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review articlePublished online: 19 February 2010 | doi: 10.1038/nchem.539

The complexity and structural diversity o natural productshave ascinated organic chemists or a very long time. Tedevelopment o new types o chemical reactions over the past

ew decades has enabled synthetic chemists to assemble almostevery discovered natural product. A main driving orce or thesehuge synthetic eorts is clearly the important biological activitieso natural products, which are not only o enormous interest orthe pharmaceutical and agrochemical industry, but also have along-lasting impact on natural sciences and the wealth and welareo our society1.

A historical retrospect on the progress o the total synthesis onatural products2,3 reveals that most o the synthetic approachesshare two main eatures: the so-called stop-and-go approach4, andthe implementation o orthogonal protecting-group strategies. Both

single-step and protecting-group operations have increased signi-cantly the number o chemical steps and waste, while simultaneouslydecreasing the synthetic eciency. Nevertheless, organic synthesisis a relatively young discipline o the natural sciences comparedwith nature, which has been optimizing its biosynthetic machineryover billions o years o evolution. Te blueprints o biosynthesisare based on some key elements, namely cascade reaction sequencesand the avoidance o protecting-group strategies, which, when puttogether, have a tremendous impact on the eciency o biosynthe-sis57. In addition, all natural products are built up via a relativelysmall number o basic biosynthetic pathways that employ simplekey building blocks. Teir complexity and diversity are achieved bythe myriads o dierent possible combinations o these key buildingblocks and by their urther enzymatic transormations.

Current developments in the eld o total synthesis indicatethat chemists have adopted the undamental principles o biosyn-thesis, namely cascade reactions810, protecting-group-ree syn-thesis11, redox economic12, atom economic13, step economic14 andbiomimetic synthesis15,16 as strategic key elements or their syntheticapproaches17. In this Review we want to draw the readers attentionto the eld o organocascade reactions, which have an importantrole in the ecient and rapid generation o complex architectures.

One o the big advantages o such domino reactions over classi-cal synthesis is that at least two reactions are carried out in a singleoperation under the same reaction conditions18. Furthermore, this

og w

cp G1*, m J2 d e2*

T totl nti o ntrl prodt nd biologill tiv opond, prtil nd groil, rd n xtrordinr lvl o opitition. W r, owvr, till r w ro t idl nti nd t tt o trt i till rqntl prd b lngt protting-grop trtgi nd otl priftion prodr drivd ro t tp-b-tp protool. In rnt r vrl nw ritri v bn brogt orwrd to olv t probl nd to iprov totlnti: to, tp nd rdox ono or protting-grop-r nti. Ovr t pt dd t rr r o orgno-tli rpidl grown to bo tird pillr o tri tli tnding nxt to tl nd biotli, t pvingt w or nw nd powrl trtg tt n lp to ddr t i orgnotlti d rtion. In ti Rviww prnt t frt pplition o tri orgnod rtion to t totl nti o ntrl prodt.

avoids time-consuming, costly protecting-group manipulations aswell as the isolation o reaction intermediates. In this way molecularcomplexity is achieved quickly, oen accompanied by high levels ostereoselectivity. A major topic o current research is the explorationo catalysed cascade reactions by employing a single catalyst capa-ble o promoting each single step. Organocatalysts are particularlyavourable when used in catalytic cascade reactions because theyallow distinct modes o activation, which can oen be easily com-bined19,20. Furthermore, organocatalysts are tolerant o numerousunctional groups and can be employed under mild reaction con-ditions. Tis enables a single organocatalyst to be used in a broadvariety o possible cascade reactions. Tereore, these small organicmolecules, such as the natural amino acid proline, are oen con-sidered as small articial enzymes. It is thus unsurprising that the

eld o asymmetric organocatalytic cascade reactions has attractedmuch attention, and a lot o powerul new reaction cascades or therapid construction o molecular complexity, starting rom simplekey precursors, have been explored in recent years.

