ProPhenol-Catalyzed Asymmetric Additions by Spontaneously Assembled Dinuclear Main Group ...

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ProPhenol-Catalyzed Asymmetric Additions by Spontaneously
Assembled Dinuclear Main Group Metal Complexes
“ ”
Published as part of the Accounts of Chemical Research special issue Synthesis, Design, and Molecular Function .
Barry M. Trost* and Mark J. Bartlett†
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
*
S Supporting Information
CONSPECTUS:Thedevelopmentofcatalyticenantioselectivetransformationshasbeenthefocusofmanyresearchgroupsover
thepasthalfcenturyandisofparamountimportancetothepharmaceuticalandagrochemicalindustries.Sincetheawardofthe
Nobel Prize in 2001, the field of enantioselective transition metal catalysis has soared to new heights, with the development of
more efficient catalysts and new catalytic transformations at increasing frequency. Furthermore, catalytic reactions that allow
higherlevelsofredox-andstep-economyarebeingdeveloped.Thus, alternativestoasymmetricalkene dihydroxylationandthe
enantioselective reduction of α,β-unsaturated ketones can invoke more strategic C−C bond forming reactions, such as
asymmetric aldol reactions of an aldehyde with α-hydroxyketone donors or enantioselective alkynylation of an aldehyde,
respectively. To facilitate catalytic enantioselective addition reactions, including the aforementioned aldol and alkynylation
reactions, our lab has developed the ProPhenol ligand.
InthisAccount,wedescribethedevelopmentandapplicationoftheProPhenolligandforasymmetricadditionsofbothcarbon-
and heteroatom-based nucleophiles to various electrophiles. The ProPhenol ligand spontaneously forms chiral dinuclear metal
complexeswhentreatedwithanalkylmetalreagent,suchasEt ZnorBu Mg.TheresultingcomplexcontainsbothaLewisacidic
2 2
sitetoactivateanelectrophileandaBrønstedbasicsitetodeprotonateapronucleophile.Initially,ourresearchfocusedontheuse
ofZn-ProPhenolcomplexestofacilitatethedirectaldolreaction.Finetuningofthereactionthroughligandmodificationandthe
use of additives enabled the direct aldol reaction to proceed in high yields and stereoselectivities with a broad range of donor
substrates, including acetophenones, methyl ynones, methyl vinylketone, acetone, α-hydroxy carbonyl compounds, andglycine
Schiffbases.Additionally,ananalogousmagnesiumProPhenolcomplexwasusedtofacilitateenantioselectivediazoacetatealdol
reactions with aryl, α,β-unsaturated, and aliphatic aldehydes.
TheutilityofbimetallicProPhenolcatalystswasextendedtoasymmetricadditionswithawiderangeofsubstratecombinations.
Effectivepronucleophilesincludeoxazolones,2-furanone,nitroalkanes,pyrroles,3-hydroxyoxindoles,alkynes,meso-1,3-diols,and
dialkylphosphineoxides.Thesesubstrateswerefoundtobeeffectivewithanumberofelectrophiles,includingaldehydes,imines,
nitroalkenes, acyl silanes, vinyl benzoates, and α,β-unsaturated carbonyls. A truly diverse range of enantioenriched compounds
have been prepared using the ProPhenol ligand, and the commercial availability of both ligand enantiomers makes it ideally
suited for the synthesis of complex molecules. To date, enantioselective ProPhenol-catalyzed reactions have been used in the
synthesis of more than 20 natural products.
■
INTRODUCTION The ProPhenol ligand (1a) is a salient member of the aza-
The efficient and selective synthesis of chiral compounds crown family of ligands,2 whose origin was inspired by the
pioneeringworkofCramonchiralcrowncompounds.3Proline-
for which asymmetric catalysis has played a pivotal role is
derived 1a forms dinuclear main group metal catalysts via the
essential to the pharmaceutical and agrochemical industries.1
Studiesonhowthesechiralcatalystsinduceenantioselectivity
Received: October 9, 2014
have inspired the evolution of new chiral catalysts and the
Published: February4, 2015
development of subsequent generations of enantioselective
reactions.
