The role of biocatalysis in the asymmetric synthesis of alkaloids

31 Pages·2013·3.55 MB·English

RSC Advances
View Article Online
REVIEW
View Journal | View Issue
The role of biocatalysis in the asymmetric synthesis of
e.
c
n
e alkaloids
c
M. d Li Citethis:RSCAdvances,2013,3,
Ae
2:31 nport 17602 Joerg H. Schrittwieser* and Verena Resch*
0U
2/2023 12:bution 3.0 Aomflokpadlheoraindrmsmaaerceodlinocoigntieco.anlAlyamcootninveigtioetfshteahlesmomemtohsaotkdienssteftonhrseivtmheelyiinrsdtpuirsdopideenudsccatlibaolsnes,edsbriouofgtencainhtgunrroealodlpgierincoatdsluaicnptspb,rtoohtaehcirhtwerasiddaietrieospngeaaclitnrauinnmdg
n 3/1Attri importance, and biocatalysis has emerged as an essential tool in this context. A number of chemo-
ded omons Received29thApril2013, ebnioztyrmanastfiocrmstaratitoengsiesnofwoardaaylksaltoaidkesyannthienscirseahsianvgelyb‘eceenntrdale’verololep.edThoisverrevitehwe syuemarms,ariniseswhdiicfhfertehnet
oam Accepted28thJune2013
wnlCo applications of biocatalysis in the asymmetric synthesis of alkaloids and discusses how recent
Dove DOI:10.1039/c3ra42123f developments and novel enzymes render innovative and efficient chemo-enzymatic production routes
013. Creati www.rsc.org/advances possible.
July 2der a 1. Introduction distribution in nature and a broad range of biological
ublished on 04 e is licensed un Tcohnetaailnkianlgoidssecaornedaarystrmucettuarbaolllyitedsivewristehgraourpelaotfivenliytrowgeidne- ci1anhc8tt1ari9rvoai,dt2ciuteeccsreo.,1dvWembrsyhoidtloheenertnlhGyeecproomlrnaicagnenitnp-daptielhordaniversemfidnaarictesiiusotbunCssotuaafarnlltlchFyee.smWtewur.micMthhe‘aiblsakrsloaknlaaeodlriiednirn’e,.
s Article. P This articl DBFaLexpD:ae+rlt3fmt1,eT1n5ht2eofN7B8ei1toh4te1erc5lha;nnTodelslo:.g+Ey3,-m1Dae1il5lf:[email protected],;Jvu.laia.rneasclaha@ntu1d36el,ft2.6n2l;8 Fdcooemfrinpiointuisontandnciconen,1ta9Si8n.3inW,gsianllyiitiarnmoggetPnheailntle‘at‘Ainenergaapltkriaovlepoooidsxeididsataaiocnvyecslrtiyacteosriwmghapniclihec
s
e
c
c
A
n
e JoergH.Schrittwieser,born1984, Verena Resch completed her MSc
p
O
studied Chemistry at the in biochemistry and molecular
University of Graz. In 2007, he biology in 2008 at the University
joined the research group ofProf. of Graz under the supervision of
Wolfgang Kroutil for working on Prof. Wolfgang Kroutil establish-
his diploma thesis dealing with ing multi-enzyme cascades.
biocatalytic cascades involving Staying in the same group she
alcohol dehydrogenases. After received her PhD in organic
participating in two short-term chemistry in 2011 working on
research projects at the the use of alkaloid pathway
Universidad Complutense in enzymes in organic synthesis.
Madrid and the Research Centre Afterashortprojectasacontract
Applied Biocatalysis in Graz, he researcher at the ACIB (Austrian
JoergH.Schrittwieser returned to Prof. Kroutil’s labs VerenaResch Centre of Industrial
where he completed his PhD, which dealt with the chemo- Biotechnology) she started as a
enzymatic synthesis of benzylisoquinoline and berbine alkaloids, post-doctoral fellow with an Erwin-Schro¨dinger Fellowship from
in2011. SinceMarch2012, he isapost-doctoral researcherwith theAustrianScienceFundattheUniversityofTechnologyinDelft
Dr Frank Hollmann at Delft University of Technology, via an inthegroupofProf.UlfHanefeld.Hermainresearchinterestsare
Erwin-Schro¨dingerFellowshipfromtheAustrianScienceFund.His alkaloid pathway enzymes, (chemo)-enzymatic cascade reactions,
researchinterestsarethedevelopmentandoptimisationofmulti- andprotein expression andcharacterisation.
enzymatic and chemo-enzymatic cascade systems, the chemo-
enzymaticsynthesisofnaturalproducts,aswellastheutilisation
offlavoenzymes for ‘‘green’’ oxidation chemistry.
