ARTICLEdoi:10.1038/nature10232

Collective synthesis of natural productsby means of organocascade catalysisSpencer B. Jones1, Bryon Simmons1, Anthony Mastracchio1 & David W. C. MacMillan1

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time,resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction ofcomplex natural products and the development of large collections of biologically relevant molecules present significantchallenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namelyorganocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities ofa range of structurally diverse natural products from a common molecular scaffold. The power of this concept has beendemonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products:strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.

The field of natural product total synthesis has evolved dramaticallyover the past 60 years owing substantially to the efforts of strategy-based organic chemists along with remarkable improvements in ourbond-forming capabilities. However, two critical challenges thatremain for this field are those of translating laboratory-level academicsuccess in total synthesis to the large-scale assembly of biologicallyimportant molecules1 and building large collections of natural productfamilies (or their analogues) for use as biological probes or in medicinalchemistry2.

To address these two fundamental challenges in small-moleculesynthesis, we have been inspired by the strategies used in nature tosolve these problems. For example, as chemists, we typically use ‘stop-and-go’ synthetic protocols, whereby individual transformations areconducted as stepwise processes punctuated by the isolation andpurification of intermediates at each stage of the sequence3. By con-trast, in nature the rapid conversion of simple starting materials tocomplex molecular scaffolds is accomplished through the use of trans-formation-specific enzymes, which mediate a continuous series ofhighly regulated catalytic cascades in what amounts to be a highlyefficient ‘biochemical assembly line’4,5. Moreover, biosynthesis in natureprovides an appealing alternative to the traditional ‘single-target’approach to chemical synthesis in that it typically involves the construc-tion of natural product collections through the assembly of a commonintermediate (Fig. 1).

Design planWe recently sought to develop a novel asymmetric approach to totalsynthesis based on the application of these two nature-inspired con-cepts, namely collective total synthesis and organocascade catalysis3,4.Whereas syntheses targeting an advanced core structure applicable tothe synthesis of closely related natural products within a family havebeen frequently reported6, much less common is the preparation ofan intermediate endowed with functionality amenable to the prepara-tion of structurally diverse natural products in different families—astrategy we term collective total synthesis7,8. We predicted that thehybridization of the strategies of collective natural product synthesisand enantioselective organocascade catalysis9 should rapidly giveaccess to useful quantities of single-enantiomer natural product col-lections or families with unprecedented levels of ease and efficiency.

1Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA.

CH2OH

Strychnine

N

N

O O

H

H

H

H

O

OGluc

CHO

MeO2C SecologaninNH

NH2

Tryptamine

N

N

H Me

MeO2C

Preakuammicine

NH

N

H Me

CHO

Norfluorocurarine

NH

CO2Me

N

Et

Didehydrosecodine

(Strychnos)

Common tetracyclic core

NH

N

Me

Vincadifformine

CO2Me

(Aspidosperma or Kopsia)

Figure 1 | Cascade catalysis in biosynthesis. In nature, transform-specificenzymes in continuous catalytic cascades rapidly produce commonbiosynthetic intermediates and natural products. Preakuammicine serves as abiosynthetic precursor to a range of structurally diverse members of theStrychnos, Aspidosperma and Kopsia alkaloid families, including strychnineand vincadifformine. Et, ethyl; Gluc, glucose; Me, methyl.

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To demonstrate this approach, we targeted for total synthesis six well-known, structurally complex members of the Strychnos, Aspidospermaand Kopsia families of alkaloids, in particular strychnine, the best-known member of the Strychnos family, which has been the focus ofintense synthetic interest for over 50 years. Moreover, this target hasserved as a key metric for the success of our nature-inspired dualtechniques10,11.

Importantly, strychnine is believed to share a biosynthetic pre-cursor with a range of prominent Strychnos, Aspidosperma andKopsia alkaloids12. This common intermediate, preakuammicine,arises biosynthetically through a controlled enzymatic cascade invol-ving a coupling of the precursors tryptamine and secologanin,

followed by skeletal rearrangement (Fig. 1). Thus, in a prime exampleof natural economy, a single intermediate is exploited in the construc-tion of a diverse collection of complex molecular products.