©2015AmericanChemicalSociety 688 dx.doi.org/10.1021/ar500374r|Acc.Chem.Res.2015,48,688−701
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Scheme1.FormationofBimetallicZn-ProPhenolComplexes
directdeprotonationofthreehydroxylgroups(Scheme1).Both
gas titration experiments and electrospray mass spectrometry
(ESI-MS) have been used to support the formation of the
Zn-ProPhenol complex 2 from diethyl zinc and 1a.4
Furthermore, Ding and co-workers were able to characterize
ap-nitrophenoxyderivative(3)ofcompound2byX-raycrystal-
lography (Scheme 2).5 In addition, the crystal structure of an
a
Scheme2.X-rayCrystalStructureofZn-ProPhenolComplex3 Figure 1. Quadrant view of the zinc-prophenol chiral pocket and
additivecoordination.
chiralpocket.Formationofthistypeofternarycomplexfollowed
by product dissociation bears a striking resemblance to the
■catalyticmechanismusedbyanumberofenzymes.
ENANTIOSELECTIVEDIRECTALDOLREACTION
Atthetimethatwebegantoexplorethedirectaldolreaction,a
potentially powerful and efficient method for the enantio-
selectiveformationofcarbon−carbonbondsbyavoidingtheuse
aTHFomitted for clarity. ofchiralauxiliariesandtheneedforpriorformationofanenolate
or enol silane, this topic was just starting to become a major
endeavor.10 The ProPhenol ligand (1a), which was initially
analogous dinuclear magnesium ProPhenol complex has also developed for the direct aldol reaction, was based on the
beenreported.6TheProPhenolligandhasbeenusedtoligatea hypothesisthatanaza-semicrownligandwouldbindmetalions
number of different main group metals including lithium, tightly enough to provide a good template for the design of a
magnesium, zinc, zinc/magnesium (heterobimetallic), cobalt, chiral pocket but not too tightly to prevent catalytic turnover.
and bismuth (vide infra).7 These bimetallic complexes contain Furthermore, the increasedbasicity ofzincboundinthismotif
both a Lewis acidic and Brønsted basic site and are capable of was envisioned to provide, after C−C bond formation, a
activatingbothanelectrophileandanucleophilewithinthechiral Zn-alkoxide (shown in red) that could serve as a base for
pocketcreatedbythetwodiaryl(oxy)methylgroups(Figure1). subsequent enolate formation and facilitate catalyst turnover
TheconciseandmodularrouteusedtopreparetheProPhenol while also avoiding unwanted epimerization and product
ligand has enabled tailoring of the chiral pocket for specific elimination(Scheme3).
reactions by introducing additional substituents on the The first report of the ProPhenol ligand by Trost and Ito in
pyrrolidineringsandthearylring(videinfra).Afacileprocedure 2000 showed that just 5 mol % of the ProPhenol ligand and
hasbeendevelopedfortherecoveryoftheProPhenolligand1a 10mol%Et Zncouldbeusedtofacilitatetheasymmetricaldol
2
onmultigramscale,wherebythebis-sodiumsaltisfilteredoffand reactionwithavarietyofacetophenonederivatives(Scheme4).4a
1aisrecoveredin95%yield.8 Zn-ProPhenol-catalyzed reactions have proven to be highly
In general, dual catalysis has proven a powerful approach to tunable,andavarietyofadditiveshavebeenusedtoboostboth
asymmetriccatalysis.9However,ProPhenolcomplexeshavethe yield and enantioselectivity. The benefits of most additives
added benefit of dictating the orientation of both electrophile appear to be somewhat substrate specific and, in aldol re-
andnucleophile bybinding the twosubstrates withinthe same actions, have been postulated to reduce aggregation, fill open
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Scheme3.CatalystTurnoverMechanism
Scheme4.CatalyticAsymmetricAldolReactionwith reaction with methyl vinyl ketone was recently used in the
AcetophenoneDerivatives synthesisoftheringAandBsubunitsofthebryostatins.12
The use of Lewis basic additives in aldol reactions with
methylynonedonorsgaverisetoanumberofsurprisingresults
(Scheme6).13Astonishingly,itwasdiscoveredthatthesenseof
Scheme6.OptimizationoftheDirectAldolReactionwith
MethylYnones
aReaction performed at −20 °C. b96%recovery of excess ketone.