17602 | RSCAdv.,2013,3,17602–17632 Thisjournalis(cid:2)TheRoyalSocietyofChemistry2013
View Article Online
RSC Advances Review
isoflimiteddistributionamonglivingorganisms’’.1d,3Thetotal above-mentioned supply limitations. For instance, genetic
number of known structures that can be categorised as modification of alkaloid-containing plants can be used to
alkaloids according to these general criteria exceeds 20,000,4 increase production levels and hence facilitate isolation.12
and around 100 new compounds are still discovered annual- Plant cell fermentation can be used to achieve production of
ly.1b The higher plants are a major source of alkaloids, as alkaloidsbythenativesourceorganismundercontrolledand
approximately 25% of all plant species contain these consti- scalableconditions.Entiresecondarymetabolicpathwayscan
tuents,1bbuttheiroccurrenceinanimals,insects,microorgan- be engineered into suitable microbial hosts, which thus
isms,and lowerplants is also well documented.1d become able to biosynthesise the corresponding natural
e. The natural functions of plant alkaloids are thought to be products.13 This approach has recently been applied to the
c
n
e mainlyassociatedwiththeinteractionsoftheplantwithother fermentativeproductionofthebenzylisoquinolinealkaloid(S)-
c
M. d Li organisms–for instance, protection against herbivores or reticuline from simple carbon sources such as glycerol or
2:31 Anporte psiantghoagneinms,alosroarttrraocottionnoodfulpeolbliancatteirniga.1idn,5seHctes,ncsee,editdiisspnenot- (gSlu)-creotsiec,uulisnineghaansebnegeinneoebrteadinEe.dcobliystfrearimn.e1n4tIantiaonrelfarotemdsdtoupday-,
0U
2:0 surprising that many alkaloids exert potent pharmacological mine, and has been further transformed into aporphine or
2/2023 1bution 3. aexcptilvoiittieeds,faorfabcotththtahterhaapseubteicenanrdecroegcnriesaetdionbaylhpuumrpaonssesafnodr pcerroetvoibsieareb.1e5rinTeheailmkaploleidmsenutastiinogn otrfanasngeennictireSabcicohsayrnotmhyecteics
ded on 3/1mons Attri tadhlrkouauglssoaidnasnddsaneodvfentyhemeairros.r1dec,e6arirvAealtsciovuersrinenhtamlvyeoudfneordunenrdmineavdpeipscltiiincgeaa,ttiioomnnanainys pSaactIhcnhwaamryoomrfyeocrecshtcehemreeivsiptsrriyao-edoruhiceatnsiotaenldsoosebfteteibnnegnrsze,yplboisirootecqdaut.i1an3l,yo1s6liisnecsaninbtoe
wnloaCom clinical trials (for a selection of therapeutically important employed for the selective modification of alkaloids toaccess
Dove alkaloids,seeTable1).Estimatedglobalsalesofover4billion non-natural or less abundant derivatives. A classical example
uly 2013. er a Creati UipnrSto$edr(ue2sc0tt0iio2nn)ftohrriosaulstkueasbl.os7tiadHnscoaewppcelvlaieesrds, iannnodmtethdaelilcninaeelckeialsllsuoisitdytrsafoteorfbefofptihucibtehlniect imisnotetrhrpcehoinnuvosenerseioorfendtouhfcetmaesonerzpfyrhmoimneasnPsmaeluokdrapolohmiiodnnsea.1s7dpeMuhotyirdderaorMgeec1en0natsfeoerxaatnmhde-
Jd
ublished on 04 e is licensed un dqoEfuestpmaeennactniiatdailelcysva,enfaornybrdemeeisxviopenlneoanrtiesfidcivosefonrlosaatmtinitoudtnheneitsitirsmpnoetah-sctseuoirbnpalsleuusromiofnuiicnrlaacgterigoiepnnrsosceucafefflfedoi,crutiiretenti.os7t cpaoanfletdtashleyivsnaiecnldlkduaodhlloeyiniddterhosexitnyolloaamctyicioeaennsldeino-cefaawtnearhilgtyyhosdteerdolaevlcckitnoarbuloolpnaild-sirnstiic,gn1h9eo,ao1fr8recnatthethhseeamcraoleanudctpichalaitisnneedge-
s Article. P This articl aarnrdiOviensoatlhtaeatioocnthheyemireilhcdaaslnlaydr,wetehtylelp-diicneaftlirlniycealdotewpm.roodluecctulcaarnabrceheitneocrtmuroeuosf, bFmiynettarhlilecy,ftubonitoagcliasAtaynnltyrttohicdeisemilsleatohsfeomdalsiksuaclpaoinnidabs2,e0taehnmedrpelCbooyyreidcooluimnsbutihnneiicnoaglsoyrtmh.2e1-
ces many alkaloids–with diverse functional groups and often flexibility of chemical routes with the high degree of chemo-
c
A multiple stereogenic centres–also makes them challenging andenantioselectivityofferedbyenzymes.Thisinterdisciplin-
n
pe targetsfortotalsynthesis.Inviewofthesedifficultiesitisjust ary approach seems to be particularly fruitful, as a consider-
O
themoreimpressivethatmanycomplexalkaloidshaveindeed ablenumber(approx.150)ofchemo-enzymatictotalsyntheses
beensynthesisedinthelab;however,longsequencesinvolving ofalkaloidshavebeenreportedoverthelast25years,whichin
extensive protective group chemistry are often required, manycasesprovemoreefficientthaneitherapurelychemical
resulting in very limited overall yields. Consequently, the synthesis or isolation of the target compound from natural
transfer of these synthetic routes to production scale usually sources.