In this Review we would like to highlight not only the rst appli-cations o organocatalytic cascade reactions in total synthesis, butalso give the reader an impression o how powerul this concept isand how it can help to simpliy the synthesis o complex naturalproducts and biological active compounds.

cp gTe use o LUMO-lowering iminium ion activation and HOMO-raising enamine activation has been studied intensively in syntheticorganic chemistry over the past 10 years. Recent advances in cata-

lyst development have demonstrated that it is possible to ecientlycontrol the iminium ion geometry in the stereoselective ormationo carboncarbon and carbonheteroatom bonds. Likewise, enam-ine activation has gained signicant attention or controlling theabsolute conguration in the -unctionalization o aldehydes andketones by a variety o electrophilic reagents. Tese two powerulmethodologies contributed signicantly to the success o the rapidlydeveloping area o asymmetric organocatalysis2127. Te combina-tions o iminium and enamine activation in a single operation oan organocatalysed cascade reaction constitute a second milestonein the area o amine-catalysis. Initiated by these rst contributions,

1Bayer CropScience AG, Alred-Nobel-Str. 50, 40789 Monheim am Rhein, Germany. 2Institute o Organic Chemistry, RWTH Aachen University, Landoltweg 1,

52074 Aachen, Germany. *e-mail: [email protected]; [email protected].

20 Macmillan Publishers Limited. All rights reserved10
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review article NaTuRe chemIsTRydoi: 10.1038/nchem.539

urther attempts in the eld o cascade reactions have been able toexplore various ways o combining enamine and iminium catalysis.Tis concept is limited not only to simple tandem processes, butalso to triple-cascade extensions and, since very recently, impres-sive quadruple-cascades have also been elaborated2830. Te numbero reactions or each activation mode and the exponential increaseo combinations or double, triple and quadruple processes pavethe way to various new reaction combinations and new and rapidentries or the synthesis o complex and valuable synthetic building

blocks (Fig. 1).Nowadays, organocatalytic cascade reactions are not limited to

amine catalysis. Signicant contributions have also been made inthe eld o hydrogen-bonding and Brnsted-acid catalysis (coun-ter-ion catalysis). Hydrogen-bonding catalysis with small chiralorganic molecules has emerged as a powerul research area in theeld o asymmetric organocatalysis. Tese catalysts activate thesubstrates by orming a hydrogen-bond (LUMO-lowering) andare able to promote several CC and Cheteroatom bond-ormingreactions. A prominent class among the hydrogen-bonding cata-lysts are the thioureas, which have already ound application incascade reactions. Chiral Brnsted acids activate the substrates byprotonation o a suitable C=X bond (X: O, NR, CR2) thereby lead toa chiral counter-ion31,32. In this manner, the LUMO energy is low-

ered and a nucleophilic addition to the C=X bond is now possible.Phosphoric acids are a very amous class o chiral Brnsted acidsand have also ound widespread application in the eld o organo-catalytic cascade reactions.

Very recently, NHC-catalysis33 has also been applied to cascadesequences3436N-heterocyclic carbenes (NHCs) are capable o acti-vating carbonyl groups through umpolung37 to undergo nucle-ophilic acylation reactions. Te combination o such nucleophilic

acylations with standard modes o activation will be o particularinterest in the uture.

Tese organocatalysed cascade processes represent a poweruland novel way o approaching bond disconnections. However, theirapplication to natural product synthesis remains a big challenge andrepresents a valuable benchmark or these new synthetic methods.

h kgTe application o organocatalysed cascade reactions in natural

product synthesis was impressively demonstrated or the rst timeby erashima and co-workers in 1998 when the eld o organoca-talysis was just in its inancy38. Tey used an asymmetric cascadereaction as the key process or their concise synthesis o ()-huper-zine A (1), a natural product isolated rom the club moss Huperziaserrata and belonging to the class o sesquiterpene alkaloids. Tiscompound shows interesting biological activities, or example,potent reversible acetylcholinesterase inhibitor activities, and iscurrently being tested in clinical trials as a promising drug or thetreatment o Alzheimers disease39. Tereore 1 is the target o manysynthetic approaches (Fig. 2).

()-Huperzine A contains a challenging bridged tricyclic core,which was obtained via a simple Michael/aldol cascade reactionsequence between -keto ester 2 and methacrolein. Te organo-

catalyst ()-cinchonidine acts as a base by deprotonating the -ketoester 2 and orming a chiral ion pair. Te secondary alcohol unc-tion o the catalyst simultaneously activates a methacrolein mol-ecule by orming a distinct hydrogen bond and incorporating itinto the ionic complex. Te Michael reaction, as the rst step othe cascade sequence, is thus initiated, ollowed by an intramo-lecular aldol condensation. Te tricyclic core 4 o ()-huperzineA was ormed with an overall yield o 60% and 64% enantiomeric

Activation modes

Enamine activation of

aldehydes and ketones

(HOMO raising)

Iminium activation of

,-unsaturated aldehydes

(LUMO lowering)

