Synthetic efforts toward cyathane diterpenoid natural products

20 Pages·2009·0.79 MB·English

REVIEW www.rsc.org/npr | Natural Product Reports
Synthetic efforts toward cyathane diterpenoid natural products
John A. Enquist, Jr. and Brian M. Stoltz*
Received20thDecember2008
FirstpublishedasanAdvanceArticleontheweb16thMarch2009
DOI:10.1039/b811227b
Covering:2000to2008.Previousreview:D.L.WrightandC.R.Whitehead,Org.Prep.Proced.Int.,
2000,32,309–330
Anoverviewofsyntheticeffortstowardcyathanediterpenoidnaturalproductsfromtheyear2000to
presentisprovided.Theemphasisofthisreviewisthevariousring-constructingandstereoforming
strategiesemployedinthesesyntheticroutes.
1 Introduction past this date.1 For the purpose of comprehensive review and
2 Overviewofthecyathanediterpenoids comparison, however, all knowncompleted totalsyntheses will
2.1 Isolation bedetailedherein.Thefocusofthisreviewiscentereduponthe
2.2 Bioactivity strategies used for ring formation and the introduction of
2.3 Biosynthesis stereochemistryenroutetocyathanenaturalproducts.
3 Strategysummary
4 Cyathanecoresyntheses 2 Overview of the cyathane diterpenoids
4.1 Wender’scyathanecoresynthesis
4.2 Desma€ele’scyathanecoresynthesis The cyathane diterpene natural products are isolated from
4.3 Takeda’scyathanecoresynthesis adiversevarietyoffungi,sponges,andfruitingplants.However,
5 Cyathanetotalsyntheses despitetheirmyriadnaturalsources,allareunifiedbythepres-
5.1 Snider’s((cid:2))-allocyathinB and(+)-erinacineA enceofacharacteristic5–6–7tricarbocyclicfusedcorestructure
2
5.2 Tori’s((cid:2))-allocyathinB (1,Fig.1).Withinthisclassofnaturalproductscanbefoundthe
2
5.3 Piers’((cid:2))-sarcodoninG cyathins, the allocyathins, the erinacines, the sarcodonins, the
5.4 Ward’s((cid:2))-allocyathinB scabronines,thestriatals,thecyanthiwigins,andthecyafrins,all
3
5.5 Ward’s((cid:3))-cyathinA ofwhichdisplay theconservedcarbonscaffoldofthecyathane
3
5.6 Nakada’s(+)-allocyathinB skeleton(1).Ofthetwentycarbonsthatcomprisethiscyathane
2
5.7 Nakada’s((cid:3))-erinacineB framework, the C(6) and C(9) carbons present all-carbon
5.8 Nakada’s((cid:3))-erinacineE quaternary stereocenters, which bear angular methyl groups at
5.9 Trost’s(+)-allocyathinB thepointsofringfusion.Almostallofthecompoundswithinthe
2
5.10 Danishefsky’s((cid:3))-scabronineG cyathaneclassdisplaythesemethylgroupswithanantirelative
5.11 Phillip’s (+)-cyanthiwigin U, (+)-cyanthiwigin W, and stereochemical relationship, though the cyanthiwigin natural
((cid:3))-cyanthiwiginZ productspossessasynarrangement.Thecyathanecorestructure
5.12 Reddy’s(+)-cyanthiwiginAC isadditionallycharacterizedbythepresenceofanisopropylside
5.13 Stoltz’s((cid:3))-cyanthiwiginF chainatC(3)andanexocycliccarbonatomconnectedtoC(12).
6 Conclusions
7 Acknowledgements 2.1 Isolation
8 References
In1971,AyerandBrodiepublishedareportinwhichanextract
from the bird’s nest fungus Cyathus helenae was scrutinized to
better understand its antimicrobial activity. Though no full
1 Introduction structural assignment was made for any compound within the
extract,theactivecomponentsofthemixturewereseparatedvia
Thisreviewisintendedtopresentanoverviewofsyntheticefforts chromatography. After isolation and elemental analysis, the
published toward the cyathane diterpenoid natural products. compounds responsible for the observed antimicrobial activity
Theworksummarizedhererepresentsanupdatetotheprevious were named (without structural elucidation) as cyathin A , A ,
3 4
reviewonthistopicwhichwasreportedin2000,andassuchwill B , B , C , and allocyathin A .2 The first fully characterized
3 4 5 4
only cover cyathane core syntheses described in the literature cyathanediterpenenaturalproductsweresubsequentlyreported
