TopCurrChem(2012)327:33–58 DOI:10.1007/128_2012_315 #Springer-VerlagBerlinHeidelberg2012 Publishedonline:6March2012 Stereoselective Synthesis of Z-Alkenes Woon-YewSiau,YaoZhang,andYuZhao Abstract This chapter offers a general review of the evolvement of methods for the stereoselective synthesis of Z-alkenes, with a focus on the development of catalyticsystemstowardsthisgoalinrecentyears. Keywords Cross coupling (cid:1) Lindlar reduction (cid:1) Olefin metathesis (cid:1) Olefination (cid:1) Z-Alkene Contents 1 Introduction................................................................................... 34 2 OlefinationReactions:fromCarbonylstoAlkenes......................................... 34 2.1 WittigReaction......................................................................... 34 2.2 Still–GennariModificationoftheHorner–Wadsworth–EmmonsOlefination....... 36 3 CrossCouplingReactions.................................................................... 38 3.1 Pd-orNi-CatalyzedCrossCoupling:ComplexityGenerationfromZ-Alkenyl HalidesorAlkenylmetals.............................................................. 38 3.2 OtherCrossCouplingReactions....................................................... 39 4 TransformationofAlkynestoZ-Alkenes.................................................... 40 4.1 PartialHydrogenationwithLindlar’sCatalystandBeyond.......................... 40 4.2 HydrometalationofAlkynestoZ-Alkenes............................................ 43 5 Z-SelectiveOlefinMetathesis................................................................ 45 5.1 EarlyExamples......................................................................... 45 5.2 RecentDevelopmentofMo-andW-AlkylideneMonoaryloxidePyrrolide ComplexesforHighlyZ-SelectiveOlefinMetathesis................................ 48 5.3 RecentDevelopmentofRu–CarbeneComplexesforHighlyZ-SelectiveOlefin Metathesis.............................................................................. 52 W.-Y.Siau,Y.Zhang,andY.Zhao(*) DepartmentofChemistryNationalUniversityofSingapore,Singapore117543,Singapore e-mail:[email protected] 34 W.-Y.Siauetal. 6 MiscellaneousReactionswithGenerationofZ-Alkenes.................................... 53 6.1 EliminationReactions.................................................................. 53 6.2 RearrangementReactions.............................................................. 53 6.3 AllylicSubstitution/AllylationReactions............................................. 54 7 Conclusions................................................................................... 55 References........................................................................................ 56 1 Introduction Alkenesareubiquitousinbiologicallyactiveentitiesandserveasversatilestarting materialsforalargenumberofchemicaltransformations[1–6].Thestereochemistry ofthealkenes,namelytheE-orZ-isomericform,notonlydeterminesthepropertyof the molecules but also in most cases alters the stereochemical outcome of the reactions utilizing alkenes as starting materials. Stereoselective access to either isomer,therefore,isakeycomponentofalkenesynthesis.Ingeneral,methodsfor highlyselectiveaccesstoZ-alkenesarelessestablishedthanthosefortheE-isomers. One of the reasons is thermodynamic control that favors the lower-in-energy E- alkenes. Since a wide variety of methods are suitable for Z-alkene synthesis (albeit not alwaysgeneralmethods),includingthemostimportantreactionsinorganicsynthesis suchasWittigolefination,crosscoupling,andolefinmetathesis,itistheintention oftheauthorstoillustratetheevolutionofmethodsforZ-alkenesynthesisthrough representative examples, with a focus on the development of catalytic methods in recentyears. 