Stereoselective Synthesis of Z-Alkenes

27 Pages·2017·2.71 MB·English

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