byAyerandcoworkersin1972, whenthesubstancepreviously
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, identified as cyathin A was found to be a mixture of isomeric
3
Divisionof Chemistry and Chemical Engineering, California Institute of
compounds, which were then named cyathin A (2) and allo-
Technology, 1200 East California Boulevard, MC 164-30, Pasadena, 3
cyathinB (3).3Numerousothercyathinandallocyathinnatural
California, 91125, USA. E-mail: [email protected]; Fax: [phone]
9297;Tel:[phone] products were discovered subsequent to this report, including
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Fig.1 Representativecyathanediterpenoidnaturalproducts.
allocyathin B (4),4 a cyathane diterpenoid which has since additional natural sources. It was discovered that the fruiting
2
becomethefocusofnumeroussyntheticstudies. bodies of Hericium erinaceum contained a number of glycosy-
Following the identification of the primary cyathin diterpe- latedallocyathinB analogues,whichwereeventuallynamedthe
2
noids,severalstructurallyrelatedcompoundswereisolatedfrom erinacines. Among the compounds obtained from Hericium
JohnEnquistwasborninSanta Brian M. Stoltz was born in
Rosa, CA, USA in 1982. He Philadelphia, PA in 1970 and
received his BA in chemistry obtainedhisBSdegreefromthe
from the University of Cal- Indiana University of Pennsyl-
ifornia, San Diego in 2004, vania in Indiana, PA. After
where he worked in the labora- graduate work at Yale Univer-
tories ofProf.Yitzhak Tor.He sityinthelabsofJohnL.Wood
has been a graduate student in and an NIH postdoctoral
the laboratories of Prof. Brian fellowship at Harvard in the
Stoltz since 2004, where his Coreylabshetookapositionat
work has focused on the total the California Institute of
synthesis of natural product Technology. A member of the
molecules.Hisresearchinterests Caltech faculty since 2000, he
JohnEnquist include cascade reactions, BrianM:Stoltz currently is the Ethel Wilson
synthesis of biologically active Bowles and Robert Bowles
naturalproducts,transitionmetal-catalyzed transformations,and Professor of Chemistry and a KAUST GRP Investigator. His
asymmetricmethodologywithafocusontheformationofmultiple research interests lie in the development of new methodology for
stereocenters. generalapplicationsinsyntheticchemistry.
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erinaceum were erinacine A (5), erinacine B (6), and the more considerable potency in the stimulation of NGF synthesis,5,7b
structurallycomplexerinacineE(7).5 acapacitythatimplicatestheirpotentialastherapeuticagentsto
In1989Nakayamaandcoworkerspublishedtheisolationand treat neurodegenerative ailments such as Alzheimer’s or Par-
structuralassignmentofeightnewcyathanemoleculesfromthe kinson’sdisease.11
fungusSarcodonscabrosuswhichtheynamedthesarcodoninsA–
H.6Thesecompoundspossesstheconserved5–6–7tricycliccore 2.3 Biosynthesis
foundinallothercyathanenaturalproducts,butaredistinctin
thattheydisplayadditionaloxidationattheC(19)position,such The details of cyathane diterpenoid biosynthesis have been
as is observed with sarcodonin G (8). An additional class of covered in Wright’s review, and as such will only be briefly
cyathane diterpene compounds was later identified from the summarized here.1 Subsequent to his isolation of the parent
same Sarcodon scabrosus fungus by Oshima in 1998, when cyathins, Ayer conducted an in-depth study to scrutinize the
isolation and characterization of scabronine A–F were dis- biosyntheticoriginofthecyathanediterpenoidcore.Bygrowing
closed.7 Six years later, Liu et al. reported the isolation of two Cyathus earlei in the presence of 13C-labelled sodium acetate,
additionalscabroninemoleculesfromthesamesource,including Ayer was able to isolate and examine the cyathin molecules