2 Olefination Reactions: from Carbonyls to Alkenes 2.1 Wittig Reaction TheWittigreactionhasprovedtobeoneofthemostimportantmethodsforalkene synthesis and has found much use in natural product synthesis [7–10]. In this transformation, the carbonyl compound reacts with a phosphorus ylide (prepared fromatriaryl-ortrialkylphosphineandanalkylhalidefollowedbydeprotonation with a suitable base) to yield the alkene product with concomitant generation of phosphine oxide as the side product. The stereoselectivity of Wittig reaction is influencedbymanyfactorsincludingtypeofylides,typeofcarbonylcompounds, natureofsolvent,andeventhecounterionfortheylideformation.Ingeneral,good tohighZ-selectivity(typically ~9:1) canbeexpectedwhen“nonstabilized”(alkyl substituted) ylides react with aldehydes under salt-free conditions in a dipolar aprotic solvent. One impressive example reported in recent years, in which two partners with a complex structure were coupled in a highly Z-selective fashion, is StereoselectiveSynthesisofZ-Alkenes 35 TBSO I TBSO PPh3I TBSO OTBS Ph3P(4equiv.) 1).NaHMDS,THF O SEt DIPEA OTBS benzene:toluene7:3 OTBS 2) OHC OTBS OTBSTBSO 12.8Kbar,6d O PMP 70% O PMP O O PMP O O SEt O TBSO -78oCtort,76%,Z:E>98:2 (+)-discodermolide Fig.1 WittigolefinationcoupledtwopieceswithacomplexstructuretoyieldZ-alkene Fig.2 WittigreactionforthepreparationofZ-alkenyliodides shown in Fig. 1 [11]. The alkene product was then transformed to the natural productnamed(+)-discodermolide,apotentinhibitoroftumorcellgrowth. The utilizationof the Wittig reactiontoprepare functionalizedalkenes such as Z-vinylhalideshasalsobeendemonstratedsincetheearly1990s(Fig.2)[12].The iodoalkyl phosphonium salt is deprotonated with sodium hexamethyldisilazane to yieldtheylidethatreactswithaldehydestogeneratetheZ-alkenylhalidesingood toexcellentselectivity.NotonlydisubstitutedZ-alkenylhalides,butalsotrisubsti- tutedonescanbepreparedusingthismethod,albeitwithmoderatechemicalyields [13]. These products are useful synthons in organic synthesis, especially in cross couplingreactions. MucheffortwasexpendedonimprovingtheZ-selectivityofWittigreactionfor a wider range of substrates by modifying the nature of the ylide or the carbonyl compounds. Very recently, the Tian group reported Wittig olefination utilizing sulfonyl imines as the substrate that provides a wide range of alkenes including conjugated dienes exclusively as the Z-isomer (Fig. 3) [14]. Traditional Wittig olefination only provides these products as a mixture of E- and Z-alkenes. It is importanttonotethatthesubstituentonthesulfonylimineshasasignificantimpact onthestereoselectivityoftheprocess.Bytuningthestericandelectronicproperties ofthesubstituents,eitherE-orZ-alkenescanbeaccessedexclusively.Eventhough 36 W.-Y.Siauetal. Fig.3 HighlyZ-selectiveWittigreactionofsulfonylimines this method is not very appealing in terms of atom economy, it represents an excitingimprovementofZ-selectiveWittigolefination. While being widely used for alkene synthesis, it is noteworthy that, as a stoichiometric transformation, Wittig reaction generates extensive waste due to thehighmassofphosphineoxidesideproductwhichisnotalwayseasilyseparable fromthedesiredproduct.WhileWittigreaction catalyticinphosphine ismerging [15],theestablishmentoffullycompatiblecatalyticolefinationprocessesisyetto beseen. 2.2 Still–Gennari Modification of the Horner–Wadsworth–Emmons Olefination AsanimportantmodificationofWittigreaction,theHorner–Wadsworth–Emmons (HWE)olefinationgivesrisetoa,b-unsaturatedketonesandesterswithsignificant advantages over Wittig reaction including easier reagent preparation, wider sub- stratescope(especiallyashinderedketonesundergoHWEbutnotWittigreaction), as well as much more straightforward separation of the dialkyl phosphate side product(sinceitiswatersoluble)fromthealkenesofinterest[16].However,HWE reactionproceedsinanexclusivelyE-selectivefashion. In1983,StillandGennariintroducedthefirstgeneralwaytoprepareZ-alkenesby coupling electrophilic bis(trifluoroalkyl) phosphonoesters in the presence of strong baseswithaldehydes(Fig.4)[17].Thebis(trifluoroethyl)phosphonoestersareeasily prepared from the