represents a major problem. An excellent example for this Threemainstrategiesforchemo-enzymaticalkaloidsynth-
discrepancy–discussed in a recent account by Walji & esis can be distinguished: (1) the biocatalytic preparation of
MacMillan8–is the case of paclitaxel (Taxol1): Six ingenious chiralbuildingblocks,whicharechemicallytransformedinto
andhighlyacclaimedtotalsynthesesofthiscomplexalkaloid the target compounds, (2) the biocatalytic kinetic resolution,
(forthestructure,seeTable1)havebeendevelopedtodate,the
desymmetrisation or deracemisation of alkaloids that have
most efficient of which gives the target compound in 0.4%
been synthesised by chemical means, and (3) the chemo-
yield over 37 steps.9 Unfortunately, large-scale production of
enzymatic synthesis of alkaloids via biocatalytic C–N and/or
paclitaxel by this route is not practical or economically
C–C bond formation in the asymmetric key step. The first
feasible, and neither is its isolation from natural sources.
approach is definitely the most versatile, and also by far the
Today,thegrowingdemandinthisnaturalanti-tumouragent
mostexplored,butinrecentyearsbiocatalyticderacemisation
is met by plant cell fermentation,10 and the environmental
andasymmetricbiocatalyticC–Cbondformationhavegained
benefitsofthisproductionmethodhavebeenrecognisedwith
momentum. This review provides an overview of all three
the 2004 Presidential GreenChemistry Award.11
above-mentioned strategies and discusses recent develop-
The paclitaxel example already illustrates that biological
ments that are likely to change the role of biocatalysis in
methods can represent favourable options for alkaloid
futurealkaloid synthesis.
production.Indeed,biotechnologyinitsbroadestsenseoffers
several strategies that may help to overcome some of the
Thisjournalis(cid:2)TheRoyalSocietyofChemistry2013 RSCAdv.,2013,3,17602–17632 | 17603
View Article Online
Review RSCAdvances
Table1Examplesofalkaloidswithmedicinalapplicationa
Alkaloid(activeingredient) Naturalsource1d Therapeuticuse
Atropabelladonna;industrially antispasmodic;treatmentoforgano-phosphatepoisoning;
isolatedfromDuboisiaspecies, againstmyastheniagravis;againstarrhythmias;
HyoscyamusmuticusandHyoscyamusniger localtreatmentformuscularrheumatism,
sciaticaandneuralgia;inophthalmologyasmydriatic
andcycloplegicdrug1d
e.
c
n
ce Caffeaarabica,Paulliniacupana, addedtoanalgesicstoincreasetheiractivity;usedinthe
M. d Li ColanititaandColaacuminata treatmentofneonatalapnoeaandatopicdermatitis1d
Ae
2:31 nport
0U
2:0
2/2023 1bution 3. Papaversomniferum asantitussiveintreatmentofcough;asanalgesic
n 3/1Attri andmildsedative1d
ded omons
oam
wnlCo
oe
Dv
013. Creati
July 2der a GwaorlaonntohwuisicaanudcaGsaicluasn,thGuaslannivthauliss inthetreatmentofAlzheimer’sdisease24
ublished on 04 e is licensed un
s Article. P This articl Papaversomniferum paincontrol;treatmentofdiarrhoea1d
s
e
c
c
A
n
e
p
O
Taxusbrevifolia;producedindustrially intreatmentofmammaandovarycarcinomaand
byTaxusplantcellfermentation severalothermalignancies1d
Pilocarpusjaborandi,Pilocarpus intreatmentofopen-angleglaucoma1d
pennatifolius,Pilocarpusracemosus
andPilocarpusmicrophyllus
17604 | RSCAdv.,2013,3,17602–17632 Thisjournalis(cid:2)TheRoyalSocietyofChemistry2013
View Article Online
RSC Advances Review
Table1(Continued)
Alkaloid(activeingredient) Naturalsource1d Therapeuticuse
Cinchonasuccirubra intreatmentofmalaria,babesiosisand
myotonicdisorders1d
e.
c
n
e
c
M. d Li
Ae
2:31 nport DDuubbooiissiiaamleiycohphoarrodidtieis, aingdauincsttioancuotfegmenoetrioalnasnicakenstehsess;iaas1dpremedicantbefore
0U
2:0
2/2023 1bution 3.