scabronineG(9).7Structuralelucidationofthesenaturalprod- produced by these fungal bodies. Analysis of these compounds
uctsrevealedthepresenceofacarboxylgroupatC(17),afeature via 13C NMR allowed Ayer to conclude that the biosynthetic
which marks the scabronines as distinct from the remainder of pathway toward the cyathane core tricycle involves cascade
thecyathanes. cyclization and subsequent rearrangement of geranylgeranyl
In1992,Kashmanandcoworkerspublishedareportdetailing diphosphate(Scheme1).12
the isolation and characterization of the first cyanthiwigin
molecules. Initially isolated from the marine sponge Epipolasis 3 Strategy summary
reiswigi, cyanthiwigins A–D were fully characterized and
Since the isolation of the first cyathane natural products in the
assigned absolute configuration via NMR, X-ray, and Mosher
early 1970s, numerous research groups have endeavoured to
ester analysis.8 A decade later the laboratories of Hamann iso-
synthesizethesecompounds.Amultitudeofdifferingstrategies
lated the same four cyanthiwigins, plus an additional 23
have been documented in the literature, and many of these
compounds of this class, from the Jamaican sea sponge Myr-
approachesarepresentedhereinschematicform.Thesynthetic
mekioderma styx. This isolation included the products cyanthi-
effortsreportedtodatecanberoughlycategorizedbytheirkey
wigin F (10) and cyanthiwigin U (11). In years subsequent to
transformations, which are further divided as either metal-
their initial report, Hamann and coworkers have isolated and
mediated reactions (Scheme 2), or alkylation/aldol reactions
characterizedtheadditionalnaturalproductscyanthiwiginAB–
(Scheme3).
AG, including the structurally unique spirocyclic cyanthiwigin
A majority of the cyathane syntheses published to date
AC(12).9
leveragevariousmetal-catalyzedtransformationstoaccomplish
difficultorcomplicatedring-formingreactions.Forexample,the
2.2 Bioactivity
strategy employed by Trost et al. relies upon Ru-catalyzed
The biological activities of the cyathane natural products vary cycloisomerization to close the central B-ring of the cyathane
widelyamongthedifferentmoleculeswithintheclass.Manyof core, an approach which leads back to allylic alcohol 17. Simi-
these diterpene compounds, such as the previously discussed larly,Desma€ele’sroutereliesuponaPd-catalyzedintramolecular
((cid:3))-cyathinA (2)and(+)-allocyathinB (3),possessantibiotic HeckcyclizationtoconstructthecoreB-ring,invokingdiene21
3 3
orantimicrobialactivity.Indeed,almostallofthesubcategories asacriticalretrosyntheticprecursor.Danishefsky’sapproachto
ofcyathanemoleculesdisplaymildactivityinthisregard.2,4,9In thetricycleimplementsanFe-catalyzedNazarovcyclizationfor
additiontoservinganantibioticfunction,somemembersofthe constructionofthefive-memberedA-ring,allowingforstrategic
cyanthiwigin compounds have displayed limited cytotoxic disconnection back to dienone 23. Beyond the A- and B-rings,
activity against human primary tumor cells, as well as P388 metal-catalyzed methodology has also been used to target the
murineleukemiacellsandA549lungtumorcells.9,10 seven-membered C-ring of the cyathane core. For example,
However, the most significant biological activity reported Snider’s method toward these diterpene molecules employs an
among these diterpenoid molecules is their powerful ability to Al-catalyzedcarbonyl-enereactionforC-ringconstructionfrom
encourage the synthesis of Nerve Growth Factor (NGF). Both bicyclicaldehyde18.Thepoweroftransition-metalcatalysishas
theerinacineandthescabroninenaturalproductshavedisplayed also enabled routes that employ a strategy of simultaneous
Scheme1 Biosynthesisofthecyathanecoretricyclefromgeranylgeranyldiphosphate.