coordination sites on the catalyst, and mitigate base-mediated
sidereactions.Thedirectaldolreactionwithmethylvinylketone
(4, MVK), a donor that has not been reported with any other
aReaction performed with 2 mol %catalyst loading.
asymmetric catalyst system, was performed with 5 equiv of
iPrOH and provided a variety of highly versatile β-hydroxy
enones(Scheme5).11 enantioinduction changes over the course of the reaction, with
These β-hydroxy enones are versatile precursors to the ent-7beingformedasthemajorproduct(69%ee)duringthefirst
corresponding1,3-synor1,3-antidiolsthroughstereocontrolled 5 min. This led to the hypothesis that aldol product 7 might
reduction of the ketone. In addition, the alkene could be beinvolvedintheenantiodeterminingstep.Indeed,theaddition
functionalizedusingeitheralkenecrossmetathesis,togive5,ora ofeitherchiralorachiralβ-hydroxycarbonylcompoundsledto
diastereoselective [3 + 2] cycloaddition with a nitrile oxide to improvements in enantioselectivity during the first 45 min of
provide 6. Furthermore, the Zn-ProPhenol catalyzed aldol thereaction(Scheme6).Interestingly,catalystloadingsaslowas
Scheme5.SyntheticUtilityofAsymmetricAldolReactionswithMVK
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2mol%gavegoodresults(Scheme6,entry6).Ultimately,the Scheme9.CatalyticEnantioselectiveAcetoneAldolReaction
use of additive-free conditions and higher temperature in the
direct aldol reaction was found to provide excellent enantio-
selectivity and good to moderate yields with silyl, alkyl, and
unsubstituted butyn-2-ones (Scheme 7). The latter two results
Scheme7.CatalyticEnantioselectiveAldolReactionwith
YnoneDonors
reinforcethechiralpocket.Amajorchallengeinaldolreactions
are particularly noteworthy given the propensity of these
withacetoneistheavoidanceofunwantedelimination,whichis
substrates to undergo unwanted conjugate addition. Further-
particularly problematic in the reaction of benzaldehyde with
more,thisreactionwasusedtogreateffectinthetotalsynthesis
acetone;only12%yieldof8wasobtainedwhenusing10mol%
oflasonolideAandfostriecin(Scheme8).14
1b.However,loweringthecatalystloadingto5mol%provideda
muchimproved78%yieldand83%eeofthedesiredproduct.
Scheme8.AsymmetricAldolReactionintheSynthesisof
The syn-1,2 diol motif is common in a number of bio-
FostriecinandLasonolideA
active natural products, and in contrast to dihydroxylation,
the asymmetric aldol reaction represents a particularly effi-
cientmeansofconstructingthisunit.16Usingjust2.5mol%of
the ProPhenol ligand and a slight excess of an α-hydroxy
acetophenone donor, we could obtain a range of syn-1,2
diols in high yield and stereoselectivity (Scheme 10).4b This
Scheme10.DirectAldolReactionwithα-Hydroxy
AcetophenoneDonors
aReaction performed with (R,R)-1afor 12h on a 16 mmolscale.
Zn-ProPhenol complexes have also been shown to facilitate
acetone aldol reactions in good yield and enantioselectivity
(Scheme 9).15 While the standard ProPhenol ligand (1a) methodologywasusedtofacilitatethedirectaldolreactionof2-
provided good results with a variety of aliphatic and aryl hydroxyacetylfuran with an enolizable aldehyde and enable
aldehydes,theuseof1b,containinga3,5-dimethylphenolmotif, theenantioselectivetotalsynthesisofboronolide.17Interestingly,
provided slightly improved yield and enantioselectivity in a the absoluteconfigurationofthe β-hydroxygroup isthe oppo-
number of cases. The two methyl groups in this motif are site of that obtained with acetophenone donors. Presumably,
believed to have a buttressing effect on the prolinol groups to thisreversalis duetothebridgingofthe α-oxygenated enolate
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Scheme12.ProPhenol-CatalyzedHydroxyacetateEquivalent
AldolReaction
Figure2.Proposedbidentatecoordinationofα-hydroxyketonedonors.
between the two zinc atoms, which results in addition to the
oppositeenantiotopicfaceofthealdehyde(Figure2).