n 3/1Attri
ded omons Catharanthusroseus itnesttriceualtamrecnatnocferHaonddgkainva’srideitsyeoafsesoalniddnoethoperlalsymmsp1hd,o5ama,
oam
wnlCo
oe
Dv
013. Creati
uly 2er a
Jd
ublished on 04 e is licensed un aadAuplatsr)t.2f5romgalantamine,alllistedsubstancesarepartoftheWorldHealthOrganization’sModelListofEssentialMedicines(17thed.,for
s Article. P This articl
s
e
cc 2. Biocatalytic asymmetric synthesis of chiral enantiomers of a chiral building block in 50% maximum
A
en building blocks yield. However, desymmetrisation of meso-compounds–which
p
O does not suffer from this limitation–is common as well. This
The chiral building block (also called ‘chiral synthon’ or strategy can also afford both enantiomers of the product,
‘chiron’) approach to asymmetric synthesis involves the provided that stereocomplementary enzymes are available, or
recognitionofstructural elementsin thetarget molecule that that the desymmetrisation can be run in both hydrolytic and
canbetracedbackretrosyntheticallytoreadilyavailablechiral acylative direction (cf. Scheme 2). Both reaction types have
molecules.22Classically,thelatterarederivedfromthe‘chiral
pool’ of amino acids, carbohydrates, terpenes, etc., while in
chemo-enzymatic approaches the chiral building blocks are
compoundsthatcanbeobtainedinhighenantiomericpurity
by a biocatalytic reaction.23 In the context of alkaloid
chemistry,lipasesandesterasesaswellastoluenedioxygenase
aremostfrequentlyusedforthegenerationofchiralbuilding
blocks, and a large number of structurally diverse alkaloids
have beensynthesised usingthese enzymes.
2.1Lipasesand esterases
Their excellent stereoselectivity and broad substrate scope,
their ability to work in organic solvents, and also their broad
commercial availability have made lipases and esterases the
mostwidelyusedbiocatalystsinorganicsynthesis.Therefore,
itisnotsurprisingthatalsothemajorityofchemo-enzymatic
synthesesofalkaloidsrelyontheseenzymes.Whenappliedin
a kinetic resolution, they can provide access to both Scheme1Chemo-enzymaticsynthesisof(2)-alloyohimbane(5).28
Thisjournalis(cid:2)TheRoyalSocietyofChemistry2013 RSCAdv.,2013,3,17602–17632 | 17605
View Article Online
Review RSCAdvances
e.
c
n
e
c
M. d Li
Ae
2:31 nport
0U
2:0 Scheme3Desymmetrisation of meso-diacetate 11 using lipase PS affords
2/2023 1bution 3. compound12,abuildingblockusedinthesynthesisofalkaloids13and14.
n 3/1Attri A later study found it difficult to reproduce the excellent
ded omons optical purity of (1S,2R)-2 in the PLE-catalysed hydrolysis
ownloae Com uScsihnegmheyd2roOlapsteios.ns for the enantioselective preparation of building block 2 pcororrceesspsoannddinmgomveedsot-doiostler6eo(sSeclhecetmivee m2)o,neomacpeltoyyliantigonpoorfctinhee
013. DCreativ pthaencsraemateiccloipmaspeou(PnPdL)inin88an%hyydieroldusanetdhy.l 9a9ce%tateee, toonagccraemss
ublished on 04 July 2e is licensed under a ttbbghhrelooee2ecu.na1kpap.us1ssp,syolemmCifdcyomacctstyloieticoctplorniricafceolwacpfolhatcaohrioectobhahlialoobclccssauoa,ynnitnpladsbitliphyidenteeeigcrcsriaiaadbstlbiellnyolgoeecoofknrbdisutase.amenriTidnvbhaeaseetdtlrikrveuobaeafclusrotc,iluilihadderinsairntldailgslyrnebbipianutloortiolorcbdtnkriteoinhiesnngef. wSo‘tsrhctvehraeedyilrcceiacshh.lo2cnl9movoviTsyapehilrae1eeellx0ddkba’apuladofoirnldildodydiimctniy(uo2gcnsli)2beac-d.allokiscinVatnkegdeperowtyrhslaieenswreaaaealsscgk(y7eaafmn,iulnotFrmlityicdhg,eo.etn(rr(+1iv1c))eeS-,lsra,ttoc2obehbRtdoaot)ra-llia2ainsntrteyieosndhdita(nhiSsinen,eStsoA)bi1-s3e9t(eh,%o83ne0f,
s Article. P This articl c1(5o9)m8f7rm,omuwnhtiihcceahthiodyndesrcborxyiybReeessntetahrtae(1SRp,ri2veRap)a-a2rna(dtSiocchnoe-mowfoer(12k)e.)r2-sa6lTlpohuyiboslhbisiumhielbddainninge F2vi0iag0.82.10)T,shyfenirttshatregitsiecotlscatoteempdsp,forwuohnmidchtwhaienscloelbuatvdaeeisnaeodnfiiAtnrlisl0teo.4nh%iyadorsvocehgroealnlalarytiisioenilnd/
es epoxide aminolysis cascade, a Fischer-type indole synthesis,
c block was obtained in 96% ee by hydrolytic desymmetrisa-
n Ac tion27 of the corresponding meso-diacetate 1 using pig liver and anoxidativelactonisation.31
pe esterase (PLE) as biocatalyst. The hydroxy ester was then Theoppositeenantiomerof2,accessibleviastereoselective
O
monohydrolysis of 1 with PPL (Scheme 2) has also found
converted into the lactone (S,S)-3, which was coupled with
application in the asymmetric synthesis of alkaloids: It has
tryptamine to give amide intermediate 4, from which 5 was
beenusedbyDanieliandco-workersinthepreparationof(+)-
preparedfollowing a literatureprocedure.