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Scheme2 TransitionmetalandLewisacid-catalyzedretrosyntheticdisconnectionstowardthecyathanediterpenoidtricycliccore.
multicyclicconstruction.Forexample,Phillips employsaneffi- also played a role in cyathane synthetic design. Reddy discon-
cientRu-catalyzedring-openingring-closingmetathesisstrategy nectsthesmallersix-memberedC-ringofcyanthiwiginACviaan
tobuildboththeA-andC-ringsofthecyathanecoreintandem, enolate spiro-alkylation strategy to invoke bicycle 29 as
thus invoking bridged bicycle 22 as a retrosynthetic precursor. a precursor (Scheme 3b). An anionic alkylation approach has
Wender’s [5 + 2] cycloaddition approach toward the cyathane also beenemployedwithafocusuponconstructionofthe five-
skeleton allows for cascade construction of both the B- and C- memberedcyathaneA-ring.Piers’retrosyntheticanalysisopens
rings simultaneously, thus retrosynthetically disconnecting the the A-ring to vinyl iodide 24, a structure, which after lithium-
core backward to ynone 20. The strategy employed by Stoltz halogenexchangeandketonetrapping,isclosedtogiveatricy-
relies upon Ru-catalyzed C-ring construction, but more imper- clicsystem.
atively, implements Pd-catalyzed alkylation for quaternary
stereocenter formation. This invokes bis-b-ketoester 19 as
4 Cyathane core syntheses
acriticalretrosyntheticprecursor.
Anotherunifyingapproachbywhichthecyathanetricyclehas Thesectiondetailedbelowisintendedasanupdatetothereview
beentargetedisthatofanalkylationstrategy,oftenspecifically published in 2000. As such, only cyathane core syntheses pub-
intheformofanaldolreaction.InordertoconstructtheC-ring lishedafterthisdatewillbesummarizedhere.
of the tricyclic diterpene core, Ward and his group employ an Several groups have devised efficient strategies toward the
ozonolysis and aldol sequence. This ring-expanding strategy cyathanetricycliccore,withpossibleextensionstowardmultiple
invokestricycle28asanimportantsyntheticprecursor(Scheme completedcyathanenaturalproducts.Theseeffortshavefocused
3a).ToriimplementsasimilartechniquetoC-ringformationin uponpreparationofthetricyclicframeworkfoundinthetypical
his synthesis, in which bis-aldehyde 26 is invoked via a discon- cyathanemolecules.
nectionofthecyathanecorebymeansofanintramolecularaldol
reaction.ThecyathaneC-ringhasalsobeentargetedviaaunique
4.1 Wender’scyathanecoresynthesis
[3+4]annulationreactiondevelopedbyTakeda,whichemploys
25 as a bicyclic precursor to the larger tricyclic skeleton. A A general route toward the construction of the 5–6–7 tricyclic
convergentstrategytargetingtheB-ringofthecyathanecoreis diterpene core was reported by the laboratories of Wender in
carriedoutinNakada’sapproachtowardthesenaturalproducts. 2001byimplementationofa[5+2]Rh-catalyzedcycloaddition
By disconnecting the central ring of the tricycle, Nakada envi- reaction.13 Beginning with ((cid:3))-limonene (30), hydrogenation,
sions tethered system 27 as the critical substrate for an intra- oxidativeolefincleavage,andintramolecularaldolcondensation
molecularaldolreaction.Non-aldolalkylationprocedureshave afforded enal 31 (Scheme 4). After reduction and vinyl ether
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33allowedaccesstodiol34,whichwasoxidized,thenexposedto
1-propynylmagnesium bromide to generate propargyl alcohol
35. Attempts to execute a [5 + 2] cycloaddition reaction using
alcohol 35 as the starting material were unfortunately unsuc-
cessful,andyieldedonlyacomplicatedmixtureofproducts.For
this purpose, enyne 35 was oxidized to conjugated ketone 20
beforeexecutingthe[5+2]cycloadditionreaction.
Upon exposure of vinylcyclopropane 20 to 5 mol% of
[Rh(CO) Cl] , the desired cycloaddition reaction proceeded in
2 2
highyieldtoprovidetricycle38asasinglediastereomer(Scheme
5).14 The critical [5 + 2] cycloaddition reaction initiates with
complexationoftherhodiumcatalysttoboththealkynemoiety
and the vinylcyclopropane group. This is then followed by
oxidative cyclometallation to form an intermediate metal-
locyclopentane (36), which in turn undergoes strain-driven
cyclopropane ring-opening and ring-expansion to generate
a transient metallocyclooctadiene species (37). Reductive elimi-
nationofrhodiumfrom37thereafteryieldstricyclicstructure38,
representingacompletedcyathanecore.Thestructureoftricyclic
enone 38 was verified by single-crystal X-ray crystallography.
