Total synthesis of solanoeclepin AKeiji Tanino1*, Motomasa Takahashi1, Yoshihide Tomata1, Hiroshi Tokura1, Taketo Uehara2,

Takashi Narabu2 and Masaaki Miyashita3*

Cyst nematodes are troublesome parasites that live on, and destroy, a range of important host vegetable plants. Damagecaused by the potato cyst nematode has now been reported in over 50 countries. One approach to eliminating the problemis to stimulate early hatching of the nematodes, but key hatching stimuli are not naturally available in sufficient quantitiesto do so. Here, we report the first chemical synthesis of solanoeclepin A, the key hatch-stimulating substance for potatocyst nematode. The crucial steps in our synthesis are an intramolecular cyclization reaction for construction of the highlystrained tricyclo[5.2.1.01,6]decane skeleton (DEF ring system) and an intramolecular Diels–Alder reaction of a furanderivative for the synthesis of the ABC carbon framework. The present synthesis has the potential to contribute toaddressing one of the critical food issues of the twenty-first century.

Cyst nematodes live on a limited range of vegetables, oftencausing destructive damage to the host plants. The soybeancyst nematode (Heterodera glycins Ichinohe), for example,

parasitizes soybean, kidney bean and azuki bean, and causesserious soybean sickness1. The specificity of the nematodesarises because it is the host plants themselves that secrete thechemicals that stimulate hatching of juvenile nematodes fromthe cysts2–5. The key hatch-stimulating substance for soybeancyst nematode, glycinoeclepin A (1), was successfully isolatedby Masamune and colleagues in 1982, and its structure wasdetermined in 1985 (ref. 6). Glycinoeclepin A has beendemonstrated to stimulate the hatching of juveniles from eggsin vitro at a high dilution of 1 × 10211 to 1 × 10212 g ml21 inwater7. Similarly, the hatching stimulus for potato cyst nematode(PCN; Globodera rostochiensis (Woll.) and G. pallida Stone;Fig. 1), designated as solanoeclepin A, was first isolated by Mulderin 1986 (ref. 8), and its absolute structure was unambiguously deter-mined by X-ray crystallographic analysis by Schenk and co-workersin 1999 (ref. 9).

The cyst comprises the swollen flask-shaped dead body of thefertilized female nematode, which acts as a firm protective coveringfor the eggs, resisting drying, extremes of temperature, frost and soon, and remains in the soil following harvesting until the next hatch-ing time. The encysted dormant eggs of PCN are able to persist inthe soil for more than 20 years in the absence of a hatch stimulus,whereas the hatched juvenile nematodes die within several weeksin the absence of potatoes (the host plant).

Extermination of PCN using existing agricultural chemicals aswell as nematicides is extremely difficult, and PCNs are inflictingserious damage on crop plants in an increasing number of countries.The use of the hatch stimulus has, in recent years, become the focusof studies investigating the extermination of PCN. When a highlydilute solution of the hatching stimulus is spread over potatofields after the harvest, PCN will hatch, but will die before fertiliza-tion due to the lack of host plants. Thus, hatch-stimulating sub-stances for cyst nematodes are expected to play a crucial role indealing with the globally increasing population and the concomitantfood issues of the twenty-first century. For this purpose, however, itis essential to produce these substances by chemical synthesis,because the hatch stimuli are scarce in nature; in one example,

only 50 mg of glycinoeclepin A was isolated from 113 kg of thedried roots of kidney bean.

Solanoeclepin A (2), the hatch-stimulating substance for PCN, isa unique triterpenoid with a hitherto unknown heptacyclic skeletoncontaining carbocycles with each of the ring sizes from three toseven (Fig. 1). Note that the structures of glycinoeclepin A (1)and solanoeclepin A (2) both include a 3,3-dimethyl-7-oxabi-cyclo[2.2.1]heptan-2-one, a structure that may be essential for thesignificant hatch-stimulating activity towards bean and potatocyst nematodes.