We expected the preparation of intermediate 1, which incorporatesthe requisite functionality for expedient conversion to each of the targetnatural products (Fig. 2), to be a central element of our design strategy.The key tetracyclic precursor 1 would itself be accessed through aone-flask, asymmetric Diels–Alder/elimination/conjugate additionorganocascade sequence commencing with a simple tryptamine-derived substrate13.

In detail, we hoped that exposure of the 2-(vinyl-1-selenomethyl)tryptamine system 2 to propynal in the presence of an imidazolidinonecatalyst (3) would set in motion a Diels–Alder [4 1 2] addition13

(Fig. 3). As a key element of enantiocontrol, the acetylenic functionalityof the catalyst-bound propynal would be expected to partition awayfrom the bulky tert-butyl (t-Bu) group, leaving the naphthyl groupeffectively to shield the bottom face of the reacting alkyne. The acti-vated dienophile would then undergo endo-selective Diels–Aldercycloaddition with the substituted 2-vinyl indole 2. By contrast withour previous studies using methyl-sulphide-substituted 2-vinylindoles, as demonstrated in our synthesis of minfiensine13, we felt aconceptually unique series of cascade cycles might arise through theincorporation of organoselenide substitution on the diene, leading to anovel, architecturally complex system. More specifically, followingthe Diels–Alder cycloaddition, the cycloadduct 4 would be poisedto undergo facile b-elimination of methyl selenide to furnish theunsaturated iminium ion 5. We proposed this change in mechanismowing to the higher propensity of selenides to undergo b-eliminationin comparison with sulphides14.

In the second cycle, iminium-catalysed 5-exo-heterocyclization of thependant carbamate was expected to occur at the d-position to the indo-linium ion (5 R 6; Fig. 3, path A, X 5 NR2) to deliver, following hydro-lysis, the enantioenriched spiroindoline core (1). We considered thepossibility of an alternative second cycle wherein iminium 5 mightundergo facile cyclization at the indoline carbon to generate pyrroloindo-line 7 transiently (Fig. 3, path B). In this situation, we recognized thatamine or Brønsted acid catalysis might thereafter induce the necessary5-exo-heterocyclization of the pendant carbamate to also furnish 6.Importantly, either cascade sequence could allow for the rapid andenantioselective production of the complex tetracyclic spiroindoline

NP

NHBoc

Common tetracycle (1)

X NP

NBoc

CHO

Im Im

Akuammicine

Strychnine

NH

N

HMe

Aspidospermidine

Kopsanone

Kopsinine

NH

N

NH

N

CO2Me

O

N

N

O O

H

H

H

NH

N

CO2Me

H

H Me NH

N

Me

Vincadifformine

CO2Me

KopsiaAspidospermaStrychnos

Figure 2 | Collective natural product synthesis: nature-inspired applicationof cascade catalysis. Synthesis of six structurally diverse Strychnos,Aspidosperma and Kopsia alkaloids is expected to proceed from a commonintermediate tetracycle prepared by means of organocascade catalysis. Boc,tert-butoxycarbonyl; Im, iminium catalysis.

Path B

NP

NBoc O

N

NH

t-Bu

Me O

1-Nap

N

NH

t-Bu

Me O

1-Nap

N

N

OMe

t-Bu1-Nap First cycle

(Im)

Second cycle

(Im) or (H+)

= HNR2

N

NH

t-Bu

Me O

1-Nap

NP

N

Boc

X

NP

N

Boc

X

NP

NH X

NP

NH

Boc

NR2

SeMe NP

NH

Boc

NR2

NP

NHBoc

Boc

•HA

•HA

A

A

A

A

A

Common intermediate (1)

O

O

•HA

A

[4+2]