Overall,thisstrategyallowsaccesstoacompleted5–6–7tricyclic
structurein14stepsand13%overallyield.
Scheme3 (a)Alkylationandaldolretrosyntheticdisconnectionsofthe
cyathane diterpenoid tricyclic core. (b) Reddy’s retrosynthetic discon-
nectionofthecyanthiwiginACcore.
formation,athermalClaisenrearrangementyieldedaldehyde32
asa10:1mixtureofinseparablediastereomers.Cyclopentane32
wasthereafteradvancedalongfoursteps,includingozonolysisof
the exocyclic methylene and addition of lithium cyclo-
propylacetylide, to furnish cyclopentanol 33 as a mixture of Scheme 5 Wender’s [5 + 2] cycloaddition reaction to construct the
diastereomers. Stereoselective reduction of cyclopropyl alkyne cyathanecoretricycle.
Scheme4 Preparationofthecritical[5+2]cycloadditionprecursor.
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4.2 Desma€ele’scyathanecoresynthesis anintramolecularHeckcyclizationinvolvingaseven-membered
ring dienone proved quite difficult to advance along this
Ageneralizedsyntheticroutetowardthetricycliccyathanecore
synthetic path, and for this reason Desma€ele opted to employ
structure was developed by Desma€ele and coworkers in 2002,
asix-memberedringtoserveasasurrogateforthecyathaneC-
and an updated version of this strategy was later published in
ring.
2005.15 When addressing the challenges present in constructing
Several attempts to cyclize precursor 43 via intramolecular
the tricyclic cyathane framework, Desma€ele states that estab-
Heck reaction under standard conditions were met with diffi-
lishing the anti relationship between the methyl groups of C(6)
culty, with most attempts yielding either undesired acetate
and C(9) represents the most significant obstacle. In order to
addition products or incorrect relative stereochemistry.15a
solvethis stereochemical issue, the strategy envisioned employs
Eventually,furtheroptimizationofthisreactionleadDesma€ele
late-stage construction of the central B-ring of the tricycle via
todiscoverthatexposureoftriflate43to20mol%ofPd(OAc) in
intramolecular Heck reaction between tethered A- and C-ring 2
the presence of PPh and n-Bu NBr could execute the desired
fragments. 3 4
Heck reaction to yield tricycle 44 in 73% yield and a 19:1 dia-
Thesynthesiswasinitiatedfromknown,enantioenrichedketo-
stereomericratiobasedonthenewlyformedstereocenteratC(6)
ester39(Scheme6).16Mukaiyamaaldolreactionwithacetalde-
(Scheme 8). This transformation constructed the central B-ring
hyde,followedbydehydrationandisomerization,yieldedenone
of the cyathane core while simultaneously establishing the
40.Aftercuprateadditiontoandsaponificationofester40,the
necessaryall-carbonquaternarystereocenteratC(6)viadesym-
intermediateketo-acidobtainedwasthensubjectedtotheKochi
metrizationofthependentC-ringprecursor.15b,c
modification of the Hunsdiecker reaction to afford primary
Elaborationoftricyclicdienone44towardthe cyathanecore
iodide41.Displacementofiodide41withthelithiumenolateof
structureproceededviahydrogenationofthedisubstitutedolefin
methyl ester 42 then provided tethered intermediate 21, which
usingWilkinson’scatalysttogiveenone45.Thisreductionwas
wassubjectedtoafourstepsequencetoaccessthecriticalHeck
then followed by treatment of tricycle 45 with trimethyl
cyclizationprecursor43(Scheme7).Notably,priorattemptsat
Scheme6 SynthesisofDesma€ele’salkyliodidecouplingpartner.
Scheme7 PreparationofthecrucialHeckcyclizationprecursor.
Scheme8 Heckcyclizationandaluminium-promotedringexpansionreactionstotargetthecyathanetricycle.