meroquinene(9),adegradationproductofcinchonineandkey
intermediate in the synthesis of Cinchona alkaloids,32 and of
the indole alkaloid(2)-antirhine(10,Fig.1).33
Lesma and co-workers, on the other hand, have extended
theconceptofhydrolyticdesymmetrisationofmeso-diacetates
to the cycloheptene derivative 11, obtaining the monoacetate
(1S,6R)-12(Scheme 3)in95%yield and.97% eeusinglipase
PS.34,35 From this building block, several 4-hydroxypiperidine
derivatives such as cis-4-hydroxy-2-pipecolic acid, a hydroxy-
lated quinolizidine 13, and the piperidine alkaloid (2)-
halosaline (14, Scheme 3) were prepared,34,36 the latter in a
very elegant sequence involving ruthenium-catalysed ring-
rearrangement metathesis asa keystep.
Anothercommonclassofchiralbuildingblocksinalkaloid
synthesis are cyclic allylic alcohols with substituents on the
double bond, such as 3-ethylcyclohexenol 15 (Scheme 4). The
kineticresolutionofthisandsimilarcompoundswithvarious
lipaseshasbeenstudiedbyPalmisanoandco-workers,37who
alsodemonstratedtheconversionof(S)-15,obtainedfromthe
Fig.1Alkaloidssynthesisedfromthechiralbuildingblock2. racematein43%yieldand99.5%eeusingBurkholderiacepacia
17606 | RSCAdv.,2013,3,17602–17632 Thisjournalis(cid:2)TheRoyalSocietyofChemistry2013
View Article Online
RSC Advances Review
e.
c
n
e
c
M. d Li
Ae
2:31 nport
0U
2:0
2/2023 1bution 3.
n 3/1Attri
ded omons
oam
wnlCo
oe
Dv
013. Creati
uly 2er a
Jd
ublished on 04 e is licensed un Scheme4Useofenzymaticallyderivedcycloalkenolbuildingblocksinthesynthesisofindolealkaloidsandspirocyclicpiperidinealkaloids.
s Article. P This articl tliyppaese(e35.g.in18n)e.3a8tAvinkyelyascteetpatien, itnhteoiraslkynaltohiedssisoifsthaetreabnusrfneranoef
s
ce chiralityfromC1ofthecyclohexenolstructuretoC3bymeans
c
A of a decarboxylative Claisen rearrangement, thus setting up a
n
pe quaternary carbon chiral centre in excellent enantiomeric
O
purity (ee = 96%). The authors followed a similar strategy in
the asymmetric synthesis of (+)-decarbomethoxy-15,20;16,17-
tetrahydrosecodine(22),whereaClaisenrearrangementofthe
ester(S)-20wasusedtoestablishatertiarycarbonchiralcentre
(Scheme 4).39 Immobilised porcine pancreatic lipase (PPL) in
neatvinylacetatewasusedforthekineticresolutionofrac-19
(the precursor to 20), and the bromine atom in the substrate
served the sole purpose of enabling a sufficiently high
enantioselectivity (E = 133) in this reaction by increasing the
steric demand of one side of the substrate. A ‘transfer of
chirality’conceptwasalsoappliedbyYamane&Ogasawarain
their chemo-enzymatic syntheses of spirocyclic piperidine
alkaloids:40 Kinetic resolution of carbethoxycyclohexenol 23
(Scheme4)withlipasePS35gavethecorresponding(R)-acetate
24in40%yieldand99%ee,alongwith53%oftheremaining
alcohol in 95% ee. Derivatisation of the alcohol (R)-23 to an
a-bromoacetal followed by a highly diastereoselective radical
cyclisation afforded the building block (1R,2S)-26, which was
further elaborated into the spirocyclic alkaloids (+)-nitramine
(27) and (+)-isonitramine (28). Similarly, its enantiomer
(1S,2R)-26was transformed into(2)-sibirine.40
Ogasawara and co-workers have developed a chemo-enzy- Scheme5Lipase-catalysed kinetic resolution of building block 29, and
matic route towards several cyclopentanoid chiral building examplesofalkaloidspreparedfromthisbuildingblock.
