Synthetic studies on cyathin terpenoids: Enantioselective synthesis of the tricyclic core of cyathin through intramolecular Heck cyclisation

FULL PAPER

DOI: 10.1002/ejoc.200600429

Synthetic Studies on Cyathin Terpenoids: Enantioselective Synthesis of the

Tricyclic Core of Cyathin through Intramolecular Heck Cyclisation

Emmanuelle Drège,^[a]Cyrille Tominiaux,^[a][‡]Georges Morgant,^[a,b]and Didier Desmaële*^[a]

Keywords: Terpenoids / Heck reaction / Palladium / Ring enlargement / Michael addition / Enantioselectivity

An enantioselective synthesis of the tricyclic ketone (+)-5,

which displays the carbon core of NGF-inducing cyathane

diterpenes, has been completed according to a strategy in

which the key step was the intramolecular Heck reaction of

the AC subunit 49 establishing the crucial anti stereochemi-

cal relationship between the two angular substituents. The

C-9 quaternary centre was set up by taking advantage of

the enantioselective Michael addition involving chiral imines

providing keto ester (R)-10 in 91% ee. After incorporation of

the isopropyl group and iododecarboxylation of the propi-

onate side chain, the iodo ketone 39 was condensed with the

lithium enolate of methyl dihydrobenzoate to give the AC

subunit 43 which was further elaborated to triflate (–)-22.

While direct Heck cyclisation of 22 was ineffective, oxidation

of the bis(allylic) position of the 1,4-cyclohexadiene moiety

enhanced the reactivity, allowing the stereoselective forma-

tion of the hexahydro-cyclopenta[a]naphthalene (+)-50a. A

key element of the construction was the final C ring enlarge-

ment, involving trimethylaluminum-promoted one-carbon

expansion of ketone 52 with trimethylsilyldiazomethane

which provided the tricyclic ketone (+)-5. Furthermore, epox-

idation of trienone (+)-50a was shown to occur exclusively on

the β face, giving rise to the C-14 functionalised advanced

intermediate 51 which has considerable potential for the syn-

thesis of natural cyathins and analogues.

Germany, 2006)

bers of the erinacine and scabronine classes stimulate the

biosynthesis of the nerve growth factor (NGF) and other

neurotrophic agents.^[2–5]Neurotrophic factors are key play-

ers in the early developments of the embryonic central ner-

vous system. Although expressed at much lower concentra-

tions in adults, these factors still play an important role

in phenotypic maintenance and cell regulation. Despite the

exciting biological profile of NGF and encouraging results

obtained in cell culture as treatments for neurodegenerative

disorders, clinical applications of NGF have failed due

mainly to its inability to cross the blood-brain barrier.^[6]

Since NGF is an endogenous compound that is synthesised

in vivo, it was reasoned that if the regulatory mechanisms

controlling its expression could be stimulated, a method of

controlling the endogenous production might be found. The

search for compounds that could stimulate the basal pro-

duction of NGF has led to the isolation of a dozen structur-

ally unique natural products with this function.^[7]Owing

to their lipophilic nature and small size, cyathins seemed

promising candidates for crossing the blood-brain barrier.

The potential therapeutic relevance and the unique syn-

thetic challenges provided by these molecules attracted in-

tense efforts from a number of research teams since the dis-

closure of their structures. However, only few total synthe-

ses of natural cyathins have been completed, namely ( )-

allocyathin B₂and (+)-erinacine A by the groups of

Snider^[8]and Tori^[9]in 1996 and 1998, ( )-sarcodonin G by

Piers’s team,^[10]( )-allocyathin B₃by the group of Ward in

Introduction

Cyathane diterpenes possess an unusual angularly fused

5–6–7 tricyclic framework with 1,4-anti quaternary methyl

groups. Ayer and coworkers isolated the first natural prod-

uct of this class in 1971 from Cyathus helenae and several

additional members of this family were discovered from a

variety of fungal sources throughout the 1970’s.^[1]Other cy-

athane congeners were isolated from the mycelia of the fun-

gus Hericium erinaceum and were termed erinacines A-F.

These compounds are essentially -xylose conjugates of cy-

athins. In the simplest case of erinacine A (1), the -xylose

moiety is anchored to the 14β position of allocyathin B₂

(2).^[2]More recently Kawagishi isolated scabronines^[3]and

sarcodonins^[4][exemplified by scabronine B (3) and sarco-

donin A (4)] from Sarcodon scabrosus. The initial members

of this diterpenoid class were isolated because of significant

antibiotic properties. However, a renewed interest in these

natural products was initiated by the discovery that mem-

[a] Unité de Chimie Organique Associée au CNRS, Centre

d’Etudes Pharmaceutiques, Université Paris Sud,

5 rue J.-B. Clément, 92296 Châtenay-Malabry, France

Fax: +33-1-46-83-57-52

E-mail: didier.desmaele@cep.u-psud.fr

[b] Laboratoire de Cristallographie Bioinorganique, Centre

d’Etudes Pharmaceutiques, Université Paris Sud,

5 rue J.-B. Clément, 92296 Châtenay-Malabry, France

[‡] Present address: Service Hospitalier Frédéric Joliot, Départe-

ment de Recherche Médicale, CEA/DSV, 4 place du Général

Leclerc, 91401 Orsay, France

Eur. J. Org. Chem. 2006, 4825–4840

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2000,^[11](+)-allocyathin B₂(2) by the groups of Nakada^[12]

in 2004 and Trost in 2005^[13]and finally (–)-scabronine G

by Danishefsky^[14]in 2005. Besides these successful synthe-

ses, a large number of approaches have been proposed over

the past decade.^[15]

The central synthetic challenge in designing a route to

cyathins is the control of the relative anti stereochemistry

between the A and C rings. We have previously reported a

simple solution to this problem based on the intramolecular

Heck cyclisation of an A-C subunit, culminating in the syn-

thesis of ketone (+)-5.^[16]In this paper we wish to give a

full account of this work detailing the final synthetic ap-

proach and some alternative strategies which, while unsuc-

cessful, provided a valuable learning process for structuring

our later work (Figure 1).

Scheme 1. Retrosynthetic analysis leading to the cyclohepta[e]in-

dene nucleus used in our early approach.

Although the Heck cyclisation was a tempting and po-

tentially expedient entry to systems such as 6, one question

associated with this plan was would the interaction between

the two angular groups be large enough to favour a transi-

tion state leading to the proper relative anti stereochemis-

try? An investigation of the literature revealed that cis fused

bicyclic systems are usually produced during intramolecular

Heck reactions using prochiral dienes tethered to vinylic ha-

lides or triflate moieties.^[18]However, the influence of an

additional control element in the vicinity of the enol triflate

moiety on the stereochemical outcome was only scarcely

reported.^[19]Furthermore, to the best of our knowledge, cy-

cloheptatriene derivatives appear to have never been used

as substrates in Heck-type processes.

Our initial goal was to demonstrate that the Heck reac-

tion would provide the ABC ring system with the requisite

relative stereochemistry. To this end, iodide (R)-13 was syn-

thesised as a model system because it could be easily pre-

pared from the readily available keto ester (R)-10 (ee =

91%).^[17a]Thus, saponification of 10 followed by iododecar-

boxylation of acid 12 according to the Barton modification

of the Kochi reaction^[20]gave rise to iodo ketone 13 in 81%

overall yield. After the protection of the carbonyl of 13 as

a trimethylsilyl enol ether using TMSOTf, the iodide 14 was

condensed with cyclohepta-2,4,6-trienecarbonitrile 8a^[21]

Figure 1. Structures of cyathin derivatives.

Results and Discussion

Our initial synthetic plan was based on the belief that using LDA as a base. Cleavage of the enol ether with TBAF,

the cycloheptatriene tethered alkenyl triflate 7a could be followed by enol triflate formation provided the desired alk-

converted into cyathin diterpenoids via the tricyclic tetraene enyl triflate 17 in 67% overall yield from 14. Having the

6 through an intramolecular Heck-type cyclisation. It was required AC subunit in hand, we next turned our attention

hoped that 7a could be prepared by alkylation of cy- to its conversion into the tricyclic system. Unfortunately,

clohepta-2,4,6-trienecarbonitrile 8a with iodide 9. The lat- when 17 was treated with palladium acetate under standard

ter could be derived from the known keto ester (R)-10 Heck conditions the starting material was recovered un-

which is easily available in high optical purity by a dera- changed. Attempts at adding phosphane ligands, varying

cemising Michael addition involving the chiral imine 11 de- the catalyst or the reaction conditions met with failure.

rived from 2-methylcyclopentanone and (S)-1-phenylethyla-

Assuming that the poor complexing ability of the conju-

gated triene would account for the lack of reactivity of 17,

mine^[17](Scheme 1).

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Synthetic Studies on Cyathin Terpenoids

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we decided to replace the cycloheptatriene moiety by a 1,3-

cycloheptadiene ring as in 7b in which the unconjugated

double bonds were expected to be more reactive. This de-

cision was based primarily on the potential availability of

7b using 2-methylcyclohepta-1,3-dione 18^[22]as a C ring

progenitor. However, alkylation of 18 with iodide 14 under

a variety of conditions gave multiple by-products. Although

disappointing from a practical standpoint, the desired alky-

lation adduct could be generated by simply switching the

enol ether to another protecting group. Since attempts to

prepare the dioxolane directly from iodo ketone 13 failed,

the temporary shielding of the keto group by reduction was

undertaken. To this end, ketone 13 was reduced with so-

dium borohydride and the mixture of epimeric alcohols 16a

obtained was protected as tert-butyldimethysilyl ether to de-

liver iodide 16b in 68% overall yield. When the dione 18

was condensed with iodide 16b, using sodium hydride as

base, a complex mixture was produced. On the other hand,

the use of caesium carbonate or the P₁-phosphazene base

19^[23]as base gave the O-alkylated derivative 20 in low yield

(14% and 22%, respectively) (Scheme 2).