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aluminium and trimethylsilyl diazomethane to effect an orga- 5 Cyathane total syntheses
noaluminium-promotedringexpansion.17Thisreactionafforded
The followingsection isintended as a comprehensivereview of
the completed 5–6–7 tricyclic framework as a 6:1 mixture of
all disclosed total syntheses of cyathane diterpenoid natural
ketone(46)andenone(47)isomers.Byobtainingthesetricyclic
structures, Desma€ele accomplished the construction of the cya- productspublishedtodate.
thanecoretricycleover15stepsandanoverallcombinedyieldof
1.4%forbothisomersobtained. 5.1 Snider’s(±)-allocyathinB2and(+)-erinacineA
The first total synthesis of any cyathane diterpenoid natural
productwasaccomplishedbySniderandcoworkersin1996with
4.3 Takeda’scyathanecoresynthesis
their preparation of allocyathin B .20 Snider’s synthetic plan
2
Asynthesisofthecyathanecoreleveraginga[4+3]annulation invokedtheuseofacarbonyl-enereactiontotargetthecyathane
strategy was disclosed by Takeda and coworkers in 2000.18 core,andthisstrategywaslaterextendedbeyondallocyathinB
2
Starting from known racemic enone 48, addition of ethynyl in order to achieve the synthesis of (+)-erinacine A via glyco-
Grignard was followed by a Rupe rearrangement to give sylation.
extendedconjugatedenonesystem25(Scheme9).Formationof Beginningwithknownracemicenone48,21triflateformation,
thelithiumenolateof25wasfollowedbyadditiontoacylsilane palladium-catalyzed carbonylation, and oxidation state manip-
49. Initial nucleophilic addition of the enolate of 25 to 49 ulation allowedaccesstoenal55(Scheme11).Conjugateaddi-
produces intermediate alkoxide 50, which undergoes Brook tionofacupratespeciesgeneratedfromGrignardreagent56to
rearrangement and nucleophilic addition to form cyclopropane the b-position of extended unsaturated system 55 provided
51. Divinyl cyclopropane species 51 subsequently undergoes aldehyde 57, which was subsequently methylated at the a-posi-
spontaneous [3,3] sigmatropic rearrangement, a mechanism tiontoaffordbicycle18.Atthispointinthesynthesis,Snider’s
whichisacceleratedbythepresenceofanalkoxide.Afterrear- route called for construction of the C-ring via intramolecular
rangement occurs, the completed cyathane core structure 52 is carbonyl-enereactionofaldehyde18.Intheevent,treatmentof
affordedasasinglediastereomer.19 18withMe AlClinitiatedrearrangementtogiveasingleisomer
2
Continued functionalization of tricycle 52 was accomplished ofalcohol58inexcellentyield,thuscompletingthefinalringof
by diastereoselective DIBAL reduction, a process which thetricyclicnaturalproduct.22
provided the isomerically pure silyl enol ether 53 (Scheme 10). The synthesis was completed over ten additional trans-
Notably, the stereochemistry imparted by this reduction affor- formations, which involved protecting group manipulation,
ded the alcohol epimer analogous to allocyathin B at C(14).19 oxidationstatemodification,andpalladium-catalyzedcarbonyl-
2
Takeda and coworkers thereafter concluded their efforts with ation starting from tricycle 58 (Scheme 12). The completed
oxidation of the enol silane present in 53 and subsequent natural product ((cid:2))-allocyathin B (4) was thus attained from
2
cleavageoftheC-boundtrimethylsilyl group.Thisprovided 54 precursor48in17stepsand6.4%overallyield.Becauseallocya-
asthefinalproductofthesyntheticsequence. thinB representsanaglyconesubstratefortheerinacinenatural
2
Beginningfromknownenone48,thedes-methylcyathanecore products,Sniderandcoworkerswerewellequippedatthispoint
was established in three steps and 19% yield, while the more to address the total synthesis of the erinacine compounds.
elaboratedcyathaneanalog54wasproducedin11%yieldover As such, glycosylation of ((cid:2))-allocyathin B with 2,3,4-tri-O-
2
fivesteps. acetyl-a-D-xylopyranosyl bromide (59) and successive global
Scheme9 Takeda’skey[4+3]annulationtotargettheC-ringofthecyathanecore.
Scheme10 AdvancementofTakeda’scyathanecorestructure.
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Scheme11 Snider’scarbonyl-enestrategytowardthecyathanetricycle.
Scheme12 Completionof((cid:2))-allocyathinB andglycosylationtoachieve(+)-erinacineA.