Thisjournalis(cid:2)TheRoyalSocietyofChemistry2013 RSCAdv.,2013,3,17602–17632 | 17607
View Article Online
Review RSCAdvances
e.
c
n
e
c
M. d Li
Ae
2:31 nport
0U
2:0
2/2023 1bution 3.
n 3/1Attri
ded omons Scheme6Fukuyama’schemo-enzymatictotalsynthesisof(2)-morphine(43).
oam
wnlCo
oe
013. DCreativ absloymckms,eturiscinkgeycysctleoppeinstatdhieenkeinaesticstraerstoinlugtiomnatoefriarla.4c1-cisT-h29e apperhmanidoirnpehi(n3e2),(3a3s, wSeclhleamseth5e).4b2enInzomadodripthioann, ailtkahlaosidb(e2en)-
July 2der a eromopmlotyeinmgpelirpaatusereP(SS3c5heinmem5e)t.hTyhlitserttr-abnustfyolrmethateiron(MpTroBcEe)edast einlatebromraetdeidatienteontrhoeutecytcoloShceexleetniuomneadlkearliovaidtisv.e4334, which is an
ublished on 04 e is licensed un (wp510uiSt%rh,e4,Rfe)or-xeracmscepeltel(aecetnteeitv.e3le0yn9).9aa%nnCtd)ioomatshnepeldeoc(ui+tnni)v-d(ih1tyiRg,2,h94aSif)shf-ooaalrlsacdtoienshdegorlyvieb2edo9ldthsians(4toh3sp%etatirct(aa2innll)dgy- uainlsstWeoedrhmbiinleeeednmtihaueteelmctsihppifllreooarylsebydsnuintithlgdoeliesnaegcsscbyeonlsfotschakelskstoiamdcloiesiecdnu‘spds,useleraidppvooassusoeer-sfmca.aratAhdalaey’vnseiocstbhaehibreaalnesl
s Article. P This articl malkaateloriiadls,ininctlhuedin(fgorm(2a)l-)phtyostoasltisgymntihneesi(s31o)fanvadri(o+u)-sasipniddoolse- Shexcyahdmeromplyleeti6ci)s,kwFinuhekitcuihcyarumesseaos’lsuthttioeotnaallcosofyhntohtlhe3ec6soi,sroreobsftpa(io2nne)d-dminiongrpa9hc9e%intaeteee(43b35y,
s
ce using lipase AK.35,44 All five stereocentres of the target
c
n A molecule were established from 36 with excellent diastereo-
pe control, and (2)-morphine was obtained in 5% overall yield
O
over 17linear steps.
2.1.2Piperidinebuildingblocks.Thefirstnitrogen-contain-
ing chiral building block derived from an enzymatic reaction
was introduced to the asymmetric synthesis of alkaloids in
1992: Momose and co-workers have investigated the stereo-
selective transesterification of N-protected meso-9-azabicy-
clo[3.3.1]nonanediol 44 (Scheme 7), as well as the
stereoselective hydrolysis of the corresponding diacetate,
catalysed by various lipases.45 In both cases, a commercial
lipase from Humicola lanuginosa35 gave the best results,
providing access to both enantiomers of the monoacetate 45
in high yield and good enantiomeric excess (ee = 90% for R,
80% for S). The monoacetate was oxidised to the correspond-
ingketone46,whichcouldbeobtainedinopticallypureform
by a single recrystallisation from diisopropyl ether. This
ketone, in turn, was transformed into the trisubstituted
piperidine building block 47 via enol ether formation and
ozonolytic cleavage of the bicyclic core structure (Scheme 7).
Compound 47 proved useful for further elaboration into
differentpiperidinealkaloids,suchas(+)-dihydropinidine(48)
Scheme7Lipase-catalyseddesymmetrisationofdiol44,itsconversionintothe and (2)-cassine (49),45,46 as well as indolizidines and
trisubstitutedpiperidinederivative47,andexamplesofalkaloidspreparedfrom
quinolizidines sequestered by the poison-dart frogs of the
thisbuildingblock.
17608 | RSCAdv.,2013,3,17602–17632 Thisjournalis(cid:2)TheRoyalSocietyofChemistry2013
View Article Online
RSC Advances Review
e.
c
n
e
c
M. d Li
Ae
2:31 nport
0U
2:0
2/2023 1bution 3.
n 3/1Attri
ded omons
oam
wnlCo
oe
Dv
013. Creati
uly 2er a
Jd
ublished on 04 e is licensed un
s Article. P This articl Spcipheermideine8Bbiuoicldaitnaglytbiclopcrkep5a2ra,taionndoefxbaomthpleensaonftioamlkearlosiodfsthpere2p,a6r-eddisufbrostmituttheids
ces buildingblock. Scheme9Biocatalyticpreparationofthe3,5-disubstitutedpiperidinebuilding
Ac blocks59and61,andexamplesofalkaloidspreparedfrom61.