Since we were unable to overcome this second deviation

from our original plan, we therefore designed an alternative

strategy targeting a C-nor-cyathane derivative such as the

ester 21. The seven-membered C ring would ultimately be

obtained from this material using a one-carbon ring en-

largement reaction as the key step. This strategy was first

tested in the synthesis of the model system lacking the iso-

propyl group. Accordingly, the crucial coupling of the chiral

A-subunit with the C ring synthon could simply be per-

formed by alkylation of the enolate of cyclohexa-2,5-diene-

carboxylic acid methyl ester 23 with iodide 16b (Scheme 3).

The coupling between the lithium enolate of methyl dihy-

drobenzoate 23^[24]and the iodo derivative 16b required

heating for several hours at 50 °C in the presence of

DMPU. Under such conditions, the diene ester 24 was ob-

tained in 83% yield. Removal of the tert-butyldimethylsilyl

group with tetra-n-butylammonium fluoride in THF at re-

flux, followed by Swern oxidation of the alcohol 25 led to

the ketone (+)-26 which was taken through alkenyl triflate

(+)-27 by using triflic anhydride in the presence of 2,6-di-

tert-butylpyridine.^[25]At this point, we were prepared to

check the crucial palladium-catalysed cyclisation. In the

event, treatment of triflate (+)-27 under standard Heck con-

ditions [Pd(OAc)₂cat., K₂CO₃] was disappointing, giving

rise to an inseparable mixture of trienes 28a–c in low yield

(Ͻ 30%), along with a minute amount of allylic acetate 29

(Ͻ 10%). Although the overall yield increased to 70% when

the reaction was conducted with Pd(PPh₃)₄in toluene, we

failed to avoid the double migration by the use of various

additives such as silver^[26]or thallium^[27]salts. Since acetate

29 was formed by addition of acetate ions from Pd(OAc)₂

Scheme 2. Attempts to condense various A-ring synthons with a

seven- membered C ring system. (a) aq. KOH, MeOH, 16 h, 20 °C,

97%; (b) Pb(OAc)₄, I₂, CCl₄, visible light, 500 W, 1 h, 80 °C, 84 %;

(c) TMSOTf, Et₃N, CH₂Cl₂, 0 °C, 3 h, 86%; (d) i: LDA, 8a, –78 °C,

10 min, ii: 14, HMPA, –20 °C, 16 h, iii: nBu₄NF, THF, 20 °C, 1 h,

71%; (e) (CF₃SO₂)₂O, 2,6-di-tBu-C₅H₃N, CH₂Cl₂, 20 °C, 20 h,

95%; (f) NaBH₄, EtOH, 20 °C, 3 h, 65%; (g) TBDMSOTf, CH₂Cl₂,

20 °C, 4 h, 96%; (h) 1 equiv. of 19, THF, 70 °C, 24 h, 22%.

Scheme 3. Retrosynthetic analysis leading to cyathin terpenoid 2.

to the intermediate η³-palladium complex, we anticipated cal assignment of 29 was inferred from ¹H NMR spec-

that adding acetate ions might drive the reaction course to- troscopy including NOESY experiments of the correspond-

ward acetate 29.^[28]Pleasingly, treatment of alkenyl triflate ing alcohol (–)-30. The pseudo-axial configuration of the

27 with Pd₂dba₃as a catalyst (5%) in the presence of cyathin hydrogen at C9a (δ = 3.44 ppm) with respect to the

3 equiv. of tetrabutylammonium acetate in DMSO at 60 °C C ring, was deduced from the coupling constants (J = 14.5

provided tricyclic acetate 29 in 85% yield. The stereochemi- and 3.5 Hz) with the vicinal 9-H_axand 9-H_eqprotons,

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respectively. Furthermore, a strong correlation between the

9-H_axproton (δ = 1.92 ppm) and the angular methyl group

in the NOESY chart are consistent only with the anti-cis

configuration. This assignment was subsequently confirmed

by X-ray crystallography of the β-hydroxy ketone 31, de-

rived from (–)-30 through a three-step sequence.^[16a,29]

Interestingly, while the formation of the cis BC ring junc-

tion could be anticipated in view of the known steric course

of such intramolecular Heck reactions,^[18]the influence of

the quaternary stereogenic centre in directing the reaction

onto the face opposite to the methyl group seemed unprece-

dented. This high stereoselectivity in the ring-closure reac-

tion could be related to steric interactions and/or the intro-

duction of conformational strain in the tether, which does

not favour a transition state that leads the angular substitu-

ents to be on the same side of the molecule. Thus, the tan-

dem Heck reaction-acetate ion capture process^[28]appears

to be a viable method for establishing the crucial anti rela-

tionship of the A and C rings of the cyathane diterpenoids

family. We therefore elected to use this method to assemble

the more challenging isopropyl-substituted substrate

(Scheme 4).

To implement this synthetic plan, we required a viable,

large-scale preparation of the keto ester 35a. Thus, treat-

ment of (R)-10 with TMSOTf led to the expected silylated

enol ether 32. Mukaiyama condensation with acetone using

TiCl₄as a Lewis acid failed to give the expected product.

On the other hand acetaldehyde reacted smoothly giving

rise to the ketol 33 in 89% yield. Sequential mesylate for-

mation and β elimination with DBU produced enone 34 as

a 5:1 E/Z mixture in 71% overall yield from 10. This com-

pound was converted into the desired keto ester 35a (as a

1:1 diastereomeric mixture at C5) upon treatment with lith-

ium dimethylcuprate.

The next task was to further functionalise compound 35a

to allow the connection with the C ring synthon 23. We

chose to first incorporate the required enol triflate assuming

it might offer suitable protection for the carbonyl group

during the anionic condensation. However, to our surprise,

when 35a was subjected to Tf₂O in the presence of 2,6-di-

tert-butylpyridine the main product was not the expected

triflate but instead the bicyclic enol trifluoromethanesulfon-

ate 36. Despite a number of attempts using more bulky ester

groups (35c or 35d) or trying to quench the lithium enolate

from 35c with the Comins’s reagent,^[30]under no circum-

stances could we produce the required alkenyl triflate

needed for the projected Heck cyclisation. We therefore re-

Scheme 4. (a) i: LDA, 23, THF, –78 °C, 15 min, ii: DMPU, –78 °C

to 50 °C, then 50 °C, 3 h, 83 %; (b) nBu₄NF, THF, 60 °C, 5 h, 78 %;

(c) (ClCO)₂, DMSO, CH₂Cl₂, –78 °C, 1 h, then Et₃N, 20 °C, 16 h,

95%; (d) (CF₃SO₂)₂O, 2,6-di-tBu-C₅H₃N, (CH₂Cl)₂, 20 °C, 15 h,

79%; (e) 10 mol-% Pd(PPh₃)₄, nBu₄NBr, K₂CO₃, toluene, 110 °C,

16 h, 28a/28b/28c = 2:1:1, 70 %; (f) 5 mol-% Pd₂dba₃.CHCl₃,

3 equiv. nBu₄NOAc, DMSO, 60 °C, 3 h; (g) K₂CO₃, MeOH, 3 h,

20 °C, 85% overall yield from 27.

We therefore decided to convert the propionate side

turned to the reduction of the keto group and protection of chain into an iodoethyl appendage before activating the car-

the resultant alcohol as previously done with model com- bonyl group. Thus saponification of 35a followed by the

pound 15. Unfortunately, due to the severe hindrance of the Kochi reaction [Pb(OAc)₄/I₂, CCl₄at reflux]^[20]produced

carbonyl group, complete recovery of the starting material the iodo ketone 39 in 65% overall yield. Unfortunately,

was routinely observed using a standard reducing procedure attempts to introduce the required enol triflate on this sensi-

[Zn(BH₄)₂, LiAl(tBuO)₃H, H₂/PtO₂/AcOH]. On the other tive material using Tf₂O met with failure. It was felt that it

hand, subjecting 35 to sodium borohydride gave a mixture would be best to temporarily replace the iodine atom by a

of alcohol 37a, lactone 38 and diol 37b. Only a marginal more stable group. At this stage new difficulties arose in

improvement was observed using Luche’s conditions^[31]what was anticipated to be a straightforward transforma-

which provided 37a and 37b in yields of 50% and 30%, tion. Thus S_N2 displacement of the iodide group with so-

respectively (Scheme 5).

dium acetate gave the acetate 40a but, once again, this ma-

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Scheme 6. (a) Pb(OAc)₄, I₂, CCl₄, reflux, hν, 65 %; (b) AcONa,

DMF, 110 °C, 3 h, 70%; (c) K₂CO₃, MeOH, 20 °C, 5 h, 80%; (d)

PivCl, py, 20 °C, 4 h, 73 %; (e) (CF₃SO₂)₂O, 2,6-di-tBu-C₅H₃N,

(CH₂Cl)₂, 90 °C, 15 h, 65%; (f) DIBAL-H, CH₂Cl₂, –78 °C, then

–20 °C 4 h, 70%; (g) PPh₃, I₂, Im, CH₂Cl₂, 25 °C, 2 h, 70%; (h) i:

23, LDA, THF, –78 °C, 15 min, ii: DMPU, –78 °C to 50 °C, 90 min,

65%.