commercially available trialkylphosphonoesters and trifluor- oethanol. Both 1,2-disubstituted and trisubstituted Z-alkenes can be accessed using thismethod,buttheproductsarelimitedtoa,b-unsaturatedketones,esters,orcyanides, sincetheelectrophilicphosphonatereagentrequiresanelectron-withdrawinggroupat StereoselectiveSynthesisofZ-Alkenes 37 Fig.4 Still–GennarimodificationofHWEolefinationleadstoZ-a,b-unsaturatedketones/esters O RO MeO FF33CCHH22CCOO P CO2Me RO MeO TBSO TBSO spinosynA KHMDS,18-crown-6 Br CHO Br HF,-78oC,57% R=Pham MeO2C Fig.5 Still–GennarimodifiedHWEolefinationforpolyenesynthesis M O O RO slower(synaddition) P RO OR' O O O RO M R'' H RO P OR' RO O O O TS(syn) P H RO OR' R'' H M HB O O M B RO slow(antiaddition) RO P OR' O H R'' TS(anti) O O M O MO OR RROO P O- fast fast O P OR TS(anti) R'' OR' R'' CO2R' P OR R'' CO2R' O OR oxaphosphetate Z-alkene Fig.6 RationaleforZ-selectivityinStill–GennarimodificationofHWEolefination its a-position tostabilizethe carbanion. Usually 18-crown-6 is used as an additive becauseanon-coordinatingmetalcationisnecessaryforthereactiontowork. Since its original report, the Still–Gennari modified HWE olefination has been widely used in natural product synthesis to access Z-alkenes [18]. One example fromtheRoushgroupisshowninFig.5,wheretheolefinationreactionwasusedto providetheconjugatedpolyeneprecursorfortheirkeyone-pottandemintramolec- ularDiels–AlderreactionandvinylogousBaylis–Hillmancyclization[19]. Although the mechanism for the HWE olefination is not fully understood, the rationale for the reverse selectivity of Still–Gennari modification merits further discussion [20]. As shown in Fig. 6, it is believed that the steps for the HWE 38 W.-Y.Siauetal. olefinationarereversible(orquasi-reversible)sothattheE-alkenethatislowerin energyisselectivelyformedinessentiallyallcases.IntheStill–Gennarimodified version,however,duetotheelectron-withdrawingeffectofthetwotrifluoroalkoxy groupsonthephosphorus,theformationoftheoxaphosphetanefromthechelated adductismuchmorefavoredthanintheregularHWEreaction,renderingafaster elimination step than the initial addition. Since the whole process becomes irre- versible,thekineticselectivityintheinitialadditionstepthatfavors anti-addition leadingtoZ-alkeneproductbasedonstericinteractionismaintained. 3 Cross Coupling Reactions 3.1 Pd- or Ni-Catalyzed Cross Coupling: Complexity Generation from Z-Alkenyl Halides or Alkenylmetals Pd- or Ni-catalyzed cross coupling reactions of alkenyl halides or alkenylmetal species have established themselves as powerful tools for accessing either E- or Z-alkenes[21].Thecrosscouplingstepisstereospecificinmostcasesandresultsin theretentionofthestereochemistryofthestartingalkenylhalidesoralkenylmetal species.Thecontrolofthealkeneisomer,therefore,hastobeestablishedbeforethe cross coupling step, which is invaluable as the complexity generation step in organic synthesis. Instead of presenting a general review of this area of research thatisbeyondthescopeofthischapter,tworepresentativeexamplesofSuzukiand NegishicouplingtoaccessZ-alkenesfromZ-alkenyliodidesorZ-alkenyl boranes areshowninFigs.7and8. TheMolandergroupreportedaformaltotalsynthesisofoximidineII,inwhichan intramolecularSuzukicrosscouplingbetweenanE-alkenylpotassiumtrifluoroborate andaZ,Z-dienylbromideconstructedthehighlystrained12-memberedmacrolactone coreofthenaturalproduct(Fig.7)[22].Importantly,thestereochemistryofthestarting partnerswasconservedtodelivertheE,Z,Z-conjugatedtrieneinthenaturalproduct. OBn BnO O NOMe OH O OMOM 105meoqlu%iv.PCds(2PCPOh33)4 OH O OMOM HN O OH O OH O THF:H2O(10:1) (E) (Z,Z) Br reflu4x2,%20h O BF3K (E,Z,Z) oximidineII Fig.7 SuzukicouplingformacrocyclizationtoinstallE,Z,Z-triene StereoselectiveSynthesisofZ-Alkenes 39 Me Me Me I Me2B R 2mol%Pd(PPh3)4 Me R TBDPSO Me + or TBDPSO Me THF,23oC,5h Me >98%Z,Z BrZn R 31-48%forSuzukicoupling; 63-84%forNegishicoupling R=CH2OH,CH2OTBS, CH=CHCH2OH,CH=CHCO2Me Fig.8 