Relative to ketone-based donors, ester enolate equivalents
have proven much less reactive as aldol donors. Furthermore, aReaction performed at −15°C for 72 h.
ester equivalents are typically not amenable to organocatalytic
direct aldol reactions, thus making an efficient synthesis of Scheme13.SyntheticUtilityofHydroxyacetateAldol
β-hydroxy esters particularly valuable. The development of a Products
formal α-hydroxyacetate aldol reaction began with the screen-
ing of a number of different activated ester equivalents in re-
actionswiththeProPhenolligand1aandEt Zn(Scheme11).18
2
Scheme11.InitialOptimizationoftheα-Hydroxyacetate
AldolReaction
Scheme14.LigandScreeningwithGlycinateSchiffBase
Donors
TheuseofanN-acylpyrroledonorwasfoundtobesuperiorto
both 2-acylimidazole and N-acylbenzoxazolinone donors.
Futhermore, substitution at the 2-position of the pyrrole
provided improved diastereoselectivity, and therefore N-(α-
hydroxyacetyl)-2-ethylpyrrole (9) was chosen as the activated
ester equivalent. Both of the ProPhenol ligands 1a and 1b
provided good yield and stereoselectivity in aldol reactions
of 9 with aliphatic, aryl, and α,β-unsaturated aldehydes, with
ligand 1b leading to slightly improved results in some cases
(Scheme 12). The products from these aldol reactions have
shown great synthetic utility because the N-acylpyrrole group
can be converted to the corresponding ester, amide, or ketone
in a single step (Scheme 13). Furthermore, this methodology
providedakeystepinthetotalsynthesisoflaulimalide.19
Esters,intheformofglycineSchiffbases(i.e.,10),alsocould aYield of the isolated pure 1,2-syn diastereomer.
be used directly as donors in ProPhenol-catalyzed aldol
reactions(Scheme14).20Optimizationbyprovidingadditional t-butyl esters of the glycinate Schiff base proved effective,
steric constraint in the chiral pocket led to higher stereo- incontrasttootherchiralcatalystsforthistransformation.21
selectivity.TheProPhenolligand[(S,S),(S,S)]-1cprovedbest. Aversatilealternativetotheaforementionedα-hydroxyandα-
Highyieldandstereoselectivitywereobtainedwitharangeof aminoesterenolateequivalentsisthediazoesteraldolreaction.22
aliphaticaldehydes(Scheme15).Furthermore,catalystcontrol The unique reactivity of the resulting β-hydroxy-α-diazo esters
wasfoundtooverridetheinfluenceofα-chiralaldehydes,and canbeusedtoprepareawiderangeof1,2-diolsandα-hydroxy-β-
while a small matched/mismatched effect was observed, high amino esters in a stereoselective manner (vide infra). For
diastereoselectivitywasobtainedregardlessoftheconfiguration this process, the use of di-n-butylmagnesium, in place of
of the α-stereocenter of the acceptor. Both the methyl and diethylzinc, provided the desired product 12 in a modest
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Scheme15.AsymmetricAldolReactionwithGlycinateSchiff Scheme17.Mg-ProPhenol-CatalyzedAldolReactionwith
BaseDonors EthylDiazoacetate
aReaction performed with (R,R)-1a. bReaction conducted at 0.5 M.
cAldehyde (2 equiv) added.
Scheme16.OptimizationoftheMg-ProPhenolDiazoEster
Scheme18.SyntheticVersatilityofDiazoEsterAldol
AldolReaction
Products
27% ee (Scheme 16).23 Guided by the notion that open β-Aminoacidderivativescanalsobepreparedfromdiazoester
coordinationsitesonzincwereoccupiedbymultipleequivalents aldoladductsusingtrichloroacetonitrileandsodiumhydrideto
ofethyldiazoacetate,theuseofabidentatecoordinatingagent, convert the alcohol to the corresponding trichloroacetamide
cis-1,2-cyclopentanediol 16 (Scheme 16), combined with a (Scheme 19).24 This C−O to C−N transfer occurs with
higherreactionconcentration(1.0M)andslowadditionofethyl r■etentionofabsoluteconfiguration.