Path A

4

NP

SeMe

NHBoc

5

8

6

6′

PNMeSe

BocHN

endo

3

3 3

3

NP

O

7

NR′

NP

NR2

NR′

R′ = Boc

R′ = Boc

X = NR2

X = OH

2

Figure 3 | Proposed mechanism of organocascade cycles for the generationof a common tetracyclic intermediate (1). An organocascade reactionbetween 2-vinyl indole 2 and propynal is expected to proceed through an

organocatalytic Diels–Alder/b-elimination/amine conjugate addition sequencealong path A, involving iminium ion catalysis, or path B, involving Brønstedacid catalysis. 1-Nap, 1-naphthyl; SeMe, selenomethyl.

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1 from simple tryptamine-derived and ynal substrates in a singleoperation.

Experimental resultsThe feasibility of the proposed organocascade sequence was firstevaluated in the context of a total synthesis of strychnine. The requisite2-vinyl indole 10 was prepared in three steps from 9 according to thestandard procedures outlined in Fig. 4 (ref. 15). The crucial organo-cascade addition–cyclization was accomplished with the use of1-naphthyl-substituted imidazolidinone catalyst 3 in the presence of20 mol% tribromoacetic acid (TBA) co-catalyst, forming the complexspiroindoline 11 in 82% yield and with excellent levels of enantioin-duction (97% e.e.). Notably, we have now gathered evidence that path Bof the cascade sequence is operational. Specifically, when the sameprotocol was performed in the presence of stoichiometric catalyst at278 uC and quenched after 10 min with Et3N, an 84% yield of pyrro-loindoline 7 (protecting group, PMB) was obtained. Moreover, expo-sure of pyrroloindoline 7 (protecting group, PMB) to catalytic 3?TBAand, separately, N-methyl 3?TBA (incapable of undergoing iminiumformation) facilitates the conversion to the spiroindoline 11 at com-parable rates.

The product of the key organocascade sequence, tetracyclicspiroindoline 11, was advanced to strychnine in only eight additionalsteps (Fig. 4). In detail, decarbonylation was achieved through the useof Wilkinson’s catalyst. Subsequent treatment with phosgene andmethanol16 served to introduce a carbomethoxy group at the diena-mine a-position. Next, on exposure to DIBAL-H, the enamine unsa-turation was reduced and the requisite tertiary indoline stereocentrewas installed to provide the unsaturated ester 12 (existing as an incon-sequential mixture of alkene isomers) in 62% overall yield for thethree steps. We converted intermediate 12 to vinyl iodide 14 througha two-step 76%-yield protocol involving allylation with the substi-tuted allyl bromide 13 and concomitant alkene isomerization, fol-lowed by DIBAL-H-mediated reduction of both ester functionalities.

As a second key step, we predicted direct conversion of the vinyliodide 14 to the protected Wieland–Gumlich aldehyde 15 through acascade Jeffery–Heck cyclization/lactol formation sequence17.Insertion of palladium into the vinyl iodide and subsequent carbo-palladation would forge the six-membered ring and produce an alkylpalladium intermediate, which would then undergo b-hydride elimi-nation to provide an enol that would rapidly engage in lactol forma-tion with the proximal alcohol-bearing side chain.

Following extensive investigations, we discovered an optimizedset of conditions to allow successful Jeffery–Heck cyclization/lactol

formation, using vinyl iodide 14 to form the PMB-protectedWieland–Gumlich aldehyde 15 in 58% yield18. Early studies showedthat the PMB protecting group was critical in facilitating regioselectiveb-hydride elimination away from the indoline ring methine (and pro-ductively towards the alcohol). Such a high degree of regiocontrol pre-sumably arises from the allylic strain that accompanies formation of theN-PMB-substituted enamine, a destabilizing element that is absentfrom the corresponding enol formation step.