Scheme 5. (a) TMSOTf, Et₃N, CH₂Cl₂, 4 h, 20 °C, 89 %; (b)

4 equiv. CH₃CHO, 4 equiv. TiCl₄, CH₂Cl₂, –78 °C, 2 h, 89%; (c)

MsCl, Et₃N, CH₂Cl₂, 0 °C, 30 min, then 1 h 20 °C, (d) DBU, tolu-

ene, 110 °C, 1 h, 90% overall from 33; (e) Me₂CuLi, Et₂O, –30 °C,

1 h, 70 %; (f) NaBH₄, CeCl₃, MeOH, 40 °C, 3 h, 37a 50%, 37b

30%; (g) 3  KOH, MeOH, 20 °C, 4 h, 75%; (h) Ti(OiPr)₄, iPrOH,

80 °C, 4 h, 70 %; (i) (tBuO)₂CHNMe₂; toluene, 110 °C, 90 min,

of the lithium enolate of 23 with iodo ketone 39 provided

60%; (j) (CF₃SO₂)₂O, 2,6-di-tBu-C₅H₃N, (CH₂Cl)₂, 90 °C, 90 min, the desired keto ester 43 in 60% yield along with a small

65 % from 35a, 80 % from 35d; (k) i: LDA, –78 °C, 1 h, ii: 5-

Cl(C₅H₃N)NTf₂, –78 °C to 20 °C, 2 h, 70 % from 35c.

amount of the volatile ether 44, arising from the aforemen-

tioned proton transfer followed by intramolecular O-alky-

lation of the ketone enolate. Therefore, the presence of the

terial gave a complex mixture when subjected to Tf₂O. Con- unprotected keto group in 39 was not prejudicial to the effi-

versely, the corresponding pivaloyl ester 40c prepared from ciency of the alkylation step, hence considerably improving

40a through a saponification and esterification two-step se- access to the AC fragment.

quence was more compliant affording the expected enol

Having thus secured the critical union of subunits A and

triflate 41 when treated with Tf₂O in the presence of 2,6-di- C, we turned our attention to the closing of the tricyclic

tert-butylpyridine. DIBAL-H reduction of the pivalate ring system through the Heck reaction/acetate anion cap-

group and iodation using the Corey iodination procedure^[32]ture process we previously employed to prepare the model

produced iodo triflate 42 in 49% overall yield from 41. Al- compound 39. Preparation of the alkenyl triflate (–)-22 oc-

though this material might potentially be used as fragment curred smoothly by treatment of 43 with triflic anhydride

A in the synthesis, the extra protection and deprotection in the presence of 2,6-di-tert-butylpyridine in 1,2-dichloro-

steps required did not make this sequence very attractive. ethane at reflux. However, the presence of the bulky isopro-

Nevertheless, we decided to continue the synthesis with this pyl group deeply affected the reactivity of triflate 22. For

material. Thus, condensation of the lithium enolate of example, treatment of 22 with Pd₂(dba)₃·CHCl₃in the pres-

methyl dihydrobenzoate 23 with 42 in the presence of ence of n-tetrabutylammonium acetate left the starting ma-

DMPU gave rise to a 65% yield of adduct 43, in which the terial unchanged. All attempts at improving this result using

enol triflate moiety was cleaved back to the carbonyl group various palladium catalysts and reaction conditions failed.

(Scheme 6). This disappointing result definitively thwarted We speculated that the lack of reactivity of 22 might be

this synthetic route and forced us to find a more suitable overcome by adding a carbonyl group at the C4 position of

alternative method for accessing alkenyl triflate 22.

the cyclohexadienyl appendage.^[33]Allylic oxidation of

The complications outlined above compelled us to inves- (–)-22 with CrO₃·3,5-DMP^[34]gave the expected dienone 45,

tigate the direct coupling of iodo ketone 39 with the enolate albeit in low yield, along with products with an aromatic C

of methyl dihydrobenzoate 23. At the outset of the work, ring the structures of which were not readily formulated.

this straightforward procedure was rejected because we sus- Despite this drawback, it turned out that use of the dienone

pected that the proton transfer between the ester enolate of C ring was beneficial to the critical Heck cyclisation in view

23 and the free ketone group would thwart the alkylation of the fact that treatment of 45 with Pd(OAc)₂in toluene

process. Contrary to our expectations, however, treatment at reflux gave a 4:1 mixture of trienones 46a and 46b in

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E. Drège, C. Tominiaux, G. Morgant, D. Desmaële

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74% yield. The stereochemistry of the major diastereomer on the face opposite the bulky pivaloyl group.^[16a]Although

was assigned by analogy with other results obtained in the we had not anticipated exclusive epoxidation from the β

series (vide infra) (Scheme 7).

face, we were very pleased with this favourable outcome

which would prove to be of great value in the completion

of the synthesis since this protocol allows the direct intro-

duction of the oxygen functionality with the proper config-

uration at the C14 centre of natural cyathins (Scheme 8).

Scheme 7. (a) i: LDA, 23, THF, –78 °C, 20 min, i: DMPU, –78 °C

to +50 °C, 1 h, 60 %; (b) (CF₃SO₂)₂O, 2,6-di-tBu-C₅H₃N,

(CH₂Cl)₂, 90 °C, 6 h, 71%; (c) CrO₃.3,5-DMP, CH₂Cl₂, 25 °C, 4 h,

40%; (d) 20 mol-% Pd(OAc)₂, PPh₃, nBu₄NBr, toluene, 120 °C, 1 h,

74%.

Due to the low yield of the allylic oxidation of 22, the

approach was revised in such a way as to avoid decarboxyl-

ation and aromatisation of the C ring. Thus it was hoped

that reduction of the ester group and protection of the re-

sultant alcohol would improve this step. In the event, when

the pivalate ester 48 [obtained in 72% yield upon treatment

of (–)-22 with DIBAL-H, followed by esterification with

tBuCOCl] was subjected to CrO₃·3,5-DMP, the desired di-

enone (S)-49 was obtained in 60% yield. Treatment of alk-

enyl triflate 49 with Pd(OAc)₂/PPh₃/nBu₄NBr in toluene at

110 °C proceeded smoothly affording trienone (+)-50a

(73% isolated yield) with good diastereoselectivity (95:5).

The assignment of the relative configuration between rings

1

A and C in the main isomer was first investigated by H

Scheme 8. (a) DIBAL-H, CH₂Cl₂, –78 °C, 1 h, 90 %; (b) PivCl,

Et₃N, DMAP, CH₂Cl₂, 20 °C, 4 h, 71%; (c) CrO₃, 2,5-dimethylpyr-

azole, 4 h, 20 °C, 60%; (d) 20 mol-% Pd(OAc)₂, PPh₃, nBu₄NBr,

toluene, 120 °C, 2 h, 73 %; (e) 50 % H₂O₂, NaOH cat, MeOH,

25 °C, 24 h, 50%.

NMR spectroscopy. Significantly, the absence of a corre-

lation between the methylene bearing the pivalate ester

group and the methyl at C9 in the NOESY chart strongly

suggested that this compound possessed the desired anti ste-

reochemistry. In search of an unambiguous determination

At this point it was considered timely to investigate the

of the stereochemistry, we chose to prepare the epoxide 51, one-carbon expansion of the C ring. However, the densely

since such a transformation was found to produce crystal- functionalised materials 50a and 51 were found to have a

line material in the nor-isopropyl series.^[16a]Accordingly, tendency to give aromatic decomposition products with a

epoxidation of (+)-50a was carried out with 50% hydrogen variety of reagents, presumably through cleavage of the piv-

peroxide in the presence of sodium hydroxide. To our de- aloyl ester group followed by a retro-aldol type process. To

light, epoxide 51 gave satisfactory single-crystals. The X-ray overcome this trend we decided to reduce the less hindered

crystallographic analysis shown in Scheme 8 confirmed the double bond of 50a before addressing the crucial ring en-

trans relationship between the two angular groups at C6 largement. Thus, homogeneous hydrogenation of the tri-

and C9.^[16b,35]In contrast to the model devoid of the iso- enone (+)-50a using Wilkinson’s catalyst^[36]furnished the

propyl group, the epoxidation reaction had taken place ex- desired dienone (+)-52 in 75% yield. With this compound

clusively on the less hindered face of the molecule, namely in hand, we initially sought to accomplish ring expansion

4830

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Synthetic Studies on Cyathin Terpenoids

FULL PAPER

through cyclopropanation or halocyclopropanation of the noids in 18 steps from 2-methylcyclopentanone. The key

corresponding silyloxydiene^[37]derived from 52. However, steps of our synthesis were the enantioselective Michael ad-

this possibility was skirted because we failed to prepare the dition to settle the absolute configuration, an intramolecu-

required silyl enol ether. A revised strategy was designed to lar Heck reaction to establish the crucial anti stereochemis-

circumvent the problematic enolisation step. We postulated try of the C-nor-cyathane (+)-50a and the organoalumin-

that an exo methylene group, such as found in 53, could be ium-promoted diazoalkane mediated ring expansion of the

of value in a modified route using a thallium nitrate medi- C ring. Further elaboration of ketone (+)-5 into erinacine

ated ring expansion reaction.^[38]Standard Wittig condensa- A and other cyathin diterpenes requires the reduction of

tion of dienone (+)-52 with the ylide derived from methyl- the angular hydroxymethyl group to a methyl group, ma-

triphenylphophonium bromide and n-butyllithium failed to nipulation of the C12 carbonyl to introduce the requisite

give the desired triene 53. The reaction of 52 with the Tebbe carbaldehyde and functionalisation at C14. Epoxide (+)-51,

reagent^[39]was more rewarding providing 53 in 20% yield which displays an oxygen atom with the correct β configu-

but, finally, a 60% yield was achieved using t-AmONa in ration at the future C14 centre of natural cyathins, might

toluene^[40]as a base in the Wittig reaction. When 53 was serve as a suitable starting material to this purpose.

exposed to thallium nitrate, a 2:1 mixture of ketones 54 and

5 was obtained in a disappointing yield of 30%. Moreover,

the yield was found to decrease on scaling up. It was thus

deemed unlikely that we could achieve the synthesis accord-

ing to this protocol. Accordingly, we examined the alumin-

ium-catalysed carbenoid insertion of 52. To our delight,

condensation of dienone (+)-52 with trimethylsilyldiazome-

thane in the presence of trimethylaluminium followed by

hydrolysis of the resultant enol ether, according to Yamam-

oto’s procedure,^[41]provided the ring-expanded ketone (+)-

5 obtained in 60% isolated yield along with 10% of the

regioisomeric enone 54 (Scheme 9). To the best of our

knowledge, the preferential migration of the unsaturated α

side of enones in such a process is unprecedented, although

a similar trend was previously observed with 1-tetralone de-

rivatives.^[42]

Experimental Section

General: Melting points: Büchi capillary tube melting point appara-

tus, uncorrected. IR spectra were obtained on solids or neat liquids

on a Fourier Transform Bruker Vector 22 spectrometer. Only sig-

nificant absorptions are listed. Optical rotations were measured on

a Perkin–Elmer 241 Polarimeter at 589 nm. The ¹H and ¹³C NMR

spectra were recorded on a Bruker AC 200 P (200 MHz and

50 MHz, for ¹H and ¹³C, respectively), a Bruker Avance-300

1

(300 MHz and 75 MHz, for H and ¹³C, respectively) or a Bruker

ARX 400 (400 MHz and 100 MHz, for ¹H and ¹³C, respectively)

spectrometer. Recognition of methyl, methylene, methine and qua-

ternary carbon nuclei in ¹³C NMR spectra rests on the J-modu-

lated spin-echo sequence. Mass spectra were recorded on a Hew-

lett–Packard G 1019 A (70 eV) or on a Bruker Esquire-LC instru-

ment. Analytical thin-layer chromatography was performed on

Merck silica gel 60F₂₅₄glass precoated plates (0.25 mm layer). Col-

umn chromatography was performed on Merck silica gel 60 (230–

400 mesh ASTM). Diethyl ether and tetrahydrofuran (THF) were

distilled from sodium/benzophenone ketyl. Methanol and ethanol

were dried with magnesium and distilled. Benzene, toluene, DMF

and CH₂Cl₂were distilled from calcium hydride under a nitrogen

atmosphere. All reactions involving air- or water-sensitive com-

pounds were routinely conducted in glassware which had been

flame-dried under a positive pressure of nitrogen. Chemicals ob-

tained from commercial suppliers were used without further purifi-

cation. Elemental analyses were performed by the Service de micro-

analyse, Centre d’Etudes Pharmaceutiques, Châtenay-Malabry,

France with a Perkin–Elmer 2400 analyser.