The remarkable biological properties and novel chemical struc-tures of the hatch-stimulating substances for cyst nematodes, aswell as their importance in agriculture, make these compoundsextremely attractive targets for chemical synthesis. The chemicalsynthesis of solanoeclepin A (2) has been impeded due to itsdensely functionalized complex stereostructure, whereas the totalsynthesis of glycinoeclepin A (1) has been achieved by a numberof research groups10–14.

The synthetic challenges posed by solanoeclepin A (2)include the construction of the highly strained and stereochemi-cally dense tricyclo[5.2.1.01,6]decane skeleton bearing three con-secutive quaternary stereocentres, that is, the DEF ring systemconsisting of the four-, five- and six-membered carbon rings15–20;the stereoselective synthesis of the ABC carbon framework consist-ing of the 6,6-dimethyl-7-oxabicyclo[2.2.1]heptan-2-one (AB ring)and a functionalized seven-membered carbocycle (C ring)21–23.

We initiated synthetic studies of solanoeclepin A (2) that aimedto develop an efficient synthetic route while allowing the synthesis ofvarious analogues for biological testing. We report here the first totalsynthesis of 2.

Results and discussionStereoselective synthesis of the right-hand segment. In theforward direction, the following key operations were proposed: (i)stereoselective construction of the strained four-membered carbonring by a base-induced intramolecular cyclization reaction of anepoxy nitrile bearing an indane skeleton based on the Storkprotocol24, leading to the tricyclo[5.2.1.01,6]decane skeleton (DEFring system); (ii) one-step synthesis of the ABC carbon frameworkby an intramolecular Diels–Alder reaction of a key precursor

1Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan, 2National Agriculture Research Center for Hokkaido Region, Sapporo 062-8555, Japan,3Faculty of Engineering, Kogakuin University, Hachioji, Tokyo 192-0015, Japan. *e-mail: ktanino@sci.hokudai.ac.jp; masaaki_miyashita@sc.kogakuin.ac.jp

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including a furan (diene component) and a,b-unsaturated ketone(dienophile) moieties in the molecule.

Our first objective focused on the stereoselective synthesis of thecrucial precursor epoxy nitrile 9 for construction of the

tricyclo[5.2.1.01,6]decane skeleton (DEF ring system). The targetedmolecule 9 was a trans-fused indane derivative bearing two quatern-ary asymmetric carbon atoms at the bridge heads; its synthesistherefore appeared very challenging. Figure 2 presents the successful

OO CO2H

HOCO2H

Glycinoeclepin A (1)

dCO2H

OHO

O

OMe

HO

O

O

H

H

Solanoeclepin A (2)

Intramolecular Diels–Alder

reactionBase-inducedintramolecular

cyclization

AC

DE

F

G Stereoselective Simmons–Smith

reaction

Coupling reaction

B

cba

Figure 1 | Cyst nematodes and their effect on crops. a, Potato cyst nematode Globodera rostochiensis. b, Cysts on potato roots, which protect the nematodes

until hatch stimulants produced by the host plant are present. c, Potato field affected by potato cyst nematodes. d, Structures of glycinoeclepin A (1) and

solanoeclepin A (2)—key hatch-stimulating substances for the soybean cyst and potato cyst nematodes, respectively. The key disconnections in a planned

total synthesis effort for solanoeclepin A (2) are shown.

AcO

CN

AcO

CN

OAcO

CN

OH

CN

OH

CN

OHO

CN

OHO

CN

OTBSTBSO O

CN

OTBSTBSO

TBSO

1) DBU, CH2Cl267% for 3 steps

2) CH2=CHMgBrCeCl3, THF

96%43 65 87

9 10

OTBSTBSO

TBSO

CO2Et

OTBSTBSO

TBSO

CH2OH

H

H

OTBSTBSO

HO

CH2OBn

H

H

1) HF•Py, THF2) TBSCl, imidazole

DMF

11

12 13 14 15

16 17

OBOMOTf

H

CH2OBn

OHC

D EF

G

H

OTBSTBSO OHO

mCPBA

CH2Cl2

Me3AlAl(OTf)3

(CH2Cl)2

TBHPTi(Oi-Pr)4

MS4Å

CH2Cl292%

TMSOTf2,6-lutidine

(CH2Cl)2then HF•Py

97%

1) DIBAL, CH2Cl22) (EtO)2P(O)CH2CO2Et

NaH, THF96% for 2 steps

1) DIBAL, THF100%

OBuB

O

CONMe2

CONMe2

Et2Zn, CH2I2, CH2Cl2100% (dr = 94:6)

