it is not surprising that much effort has been
devotedtoimproving theorganocatalytic aldol cyclization of9
andofrelatedcompounds.Aswehavealreadyseen,inthecaseof
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Scheme 4. RepresentativeMechanisticCycleforAsymmetricOrgano-SOMOActivationCatalysis
Scheme 5. BasicProcessesinCarbeneActivationCatalysis hinderedketones,theuseofprimaryaminoacidscanleadtogood
enantioselectivities.Thus,Agami58hasdescribedthatthecycliza-
tionoftheethylketone14takesplacewith95%eeundercatalysis
by(S)-phenylalanine(II)(Scheme9).Theuseof(S)-proline(I)
inDMSOgavethesamecompound15inonly32%ee.
Inasimilarway,DaviesandSmith59havefoundthattheprimary
β-aminoacid(1R,2S)-cispentacin(III)(30mol%,DMF,rt,108h)
catalyzesthecyclizationof9,affording(afterdehydrationof10with
pTsOHinrefluxingtoluene)theWieland(cid:1)Miescherketone(R)-11
in75%overalyieldandwith86%ee.Averysimilarenantiomeric
purity(87%ee)for(S)-11canbeachievedbyusing(S)-prolinamide
(IV)asthecatalyst,60whileslightlybetterresults[88%yieldand92%
ee for (S)-11] have been described by Reiser61 by catalysis with
proline-containing tripeptides. On the other hand, N(cid:3)ajera and co-
workershavereportedontheuseofthe(R)-1-aminoindane-derived
prolinethioamide(V)62andoftheN-tosyl-(S)-binam-(S)-prolina-
a
mide(VI)63asefficientcatalystsforthecyclizationof9(Figure16).
Recently, Bradshaw et al. have reported that the use of VI
resultsinahighlyefficient(93%overallyield)andenantioselec-
tive(94%ee)synthesisofthe(S)-Wieland(cid:1)Miescherketone11
(10 g scale) through a single-step, solvent-free aldol cycliza-
tion(cid:1)dehydrationof9.64Theprocessinvolvesonly2mol%of
thecatalystVIandbenzoicacid(0.5mol%)andcanbeapplied
tothepreparationofawiderangeofanaloguesof11(Figure17).
The allyl derivative 16 (obtained in a 20 g scale in 94%
eeunderslightlydifferentreactionconditionsfromthoseofref
64, 1 mol % of VI and 2.5 mol % of benzoic acid) has been
employed by Bradshaw et al. as the starting material in a very
eleganttotalsynthesisofthestructurallychallengingditerpenoid
((cid:1))-anominine.57g
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Figure6. ChiraltriazoliumsaltsusedasprecursorsofNHC’s.
TheperformanceoftheHajos(cid:1)Parrish(cid:1)Eder(cid:1)Sauer(cid:1)Wiechert cyclizationofboth1and9.Inthisway,boththeHajos(cid:1)Parrish
reactionwithimmobilizedcatalystswasexaminedseveralyearsago diketone(S)-3andtheWieland(cid:1)Miescherketone(S)-11were
by Takemoto et al.65 by means of a polystyrene-grafted proline obtainedinyieldsandenantiomericpuritiescomparabletothose
catalyst.Surprisinglyenough,inspiteofthefastdevelopmentof obtainedwithproline(Scheme13).70
the field of supported asymmetric organocatalysts,66 no further In 2009, Akiyama and co-workers disclosed the first useful
attentionhasbeenpaidtothistopic. asymmetric synthesis of chiral cyclohexenones through the
Agami and co-workers have studied the application of the desymmetrization of prochiral 2,2-disubstituted-1,3-dicarbonyl
proline-catalyzedcyclizationofprochiraltriketonestothekinetic compounds induced by a chiral phosphoric acid.71 Under the
resolution of chiral racemic diketones.67 Interestingly enough, optimalreaction conditions,treatmentoftheprochiralindane-
they found that the enantiodifferentiation depends on the pre- diones 37a(cid:1)e with 5 mol % of the (R)-BINOL-derived phos-
senceortheabsenceofanangularmethylgroup.Thus,cyclization phoricacidVIIIinrefluxinghexanegaveaccesstothecyclized
of the methyl-substituted cyclohexanone rac-26 afforded the compounds 38a(cid:1)e in excellent yield and enantioselectivity
bicyclicketone(S)-27in43%ee,leavingopticallyactiveketone (Scheme 14). It is worth noting that for these substrates the
(R)-26 (ee not determined) unreacted; on the other hand, use of proline gave much inferior results (cf. 57% yield and
cyclization of the unsubstituted compound rac-28 gave the 60% ee for 38a). Under these conditions, the cyclization of 1
cyclization product (R)-29 in 46% ee, together with unreacted afforded(R)-3in86%yieldand70%eeandthatof9produced
ketone(S)-28(eenotdetermined;Scheme10). (R)-11 in 64% yield and 82% ee. The stereochemical sense of
The domino Michael(cid:1)aldol reaction of symmetrical 1,3- inductionprovidedbyVIIIisthereforeoppositetothatof(S)-
diaryl-1,3-propanediones 30 with methyl vinyl ketone (13) in proline.