Methyl (1R)-3-(1-Methyl-2-oxocyclopentyl)propanoate (10): In a

round-bottom flask equipped with a Dean–Stark apparatus was

placed 2-methylcyclopentanone, (24.6 g, 0.25 mol), (S)-1-phenyl-

ethylamine (30.0 g, 0.25 mol) and p-toluenesulfonic acid (50 mg) in

toluene (150 mL). The reaction mixture was heated at reflux for

16 h and concentrated under reduced pressure. The residue was dis-

tilled (b.p. 92 °C, 0.2 Torr) to give imine 11 as a colourless oil (1:1

diastereomeric mixture, 42.0 g, 87%). IR (film): ν = 1673 cm^–1

˜

(C=N). To the imine 11 (41.7 g, 0.22 mol) was added freshly dis-

tilled methyl acrylate (89.4 g, 1.04 mol) and hydroquinone (0.05 g).

The mixture was stirred at 50 °C for 48 h and concentrated under

reduced pressure. To the residue was added 20% aqueous acetic

acid (70 mL) and THF (120 mL). After being stirred for 3 h at

20 °C, the mixture was concentrated in vacuo and 3  hydrochloric

acid (40 mL) was added. The mixture was extracted with diethyl

ether (4×100 mL) and the collected organic phases were washed

Scheme 9. (a) Rh(PPh₃)₃Cl 20 mol-%, EtOH, 25 °C, 60 h, 75%; (b)

t-AmONa, CH₃PPh₃Br, toluene, 25 °C, 5 h, 60 %; (c) Tl(NO₃)₃,

MeOH, CH₂Cl₂, 2 min, 20 °C, 30%; (d) i: TMSCHN₂, Me₃Al,

CH₂Cl₂, 20 °C, 4 h, ii: 3  HCl, acetone, 20 °C, 2 h, 70% 5/54 =

6:1.

In summary we have successfully assembled, in optically

active form, the tricyclic carbon core of the cyathin terpe- with brine, dried with MgSO₄and concentrated. Distillation af-

Eur. J. Org. Chem. 2006, 4825–4840

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4831

E. Drège, C. Tominiaux, G. Morgant, D. Desmaële

FULL PAPER

forded (+)-10 as a colourless oil (27.8 g, 70% overall yield from 2-

ing stirred at 0 °C for 3 h, the mixture was poured into pentane

(15 mL) and washed with cold brine. The organic layer was dried

with MgSO₄and concentrated under reduced pressure to give

160 mg of crude silyl ether 14 (86%) as a yellow oil, which was

used directly for the next steps.

methylcyclopentanone), b.p. 110 °C/0.05 Torr. [α]²_D⁰= +35.5 (c =

1.7, EtOH). IR (film): ν = 2957, 1731 (C=O, CO Me), 1436, 1374,

˜

2

1199, 1164 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 3.62 (s, 3 H,

OCH₃), 2.36–2.12 (m, 4 H, CH₂CO₂CH₃and 3-H), 1.93–1.63 (m,

6 H, CH₂CH₂CO₂CH₃, 4-H and 5-H), 0.97 [s, 3 H, C(CH₃)-

CO] ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 222.4 (C, CO), 173.6

(CO₂Me), 51.4 (CH₃, OCH₃), 47.2 (C, C1), 37.2 (CH₂, C3), 35.8

(CH₂, C5), 31.2 (CH₂, CH₂CO₂Me), 29.0 (CH₂, CH₂CH₂CO₂Me),

21.1 (CH₃), 18.3 (CH₂, C4) ppm. C₁₀H₁₆O₃(184.2): calcd. C 65.19,

H 8.75; found C 65.03, H 8.89.

A solution of n-butyllithium (2.5  in hexane, 0.55 mL, 1.37 mmol)

was added to a solution of diisopropylamine (162 mg, 1.6 mmol)

in THF (4 mL) at –5 °C. The mixture was stirred at –5 °C for

15 min and cooled to –78 °C. A solution of cyclohepta-2,4,6-triene-

carbonitrile 8a^[21](160 mg, 1.35 mmol) in THF (0.5 mL) was added

dropwise. The resultant mixture was stirred at –78 °C for 10 min

and a solution of iodide 14 (160 mg, 0.50 mmol) in a mixture of

THF (1 mL) and HMPA (2 mL) was then added. The reaction mix-

ture was stirred while the temperature was gradually raised to

–20 °C. After 16 h at –20 °C, saturated aqueous ammonium chlo-

ride was added and the mixture was extracted with diethyl ether

(4×15 mL). The collected organic phases were washed with brine,

dried with MgSO₄and concentrated under reduced pressure. The

residue was taken up in THF (2 mL) and nBu₄NF (1.5 mL, 1 ,

1.5 mmol) was added. After 1 h at 20 °C, water was added (10 mL)

and the mixture was extracted with diethyl ether (4×15 mL). The

combined organic phases were dried with MgSO₄and concen-

trated. Purification by silica gel chromatography (cyclohexane/ethyl

acetate, 7:1) gave 86 mg of (+)-15 as a colourless oil (71% yield).

Methyl (1R)-3-(1-Methyl-2-oxocyclopentyl)propanoate (12): To a

solution of ester (+)-10 (29.9 g, 0.16 mol) in methanol (200 mL)

was added potassium hydroxide (200 mL, 2 , 0.4 mol) and the

mixture was stirred at 20 °C for 16 h. The reaction mixture was

concentrated under reduced pressure and the residue extracted with

diethyl ether. The organic layer was discarded and 5  hydrochloric

acid was added to the aqueous layer until a pH of 2 was obtained.

The mixture was extracted with CH₂Cl₂(3×100 mL). The com-

bined organic phases were dried with MgSO₄and concentrated un-

der reduced pressure to leave (+)-12 as a pale yellow oil (26.7 g,

97%). [α]²_D⁰= +14 (c = 1.7, EtOH). IR (film): ν = 3600–2400 (OH),

˜

1

1730 (C=O), 1705 (CO₂H), 1459, 1406, 1291, 1200, 1165 cm^–1. H

NMR (CDCl₃, 300 MHz): δ = 8.0–6.0 (br. s, CO₂H), 2.50–2.15 (m,

[α]²_D⁰= +33 (c = 0.4, EtOH). IR (neat): ν = 3031, 2966, 2220 (CN),

˜

4

H, 3-H, CH₂CO₂H), 1.99 –1.60 (m, 6 H, 4-H, 5-H,

1

1731 (C=O), 1638 (C=C), 1461, 1406, 1373, 1063 cm^–1. H NMR

CH₂CH₂CO₂H), 1.02 [s, 3 H, C(CH₃)] ppm. ¹³C NMR (CDCl₃,

75 MHz): δ = 222.1 (C, CO), 179.0 (C, CO₂H), 47.5 (C, C1), 37.5

(CH₂, C3), 36.0 (CH₂, C5), 31.3 (CH₂, CH₂CH₂CO₂H), 29.1 (CH₂,

CH₂CH₂CO₂H), 21.3 (CH₃), 18.6 (CH₂, C4) ppm. C₉H₁₄O₃

(170.2): calcd. C 63.51, H 8.29; found C 63.29, H 8.54.

(400 MHz, CDCl₃): δ = 6.73 [m, 2 H, (CN)CCH=CH–CH=], 6.31

[m, 2 H, (CN)CCH=CH–CH=], 4.76 [dd, J = 14.1, 9.8 Hz, 2 H,

(CN)CCH=CH–CH=], 2.42–2.17 (m, 2 H, 3-H), 1.96–1.71 (m, 8

H), 1.06 [s, 3 H, C(CH₃)] ppm. ¹³C NMR (50 MHz, CDCl₃): δ =

221.9 (C, CO), 129.7 [2 CH, (CN)CCH=CH–CH=], 125.9 [2 CH,

(CN)CCH=CH–CH=], 118.9 (CN), 106.3 [2 CH, (CN)CCH=CH–

CH=], 47.2 (C, C1), 37.0 (CH₂, C3), 35.3 (CH₂), 34.1 [C,

(CN)CCH=], 31.4 (CH₂), 30.7 (CH₂), 21.1 (CH₃), 18.1 (CH₂,

C4) ppm. MS (ESI, MeOH): m/z (%): 264 (100) [M + Na]⁺.

C₁₆H₁₉NO (241.3): calcd. C 79.63, H 7.94, N 5.80; found C 79.44,

H 7.96, N 5.88.

(2R)-2-(2-Iodoethyl)-2-methylcyclopentanone (13): A solution of

crude acid (+)-12 (2.20 g, 13 mmol) in CCl₄(160 mL) was placed

in a round-bottomed flask equipped with a dropping funnel, sur-

mounted with a condenser and charged with solid iodine (3.40 g,

13.4 mmol) set down on a glass-wool plug sealing the stopcock.