2)

1) NaH, BnBrTBAI, DMF

2) TBAF, THF75% for 2 steps

1) DIBAL, THF2) TBSOTf, 2,6-lutidine CH2Cl2 93% for 2 steps3) mCPBA, (CH2Cl)2(S)-epoxide 9 74%(R)-epoxide 9' 14%

LDA thenTBSCl, HMPA

THF99%

1) o-NO2C6H4SeCNBu3P, THF

2) H2O2, THF88% for 2 steps

3) DMP, CH2Cl24) HF•Py, THF86% for 4 steps

1) BOMCl, DIPEATBAI, CH2Cl2

99%

2) t-BuOCH(NMe2)2DMF

OBOMO

Me2N

Tf2O2,6-(t-Bu)2Py

CH2Cl292% for 2 steps

Figure 2 | Stereoselective synthesis of right-hand segment 17. The DEFG ring system was constructed via 1,2-rearrangement of the vinyl group and the

key intramolecular cyclization reaction of epoxy nitrile 9. mCPBA, m-chloroperbenzoic acid; Al(OTf)3, aluminium trifluoromethanesulfonate; DBU,

1,8-diazabicyclo[5.4.0]undec-7-ene; TBHP, tert-butyl hydroperoxide; MS4Å, molecular sieves 4Å; TMSOTf, trimethylsilyl trifluoromethanesulfonate; HF†Py,

hydrogen fluoride pyridine complex; DIBAL, diisobutylaluminum hydride; TBSOTf, tert-butyldimethylsilyl trifluoromethanesulfonate; LDA, lithium

diisopropylamide; TBSCl, tert-butyldimethylsilyl chloride; HMPA, hexamethylphosphoramide; BnBr, benzyl bromide; TBAI, tetrabutylammonium iodide; DMF,

N,N-dimethylformamide; TBAF, tetrabutylammonium fluoride; THF, tetrahydrofuran; DMP, Dess–Martin periodinane; BOMCl, benzyl chloromethyl ether;

DIPEA, N,N-diisopropylethylamine; Tf2O, trifluoromethanesulfonic anhydride; 2,6-(t-Bu)2Py, 2,6-di-(tert-butyl)pyridine.

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synthesis of the requisite precursor 9, starting from bicyclic acetoxynitrile 3, available on a large scale in an optically active form using aprotocol recently reported by us25. Epoxidation of 3 with m-chlor-operoxy- benzoic acid (mCPBA) in dichloromethane (CH2Cl2) pro-vided b-epoxide 4 stereoselectively, which, on treatment withtrimethylaluminium (Me3Al) in the presence of aluminium tri-fluoro- methanesulfonate (Al(OTf)3) in 1,2-dichloroethane((CH2Cl)2), underwent a Meinwald rearrangement to give ketoacetate 5 as a single product. After treatment of the keto acetatewith 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in CH2Cl2, theresulting enone (67% yield, three steps) was subjected to theGrignard reaction with vinylmagnesium bromide in the presenceof cerium(III) chloride (CeCl3) in tetrahydrofuran (THF) to affordallylic alcohol 6 in 96% yield. As expected, addition of theGrignard reagent occurred exclusively from the opposite side ofthe angular methyl group. Oxidation of the allylic alcohol withtert-butyl hydroperoxide (TBHP) in the presence of titanium(IV)isopropoxide (Ti(OiPr)4) and molecular sieves 4Å (MS4Å) inCH2Cl2 afforded a-epoxy alcohol 7 in 92% yield.