2
deprotection generated the natural product (+)-erinacine A (5) condensation completed the cyathane C-ring and produced
andisomericstructure60asa1:1mixtureofdiastereomers. ((cid:2))-allocyathinB (4).Overall,both((cid:2))-allocyathinB andthe
2 2
Erinacine A was prepared in 19 steps and 1.0% yield. The cyathane core structure were synthesized in 19 steps and 0.5%
cyathanecoreframeworkwasconstructedinsevenstepsand38% yield,startingfrom61.
overallyield. Subsequenttothepreparationof((cid:2))-allocyathinB ,Torialso
2
disclosed a different strategy toward the construction of the
5.2 Tori’s(±)-allocyathinB cyathane tricyclic core via ring-closing metathesis.25 Modifica-
2
tion of their route toward ((cid:2))-allocyathin B allowed access to
2
Ina reportpublished byToriand coworkersin 1998, anintra- bicyclic intermediate 67 (Scheme 14). Upon treatment of this
molecular aldol strategy targeting the synthesis of the natural materialwith20mol%ofGrubbssecond-generationmetathesis
productallocyathinB2wasdescribed.23 catalyst (69) and subsequent deprotection, completed cyathane
Starting from 3-methyl cyclohexenone (61), conjugate addi- tricycle68wasobtainedasthesoleproductofreaction.
tion, ozonolysis, and oxidation yielded diketone 62 after five
steps (Scheme 13). Intramolecular aldol condensation of cyclo-
5.3 Piers’(±)-sarcodoninG
hexanone 62 afforded bicyclic enone 63, a structure containing
thecompletedfive-memberedA-ringofallocyathinB ,including The first total synthesis of ((cid:2))-sarcodonin G was described by
2
the requisite isopropyl group. Subsequent acylation of 63 with Piers in 2000.26 Their approach to this cyathane diterpenoid
acid chloride 64 was followed by methylation and a highly addressed the tricyclic core with an alkylation and ring-expan-
optimized diastereoselective reduction employing Zn(BH ) to sion strategy, and employed late-stage installation of the
42
affordketo-alcohol65.24Additionaltransformationsoverseven peripheral functionality. Piers’ synthesis began from known
steps provided access to allylic alcohol 66, which was readily ketone 70 (introduced as a mixture of diastereomers),27 which
oxidizedunderSwernconditionstogivebis-aldehyde26.Upon was subject to hydrazone formation, epimerization at the ring
exposureof26tomethanolicKOH,afinalintramolecularaldol fusion,andnucleophilicattackonalkyliodide71toaffordvinyl
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Scheme13 Tori’sstrategytoward((cid:2))-allocyathinB.
2
Scheme14 Tori’sring-closingstrategytowardconstructionoftheseven-memberedC-ringandcompletionofthecyathanecore.
germane72(Scheme15).Furthertransformationofgermane72 convertedin71%yieldtotheone-carbonringexpandedproduct
eventuallyproducedthevinyliodidespecies24. 76. This process smoothly forms the seven-membered C-ring,
Upontreatmentof24withn-BuLi,lithium-halogenexchange and thus completes the tricyclic cyathane core. The total
and intramolecular trapping of the ketone moiety constructed synthesis is thereafter concluded in six steps to yield ((cid:2))-sarco-
the five-membered A-ring of the natural product (Scheme 16). doninG(8).
AfterdeprotonationwithKHandadditionofBu SnCH I,ether Overall the synthesis of ((cid:2))-sarcodonin G (8) was accom-
3 2
73was isolated as the major product. From this ether interme- plished in a total of 21 steps and 4.0% yield. The cyathane
diate, a Still-Mitra [2,3]-sigmatropic rearrangement provided tricycliccorewasattainedin15stepsand7.0%overallyield.
tricycle74,whichcontainstheprimaryhydroxylgroupatC(19)
requiredforsarcodoninG.28
5.4 Ward’s(±)-allocyathinB
Additional synthetic transformation of 74 over four steps 3
yieldedb-ketoester75,whichbearsana-alkyliodidegroupwell Thetotalsynthesisof((cid:2))-allocyathinB wasachievedbyWard
3
suitedforring-expansionmethodologydevelopedbyHasegawa andcoworkersin2000byleveraginganinterestingcycloaddition
(Scheme17).29UponexposuretoSmI inTHF,alkyliodide75is strategy for rapid construction of the central B-ring.30 The
2
Scheme15 VinyliodideconstructioninPier’ssarcodoninsynthesis.