diazoacetate led to further improvements, providing 12 in
CATALYTICENANTIOSELECTIVEMANNICHAND
95% yield and 95% ee. Scheme 17 illustrates the scope of the
reaction. Further, the resulting enantioenriched β-hydroxy-α- HENRYREACTIONS
diazo esters serve as versatile synthetic intermediates with a The Mannich reaction is a highly efficient method for the
wealthofpossiblereactivityasdepictedinScheme18,whereby preparation of β-amino carbonyl compounds.26 The Zn-
oxidationofthediazogroupwithdimethyldioxirane(DMDO)is ProPhenolcatalyst(1a/Et Zn)wasfoundtofacilitatethedirect
2
followed by nucleophilic addition to the resulting ketone. This Mannich reaction with a range of α-hydroxy acetophenones
reaction sequence enables the rapid and stereoselective (Scheme 20).27 An o-methoxyaryl imine improved the stereo-
preparationofvicinaldiolsofconsiderablemolecularcomplexity. control comparedwithap-methoxyanalog, presumablydueto
For example, a three step sequence was used to convert a coordination of the ortho methoxy group to zinc. Improved
β-hydroxy-α-diazoesterintocompound17,afragmentpresent diastereoselectivity was obtained with the ProPhenol ligands
inanumberofpolyketide antibiotics including azithromycin.23 1f and 1g, which contain bulky 4-biphenyl and 2-naphthyl
Interestingly, the ProPhenol ligand was used to facilitate the groups, respectively. Substrates containing more labile N-
diastereoselective methylation of a β-hydroxy-α-keto ester en protecting groups on the imine, such as diphenylphosphinoyl
routeto17.Intheabsenceof1a,acomplexmixtureofproducts (DPP)andBoc,werealsofoundtobeeffectiveintheProPhenol-
wasobtainedfromthismethyladdition. catalyzed Mannich reaction and enabled the use of enolizable
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Scheme19.ConversionofDiazoEsterAldolAdductsinto Scheme21.anti-SelectiveMannichReactionwith
β-AminoAcidDerivatives25 DPP-Imines
aStarting material had an ee of 97%. bFor experimental details see
ref25.
Scheme22.syn-SelectiveDirectMannichReactionwith
Scheme20.ProPhenol-CatalyzedDirectMannichReaction
Boc-Imines
Scheme23.ProPhenol-CatalyzedMannichReactionwith
5H-Oxazol-4-ones
aliphatic imines, which are typically challenging substrates.28
Interestingly,thebulkyDPPgroupledtoselectiveformationof
theanti-1,2-aminoalcohol(Scheme21),whereastheBoc-imine
resultedinthepreferentialformationofthecorrespondingsyn-
diastereomer (Scheme 22). In both cases, the absolute
configurationattheα-positionisthesameandislikelyattributed
tobidentatecoordinationoftheα-hydroxyketoneenolatewith diastereoselectivity, relative to 1a, and the Mannich product
thedinuclearzinccatalyst. 19wasobtainedin89%yield,97:3dr,and95%ee.Furthermore,
Wang and co-workers have recently reported an elegant the preformed Zn-complex derived from 1h/Et Zn/18 was
2
application of the Zn-ProPhenol catalyzed Mannich reaction, found to be relatively air stable, and identical results were
using 5H-oxazolones as donors to form two adjacent stereo- obtainedwhenthereactionwasperformedopentoairwiththe
centers,oneofwhichistetrasubstituted(Scheme23).29Inthis preformedcomplex.