n
e
p
O
Dendrobatidae family, e.g. (2)-indolizidine 235B9 (50,
Scheme7).47 enzymes for this transformation, affording (2S,6R)-38 in 80%
yield(ee=95%)and90%yield(ee=98%),respectively.50Inthe
The obvious advantages of nitrogen-containing chiral
former case, the piperidine intermediate was further trans-
building blocks in the asymmetric synthesis of alkaloids led
formedintothenon-naturalenantiomeroftheDendrobatidae
several other research groups to investigate biocatalytic
alkaloidindolizidine209D[(+)-56],50awhileinthelatteritwas
methodsfortheirpreparation,andpiperidinederivativeshave
attracted particular interest. Chˆenevert and Dickman have elaborated into polyhydroxylated indolizidines and quinolizi-
investigated the hydrolytic desymmetrisation of meso-diace- dines, e.g. (2)-57 (Scheme 8), via a sequence featuring ring-
tates 51 (Scheme 8) with various lipases and have identified closing metathesis and OsO4-catalysed dihydroxylation as key
the enzyme from Aspergillus niger as the most selective steps.50b
biocatalyst.48 The (2R,6S)-monoacetates 52 were isolated in 3,5-cis-Disubstituted piperidines also form a common
good yields (76–92%) and excellent optical purity (ee . 98%), structural motif in natural products, for example in indole
butthereactiontookseveraldays(72–108h)tocomplete.Still, alkaloidsoftheiboganandtacamantype,orin(2)-sparteine,
the authors could demonstrate the synthetic utility of the which has found broad application as a chiral ligand. Lesma
method by converting the monoacetates into (+)-dihydropini- and co-workers first tried to establish an asymmetric entry to
dine (48, Scheme 7) and the dendrobate frog alkaloids (+)- 3,5-disubstitutedpiperidinebuildingblocksviastereoselective
hydroxypiperidine 241D (54) and (2)-indolizidine 167B (55, enzymatichydrolysisofmeso-diesters58(Scheme9),butboth
Scheme 8).48b,49 Later studies avoided the time-consuming yield and optical purity of the obtained monoesters 59 were
hydrolysis protocol and focused on the preparation of the only moderate.51 Stereoselective monoacetylation of the
opposite enantiomer of 52 by lipase-catalysed stereoselective analogouspiperidine-3,5-dimethanols60(Scheme9)catalysed
monoacetylation. The lipases from Candida antarctica and by the lipase from Pseudomonas fluorescens turned out to be
Candida cylindracea (the latter employed in the ionic liquid more efficient, providing the (3S,5R)-enantiomer of mono-
BMIM-PF as reaction medium) were found to be suitable acetates61ingoodyield(74–78%)andexcellentopticalpurity
6
Thisjournalis(cid:2)TheRoyalSocietyofChemistry2013 RSCAdv.,2013,3,17602–17632 | 17609
View Article Online
Review RSCAdvances
e.
c
n
e
c
M. d Li
Ae
2:31 nport Senchaenmtioeco1m0pPlreempaernattaiorynlipoafsesb.oth enantiomers of the 2-substituted piperidine building block 67 via a triple kinetic resolution protocol employing
0U
2:0
2/2023 1bution 3. (ee.98%).52Theoppositeenantiomercouldconvenientlybe (Scheme 10). The optically enriched building blocks were
n 3/1Attri accessed by hydrolytic desymmetrisation of the diacetates 62 transformed into both enantiomers of sedamine (69) and
ded omons uobsitnaginetdhesesravmede aesnzaymbea.siTshfeorchthirealpbreupiladriantgionbloocfkssevtehruasl afallsohsieodna,m(+i)n-deu(7m0e,tFoirgin.2e)(i7n1)t,h58re(e2a)d-cdointiioinneal(7s2te)p,5s9.aInnda(s2im)-eilpair-
wnloaCom compounds featuring cis-fused piperidine rings as core dihydropinidine(73)wereprepared,wherebyinthelattercase
oe structure, e.g. the 3,7-diazabicyclo[3.3.1]nonane derivative the N-Boc group served as a lithiation director in the
Dv
013. Creati 6an3,d53athteruLnecgautmedino(+sa)-espaalrktaelionieda(2na)-lcoygtuisei.n55e F(6u4r,thSecrhmemoree,9t)h,5e4 liunptriondinuectaiolknaloofidth(e+)6-a-mlopetehryinlesu(7b4s)tiwtuaesnst.y5n8tFhuesrtisheedrmfroorme, (tRh)e-
uly 2er a conversion of derivatives of 61 into the ibogan type indole 67 in a 12-step sequence that featured the use of a laccase–