Scheme16 Still-Mitra[2,3]sigmatropicrearrangementtoconstructtheA-ringof((cid:2))-sarcodoninG.
ThisjournalisªThe RoyalSociety ofChemistry 2009 Nat.Prod.Rep.,2009, 26, 661–680 | 669
Scheme17 Ringexpansionandendgamefor((cid:2))-sarcodoninG.
Scheme18 Ward’scycloadditionstrategytowardtricyclicformation.
synthesiswasinitiatedwithaDiels–Aldercycloadditionbetween transformed to propargyl ether 83 (Scheme 20). Treatment of
2,5-dimethyl-p-benzoquinone (78) and 2,4-bis(- alkyl bromide 83 with AIBN in the presence of Ph SnH and
3
trimethylsilyloxy)-1,3-pentadiene(77,Scheme18).Subsequent[2 subsequent hydrogenation produced the cyclized tetrahydro-
+2]cycloadditionwithalleneandexposuretoacidicconditions furan84.Uponexposuretomildacid,tetracycle84wasopened
thereafter afforded a 4–6–6 tricyclic system as a 4:1 mixture of totricycle85,astructurewhichcontainsallofthecarbonatoms
structural isomers (28 to 79), wherein each was produced as requiredforcompletionoftheA-ring.Fromthispoint,thetotal
asinglediastereomer.30a synthesiswascompletedinelevenstepstoyield((cid:2))-allocyathin
Thoughonlyisomer28wasdesired,the4:1mixtureof29and B (3).
3
79wasepoxidized,reducedattheenonemoiety,andthentreated Overall,Ward’sstrategytoward((cid:2))-allocyathinB comprises
3
with benzenethiol at reflux under basic conditions to effect 34 steps and is concluded in 0.1% yield. The tricyclic cyathane
closureofthecyathanecoreA-ring.Thisfurnisheda-thiophenyl corewasattainedin18stepsand11%overallyield.
enone 80 in excellent yield, in a sequence that required only
asinglepurification.30b
5.5 Ward’s((cid:3))-cyathinA
Desulfurization, deoxygenation, protection, and epimeriza- 3
tionoverninestepsthenallowedaccessto5–6–6allylicbenzoyl A variant of Ward’s ((cid:2))-allocyathin B strategy was later
3
ester 81 (Scheme 19). The six-membered ring olefin of this rendered enantioselective to achieve the total synthesis of the
intermediate provided the reactivity required to construct the relatedditerpenenaturalproduct((cid:3))-cyathinA .30,31
3
seven-membered C-ring of the natural product. Ozonolysis of The initial Diels–Alder reaction between 2,5-dimethyl-p-ben-
enone 81 in the presence of Sudan III indicator generated zoquinone(78)and2,4-bis(trimethylsilyloxy)-1,3-pentadiene(77)
a sensitive keto-aldehyde intermediate which was subjected to was made asymmetric by employing Mikami’s titanium-based
aldol reaction, transacylation, and successive trapping via O- BINOLcatalyst(Scheme21).32Afterextensiveoptimizationofthis
methylationtoafford5–6–7tricycle82.Thisthreestepsequence cycloaddition, Ward and coworkers found that addition of Mg
completed the core framework and simultaneously established powder and silica gelaffordedcycloadduct86in90%yieldand
thetrans-annularketalbridgepresentinallocyathinB . 93%ee.With86inhand,[2+2]cycloadditionandacidichydrolysis
3
Inordertoinstallthenecessaryisopropylside-chainappended proceededasinthecaseofWard’s((cid:2))-allocyathinB synthesisto
3
to the A-ring of the natural product, intermediate 82 was then furnish28and79asa4:1mixtureofstructuralisomers.
Scheme19 Ringexpansionviaozonolysisandaldolreactiontotargetthecyathanecore.
670 | Nat.Prod.Rep.,2009,26, 661–680 Thisjournal isªTheRoyalSociety ofChemistry2009