Lead(IV) acetate (6.50 g, 14.5 mmol) was added to the solution in

one portion. The apparatus was illuminated with a 500 W visible

light lamp set 15 cm from of the flask while the mixture was heated

to reflux in such way that the condensed solvent slowly dragged

iodine into the reaction flask. After stirring for 1 h all the iodine

had been consumed and the milky solution was cooled to room

temperature. The reaction mixture was filtered through celite and

the solid was washed thoroughly with CH₂Cl₂. The organic layer

was sequentially washed with aqueous potassium thiosulfate

(20 mL), 2  potassium hydroxide (20 mL) and brine (20 mL). The

organic phases were dried with MgSO₄and concentrated in vacuo

to give an oil which was chromatographed on silica gel (cyclohex-

ane/ethyl acetate, 4:1) to give iodide (+)-13 as a colourless, light-

sensitive oil (2.74 g, 84%) [α]²_D⁰= +12 (c = 1.1, EtOH). IR (film):

tert-Butyl-{[(1R,2R)- and (1S,2R)-2-(2-iodoethyl)-2-methylcyclo-

pentyl]oxy}dimethylsilane (16b): To a solution of iodo ketone 13

(3.53 g, 14 mmol) in dry EtOH (40 mL) was added, in portions,

NaBH₄(300 mg, 7.9 mmol) and the mixture was stirred under ni-

trogen for 3 h at 20 °C. The reaction mixture was concentrated un-

der reduced pressure, brine (10 mL) was added and the mixture

was extracted with diethyl ether (3×10 mL). The combined organic

phases were dried with MgSO₄and concentrated under reduced

pressure to give iodo alcohol 16a (2.34 g, 65%) as a yellow oil

which was used directly for the next steps without further purifica-

tion. To the crude alcohol 16a (2.34 g, 9.2 mmol) in CH₂Cl₂

(30 mL) was added tert-butyldimethylsilyl chloride (3.0 g,

19.9 mmol) and imidazole (2.0 g, 29.4 mmol). After being stirred

at 20 °C for 16 h, water was added and the reaction mixture was

extracted with CH₂Cl₂(3×10 mL). The organic phases were dried

with MgSO₄and concentrated in vacuo. Purification by

chromatography on silica gel (cyclohexane/ethyl acetate, 7:1) gave

ν = 2960, 1731 (C=O), 1456, 1404, 1373, 1319, 1269, 1201,

˜

1

1161 cm^–1. H NMR (400 MHz, CDCl₃): δ = 3.19 (ddd, J = 11.4,

9.4, 5.8 Hz, 1 H, CH₂I), 3.05 (ddd, J = 11.4, 9.4, 6.3 Hz, 1 H,

CH₂I), 2.34–2.16 (m, 2 H, 5-H), 2.16–2.00 (m, 2 H, CH₂CH₂I),

1.95–1.68 (m, 4 H, 3-H, 4-H), 1.00 [s, 3 H, C(CH₃)CO] ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 221.4 (C, CO), 50.1 (C, C1), 41.7

(CH₂, CH₂CH₂I), 37.3 (CH₂, C5), 35.6 (CH₂, C3), 20.9 (CH₃), 18.6

(CH₂, C4), –0.9 (CH₂, CH₂CH₂I) ppm. C₈H₁₃IO (252.1): calcd. C

38.12, H 5.20; found C 38.23, H 5.21.

16b as a colourless oil (3.04 g, 96%). IR (film): ν = 2963, 2932,

˜

2860, 1464, 1382, 1257, 1146, 1112 cm^–1. ¹H NMR (300 MHz,

CDCl₃): δ = 3.67 (t, J = 7.0 Hz, 1 H, CHOSi), 3.30–3.00 (m, 2 H,

CH₂CH₂I), 2.05 (td, 1 H, J = 13.1, 5.0 Hz, 1 H), 1.92–1.30 (m, 7

H), 0.88 [s, 9 H, Si(CH₃)₂C(CH₃)₃], 0.86 [s, 3 H, C(CH₃)], 0.04 [s,

3 H, Si(CH₃)₂C(CH₃)₃], 0.03 [s, 3 H, Si(CH₃)₂C(CH₃)₃] ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 80.0 (CH_,CHOSi), 47.3 [C, C(CH₃)],

46.4 (CH₂, CH₂CH₂I), 34.9 (CH₂, C3), 32.3 (CH₂, C5), 25.9 [3

CH₃, SiCH₂C(CH₃)₃], 19.2 (CH₂, C4), 17.7 [CH₃and C, C(CH₃)

(1R)-1-[2-(1-Methyl-2-oxocyclopentyl)ethyl]cyclohepta-2,4,6-triene-

1-carbonitrile (15): To a solution of iodo ketone 13 (150 mg,

0.60 mmol) in CH₂Cl₂(6 mL) was added, at 0 °C, triethylamine

(225 mg, 2.24 mmol) and TMSOTf (450 mg, 1.6 mmol). After be-

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Eur. J. Org. Chem. 2006, 4825–4840

Synthetic Studies on Cyathin Terpenoids

and Si(CH₃)₂C(CH₃)₃], 1.48 (CH₂, CH₂CH₂I), –4.2 [CH₃, Si- C3), 35.6 (CH₂), 33.8 (CH₂), 30.8 (CH₂), 26.1 (CH₂,

FULL PAPER

(CH₃)₂C(CH₃)₃], –4.8 [CH₃, Si(CH₃)₂C(CH₃)₃] ppm. C₁₄H₂₉IOSi

C=CHCH₂CH=C), 21.5 [CH₃, (CH₃)C], 18.6 (CH₂, C4) ppm.

(368.4): calcd. C 45.65, H 7.94; found C 45.71, H 7.87.

C₁₆H₂₂O₃(262.3): calcd. C 73.25, H 8.45; found C 72.24, H 8.48.

Methyl (1R,2R)- and (1S, 2R)-1-[2-(2-Hydroxy-1-methylcyclopentyl)- Methyl

(1R)-1-[2-(1-Methyl-2-{[(trifluoromethyl)sulfonyl]oxy}-

ethyl]cyclohexa-2,5-diene-1-carboxylate (25): To a solution of diiso-

propylamine (605 mg, 6.0 mmol) in dry THF (3 mL) was added,

at –5 °C, a hexane solution of n-butyllithium (2.5 , 2.0 mL,

5.0 mmol). The mixture was stirred at –5 °C for 15 min and cooled

to –78 °C. A solution of cyclohexa-2,5-dienecarboxylic acid methyl

ester 23 (550 mg, 4 mmol) in dry THF (3 mL) was added dropwise

with a syringe. The resultant mixture was stirred at –78 °C for

15 min and iodide 16b (740 mg, 2.00 mmol) in DMPU (3 mL) was

added. The reaction mixture was stirred while the temperature was

gradually raised to 50 °C. After 3 h at 50 °C, water (3 mL) was

added and the mixture was extracted with diethyl ether (3×10 mL).

The collected organic phases were washed with brine, dried with

MgSO₄and concentrated. Purification by silica gel chromatog-

raphy (cyclohexane/Ethyl acetate, 4:1) gave 630 mg of 24 (83%

yield). To a solution of silyl ether 24 (630 mg, 1.67 mmol) in THF

(2 mL) was added a solution of n-tetrabutylammonium fluoride

(1.0  in THF, 8.0 mL, 8 mmol). The mixture was stirred at 20 °C

for 5 h. Water (6 mL) was added and the mixture was extracted

with diethyl ether (3×10 mL). The collected organic phases were

washed with brine, dried with MgSO₄and concentrated. Purifica-

tion by silica gel chromatography (cyclohexane/ethyl acetate, 2:1)

cyclopent-2-en-1-yl)ethyl]cyclohexa-2,5-diene-1-carboxylate

(27):

Trifluoromethanesulfonic anhydride (3.35 g, 11.9 mmol) was added

dropwise with a syringe to a mixture of 2,6-di-tert-butylpyridine

(1.87 g, 9.8 mmol) and keto ester (+)-26 (2.35 g, 9.0 mmol) in dry

dichloromethane (40 mL). The resultant mixture was stirred for

15 h at 20 °C. Water was added (40 mL) and the mixture was ex-

tracted with dichloromethane (3×15 mL). The combined organic

phases were dried with MgSO₄and concentrated under reduced

pressure. The crude product was purified by silica gel chromatog-

raphy (cyclohexane/ethyl acetate, 4:1) to give triflate (+)-27 as a

yellow oil (2.80 g, yield 79%). [α]²_D⁰= +34.6 (c = 2.1, EtOH). IR

(neat): ν = 3030, 2954, 1730 (CO Me), 1656 (C=C), 1419, 1202,

˜

2

1139 1045 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 5.91 (dt, J =

11.8, 3.1 Hz, 2 H, HC=CHCH₂CH=CH), 5.68 (dddd, J = 11.8,

5.8, 2.3, 1.5 Hz, 2 H, HC=CHCH₂CH=CH), 5.57 [t, J = 2.7 Hz, 1

H, CH=C(OTf)], 3.59 (s, 3 H, OCH₃), 2.68 (ddt, J = 23.2, 3.5,

2.1 Hz, 1 H, =CHCH₂CH=), 2.61 (d, J = 23.2, 3.5, 2.1 Hz, 1 H,

=CHCH₂CH=), 2.36 (ddt, J = 16.4, 5.6, 2.7, Hz, 1 H, 4-H), 2.29

(ddt, J = 16.4, 5.8, 2.6 Hz, 1 H, 4-H), 1.89 (ddd, J = 13.6, 8.4,

5.8 Hz, 1 H, 5-H), 1.75–1.54 [m, 3 H, CH₂CH₂(C)CO₂Me, 5-H],

1.31 [t, J = 8.6 Hz, 2 H, CH₂CH₂(C)CO₂Me], 1.11 [s, 3 H,

C(CH₃)] ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 175.1 (C,

CO₂Me), 154.0 (C, C2), 126.8 (2 CH, C=CHCH₂CH=C), 126.1 (2

gave 342 mg of alcohol 25 as a yellow oil (78% yield). IR (neat): ν

˜

= 3600–3100 (OH), 3032, 2953, 2872, 1729 (CO₂Me), 1637 (weak,

1

C=C), 1452, 1434, 1234, 1201 cm^–1. H NMR (CDCl₃, 200 MHz) CH, C=CHCH₂CH=C), 118.5 (q, J = 320 Hz, C, CF₃SO₂), 113.2

the presence of two diastereomers induced the splitting of some

signals, δ = 5.90–5.70 (m, 2 H, HC=CHCH₂CH=CH), 5.62 (d, J

(CH, C3), 52.1 (CH₃, OCH₃), 47.5 (C, CCO₂Me), 46.1 (C, C1),

34.0 (CH₂), 33.8 (CH₂), 32.6 (CH₂), 26.1 (CH₂, C=CHCH₂CH=C),

= 11.0 Hz, 2 H, HC=CHCH₂CH=CH), 3.67 (br. s, 4 H, CHOH 25.5 (CH₂, C5), 24.4 [CH₃, (CH₃)C] ppm. ¹⁹F NMR (CDCl₃,

and CO₂CH₃), 2.52 (br. s, 2 H, =CHCH₂CH=), 2.08–1.87 (m, 1 188 MHz): δ = –74.1 (s) ppm. MS (ESI, MeOH) m/z (%): 412 (100)

H), 1.81–0.93 (m, 10 H), 0.86 [s, 3 H, C(CH₃)] ppm. ¹³C NMR [M + Na]⁺, 395 (70) [M + H]⁺, 245 (12).