s Article. Published on 04 J This article is licensed und atbdlaienelleeskktvIesrsaanecanllsrcooatirycitbiiegcddtoeeplamsidnotce(tpra+idatfaro)erbe-rnaddNoim,s.ivk-5hoBe6naeny,olwodtcmhwor-topoornokciu.nplgteoethPhahrsaeviuadsastbsimednascvitrie-oeine-rtn2lueoalt-alrtaee,ti(mdnh6pR5saooid)nlvn,ayeaoosr,lufi9sevub-6aaambn6stttiusdeivattmreiusitcsnutbocegteh-hdewradiearovdpanerplikpriaebpiuetrnuertnsgririduali,hddcishnaitiunneaveadgeessl TasrinetnEepg2dMrr.e1efPoos.o3OcerfhnsetNtahymicsethtDiresoisitmrenyranylelsft–abohAtbruelutisdthlihideslrderienioeongrfxgceibhandlciibaortttlarciiooolkocngsnckeestnonhf.oftarrhOpteerspasti.retem6ei0rtctoaapicrnlayylgyrcatlielucacsucpo.tlhiaTvotrehhllyeemninnoicttiioreteorrrtroenieensecstest-,
s
ce block, but this compound proved a challenging substrate for
c
A
n lipase-catalysed kinetic resolution due to its conformational
e
p flexibility and the distance of the alcohol moiety from the
O
stereogenic centre.57 The enantioselectivities observed were
generally low (E ¡ 8), but the identification of two
enantiocomplementaryenzymes–(S)-selectiveporcinepancrea-
tic lipase (PPL), and (R)-selective lipase PS (from Burkholderia
cepacia)35–allowed the preparation of both enantiomers of
acetate67indecentopticalpurity(ee=90%forR,95%forS)
via a complex, but scalable triple kinetic resolution protocol
Scheme11Synthesisof(+)-allopumiliotoxin323B9(80)fromthelipase-derived
Fig.2Examplesofalkaloidspreparedfrombuildingblock67. buildingblock(R)-75.
17610 | RSCAdv.,2013,3,17602–17632 Thisjournalis(cid:2)TheRoyalSocietyofChemistry2013
View Article Online
RSC Advances Review
e.
c
n
e
c
M. d Li
Ae
2:31 nport
0U
2:0
2/2023 1bution 3.
n 3/1Attri
ded omons
oam
wnlCo
oe
Dv
013. Creati
uly 2er a
Jd
ublished on 04 e is licensed un S(2ch)-eromsema1r2inCeacsincaed(e92re).actionsinvolvingnitrone–olefin(3+2)-cycloadditionsinthechemo-enzymaticsynthesesof(+)-febrifugine(86),(+)-isofebrifugine(87),and
s Article. P This articl moietycanreactwitholefinsininter-orintramolecular(3+2)- procedure forms the cornerstone of Kita’s asymmetric synth-
s
e
cc cycloadditions, which often proceed with excellent regio- and esis of (2)-rosmarinecine (92): the racemic hydroxynitrone 88
A
n diastereoselectivity,andfurthermorethisfunctionalgroupcan was stereoselectively acylated with the maleate ester 89 using
e
Op provideanitrogenatompresentinthetargetmolecule.These immobilised CAL-B (Chirazyme L-2),35 and the acylation
features were exploited by Holmes and co-workers,61 who product underwent a spontaneous intramolecular (3 + 2)-
prepared nitrone 76 from the chiral alcohol (R)-75 cycloaddition to afford compound 91, featuring 4 contiguous
(Scheme 11), which was obtained in 47% yield and 92% ee stereocentres, asa single diastereomer in58% yieldand 92%
by kinetic resolution of the racemate using lipase PS35 under ee (Scheme 12). Recrystallisation and minor functional group
previouslyreportedconditions.62Intramolecularcyclisationof interconversionscompletedthesynthesisofopticallypure92,
76affordedaseparablemixtureofisomers,ofwhichthemajor which was obtained in 45% overall yield from rac-88.64 An
one (77, 32%) was converted into the indolizidine (2)-79,61a improved procedure for the preparation of rac-88 published
and further into the dendrobate frog alkaloid (+)-allopumilio- some years later even rendered the use of protective groups
toxin323B9 (80).61b unnecessary.65
Hatakeyama and co-workers have devised a synthetic
sequence towards the antimalarial Hydrangea alkaloids (+)-
febrifugine (86) and (+)-isofebrifugine (87), in which the
nitrone 84 is a key intermediate (Scheme 12).63 Kinetic
resolutionofalcohol81usingimmobilisedCandidaantarctica
lipase B (CAL-B; Novozym 435)35 provided the corresponding
(S)-acetate 82 in 43% yield and 91% ee (enantioselectivity E =
50). The key step of the synthesis is a cascade nitrone
formation–cycloadditionreaction,whichjoinsthreemolecules
andsetsuptworingsandtwochiralcentresinoneoperation,
albeit in only moderate diastereoselectivity. The mixture of
Scheme13Preparation of aromatic cis-dihydrodiols, e.g. 94, by biocatalytic
isomersobtainedwastransformedintothetargetalkaloids86
dioxygenation of arenes, and some general methods for their further
and 87 in six additional steps. An even more elegant one-pot functionalisation.
Thisjournalis(cid:2)TheRoyalSocietyofChemistry2013 RSCAdv.,2013,3,17602–17632 | 17611