NH

Typical reaction steps

Michael reaction

DielsAlder reaction

FriedelCrafts reaction

Aldol reaction

-Functionalization

Michael reactionMannich reaction

EN

Established combinations*

NH

NO

Simple Triple Quadruple

Catalysts

Protonation

(LUMO lowering)

(counterion catalysis)

Hydrogen bonding

(LUMO lowering)

IM IM

IM

IMEN

EN EN

EN

IM IM EN IM ENEN

H+

Reduction

Mannich reaction

FriedelCrafts reaction

Michael reaction

Michael reaction

Henry reaction

Mannich reaction

Strecker reaction

HN

HN

S

H+ H+

H+

EN

O

OP

O

OH

IMEN EN

H+ H+ H+

IM IMEN

EN

H Do

N N

N UmpolungBreslow intermediate NHC

Nucleophilic acylation

Benzoin reaction

Stetter reaction

IM NHC

H Do H Do

IM

EN

Figr 1 | Orgnotld d rtion. Summary o the dierent combinations o organocatalytic activation modes so ar described. *Only the

organocatalysed bond-ormation steps are taken into account. Simple (double, tandem) is the simplest case o a cascade reaction (two steps).



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excess (e.e.). By employing this key cascade sequence, the comple-tion o the total synthesis starting rom 4 could be achieved in onlyve urther steps.

a- Te area o amine-catalysed cascade reactions is clearly dominatedby secondary amines due to the versatility o possible combinationso enamine (EN) and iminium (IM) activation4042. Among them,the IMEN combination has turned out to be very powerul. In2005 several contributions were made by the groups o Jrgensen43,List44 and MacMillan45. oday, numerous examples o this combi-nation can be ound in the literature19. Hence it is not surprisingthat simple IMEN sequences have already been utilized in totalsynthesis (Fig. 3).

Te rst example comprises a cascade oxa-Michael/aldol con-densation reaction or the rapid construction o dierent tetra-hydroxanthones. Tese intermediates are key building blocksor the synthesis o diversonol or blennolide C, natural products

belonging to the large class o mycotoxins ound in many dier-ent ungi. Teir biological activity ranges rom antibiotic to anti-bacterial46. Starting rom the salicylaldehyde derivative 5 and thecyclohexenone rac-6, Brse and colleagues developed an elegantimidazol-catalysed oxa-Michael/aldol cascade sequence to build upthe tetrahydroxanthenone core 7 (Fig. 3a). Aerwards, only a ewtransormations were necessary to aord rac-diversonol 8 (re. 47),a potent metabolite isolated rom the ungus Penicillium diversum,or to accomplish the total synthesis o blennolide C (9)48. Althoughone new stereogenic centre is ormed during the cascade reaction,this stereochemical inormation is eventually erased later in thesynthesis. Tereore, stereocontrol was not required and the use oan achiral base catalyst such as imidazol was sucient. Later on, thesame research group demonstrated that, to access ()-diversonol,

enantiomerically pure6

could be also employed in this reactionwithout the loss o any enantiomeric excess49. Te mechanism othis oxa-Michael/aldol condensation reaction was studied in detail,and it was shown that tertiary amines (or example, 1,4-diazabi-cyclo[2.2.2]octane; DABCO) can promote this reaction as well50.Although this example does not constitute an IMEN sequence, itopened the way or related organocatalysed hetero-/aldol cascadereactions involving a secondary amine catalyst which promotes IMand EN activation modes.

Camptothecin (13), a pentacyclic alkaloid, isolated rom thebark and stem o Camptotheca acuminate, and rst synthesizedby Stork and Schultz51 in 1971, is a powerul inhibitor o the DNAenzyme topoisomerase I and has thereore attracted considerableattention rom the academic community and the pharmaceuti-cal industry52. Because o its very promising anticancer activity,

several highly potent derivatives o camptothecin were synthesized,and some o them have already been launched as eective cancerdrugs (topotecan, irinotecan). Both topotecan (Hycamtin) andirinotecan (Camptosar) are semisynthetic drugs derived rom 13,