Finally, the synthetic sequence was completed by TFA-mediatedremoval of the PMB group13 to furnish the Wieland–Gumlich aldehyde(16), which, on heating in a mixture of malonic acid, acetic anhydride andsodium acetate18, delivered enantioenriched (2)-strychnine in 12 stepsand 6.4% overall yield from commercial materials. To our knowledge,this asymmetric organocascade-based sequence is the shortest route toenantioenriched strychnine that has been accomplished so far19–22.

We next turned to the construction of related alkaloids of theStrychnos, Aspidosperma, and Kopsia families based on the strategyof collective total synthesis outlined above. The total synthesis of (2)-akuammicine11 (Fig. 5) was achieved starting with unsaturated ester12 (prepared in the course of the synthesis of strychnine; see Fig. 4).Treatment of the PMB-protected spiroindoline 12 with TFA andthiophenol at 60 uC resulted in the cleavage of the PMB protectinggroup as well as isomerization of the alkene into conjugation with the

NN

N

I OH

OH

H

(–)-strychnine 12 steps

N

O O

H

H

H

HN

N

HO O

H

H

HPMB PMB

61%

58% 66%NH

N

HO O

H

H

H

69%

Wieland–Gumlich

aldehyde (16)

N

NH

CO2MeH

PMB

76%

g, h i j k

12

14 15

–40 °C to RT, toluene

20 mol% 3•TBA

11N

NBoc

CHO

PMB

N

PMB

NHBoc

SeMe

82%, 97% e.e.

NH

NBoc

109

63%

a–c d–f

O

Figure 4 | Twelve-step enantioselective total synthesis of (2)-strychnine.Reagents and conditions are as follows. a, NaH, PMBCl, dimethylformamide(DMF), 0 uC. PMB, para-methoxybenzyl. b, SeO2, dioxane, H2O, 100 uC.c, (EtO)2P(O)CH2SeMe, 18-crown-6, potassium bis(trimethylsilyl)amide(KHMDS), tetrahydrofuran (THF), 278 uC to room temperature (RT, 23 uC).e.e., enantiomeric excess. d, (Ph3P)3RhCl, toluene, PhCN, 120 uC. e, COCl2,

Et3N, toluene, 245 uC to RT, then MeOH, 230 uC to RT. f, DIBAL-H, CH2Cl2,278 uC to RT, then trifluoroacetic acid (TFA), 278 uC to RT. g, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), K2CO3, DMF, (Z)-4-bromo-3-iodobut-2-enyl acetate (13), RT. h, DIBAL-H, CH2Cl2, 278 uC. i, 25 mol%Pd(OAc)2, Bu4NCl, NaHCO3, EtOAc, RT. j, PhSH, TFA, 45 uC. k, NaOAc,Ac2O, AcOH, malonic acid, 120 uC. Ac, acetyl.

NH

N

CO2Me

I

HNH

N

CO2Me

H Me47%

(–)-akuammicine10 steps, 10% overall yield

N

NH

CO2MeH

PMB

c

12

19

Me

NH

NH

CO2MeH

17

76%

b

91%

a

Figure 5 | Ten-step enantioselective synthesis of (2)-akuammicine.Reagents and conditions are as follows. a, TFA, PhSH, 60 uC. b, (Z)-1-bromo-2-iodobut-2-ene (18), K2CO3, DMF, RT. c, 20 mol% Pd(OAc)2, NaHCO3,Bu4NCl, MeCN, 65 uC.

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ester to give diamine 17 in 91% yield. Allylation of the pyrrolidinenitrogen with functionalized allyl bromide 18 (ref. 23) gave vinyliodide 19, a precursor to akuammicine, by means of a Heck cycliza-tion11. We expected insertion of palladium into the vinyl iodide fol-lowed by carbopalladation of thea,b-unsaturated ester to give an alkylpalladium intermediate. b-hydride elimination would then furnishthe natural product. In the event, treatment of vinyl iodide 19 withpalladium acetate under Jeffery conditions24 gave (2)-akuammicine,prepared in a total of ten steps and 10% overall yield.