CrosscouplingofZ-alkenylhalideleadstoZ-alkenes OH n-BuLi,followedby R R'' + SiR1 TiCl(Oi-Pr)3,c-C5H9MgCl R R' R' Me2 Et2O,-78to0oC,2h R'' SiMe2R1 RR'/=Ra''l=kyHl,Me R1=MeorCl 50-71%for15examples Z:Eupto95:5 Proposed transition state model: R R' R' R' SiR3 SiR3 R' Ti Ti R O O R'' R'' R H R'' SiMe2R1 R'' SiMe2R1 H R minor(E) A(1,2)strain major(Z) between R and R' Fig.9 CrosscouplingofallylicalcoholsandvinylsilanesmediatedbyTicomplex Negishiandco-workerscomparedNegishicouplingandSuzukicouplingforthe preparation of conjugated dienes (Fig. 8) [23]. In particular, Z,Z-dienes are constructed in high purity starting from Z-alkenyl iodides and either Z-alkenyl borane or zinc species. The Negishi coupling, however, was found to be more efficientandtodelivertheproductsinhigherchemicalyields. 3.2 Other Cross Coupling Reactions TheMicaliziogroup reportedaninterestingcrosscouplingofallylic alcoholsand vinylsilanesmediatedbyatitaniumcomplex(Fig.9)[24].GoodZ-selectivity(95% inmostcases)wasobtainedforawiderangeofsubstrates.Thetitaniumcomplexis proposed to coordinate to both substrates and join them together in a closed transitionstate.Asshownintheproposedmodel,theminimizationofA-1,2strain isbelievedtobethesourceofZ-selectivityofthesystem. 40 W.-Y.Siauetal. 4 Transformation of Alkynes to Z-Alkenes 4.1 Partial Hydrogenation with Lindlar’s Catalyst and Beyond 4.1.1 LindlarReduction ThepartialhydrogenationofalkynesusingLindlar’scatalystiswidelyutilizedfor accessing disubstituted Z-alkenes. In contrast to Pd on activated carbon which readily catalyzes the hydrogenation of alkynes and alkenes to the corresponding alkanes,inLindlarcatalystthePdcatalyst(5–10wt%)isdepositedonCaCO and 3 further“poisoned”withaleadco-catalyst(leadacetateorleadoxide)andquinoline inordertodecreaseitscatalyticactivitysothatthereactioncanbeinterceptedatthe alkenestage.ThemechanismisbelievedtobesimilartotheheterogeneousPd-or Pt-catalyzed hydrogenation of alkenes. Due to the nature of heterogeneous catalysts, H is bound to the surface of the catalyst and Z-configured alkenes 2 couldbegeneratedexclusively. EversinceitsintroductionbyHebertLindlar[25],Lindlarreductionhasfound extensive application in organic synthesis. One representative example from the Ghoshgroup,whereLindlarreductionwasusedatalatestageofthetotalsynthesis ofthepotentantitumormacrolide((cid:3))-laulimalide,isshowninFig.10[26].Thus, Yamaguchi macrolactonization of the hydroxy alkynoic acid followed by Lindlar reduction yielded the Z-a,b-unsaturated ester in high efficiency that is only a few deprotectionstepsawayfromthenaturalproduct.Itisimportanttopointoutthatin their earlier attempts, when the corresponding Z-a,b-unsaturated acid was first preparedandusedfortheYamaguchimacrolactonizationstep,significantisomeri- zation of Z-alkene to the E-isomer was observed. It was postulated that this undesired isomerization was the result of the reversible Michael addition of DMAP (instead of 1,2-addition for Yamaguchi macrolactonization) to the mixed anhydride intermediate of thismacrocyclization step. The fact that Lindlar reduc- tioncanbecarriedoutefficientlyatsuchalatestagewaskeyforthesuccessofthe synthesis. OPMB MOMO 1)Yamaguchi OPMB MOMO O macrolactonization: OH EtN(i-Pr)2,Cl3C6H2COCl, O thenDMAP Me O O Me Me 2)Lindlar'scatalyst, O O H2,EtOAc,94% Me CO2H (-)-Laulimalide Fig.10 Lindlarreductionofmacrocyclesinnaturalproducttotalsynthesis StereoselectiveSynthesisofZ-Alkenes 41 NFmoc 5mol% NFmoc NH O n-Pr (t-BuO)3W C-t-Bu O n-Pr 1.LinHdl2a,r'9s4c%atalyst O n-Pr O O O 71% 2.TBAF62% Azamacrolide MeO O OH O O OH O OH m O n-Pentyl HO n 13-17memberedrings PGE2-1,15-lactone Turriane Fig.11 RCAM/LindlarreductionforthesynthesisofmacrocyclicZ-alkenes In an effort to address the problem of lack of stereo-control for the alkene geometry in ring closing olefin metathesis macrocyclization, the F€urstner group introducedring-closingalkynemetathesis(RCAM)followedbyLindlarreduction as a