which has to be isolated rom Camptotheca acuminate. Althoughnumerous research groups have elaborated dierent total synthe-ses o camptothecin and its derivatives, none o them are attractiveenough rom an industrial point o view. o achieve a more practi-cal and ecient total synthesis, the Yao research group employeda piperidine-catalysed cascade reaction ollowed by oxidation toassemble the cyclic A and B core o13 (Fig. 3b)53,54. Teir approachwas based on inexpensive starting materials, namely the ortho-aminobenzaldehyde and the simple ,-unsaturated aldehyde 10.In this IMEN sequence, piperidine rst activates 10 by iminiumion ormation, which subsequently undergoes a conjugate additionwith ortho-aminobenzaldehyde. Te enamine intermediate result-ing rom this addition promotes an intramolecular aldol condensa-tion and the subsequent ormation o 11, which is then oxidized

by MnO2 into the key precursor 12. Tis simple cascade-oxidationsequence proceeds in 75% overall yield.A very similar IMEN cascade sequence was used or the or-

mal synthesis o martinelline by Hamada and co-workers55 (Fig. 3c).Martinelline 20 and martinellic acid 19 were isolated rom the rootsoMartinella iquitosensis. Tese pyrroloquinoline alkaloids act asnon-peptidic bradykinin receptor agonists and are characterizedby an unusually used pyrrolidino-tetrahydroquinoline core56. TeHamada approach employed an asymmetric aza-Michael/aldol cas-cade reaction to orm the dihydroquinoline 17. A series o dierentamine catalysts as well as solvents were screened in order to improvethe yield and the enantioselectivity. Best results were ound with thecatalyst/solvent combination o the triethylsilyl-protected diphenyl-prolinol 16 in acetonitrile at 20 C, which gave 17 in almost quan-

titative yield and 99% e.e.Besides the amous IMEN cascade sequence, many successulreactions were achieved by simply changing the order o activa-tion. Te ENIM cascade sequence also paves the way or a rapidaccess to molecular complexity as well. Tis sequence can alreadybe ound in some natural product total syntheses, like the syn-thesis oent-dihydrocorynantheol, -tocopherol or 4-dihydroxy-diversonol (Fig. 4).

In a rst example, Itoh and co-workers established a proline-catalysed Mannich/Michael cascade reaction or the total synthesisoent-dihydrocorynantheol (24) (Fig. 4a)57. Dihydrocorynantheolis a member o the corynantheines, archetypal indole alkaloidsexhibiting interesting antiparasitic, antiviral or analgetic activities.Dihydrocorynantheol was rst isolated in 1967 rom the bark oAspidosperma marcgravianum and has since been an interesting

NH2

HN

O

N

CO2Me

HO

OMe

CHO

OCO2Me

N OMe

OCO2Me

N OMe

HO

5 stepsAcONa, AcOH

120 C, 24 h

77%64% e.e.

()-Huperzine A2 3 4

()-Cinchonidine

DCM, 10 d, 10 C

45%

()-Cinchonidine

N

OH

NH

1

N

O

OMe

N O

H

O

N

H

O

MeO

Intermediate ionic complex

H

DoH DoH

Figr 2 | Firt pplition o n orgnotld d rtion in totl nti. Preparation o the sesquiterpene ()-huperzine A by means o an

organocatalysed Michael/aldol cascade reaction sequence. DCM, dichloromethane; AcONa, sodium acetate; AcOH, acetic acid.



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protonating the nitrogen and orming the iminium ion 75. Te rsthydride transer rom the Hantzsch ester 71 generates the enamineintermediate 76, which can be activated again as an iminium ionand undergo another hydride transer. etrahydroquinolines 73 areobtained with good yields and 90-91% e.e., and the desired alkaloidsare nally obtained rom 73a-c byN-methylation.

A similar approach was also used by the Rueping group to syn-thesize some decahydroquinolines (Fig. 7b)81. Tese are very impor-tant scaolds in natural products and, in particular, the main core o

the pumiliotoxin amily derivatives. Pumiliotoxins are toxins oundin the skin o poison dart rogs native to central and south America.Tese very powerul toxins interere with the calcium channelaecting muscle contraction and resulting in death. Te Brnstedacid catalyst 81 can activate the pyridine 80 as an iminium ion andpromote a double-cascade hydrogenation in which the Hantzschester 71 has the role o the hydride source. Tis cascade sequenceenables the ormation o the decahydroquinolines 82, which canbe converted into the di-epi-pumiliotoxin C (83) according to themethod developed by Hsung and co-workers82.

og f pTe true acid test or a new synthetic methodology is the successulapplication to the production on an industrial scale o biologically

active compounds such as pharmaceuticals and agrochemicals. Withthe recent advance o the so called swine fu (H1N1), which can eas-ily spread rom human to human, the World Health Organizationwas orced to rate the new disease as a pandemic and recommendedthe use o the neuramidase inhibitors amifu and Relenza. Demandor both drugs increased rapidly within a short time, because mostcountries stockpile these therapeutics to be prepared in the event oa severe outbreak.