(50 MHz, CDCl₃):

δ = 175.3 (C, CO₂Me), 127.1 (2 CH,

Methyl (3aR,5aR,8R,9aS)-8-Hydroxy-3a-methyl-2,3,3a,4,5,8,9,9a-

octahydro-5aH-cyclopenta[a]naphthalene-5a-carboxylate (30): To a

mixture of triflate (+)-27 (2.8 g, 7.1 mmol), n-tetrabutylammonium

acetate (6.3 g, 21.0 mmol) and lithium chloride (600 mg,

14.2 mmol) in DMSO (10 mL) was added tris(dibenzylideneace-

tone) dipalladium–chloroform adduct (370 mg, 0.4 mmol). The

mixture was stirred at 60 °C for 3 h. After cooling, water (10 mL)

C=CHCH₂CH=C), 125.5 (2 CH, C=CHCH₂CH=C), 80.0 (CH,

CHOH), 51.9 (CH₃, OCH₃), 47.6 (C, CCO₂Me), 44.0 (C, C1), 35.6

(CH₂), 34.7 (CH₂), 34.2 (CH₂), 32.3 (CH₂), 26.0 (CH₂,

C=CHCH₂CH=C), 19.2 (CH₂, C4), 18.1 [CH₃, (CH₃)C] ppm. MS

(ESI, CH₃CN): m/z (%): 287 (100) [M + Na]⁺. C₁₆H₂₄O₃(264.4):

calcd. C 72.69, H 9.15; found C 72.58, H 9.30.

Methyl (1R)-1-[2-(1-Methyl-2-oxocyclopentyl)ethyl]cyclohexa-2,5- was added and the reaction mixture was extracted with diethyl

diene-1-carboxylate (26): To a solution of oxalyl chloride (240 mg,

1.9 mmol) in CH₂Cl₂(2 mL) was added dropwise, at –78 °C, anhy-

drous DMSO (156 mg, 2 mmol). The mixture was stirred at –78 °C

for 20 min and a solution of alcohol 25 (342 mg, 1.3 mmol) in dry

ether (3×20 mL). The combined organic phases were dried with

MgSO₄and concentrated under reduced pressure to leave a brown

oil (3.0 g) which was taken up in dry methanol (50 mL). Potassium

carbonate (1.1 g, 8.0 mmol) was added and the mixture was stirred

CH₂Cl₂(2 mL) was added. After 1 h at –78 °C, Et₃N (710 mg, at 20 °C for 3 h. The reaction mixture was concentrated under re-

7.0 mmol) was added and the reaction mixture was stirred for 5 min

and then warmed to room temperature. After being stirred 8 h at

20 °C, water (10 mL) was added and the aqueous layer was ex-

tracted with CH₂Cl₂(2×10 mL). The combined organic layers were

washed with brine, dried with MgSO₄and concentrated in vacuo.

Purification by silica gel chromatography (cyclohexane/ethyl ace-

duced pressure, 1  HCl (10 mL) was added and the mixture was

extracted with diethyl ether (3×15 mL). The combined organic

phases were washed with brine, dried with MgSO₄and concen-

trated under reduced pressure. The crude product was purified by

silica gel chromatography (cyclohexane/ethyl acetate, 4:1) to give

alcohol (–)-30 as a colourless oil (1.6 g, yield 85% from 27). [α]²_D⁰

tate, 4:1) gave 323 mg of (+)-26 as a yellow oil (95% yield). [α]²_D⁰

+36.2 (c = 1.3, EtOH). IR (neat): ν = 3032, 2954, 1727 (C=O,

=

= –4.4 (c = 2.3, EtOH). IR (neat): ν = 3500–3000 (OH), 2947, 2852,

˜

1726 (CO₂Me), 1638 (C=C), 1454, 1431, 1265, 1202 1146 cm^–1. ¹H

˜

CO₂Me), 1637 (weak, C=C), 1458, 1433, 1406, 1231, 1201 cm^–1. NMR (400 MHz, CDCl₃): δ = 5.92 (ddd, J = 9.9, 5.5, 1.4 Hz, 1 H,

¹H NMR (CDCl₃, 200 MHz): δ = 5.89 (dt, J = 12.7, 2.9 Hz, 2 H, 7-H), 5.76 (d, J = 9.9 Hz, 1 H, 6-H), 5.46 (dd, 1 H, J = 2.8, 2.0 Hz,

HC=CHCH₂CH=CH), 5.66 (d,

J

=

12.7 Hz,

2

H, 1-H), 4.11 (ddd, J = 5.6, 3.9, 2.0 Hz, 1 H, 8-H), 3.65 (s, 3 H,

HC=CHCH₂CH=CH), 3.66 (s, 3 H, OCH₃), 2.63 (br. s, 2 H, CO₂CH₃), 3.44 (dd, J = 14.3, 3.5 Hz, 1 H, 9a-H), 2.35–2.25 (m, 1

=CHCH₂CH=), 2.53–2.06 (m, 2 H, 3-H), 1.99–1.42 (m, 6 H, CH₂), H, 2-H), 2.15 (dddd, J = 15.9, 9.1, 3.1, 1.3 Hz, 1 H, 2-H), 2.05

1.34–1.20 (m, 2 H, CH₂), 0.96 [s, 3 H, C(CH₃)] ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 221.3 (C, CO), 175.2 (C, CO₂Me), 126.8

(CH, C=CHCH₂CH=C), 126.0 (CH, C=CHCH₂CH=C), 52.0

(CH₃, OCH₃), 47.7 (C, CCO₂Me), 41.9 [C, C(CH₃)CO], 37.5 (CH₂,

(ddd, J = 14.5, 3.8, 1.4 Hz, 1 H, 5-H), 2.00–1.90 (br. s, OH), 1.92

(td, J = 14.3, 3.9 Hz, 1 H, 9-H_ax), 1.76–1.69 (m, 2 H, 3-H, 9-H_eq),

1.64 (dt, J = 13.4, 3.2 Hz, 1 H, 5-H), 1.62 (dt, J = 14.3, 3.4 Hz, 1

H, 4 -H_eq), 1.59–1.52 (m, 1 H, 3-H), 1.21 (td, J = 14.2, 3.5 Hz, 1 H,

Eur. J. Org. Chem. 2006, 4825–4840

www.eurjoc.org

4833

E. Drège, C. Tominiaux, G. Morgant, D. Desmaële

FULL PAPER

4-H_ax), 1.06 [s, 3 H, C(CH₃)] ppm. ¹³C NMR (100 MHz, CDCl₃): δ Methyl (1R,3R)- and (1R,3S)-3-(3-Isopropyl-1-methyl-2-oxocyclo-

= 175.1 (C, CO₂CH₃), 149.4 (C, C9b), 134.7 (CH, C6), 128.1 (CH, pentyl)propanoate (35a): To a suspension of anhydrous CuI (5.1 g,

C7), 124.1 (CH, C1), 63.1 (CH, C8), 52.2 (CH₃, CO₂CH₃), 50.7 (C, 30.5 mmol) in diethyl ether (40 mL) was added dropwise at –30 °C

C5a), 44.5 (C, C3a), 43.2 (CH₂, C3), 37.9 (CH₂, C4), 35.5 (CH₂, methyllithium (1.6  in Et₂O, 37 mL, 59.4 mmol) and the mixture

C9), 32.5 (CH, C9a), 29.1 (CH₂, C2), 27.5 (CH₂, C5), 25.1 [CH₃, was stirred 5 min. To the homogeneous colourless solution ob-

C(CH₃)] ppm. C₁₆H₂₂O₃(262.3): calcd. C 73.25, H 8.45; found C

73.27, H 8.61.

tained, enone 34 (1.6 g, 7.6 mmol) in Et₂O (10 mL) was added and

the reaction mixture was stirred for 1 h. The solution was then

poured into an ice-cooled saturated aqueous solution of ammo-

nium chloride (50 mL). The resultant mixture was vigorously

stirred in air for 1 h and thoroughly extracted with Et₂O

(4×50 mL). The combined organic layers were washed with brine,

dried with MgSO₄, filtered and concentrated. Chromatographic pu-

rification (cyclohexane/ethyl acetate, 4:1) gave keto ester 35a

Methyl

(1R)-3-{1-Methyl-2-[(trimethylsilyl)oxy]cyclopent-2-en-1-

yl}propanoate (32): To an ice-cooled solution of keto ester (+)-10

(2.0 g, 10.9 mmol) in dry CH₂Cl₂(15 mL) were sequentially added

Et₃N (1.65 g, 16.3 mmol) then trimethylsilyl(trifluoromethane)sul-

fonate (2.90 g, 13.0 mmol). The mixture was warmed to 20 °C and

stirred for 4 h. The solution was diluted with pentane (120 mL),

washed with cold water (2×10 mL) dried with MgSO₄and concen-

trated under reduced pressure to leave a yellow oil (2.47 g, 89%)