the presence of (S)-proline (I) was examined by Gryko in Theoriginoftheenantioselectivitycouldbeclarifiedbymeans
2005.68Whenthereactionwasrunin1-methyl-2-pyrrolidinone ofONIOMhybridDFT-HFcalculations.Inthetransitionstate,
(NMP), high yields (up to 93%) and moderate to good thechiralphosphoricacidsimultaneouslyactivatesthecarbonyl
enantioselectivities(43(cid:1)80%ee)ofthecyclohexanones32were andenolmoieties,withpreferrednucleophilicattacktothepro-(S)
obtained, together with variable amounts of the intermediate carbonyl of the indanone (1.3 kcal mol(cid:1)1 energy difference for
triketones 31. It is noteworthy that this procedure can also be 37a,inagreementwiththeexperimentalresults).71
appliedtounsymmetricaldiketones.Thus,diketone33gavethe Thedesymmetrizationof2-substituted-2-(3-formylpropyl)-1,3-
cyclohexanonederivative34(resultingfromtheintramolecular cyclohexanediones39a(cid:1)cbymeansofanorganocatalyticexoaldol
enolateadditiontothemoreelectron-defficientcarbonylgroup) cyclization was reported in 2007 by Hayashi et al.72 After testing
asthesoleproductin93%yieldand50%ee(Scheme11). several chiral secondary amines, the trifluoroacetic salt of 2-
Proline has also been found to promote, although rather (pirrolidinylmethyl)pyrrolidine (IX) was found to be the catalyst
inefficiently, the asymmetric Robinson annulation of 2-formylcy- of choice, affording the bicyclo[4.3.0]nonane derivatives 40a(cid:1)c
clohexanone35with13(Scheme12).69Morerecentexamplesof with a high enantioselectivity (Scheme 15). The absolute config-
dominoMichael(cid:1)aldolcyclizationswillbediscussedinsection6.1. uration of 40a, ascertained by chemical correlation with the
Catalysts other than amino acids can also be used for the Wieland(cid:1)Miescher ketone (S)-11, could be accounted for by a
Hajos(cid:1)Parrish(cid:1)Eder(cid:1)Sauer(cid:1)Wiechert process. Kanger et al. modeltransitionstateinwhichaprotoncoordinatedtothenitrogen
havereportedontheuseofthetrifluoromethanesulfonatesaltof ofthepyrrolidineringinthekeyenamineintermediatederivedfrom
a chiral bimorpholine (VII) (5 mol %) for the asymmetric 39apreferentiallyactivatesthepro-(R)carbonylgroup.72
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Figure7. RepresentativeLewisbaseorganocatalysts.
Thedesymmetrizingaldolcyclodehydrationof4-substituted- particularly powerfulinthis desymmetrization,andavarietyof
2,6-heptanediones (41) to the chiral 5-substituted 3-methyl-2- chiral cyclohexenones 42a(cid:1)l were obtained in excellent yields
cyclohexenones(42)wasinitiallystudiedbyAgamiandSevestre.73 andenantioselectivities(Scheme17).
Intheirpioneeringinvestigation,theseauthorsfoundthat(S)- As expected, the quinidine-derived catalyst XI gave the
proline(I)wasabletocatalyzethisprocess.Thus,treatmentof opposite enantiomers, also with high enantioselectivity. This is
aDMFsolutionof4-methylheptane-2,6-dione(41a)with(S)- illustratedinScheme18,whichshowshowthe(R)-enantiomer
prolineaffordedthe(R)-enone42a(arisingfromnucleophilic of42c(theso-calledceleryketone)canbeobtainedin91%ee.
attackontothepro-(S)carbonylgroupof41a)in75%yieldand However,theauthorsdidnotprovideamechanisticmodelthat
43%ee(Scheme16).Catalysisofthesamereactionwith(S)- couldaccountforthestereochemicaloutcomeofthisreaction.
phenylalanine(II)gaveamuchlowerenantiomericpurity(7% A related transformation, based on the intramolecular aldol
ee).73a The stereochemical outcome of the reaction fits with cyclodehydration of the macrocyclic diketone 43, had been
the Houk mechanism for the Hajos(cid:1)Parrish(cid:1)Eder(cid:1)Sauer(cid:1) previously disclosed by Knopff et al.77 The use of 8 mol equiv
Wiechertreaction.74 of the sodium alkoxide derived from (þ)-N-methylephedrine
Catalyticantibody38C2,developedin1999byLerneretal., (XII)wasnecessarytoachievea76%eeofthebicycicenone(S)-
gaveasomewhathigherbutstillmoderateenantiomericexcess.75 44, by a process that apparently involves the dinamic kinetic
Asubstantialimprovementcouldbeachievedonlyin2008bythe resolutionoftheracemicaldolintermediate.Thefinalenonewas
researchgroupofList.76Theacetate saltof9-amino-9-deoxye- subsequentlytransformedintothemuskodorants(R)-muscone
piquinine (X), in which the protonated quinuclidine nitrogen (45)and(R,Z)-5-muscenone(46)withoutlossofenantiomeric
probablyactsasahydrogen-bond-directinggroup,provedtobe purity(Scheme19).
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