The next 1,2-rearrangement of the vinyl group was efficientlyperformed with trimethylsilyl trifluoromethanesulfonate (TMSOTf)and 2,6-lutidine in (CH2Cl)2 to furnish the desired hydroxy ketone8 in 97% yield. Thus, the stereoselective synthesis of the trans-fused indane derivative bearing two quaternary asymmetric carbonatoms was established. The requisite epoxy nitrile 9 was synthesizedin 69% yield by a three-step reaction sequence comprising:(i) stereoselective reduction of the ketone moiety with diisobutylalu-minium hydride (DIBAL) in THF, (ii) protection of the hydroxylgroups with a tert-butyldimethylsilyl (TBS) group, (iii) epoxidationof the vinyl group with mCPBA in CH2Cl2 giving rise to a separablemixture of the (S)-epoxide 9 (74%) and (R)-epoxide 9′ (14%).

The next step was the key intramolecular cyclization reaction to con-struct the four-membered carbocycle. The reaction proceeded with highefficiency by treatment of 9 with lithium diisopropylamide (LDA) inTHF at 0 8C and subsequent addition of tert-butyldimethylsilyl chloride

(TBSCl) and hexamethylphosphoramide (HMPA) in a one-potoperation to produce the tricyclo[5.2.1.01,6]decane derivative 10 innearly quantitative yield. The stereochemistry of the product wasunambiguously confirmed by X-ray crystallographic analysis ofthe corresponding p-bromobenzoate. (An ORTEP drawing andthe CIF file of the crystalline compounds are provided in theSupplementary Information.)

With intermediate 10 in hand, we next focused on the synthesisof the cyclopropane ring of the side chain. For this purpose, 10 wastransformed into unsaturated ester 11 (96%, two steps). Afterreduction of the ester with DIBAL, the resulting allylic alcoholwas subjected to the Simmons–Smith reaction in the presence of1,3,2-dioxaborolane ligand26 to give cyclopropane 12 with thedesired stereochemistry in quantitative yield. We had thus estab-lished the carbocyclic framework of the DEFG ring system.Product 12 was further converted to hydroxy ketone 15 in severalsteps, from which enol triflate 17, the key fragment, was successfullysynthesized by way of keto enamine 16 (91%, three steps). This pro-vided the fully functionalized DEFG ring system bearing three con-secutive stereocentres in a highly stereoselective manner.

Construction of the left-hand segment and completion of thetotal synthesis. We then focused on the construction of the ABCring system including the 7-oxabicyclo[2.2.1]heptan-2-one moiety.To construct this particular ring system effectively, we designedthe synthetic route shown in Fig. 3, which involved anintramolecular Diels–Alder reaction between the furan and anunsaturated ketone moiety in precursor 20.

Synthesis of 20 began with the addition reaction of 17 with4-methoxy-5-(trimethylsilyl)fur-2-yl lithium in THF at –78 8C,which afforded a 2 alcohol 18 quantitatively. Removal of theTMS group in the furan with pyridinium p-toluenesulfonate(PPTS) in wet DMF and protection of the hydroxyl group withchlorotrimethylsilane (TMSCl) and imidazole in DMF furnished19 (94% yield, three steps). The crucial palladium-catalysed

17

O

MeO

TMSOTMS

1) SeO21,4-dioxane, H2O

2) Cu(OAc)2MeOH

74% for 2 steps

+

18 19 20

21 22

OBOM

O

HO

OMeO

CH2OBn

H

H

O

23

25 2726

OBOM

H

CH2OBn

OTfO

MeO

HO

TMS

H

OBOMOTfO

MeO

TMSO

O

O

MeO

TMSO

t-BuLi

THF

1) PPTSDMF, H2O

2) TMSClimidazole, DMF94% for 3 steps

Me2AlCl

diethyl ether

Bu3SnFPdCl2[P(o-tol)3]2

DMF44%

1) CH3CO2H, H2O62% for 2 steps

2) DMP, CH2Cl290%O

TMSO

O

H

MeO OO

O

H

O

O

OHO

O

O

24

O

OMeO

O

O

MeI, Ag2O

DMF97%

DIBAL

toluene

IBX

CH2Cl2DMSO

43% for 2 stepsO

OMeHO

O

HO

O

OMeHO

OH

HO

Figure 3 | Stereoselective synthesis of the heptacyclic compound 27. The ABC ring system was constructed based on the Lewis acid-induced intramolecular

Diels–Alder reaction of 20 and subsequent functionalization of the C ring. PPTS, pyridinium p-toluenesulfonate; TMSCl, trimethylsilyl chloride; IBX,

2-iodoxybenzoic acid.