case,a2-thienylvariantoftheProPhenolligand,(S,S)-1h,plus TheZn-ProPhenolcatalystwasalsofoundtobeeffectivewith
the use of an additive, diethyl phosphoramidate (18), to block nitronate-based nucleophiles in enantioselective nitro-Mannich
open coordination sites on zinc was found to provide superior (or aza-Henry) reactions (Scheme 24).30 While a number of
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Scheme24.Zn-ProPhenol-CatalyzedAza-HenryReaction Scheme26.ProPhenol-CatalyzedNitroalkeneConjugate
Addition
relative to β-nitrostyrene. Further, 2-hydroxyacetylfuran also
servedasanexcellentdonor.Theγ-nitroketonesproducedfrom
these reactions are particularly useful intermediates in the
stereoselectivesynthesisofpyrrolidines.34
aReaction performed with 30 mol % ProPhenol, 60 mol % EtZn. Oxazolones were found to be effective pronucleophiles in
2
bReaction performed at roomtemperature. ProPhenol-catalyzedasymmetricconjugateadditionswithnitro-
alkenes using the bulky 2-naphthyl variant 1g to provide 23 in
effective catalyst systems have been reported for the excellent yield and stereoselectivity (Scheme 27).35 The aryl
enantioselective aza-Henry reaction with aryl- and aliphatic
imines,31the resultsinScheme24constitute arare example of Scheme27.Zn-ProPhenolCatalyzedNitro-MichaelReaction
asymmetricadditiontoα,β-unsaturatedimines.Giventhefacile withOxazolones
conversionofβ-nitroaminesinto1,2-diaminesandthesynthetic
utilityofenantioenrichedallylicamines,theseresultsrepresenta
valuable extension of the aza-Henry reaction. Analogous
reactivity was also exploited in a ProPhenol-catalyzed Henry
reaction with aryl aldehydes (Scheme 25).32 Subsequent
reduction of the nitro groups in 20 and 21 led to the total
synthesisof(−)-denopamineand(−)-arbutamine,respectively.
Scheme25.ProPhenol-CatalyzedEnantioselectiveHenry
Reaction
groupoftheoxazolonewasfoundtohaveasignificantimpacton
diastereoselectivity,with3-methylbenzeneprovidingthehighest
stereoselectivity. The products obtained from this reaction can
be readily converted to the corresponding α-hydroxy carbox-
■ amideusingNaOH.35
An analogous transformation with 2(5H)-furanone was
ENANTIOSELECTIVECONJUGATEADDITIONS
developed, harnessing vinylogous nucleophilicity to create
The Zn-ProPhenol catalyst was found to facilitate the asym- enantioenrichedbutenolides(Scheme28).Thereactionconcen-
metricconjugateadditionofα-hydroxyketonestonitroalkenes tration at 0.5 M proved significant in obtaining high diastereo-
(Scheme 26) to form the adducts 22.33,34 Interestingly, selectivity.
generatingthecatalystwithanequimolarmixtureofEt Znand NitroalkenesalsoserveasefficientacceptorsintheProPhenol-
2
Bu Mg led to a synergistic effect, whereby higher diastereo- catalyzedFriedel−Craftsalkylationofpyrroles.36Using10mol%
2
selectivity was obtained while also maintaining high ee. The catalyst loading and 3 equiv of pyrrole, we obtained high yield
presenceofalkyl,alkynyl,andelectron-richarylsubstituentson and enantioselectivity with both aryl and alkyl substituted
the nitroalkene typically provided higher diastereoselectivities nitroalkenes (Scheme 29). Additionally, Wang and co-workers
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Scheme28.Enantioselectiveγ-Alkylationof2-Furanone Scheme31.ProPhenol-CatalyzedAsymmetricPhospha-
MichaelAdditions
aAbsolute configuration determined by X-ray crystallography.
Scheme29.AsymmetricFriedel−CraftsAlkylationofPyrroles
aMeZnwasusedinplaceofEtZn.bReactionrunat40°C.cAbsolute
2 2
configuration determined by X-ray crystallography.
ofthestandardProPhenolligand1atofacilitatetheadditionof
diethylphosphite to a variety of enones.40 This reactivity was
extended to included the addition of less reactive dialkyl
phosphineoxidestoα,β-unsaturatedN-acylpyrrolesandketones.
ThisreactioninspiredthedesignofanewProPhenolligand,
1h,containingfour2-thienylgroupsinplaceofthetypicalphenyl
aYield based on recovered starting material.
rings (see Scheme 23). The smaller heteroaromatic groups are
postulatedtocreatealargerchiralpocketandserveasaninternal
havereportedtheProPhenol-catalyzedFriedel−Craftsalkylation Lewisbase,whichoccupiestheopencoordinationsitesofeach
ofindoleswithaldimines.37 metal,therebyincreasingtheeeandenhancingthescopetoβ,β-
The ProPhenol ligand has also been used to facilitate the disubstituted acceptors, thus generating a tetrasubstituted
enantioselective alkylation of hydroxyoxindoles 24 to form s■tereocenter.