(1.20 g, 70%) as colourless oil. IR (film): ν = 2958, 2929, 2852,

˜

1730 (C=O, CO₂H), 1451, 1370 cm^–1. ¹H NMR (200 MHz, CDCl₃)

the presence of a 2:1 mixture of diastereomers induced the splitting

of some signals, only the major isomer is described, δ = 3.63 (s, 3

H, CO₂CH₃), 2.36–1.57 (m, 10 H), 0.95 [d, J = 6.3 Hz, 3 H, (CH₃)₂-

CH], 0.90 [s, 3 H, C(CH₃)], 0.79 [d, J = 6.3 Hz, 3 H, (CH₃)₂-

CH] ppm. ¹³C NMR (75 MHz, CDCl₃) only the major isomer is

described, δ = 222.6 (C, CO), 173.9 (CO₂CH₃), 55.7 (CH, C3), 51.6

(CH₃, CO₂CH₃), 48.1 (C, C1), 33.4 (CH₂), 32.4 (CH₂), 29.4 (CH₂),

27.2 [CH, (CH₃)₂CH], 21.0 [CH₃, C(CH₃) or (CH₃)₂CH], 20.9

[CH₃, C(CH₃) or (CH₃)₂CH], 20.4 (CH₂, C4), 18.3 [CH₃, (CH₃)₂-

CH] ppm. C₁₃H₂₂O₃(226.3): calcd. C 68.99, H 9.80; found C 69.15,

H 9.91.

which was used directly for the next steps. IR (film): ν = 2957,

˜

2854, 1740 (CO₂Me), 1643 (C=C), 1449, 1436, 1376, 1342, 1251,

1

1194 cm^–1. H NMR (200 MHz, C₆D₆): δ = 4.41 (t, J = 2.4 Hz, 1

H, 3-H), 3.37 (s, 3 H, OCH₃), 2.28 (t, J = 8.1 Hz, 1 H,

CH₂CO₂CH₃), 2.15–2.00 (m, 2 H, 4-H), 1.75–1.27 (m, 4 H,

CH₂CH₂CO₂CH₃and 5-H), 1.02 [s, 3 H, C(CH₃)]. 0.10 [s, 9 H,

Si(CH₃)₃] ppm. ¹³C NMR (50 MHz, C₆D₆): δ = 173.4 (CO₂Me),

158.9 (C, C2), 99.1 (CH, C3), 50.5 (CH₃, OCH₃), 45.7 (C, C1), 34.1

(CH₂, C5 or CH₂CH₂CO₂Me), 33.8 (CH₂, C5 or CH₂CH₂CO₂Me),

29.7 (CH₂, CH₂CO₂Me), 25.3 (CH₂, C4), 24.5 (CH₃), –0.5 [3 CH₃,

Si(CH₃)₃] ppm.

(1R,3R)- and (1R,3S)-3-(3-Isopropyl-1-methyl-2-oxocyclopentyl)-

propanoic Acid (35b): To

a solution of ester 35a (500 mg,

Methyl (1R,E)- and (1R,Z)-3-(3-Ethylidene-1-methyl-2-oxocyclo-

pentyl)propanoate (34): To a solution of silyl enol ether 32 (2.40 g,

9.37 mmol) and acetaldehyde (1.65 g, 37.5 mmol) in CH₂Cl₂

(20 mL) was added dropwise, at –78 °C, TiCl₄(1.80 g, 9.61 mmol).

The reaction mixture was stirred at –78 °C for 2 h and then aque-

ous NaHCO₃(10 mL) was added. The organic layer was separated

and the aqueous phase extracted with CH₂Cl₂(4×20 mL). The

combined organic layers were dried and concentrated under re-

duced pressure to leave the cetol 33 as a 4:4:1:1 mixture of ste-

reomers which was used directly for the next steps (2.02 g, 89%).

Methanesulfonyl chloride (1.15 g, 10.4 mmol) was added to a solu-

tion of ketol 33 (2.0 g, 8.42 mmol), triethylamine (1.27 g,

12.6 mmol) and DMAP (75 mg) in CH₂Cl₂(20 mL) at 0 °C. The

reaction mixture was stirred at 0 °C for 30 min. then warmed to

20 °C. After being stirred for 1 h at 20 °C, aqueous ammonium

chloride was added. The organic layer was separated and the aque-

ous phase extracted with CH₂Cl₂(4×20 mL). The combined or-

ganic layers were dried and concentrated under reduced pressure

to leave a yellow oil which was dissolved in toluene (20 mL). DBU

(1.92 g, 12.7 mmol) was added and the reaction mixture was heated

at reflux for 1 h. After cooling, HCl 1  was added until a pH of

7 was reached and the mixture was extracted with CH₂Cl₂

(4×20 mL). The combined organic layers were dried and concen-

trated under reduced pressure. Chromatography (cyclohexane/ethyl

acetate, 4:1) gave enone 34 as a 5:1 E/Z mixture (1.35 g, 90%). Only

the major E isomer is described, [α]²_D⁰= +4.9 (c = 5, EtOH). IR

2.21 mmol) in methanol (25 mL) was added 3  sodium hydroxide

(15 mL, 45 mmol). After stirring for 4 h at room temperature, 2 

hydrochloric acid was added until a pH of 2 was reached. The

mixture was concentrated under reduced pressure and the residue

extracted with CH₂Cl₂(4×15 mL). The combined organic extracts

were washed with aqueous sodium chloride, dried with MgSO₄, to

give crude acid 35b (350 mg, 75%) as a pale yellow oil which was

used directly for the next steps without further purification. IR

(film): ν = 3600–3400 (OH), 1728 (C=O), 1708 (CO H), 1459, 1415,

˜

2

1

1386, 1369, 1295 cm^–1. H NMR (200 MHz, CDCl₃) the presence

of a 2:1 mixture of diastereomers induced the splitting of some

signals, only the major isomer is described, δ = 10.3–10.2 (br. s, 1

H, OH), 2.45–1.53 (m, 10 H), 0.94 [d, J = 6.8 Hz, 3 H, (CH₃)₂CH],

0.90 [s, 3 H, C(CH₃)CO], 0.76 [d, J = 6.8 Hz, 3 H, (CH₃)₂CH] ppm.

¹³C NMR (50 MHz, CDCl₃) only the major isomer is described, δ

= 222.6 (C, CO), 179.9 (CO₂H), 55.5 (CH, C3), 47.9 (C, C1), 33.3

(CH₂), 32.3 (CH₂), 29.2 (CH₂), 27.1 [CH, (CH₃)₂CH], 21.9 [2 CH₃,

C(CH₃) and (CH₃)₂CH], 20.6 (CH₂, C4), 18.2 [CH₃, (CH₃)₂-

CH] ppm. C₁₂H₂₀O₃(212.3): calcd. C 67.89, H 9.50; found C 67.74,

H 9.45.

tert-Butyl (1R,3R)- and (1R,3S)-3-(3-Isopropyl-1-methyl-2-oxocy-

clopentyl)propanoate (35d): To a solution of acid 35b (100 mg,

0.47 mmol) in toluene (3 mL) was added di-tert-butoxymethyl-di-

methylamine (450 mg, 1.88 mmol) and the mixture was heated to

reflux for 90 min. After cooling, the reaction mixture was concen-

trated under reduced pressure and the residue purified by silica

gel chromatography (cyclohexane/ethyl acetate, 4:1) to provide keto

(film): ν = 2953, 2869, 1754 (CO Me), 1716, (C=O), 1649, (C=C),

˜

2

1436, 1374, 1288, 1198, 1170 cm^–1. ¹H NMR (200 MHz, CDCl₃):

δ = 6.55 (m, 1 H, CH₃CH=C), 3.62 (s, 3 H, CO₂CH₃), 2.56–2.42

ester 35d (75 mg, 60%) as a colourless oil. IR (film): ν = 2962,

˜

(m, 2 H, CH₂CO₂CH₃), 2.40–2.20 (m, 2 H, 4-H), 1.82–1.62 (m, 7 2929, 2871, 1726 (C=O, CO₂tBu), 1458, 1153 cm^–1. ¹H NMR

H, CH₃CH=C, CH₂CH₂CO₂CH₃), 1.02 [s, 3 H, C(CH₃)] ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 208.6 (C, CO), 173.6 (CO₂CH₃),

(200 MHz, CDCl₃) the presence of a 2:1 mixture of diastereomers

induced the splitting of some signals, only the major isomer is de-

137.5 (C, CH₃CH=C), 132.3 (CH, CH₃CH=C), 51.2 (CH₃, OCH₃), scribed, δ = 2.25–1.43 (m, 10 H), 1.36 [s, 9 H, OC(CH₃) ₃], 0.91 [d,

47.9 (C, C1), 32.7 (CH₂), 31.1 (CH₂), 29.0 (CH₂), 22.5 (CH₂), 21.2 J = 6.7 Hz, 3 H, (CH₃)₂CH], 0.86 [s, 3 H, C(CH₃)], 0.78 [d, J =

[CH₃, C(CH₃)], 14.9 (CH₃, CH₃CH=C) ppm. C₁₂H₁₈O₃·¹⁄₆H₂O 6.7 Hz, 3 H, (CH₃)₂CH] ppm. ¹³C NMR (50 MHz, CDCl₃) only

(213.3): calcd. C 67.58, H 8.66; found C 67.67, H 8.69. the major isomer is described, δ = 222.1 (C, CO), 172.7 (CO₂tBu),

4834

www.eurjoc.org

Eur. J. Org. Chem. 2006, 4825–4840

Synthetic Studies on Cyathin Terpenoids

FULL PAPER

80.1 [C, OC(CH₃)₃]_,55.6 (CH, C3), 48.0 (C, C1), 33.3 (CH₂), 32.5

CH(CH₃)₂], 22.6–20.5 [3 CH₃, CH₃CO₂, C(CH₃) and CH(CH₃)₂],

(CH₂), 30.8 (CH₂), 28.0 [3 CH₃, OC(CH₃)₃], 27.6 [CH, (CH₃)₂CH], 21.5 (CH₂, C4), 18.2 [CH₃, CH(CH₃)₂] ppm. C₁₃H₂₂O₃(226.3):

20.9 [2 CH₃, C(CH₃) and (CH₃)₂CH], 20.4 (CH₂, C4), 18.3 [CH₃,

(CH₃)₂CH] ppm.

calcd. C 68.99, H 9.80; found C 68.73, H 9.96.