Although amifu (91) and Relenza (92) look small and not toocomplex, the diculty o their preparation is caused by the highdensity o unctional groups (Fig. 8a). Te imminent shortage oamifu supply made chemists rom all over the world think o newand more ecient syntheses83. Among the various new approaches,Hayashi and colleagues have developed a powerul one-pot reac-

tion or the rapid construction o the amifu core84

. Te rst stepo this process is the addition o aldehyde 84 to nitroalkene 85. TisMichael addition is catalysed by the diphenylprolinol silyl ether86 via an EN activation mode and proceeds in almost quantitativeyield and excellent enantioselectivity. Intermediate 95 then entersa classical cascade reaction by reacting with vinylphosphonate87 via a Henry-type Michael addition to orm 96, ollowed by anintramolecular HornerWadsworthEmmons olenation, whichassembles the cyclohexene core o88. Unortunately, a mixture o(5R)-88 and (5S)-88, in which the undesired 5R isomer predomi-nates, was obtained. reatment o this mixture with an acid or abase allows only partial conversion o the 5R isomer into the 5S iso-mer. Te authors circumvented this problem by adding thiophenolat the end o the cascade reaction and the resulting sula-Michael 85

product89

was generated predominantly as the desired 5S isomer.Tis sophisticated cascade sequence enabled Hayashi et al. to buildup the polyunctionalized cyclohexene core o amifu in a conciseway. Te synthesis was completed by employing two urther one-potreaction sequences with a total yield o 57%. Te Hayashi amifusynthesis demonstrates the power o asymmetric organocatalysisand cascade reactions and may well allow the fexible synthesis onew derivatives active against amifu-resistant viruses. Althoughthis example does not truly belong to the chapter o organocatalyticcascade reactions, the possibility o combining an organocatalyticreaction with a non-catalytic reaction in a cascade procedure show-cases prospective applications o organocatalytic cascade reactionsto pharmaceutically relevant targets like amifu.

In a similar manner, the powerul combination o organocataly-sis and cascade reactions or one-pot processes in the synthesis o

therapeutics can also be illustrated by the synthesis o ()-epibati-dine developed by akemoto and colleagues (Fig. 8b)86. Tis groupdeveloped an organocatalytic one-pot procedure involving an enan-tioselective double Michael addition. Te thiourea 99 catalysedthe rst Michael addition o the ,-unsaturated -ketoester to thenitroalkene 98. Ten, on addition o some potassium hydroxide,the newly ormed nitroalkane cyclized to orm the polysubstitutedcyclohexene 100 in a high yield and 75% e.e. Te total synthesis o()-epibatidine (102) was achieved in seven steps rom 100. Tis

alkaloid was isolated in the late 1990s rom the skin o a poison-ous rog living in the Amazon rainorest. Te biological activityo this alkaloid was well known, and it was rumoured that nativeAmericans used it to coat the tips o their arrows. Owing to its hightoxicity this alkaloid is some 200 times more potent than mor-phine and its lack o selectivity on nicotinic receptors, ()-epiba-tidine will never be a candidate or pharmaceutical development.Nevertheless, it is an amazing lead compound and it will certainlyopen the route or the development o more selective derivatives,or example, ebanicline. Furthermore, it was ound that it is a pow-erul agonist or the insecticidal nicotinic acetylcholine receptors,analogous to the mode o action o the chloronicotinyl insecticides,or example, Imidacloprid.

cTis Review summarizes the initial development o the applicationo organocatalytic cascade reactions in natural product synthesisand gives a perspective o uture industrial applications in drugsynthesis. Although this concept is still in its inancy, it is clearlyan emerging approach in total synthesis with advantages such asrapid one-pot entries to molecular complexity via atom, step andredox economic protocols. A survey through the literature revealsthat the number o publications rom 2005 to 2009 has increasedyear by year and the target molecules have become more complex,with a tendency rom simple cascade reactions to triple and evenquadruple cascades. With the various recently developed organo-catalytic activation modes at hand, including the concept o biunc-tional organocatalysts and multicatalytic systems, numerous novel

cascade sequences can be envisaged. We hope that this short Reviewwill inspire the synthetic community to continue the search or neworganocatalytic cascade reactions and to implement this conceptinto their uture synthetic strategies.

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