powerful tool for accessing Z-macrocycloalkenes stereoselectively [27]. The Schrocktungstencarbynecomplex[(t-BuO) W(cid:4)C-t-Bu][28]orthemolybdenum 3 chloride species formed in situ from [Mo{N(t-Bu)(Ar)} ] and CH Cl [29] were 3 2 2 found to be efficient precatalysts for these processes. Unlike alkene metathesis, where terminal diene serves effectively as the substrate, the substrate for alkyne metathesishastobeinternalalkynes.InthepastdecadetheF€urstnergrouphasused thismethodtoprepareawiderangeofmacrocyclicnaturalproducts,representative examplesofwhichareshowninFig.11[30].TheZ-alkeneshighlightedinredwere allpreparedusingtheRCAM/Lindlarreductionsequence. In spite of the great synthetic utility, Lindlar’s catalyst suffers from several significant drawbacks. As a heterogeneous catalyst, the performance of Lindlar’s catalystmayvaryfrombatchtobatch.Whiletheuseofnotenoughcatalystresults inincompleteconversion,addingexcesscatalystveryoftenleadstooverreduction tothesaturatedalkanes.Thisisaseriousproblembecauseitisextremelydifficultto convertthealkanebacktothedesiredalkeneproduct.Asamatteroffact,addition ofLindlar’scatalystinportionswhilecloselymonitoringthereactionconversionis a common practice, which makes this procedure tedious and impractical. In addi- tion,theuseoftoxicleadco-catalystposesproblemsintermsofenvironmentaland safetyissues. Mucheffortwasexpendedtoimprovetheperformanceofthecatalyticsystem, including using Pd on pumice [31] as well as different amine co-catalysts to deactivatePdsuchasethylenediamine[32].Anewgeneralcatalyticsystemsupe- riortotheoriginalLindlar’scatalysthasnotbeendiscoveredsofar. 42 W.-Y.Siauetal. 4.1.2 OtherMetalsforPartialHydrogenationofAlkynestoZ-Alkenes In 1973, Brown and Ahuja introduced an interesting alternative method to Lindlar reduction that uses P-2 nickel in the presence of ethylenediamine for the partial hydrogenationofalkynestoZ-alkenes[33].Thenickelcatalystcanbegeneratedin situthroughthereductionofnickelacetatebyNaBH ,whichmakesitstraightforward 4 tocontroltheexactcatalystloadingforthereaction. In their efforts to prepare a [D ]-labeled F -neuroprostane, the Galano group 4 4t carried out partial reduction of the skipped diyne substrate in order to access the Z,Z,Z-triene moiety of the final product (Fig. 12) [34]. While Lindlar’s catalyst provided a mixture of mono-reduction of the less hindered alkyne (with the ethyl substituent), the desired triene as well as over-reduced diene product, P-2 nickel yielded a much cleaner conversion to the desired product with 98% purity. The product was then transformed into the target molecule by a sequence of TBAF deprotection of the TBS ether and saponification. In 1995, Sato and co-workers reported that low-valent titanium alkoxide prepared from Ti(Oi-Pr) and i-PrMgCl (1:2) can readily incorporate alkynes to 4 give a titanacyclopropene complex, hydrolysis of which then leads to Z-alkenes withhighefficiencyandexcellentstereoselectivity(Fig.13)[35]. Very recently, the groups of Bergman and Arnold reported that a d2 niobium–imidocomplexcatalyzesanefficientandselectivepartialhydrogenation of1-phenyl-1-propynetoZ-b-methylstyreneunderH /COmixtures(Fig.14)[36]. 2 An Nb(V) metallacyclopropene complex similar to the previous Ti system was proposed, which was followed by s-bond metathesis with H and subsequent 2 reductive elimination to yield the Z-alkene. An excess of CO is required not only for catalyst stability but also for achieving catalyst turnover by replacing the product from the Nb complex. However, only one substrate was included in this report. TBSO TBSO CO2Me Ni(OAc)2·4H2O,D2 TBSO TBSO CO2Me NaBH4,NH2CH2CH2NH2 D D D D EtOH,16oC,6h TBSO Et 75% TBSO Et 98%pure (+2%over-reducedproduct) Fig.12 P-2Nickel-catalyzedhydrogenationofskippeddiyne Ti(Oi-Pr)2 R2 D Ti(Oi-Pr)4 i-PrMgCl R1 R1 Ti(Oi-Pr)2 D2O D R2 Ti(Oi-Pr)2 R2 >R981%Z Fig.13 Z-Alkenesfromreactionoflow-valentTialkoxidewithalkynesfollowedbyhydrolysis