The alkaloids aspidospermidine25 and vincadifformine26 are amongthe most highly sought Aspidosperma alkaloid targets. Aspidospermidine,in particular, has been the subject of extensive investigation, havingbeen synthesized by over 30 research groups27,28. Application of ourcascade catalysis approach allowed access to both of these alkaloidsaccording to the following sequence. Conversion of the cascade product21 into the vinyl iodide 23 was achieved in a three-step sequence asoutlined in Fig. 6. After optimization, we found that a Heck cyclizationof the vinyl iodide onto the tri-substituted double bond could be used toform triene 24 in 65% yield, thus completing the pentacyclic core ofaspidospermidine. We achieved a simultaneous global hydrogenation/debenzylation of triene 24 using palladium hydroxide on carbon underhydrogen pressure, to afford (1)-aspidospermidine in nine linear stepsand 23% overall yield (Fig. 6), which constitutes the shortest enantio-selective synthesis of aspidospermidine reported so far29,30. Finally, werecognized the potential to synthesize (1)-vincadifformine from (1)-aspidospermidine by means of an oxidation and carbomethoxylation

sequence30. Indeed, Swern oxidation of aspidospermidine leads to theformation of imine 25, which can be treated with n-butyllithium fol-lowed by methyl cyanoformate to obtain (1)-vincadifformine (Fig. 6)in 11 steps and 8.9% overall yield31.

We further extended our strategy of collective total synthesis to thesynthesis of kopsinine32–35 and the related compound kopsanone33,36.A unified approach to producing both alkaloids was implemented,allowing for a two-step conversion of kopsinine to kopsanone bymeans of a biomimetic thermocyclization33,37 (Fig. 7). Kopsininewas synthesized by first treating enantio-21 with trimethylsilyl iodideand then by vinyl triphenylphosphonium bromide to induce a depro-tection/conjugate addition. Further treatment with KOt-Bu promoteda Wittig olefination to form the cyclic alkene found in triene 26. Anenamine a-carbomethoxylation was then accomplished with phos-gene–methanol16 to afford an intermediate ester, which was selec-tively reduced to diene 27 by treatment with palladium on carbon(Pd/C) and H2 in 69% over two steps.

Dienes such as 27 can undergo [4 1 2] cycloadditions with a rangeof dienophiles, including vinyl sulfones33,38. We were able to obtaincycloadduct 28 in 83% yield through treatment of diene 27 withphenylvinyl sulfone in refluxing benzene. Furthermore, we were ableto obtain (2)-kopsinine by performing a simultaneous desulfonyla-tion, benzyl hydrogenolysis and diastereoselective alkene reduction ofsulfone 28 with Raney nickel33 to give (2)-kopsinine in only ninesteps, which is a significant improvement over the previous 19-stepchiral-auxiliary-mediated approach32. Our attempts to directly

–40 °C to RT, toluene

20 mol% ent-3•TBA

21N

NBoc

CHO

Bn

N

Bn

NHBoc

SeMe

83%, 97% e.e.

NH

NBoc

20961%

a–c

O

N

N

HBn

I

N

N

HBn

(+)-vincadifformine11 steps, 8.9% overall yield

NH

N

HMe

(+)-aspidospermidine9 steps, 24% overall yield

65%

g

98%

h

57%

j

NH

N

Me

CO2Me

23

24

N

N

Me65%

i

25

73%

d–f

Figure 6 | Enantioselective total syntheses of (1)-aspidospermidine and(1)-vincadifformine. Reagents and conditions are as follows. a, NaH, DMF,BnBr, RT. b, SeO2, dioxane, H2O, 100 uC. c, (EtO)2P(O)CH2SeMe, 18-crown-6,KHMDS, THF, 278 uC to RT. ent-, enantio-. d, Ph3PCH3I, n-butyllithium,

THF, 0 uC, then AcOH, NaCNBH3, 0 uC. Bn, benzyl. e, TFA, CH2Cl2, RT. f, (Z)-3-bromo-1-iodoprop-1-ene (22), K2CO3, DMF, RT. g, (Ph3P)4Pd, Et3N,toluene, 80 uC. h, Pd(OH)2, H2 (200 p.s.i.), MeOH, EtOAc, RT. i, CH2Cl2,DMSO, (COCl)2. j, n-butyllithium, NCCO2Me, THF, 278 uC to RT.