spirocyclic γ-lactones (Scheme 30) in a 2:1 mixture of
PROPHENOL-CATALYZEDASYMMETRICALKYNE
Scheme30.AsymmetricHydroxyoxindoleAnnulation ADDITION
Chiral propargylic alcohols serve as both robust and versatile
syntheticintermediates,providingawealthofpotentialreactivity
with a high degree of orthogonality. Furthermore, propargylic
alcohols are present in numerous natural products and
therapeutic agents.41 The success of the Zn-ProPhenol catalyst
with stabilized nucleophiles prompted the examination of this
system to facilitate the addition of zinc acetylides to aldehydes
(Scheme32).Initialresultsrevealedthat,incontrasttoprevious
ProPhenol-catalyzed methodologies, asymmetric alkynylation
required2−3equivofdialkynylzincforefficientcatalystturnover
and enantioinduction.42 Nonetheless, good yield and enantio-
selectivity was obtained in the addition of aryl, alkyl, and silyl
acetylenestoarylandα,β-unsaturatedaldehydeswith10mol%
of(S,S)-1a(Scheme33).43Extensiontotheadditionofdiynesto
aAbsolute configuration determined by X-ray crystallography.
aldehydesrequiredtheadditionof20mol%triphenylphosphine
oxide(TPPO)forhigherenantioselectivityasillustratedbythe
acetonitrileandtolueneat40°C.38Interestingly,thecatalystis formation of 27 and 28.44 The efficiency of the catalytic diyne
involved in both the conjugate addition and the trans- addition to form 28, an intermediate for the synthesis of the
esterification to form the spirocyclic oxindole product; in the antitumor agent strongylodial, contrasts with the use of an
absenceof1a,theopen-chainedMichaeladductdidnotcyclize ephedrine mediated reaction, which required 4 equiv of the
toformaγ-lactone. “catalyst”togivetheadductin68%yieldand80%eecompared
Wang and co-workers have used the ProPhenol ligand to with the ProPhenol method, which utilized only 20 mol %
facilitatetheasymmetricphospha-Michaelreactionwithawide catalyst to give the desired adduct in 90% yield and 87% ee.45
rangeofsubstrates(Scheme31).39Initialworkoutlinedtheuse CombiningtheuseofTPPOwithhigherreactionconcentrations
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Scheme32.ProposedMechanismforProPhenol-CatalyzedAlkyneAddition
Scheme33.ProPhenol-CatalyzedAsymmetricAlkyne Scheme34.AlkyneAdditionintheEnantioselectiveSynthesis
Addition ofAsteriscunolideD
and alkyne typically led to exemplary results, as seen in the
yield and ee of 25 and 26. This strategy was recently
applied to the total synthesis of asteriscunolide D to convert
methylpropiolateintothechiralbutenolide31(Scheme34).47
Enolizable aldehydes, most notably acetaldehyde, are
particularly challenging substrates for enantioselective alkyne
additionduetoself-aldolsidereactions.Theprevalenceofchiral
1-methyl propargylic alcohols (i.e., 32) in natural products
prompted attempts to form these products using the Zn-
ProPhenolcatalyst.48Minimizingtheconcentrationofacetalde-
hyde by its slow addition over 30 min provided high yield and
enantioselectivity with a variety of alkynes (Scheme 35). This
enabled use of just 1.2 equiv of alkyne more generally, while methodology was applied to the synthesis of minquartynoic
maintaining good enantioselectivity and yield. For example, acid,48 tetrahydropyrenophorol, and the proposed structure of
these conditions allowed use of an equimolar amount of a trocheliophorolideB.49
preciousalkynewithfumaraldehydedimethylacetaltoprovide Marekandco-workershaverecentlyreportedanelegantone
the desired product 30, an intermediate in the total synthesis pot application of the Zn-ProPhenol asymmetric alkynylation
of aspergillide B, in 82% yield and 19:1 dr.46 The alkynol in tandem with a Brook-type rearrangement and ene−allene
29 served as a substrate in a second ProPhenol catalyzed cyclization (Scheme 36) ultimately to provide a 1,3-diol 33
alkynylationleadingultimatelytothebioactivenaturalproduct via oxysilanes 34.50 Overall, this sequence forms three new
spirolaxinemethylether.51Theasymmetricadditionofmethyl bonds and two new stereocenters in a highly stereoselective
propiolate using nearly stoichiometric amounts of aldehyde manner.
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