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coupling reaction of 19 with 4-methyl-2-trimethylsilyloxy-1,3-pen-tadiene successfully occurred by combination of bis[(tris-o-tolyl)-phosphine]palladium dichloride and tributyltin fluoride27 in DMFresulting in the formation of 20 as a single product in 44% yield.The crucial intramolecular Diels–Alder reaction occurred in the pres-ence of dimethylaluminum chloride (Me2AlCl) in ether giving rise tothe heptacyclic compound 21 in a stereoselective manner.

To introduce the oxygen functionality at the C7 position, 21 wasfurther transformed into triketone 22 in two steps (90%). Oxidationof the C7 methylene group was successfully performed by initialtreatment of 22 with selenium dioxide (SeO2) in 1,4-dioxane fol-lowed by treatment of the resulting hydroxy ketone withcopper(II) acetate in MeOH, giving rise to 23 in 74% yield. The

product 23 was further converted to 27 by way of 25 in threesteps (42%). By-products including 26 produced upon reductionof 24 were recycled to 24 by oxidation with Dess–Martin periodi-nane (DMP).

With the functionalized heptacyclic compound 27 in hand, thefinal remaining tasks for the total synthesis of solanoeclepin Awere: (i) oxidative cleavage of the exo-methylene group on thefour-membered carbon ring to the corresponding ketone; (ii) con-version of the primary alcohol protected with a benzyl group to car-boxylic acid as shown in Fig. 4.

The first task was performed by treatment of 28 with osmiumtetroxide (OsO4) followed by oxidative cleavage of the resultingdiol with sodium periodate (NaIO4) to give cyclobutanone 30.

27

CH3CO2H, H2O

OBOM

O

TMSO

OMeO

CH2OBn

H

H

O

30

31

28

OBOM

O

O

TMSO

OMeO

CH2OBn

H

H

O

35

OTMS

O

OOMe

O

CO2H

H

H

O

TMSO

OH

O

O

OMeO

CO2H

H

H

O

HO

29

Solanoeclepin A (2)

OBOM

O

O

HO

OMeO

O

33 3432

TMSClimidazole

DMF90%

1) OsO4, pyridinet-BuOH

45% (68% basedon recovered 28)

2) NaIO4, CH3CN

H2Pd(OH)2

THF

TMSClimidazole

DMF70% for 2 steps

TMSClimidazole

DMF

then aq. THF88% for 3 stepsO

O

CH2OH

H

H

OH OH

O

CH2OH

H

H

OTMS

O

CH2OH

H

H

OTMS

O

CHO

H

H

DMP

CH2Cl2

NaClO2, NaH2PO42-methyl-2-butene

t-BuOH, H2O97% for 2 steps

3 M HCl

CH3CO2H, H2O63%

Figure 4 | Total synthesis of solanoeclepin A (2).

b

0

20

40

60

80

100

1:2 1:10 1:100

Dilution

Hat

ch o

f G. r

osto

chie

nsis

(%

)

a

0

20

40

60

80

100

–6 –7 –8 –9 –10 –11 –12 –13 Water

Concentration (log M)

Hat

ch o

f G. r

osto

chie

nsis

(%

) Solanoeclepin A Tomato rootleachate

Figure 5 | Hatching stimulation effect of synthetic solanoeclepin A on G. rostochiensis. a, Dosage response to synthetic solanoeclepin A of in vitro % hatch

of G. rostochiensis after 21 days at 22 8C. Solanoeclepin A was diluted to produce a series of concentrations from 1× 1026 to 1 × 10213 g ml21 in water. %

hatch¼ (Nj21 – Nj0)/Ne0; Nj21, number of hatched juveniles at 21 days; Nj0, number of hatched juveniles at 0 day; Ne0, number of eggs at 0 day, 250 ,

Ne0 , 350 eggs/each in 10 ml petri dish. Results are shown as means+s.e.m. (n¼ 3). b, Dosage response to tomato root leachate (TRL) of in vitro % hatch

of G. rostochiensis. Results are shown as means+s.e.m. (n¼ 3). TRL was collected from a commercial hydroponic tomato production system (�500 l of

nutrient feed solution per day passed through 12,000 plants of tomato in a 4,300 m2 greenhouse). Dilutions refer to the original tomato culture media

filtrate preparations.