NH

N

N

Bn26

R

N

N

Bn27 CO2Me

N

N

Bn28 CO2Me

N

CO2Me

(–)-kopsanone11 steps, 10% overall yield

NH

N

O

R = SO2Ph

58%

a

69%

b, c

86%

d

83%

e

Ent-21

N

NBoc

CHO

Bn

(–)-kopsinine9 steps, 14% overall yield

NH

N

CO2

NH

HN

200 °Cf

29

74%

H

B:

OHO

H

(two steps)Neat

Figure 7 | Enantioselective total syntheses of (2)-kopsinine and (2)-kopsanone. Reagents and conditions are as follows. a, Et3N, CH2Cl2, Me3SiI,0 uC, then MeOH, H2C5CHPPh3Br, 40 uC, then CH2Cl2, THF, KOt-Bu, 0 uC.

b, COCl2, Et3N, toluene, 245 uC to RT, then MeOH, 230 uC to RT. c, Pd/C, H2,EtOAc, EtOH, 0 uC. d, H2C5CHSO2Ph, benzene, 100 uC. e, Raney Ni, EtOH,78 uC. f, 1 N HCl, 130 uC.

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convert (2)-kopsinine to (2)-kopsanone thermally according to themethod of ref. 33 were unsuccessful. However, simple acid-mediatedhydrolysis to give kopsinic acid (29), and subsequent heating of thismaterial without solvent37, furnished (2)-kopsanone in only 11chemical steps.

As anticipated, application of collective total synthesis to each ofthe target compounds—strychnine, akuammicine, aspidospermidine,vincadifformine, kopsinine and kopsanone—was readily accomp-lished with unprecedented levels of efficiency (Table 1). Perhaps mostnotably, these collective asymmetric syntheses took a total of 34 stepsfor the six natural products described (in comparison with 76 totalsteps in previous studies).

ConclusionWe have demonstrated the capabilities of collective total synthesis incombination with organocascade catalysis, a synthetic strategy thatprovides researchers with the tools to gain ready access to large col-lections of complex molecular architectures. In particular, we describethe shortest asymmetric synthesis of (2)-strychnine, the best-known

member of the Strychnos alkaloid family. We hope to describe thevalue of this approach in terms of other natural product and medicinalagent families in the near future.

METHODS SUMMARYAll reactions were performed under an inert atmosphere using dry solvents inanhydrous conditions, unless otherwise noted. Full experimental details andcharacterization data for all new compounds are included in SupplementaryInformation.

Received 4 February; accepted 26 May 2011.

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29. Gnecco,D.et al.Synthesisof anaspidospermaalkaloidprecursor: synthesis of (1)-aspidospermidine. Arkivoc 2003 (xi), 185–192 (2003).

30. Kozmin, S. A., Iwama, T., Huang, Y. & Rawal, V. H. An efficient approach toAspidosperma alkaloids via [4 1 2] cycloadditions of aminosiloxydienes:Stereocontrolled total synthesis of (6)-tabersonine. Gram-scale catalytic

Table 1 | Enantioselective synthesis of six well-known indolealkaloids

N

NBoc

P

O

Common intermediate (1)

Synthetic

elaboration

≤8 steps

Enantioselective syntheses

of Strychnos, Aspidospermaand Kopsia alkaloids

Compound No. stepshere*

Overallyield (%)

PSACsteps

PSCAsteps

N

N

O O

H

H

H

H

(2)-strychnine

12 6.4 25 (refs 19, 20) 16 (ref. 21)

NH

N

HMe

(1)-aspidospermidine

9 24 13 (ref. 30) 11 (ref. 29)

NH

N

CO2Me

(2)-kopsinine

9 14 NA 19 (ref. 32)

NH

N

CO2Me

H Me

(2)-akuammicine

10 10 NA NA

NH

N

Me

CO2Me

(1)-vincadifformine

11 8.9 NA 10 (ref. 31)

NH

N

O

(2)-kopsanone

11 10 NA NA

Step counts represent the longest linear sequence from commercially available 9. NA, not applicable.PSAC, previous shortest asymmetric catalytic synthesis; PSCA, previous shortest chiral auxiliary orchiral pool synthesis.*See Supplementary Information for details of these syntheses.

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asymmetric syntheses of (1)-tabersonine and (1)-16-methoxytabersonine.Asymmetric syntheses of (1)-aspidospermidine and (2)-quebrachamine. J. Am.Chem. Soc. 124, 4628–4641 (2002).

31. Kuehne, M. et al. Application of ferrocenylalkyl chiral auxiliaries to syntheses ofindoleninealkaloids: enantioselective synthesesof vincadifformine,y- and20-epi-y-vincadifformines, tabersonine, ibophyllidine, andmossambine. J.Org.Chem.63,2172–2183 (1998).

32. Magnus, P. & Brown, P. Total synthesis of (2)-kopsinilam, (2)-kopsinine, and thebis-indole alkaloids (2)-norpleiomutine and (2)-pleiomutine. J. Chem. Soc. Chem.Commun. 184–186 (1985).

33. Kuehne, M. E. & Seaton, P. J. Studies in biomimetic alkaloid syntheses. 13. Totalsyntheses of racemic aspidofractine, pleiocarpine, pleiocarpinine, kopsinine,N-methylkopsanone, and kopsanone. J. Org. Chem. 50, 4790–4796 (1985).

34. Wenkert, E. & Pestchanker, M. J. A formal total synthesis of kopsinine. J. Org. Chem.53, 4875–4877 (1988).

35. Ogawa, M., Kitagawa, Y. & Natsume, M. A high-yield cyclization reaction for theframework of aspidosperma alkaloids synthesis of (6)-kopsinine and its relatedalkaloids. Tetrahedr. Lett. 28, 3985–3986 (1987).

36. Gallagher, T. & Magnus, P. Synthesis of (6)-kopsanone and (6)-10,22-dioxokopsane, heptacyclic indole alkaloids. J. Am. Chem. Soc. 105, 2086–2087(1983).

37. Kump, C., Dugan, J. J. & Schmid, H. Ringschlussreaktionen an Pleiocarpa-Alkaloiden. Helv. Chim. Acta 49, 1237–1243 (1966).

38. Magnus, P., Payne, A. H. & Hobson, L. Synthesis of the kopsia alkaloids (6)-11,12-demethoxylahadinine B, (6)-kopsidasine and (6)-kopsidasine-N-oxide. Tetrahedr.Lett. 41, 2077–2081 (2000).

Supplementary Information is linked to the online version of the paper atwww.nature.com/nature.

Acknowledgements Financial support was provided by NIHGMS (R01GM078201-05) and gifts from Merck, Bristol-Myers Squibb and Abbott. S.B.J. and B.S.thank Bristol-Myers Squibb and Merck, respectively, for graduate fellowships.

Author Contributions S.B.J., B.S. andA.M.participated in theperformanceandanalysisof the experiments. S.B.J., B.S., A.M. and D.W.C.M. designed the experiments. S.B.J. andD.W.C.M. wrote the paper.

Author Information Reprints and permissions information is available atwww.nature.com/reprints. The authors declare no competing financial interests.Readers are welcome to comment on the online version of this article atwww.nature.com/nature. Correspondence and requests for materials should beaddressed to D.W.C.M. (dmacmill@princeton.edu).

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