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The second task was achieved through hydrogenation of 30 overpalladium(II) hydroxide (Pd(OH)2), selective protection of thesecondary hydroxyl group of the diol 32 with a TMS group, andoxidation of primary alcohol 33 to the carboxylic acid 35, in 85%overall yield from 30. The stereochemistry of 35 was unambiguouslyconfirmed by X-ray crystallographic analysis. (An ORTEP drawingand the CIF file of the crystalline compounds are provided inthe Supplementary Information.) Finally, treatment of 35 with3 M HCl in aqueous AcOH furnished solanoeclepin A (2)([a]26

D ¼þ271.58 (c¼ 0.18, MeOH)) in 63% isolated yield.The total yield of synthetic solanoeclepin A was 0.18% in 52

steps, starting from 3-methylcyclohexenone. The spectroscopiccharacteristics (1H nuclear magnetic resonance (NMR) spectra,and mass spectra) of the synthetic compound were in good agree-ment with the structure of solanoeclepin A (2), although fulldetails of the spectral data of natural solanoeclepin A are notrecorded in the literature8.

A bioassay of the synthetic compound to determine the hatchingstimulation effect of synthetic 2 was performed at 22 8C for 21 days;the results are summarized in Fig. 5.

We were pleased to find that the synthetic solanoeclepin A stimu-lated hatching activity at a high dilution (1 × 1028 to 1 ×10210 g ml21 in water). The fact that the activity of the syntheticcompound was only 65% of that measured using standard tomatohydroponics may suggest the presence of a cofactor necessary forhatching, which will be studied in our laboratory.

ConclusionWe have achieved the first chemical synthesis of solanoeclepin A,the key hatch-stimulating substance for potato cyst nematode. Thecrucial intramolecular cyclization reaction for the construction ofthe highly strained tricyclo[5.2.1.01,6]decane skeleton (DEF ringsystem) and an intramolecular Diels–Alder reaction of a furanderivative for the synthesis of the ABC carbon framework werethe key steps. Synthetic solanoeclepin A was shown to stimulatehatching activity at high dilutions in water.

The chemistry described here not only offers a solution to aformidable synthetic challenge, but also opens a chemical avenueto solanoeclepin A, other naturally occurring solanoeclepinanalogues, and synthetic, designed solanoeclepin derivatives thatcould contribute to solving a critical food supply issue of thetwenty-first century.

Received 30 November 2010; accepted 4 April 2011;published online 23 May 2011

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AcknowledgementsThe authors thank Prof. T. Inabe (Hokkaido University) for X-ray diffractionmeasurements. This research was partly supported by the Global COE Program (project no.B01: Catalysis as the basis for innovation in materials science) and a Grant-in-Aid forScientific Research on Innovative Areas (project no. 2105: Organic synthesis based onreaction integration) from the Ministry of Education, Culture, Sports, Science, andTechnology, Japan.

Author contributionsK.T. and M.M. conceived the experiments and analysed the results. M.T., Y.T. and H.T.performed the laboratory experiments and optimized the reaction conditions. T.U. andT.N. performed biological testing and evaluation of synthetic solanoeclepin A. K.T. andM.M. wrote the paper.

Additional informationThe authors declare no competing financial interests. Supplementary information andchemical compound information accompany this paper at www.nature.com/naturechemistry. Reprints and permission information is available online at http://www.nature.com/reprints/. Correspondence and requests for materials should be addressed toK.T. and M.M.

ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.1044

NATURE CHEMISTRY | VOL 3 | JUNE 2011 | www.nature.com/naturechemistry488

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