(2R,5R)- and (2R,5S)-2-(2-Hydroxyethyl)-5-isopropyl-2-methylcy-

clopentanone (40b): A mixture of acetate 40a (120 mg, 0.53 mmol)

and potassium carbonate (73 mg, 0.53 mmol) in methanol (15 mL)

was stirred at 20 °C for 5 h. The reaction mixture was concentrated

7-Isopropyl-4a-methyl-4,4a,5,6-tetrahydrocyclopenta[b]pyran-2-yl

Trifluoromethanesulfonate (36): Trifluoromethanesulfonic anhy-

dride (172 mg, 0.61 mmol) was added dropwise with syringe to a

mixture of 2,6-di-tert-butylpyridine (116 mg, 0.61 mmol) and keto in vacuo and 1  HCl was added until a pH of 7 was reached. The

ester 35d (66 mg, 0.24 mmol) in 1,2-dichloroethane (3 mL). The re-

sultant mixture was stirred for 90 min at 90 °C. After cooling, the

mixture was diluted with pentane (15 mL) and filtered through ce-

lite. 3  HCl (1 mL) was added and the mixture was extracted with

dichloromethane (3×10 mL). The combined organic phases were

washed with brine, dried with MgSO₄and concentrated under re-

duced pressure. The crude product was purified by chromatography

on silica gel. (cyclohexane/ethyl acetate, 4:1) to give 63 mg of trifl-

mixture was extracted with ethyl acetate (3×15 mL). The organic

phases were dried with MgSO₄and concentrated under reduced

pressure. The crude product was purified by silica gel chromatog-

raphy (cyclohexane/ethyl acetate, 4:1) to give hydroxy ketone 40b

as 3:1 mixture of diastereomers (78 mg, yield 80%). IR (neat): ν =

˜

3500–3000 (OH), 3414, 1728 (C=O), 1458 cm^{–1 1}H NMR

.

(400 MHz, C₆D₆) only the major isomer is described, δ = 3.63–3.42

(m, 2 H, CH₂OH), 2.20 [m, 1 H, CH(CH₃)₂], 1.93–1.81 (m, 1 H,

5-H), 1.90–1.70 (br. s, 1 H, OH), 1.70–1.50 (m, 4 H, CH₂CH₂OH,

ate 36 as a yellow oil (yield 80%). IR (neat): ν = 2962, 1691, 1428,

˜

1329, 1209, 1127 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 4.77 (dd, 4-H, 3-H), 1.45–1.30 (m, 2 H, 4-H, 3-H), 0.93 [d, J = 6.3 Hz, 3 H,

J = 5.2, 3.3 Hz, 1 H, 3-H), 2.71 [hept, J = 6.6 Hz, 1 H, CH- CH(CH₃)₂], 0.83 [s, 3 H, C(CH₃)], 0.80 [d, J = 6.0 Hz, 3 H,

(CH₃)₂], 2.38–2.28 (m, 1 H, 6-H), 2.24–2.17 (m, 1 H, 6-H), 2.18– CH(CH₃)₂] ppm. ¹³C NMR (100 MHz, C₆D₆) only the major iso-

2.16 (m, 2 H, 4-H), 1.92 (ddd, 1 H, J = 12.6, 7.8, 1.6 Hz, 5-H), mer is described, δ = 222.8 (C, CO), 59.1 (CH₂, CH₂CH₂OH), 55.2

1.69–1.64 (m, 1 H, 5-H), 1.15 [s, 3 H, C(CH₃)], 1.02 [d, J = 6.6 Hz,

(CH, C5), 47.7 (C, C2), 40.4 (CH₂, CH₂CH₂OH), 33.8 (CH₂, C3),

3 H, CH(CH₃)₂], 1.00 [d, J = 6.6 Hz, 3 H, CH(CH₃)₂] ppm. ¹³C 27.4 [CH, CH(CH₃)₂], 21.4 [CH₃, C(CH₃)], 21.0 [CH₃, CH-

NMR (50 MHz, CDCl₃): δ = 157.4 (C, C7a), 146.6 (C, C2), 122.2 (CH₃)₂], 20.8 (CH₂, C4), 18.5 [CH₃, CH(CH₃)₂] ppm.

(C, C7), 118.4 (q, J = 314 Hz, C, CF₃), 87.5 (CH, C3), 38.8 (C, C₁₁H₂₀O₂·¼H₂O (188.8): calcd. C 69.99, H 10.95; found C 70.02,

C4a), 36.6 (CH₂, C5), 35.1 (CH₂, C4), 25.4 (CH₂, C6), 24.9 [CH, H 11.14.

CH(CH₃)₂], 23.7 [CH₃, C(CH₃)], 20.6 [CH₃, CH(CH₃)₂], 20.5 [CH₃,

(1R,3R)- and (1R,3S)-2-(3-Isopropyl-1-methyl-2-oxocyclopentyl)-

CH(CH₃)₂] ppm. ¹⁹F NMR (CDCl₃, 188 MHz): δ = –73.6 (s) ppm.

ethyl 2,2-Dimethylpropanoate (40c): To a solution of alcohol 40b

(2R,5R)- and (2R,5S)-2-(2-Iodoethyl)-5-isopropyl-2-methylcyclo-

pentanone (39): Treatment of acid 35b (500 mg, 2.35 mmol) as de-

scribed for acid 12 gave iodide 39 as a colourless light sensitive oil

(90 mg, 0.48 mmol) in pyridine (2 mL) was added at 0 °C pivaloyl

chloride (117 mg, 0.97 mmol). After being stirred at 20 °C for 4 h

the reaction mixture was concentrated in vacuo. The residue was

taken in water (2 mL) and extracted with diethyl ether (3×15 mL).

The organic phases were dried with MgSO₄and concentrated un-

der reduced pressure. The crude product was purified by silica gel

chromatography (cyclohexane/ethyl acetate, 4:1) to give ester 40c

(0.45 g, 65%). IR (film): ν = 2555, 2872, 1730 (C=O), 1455, 1372,

˜

1234 cm^–1. ¹H NMR (200 MHz, CDCl₃) the presence of a 2:1 mix-

ture of diastereomers induced the splitting of some signals, only

the major isomer is described, δ = 3.28–2.91 (m, 2 H, CH₂I), 2.20–

1.55 (m, 8 H), 0.95 [d, J = 6.6 Hz, 3 H, (CH₃)₂CH], 0.91 [s, 3 H,

C(CH₃)], 0.77 [d, J = 6.6 Hz, 3 H, (CH₃)₂CH] ppm. ¹³C NMR

(50 MHz, CDCl₃) only the major isomer is described, δ = 221.8 (C,

as a pale-yellow oil (96 mg, yield 73%). IR (neat): ν = 2960, 2873,

˜

1727 (broad, CO, OCOtBu), 1480, 1461, 1283, 1151 cm^{–1 1}H NMR

(CDCl₃, 200 MHz) the presence of a 2:1 mixture of diastereomers

CO), 55.5 (CH, C5), 50.6 (C, C2), 42.6 (CH₂, CH₂CH₂I), 33.0 induced the splitting of some signals, only the major isomer is de-

(CH₂), 27.1 [CH, (CH₃)₂CH], 20.8 [CH₃, C(CH₃)], 20.6 (CH₂, C4), scribed, δ = 4.08 (t, J = 7.1 Hz, 2 H, CH₂OPiv), 2.20–1.55 (m, 8

18.5 [CH₃, (CH₃)₂CH], 18.3 [CH₃, (CH₃)₂CH], –0.80 [CH₂, H), 1.17 [s, 9 H, C(CH₃)₃], 1.06 [s, 3 H, C(CH₃)], 0.97 [d, J =

CH₂CH₂I] ppm.

6.7 Hz, 3 H, CH(CH₃)₂], 0.80 [d, J = 6.7 Hz, 3 H, CH(CH₃)₂] ppm.

¹³C NMR (50 MHz, CDCl₃) only the major isomer is described, δ

= 222.9 (C, CO), 178.3 [C, OCOC(CH₃)₃], 61.0 (CH₂, CH₂CH₂O-

Piv), 54.0 (CH, C3), 47.3 (C, C1), 38.5 [C, OCOC(CH₃)₃], 34.3

(CH₂, C5 or CH₂CH₂OPiv), 33.6 (CH₂, C5 or CH₂CH₂OPiv), 27.6

[CH, CH(CH₃)₂], 27.0 [3 CH₃, OCOC(CH₃)₃], 22.4 [CH₃, C(CH₃)],

21.0 [CH₃, CH(CH₃)₂], 20.7 (CH₂, C4), 18.6 [CH₃, CH-

(CH₃)₂] ppm. C₁₆H₂₈O₃(268.4): calcd. C 71.60, H 10.52; found C

71.32, H 10.75.

(1R,3R)- and (1R,3S)-2-(3-Isopropyl-1-methyl-2-oxocyclopentyl)-

ethyl Acetate (40a): A mixture of iodide 39 (520 mg, 1.77 mmol)

and sodium acetate (420 mg, 5.13 mmol) in DMF (50 mL) was

stirred at 110 °C for 3 h. After cooling, the reaction mixture was

concentrated in vacuo. The residue placed in water (5 mL) and ex-

tracted with diethyl ether (3 ×10 mL). The organic phases were

dried with MgSO₄and concentrated under reduced pressure. The

crude product was purified by silica gel chromatography (cyclohex-

ane/ethyl acetate, 4:1) to give acetate 40a as a pale yellow oil

(1R)-2-(3-Isopropyl-1-methyl-2-{[(trifluoromethyl)sulfonyl]oxy}-

cyclopent-2-en-1-yl)ethyl 2,2-Dimethylpropanoate (41a): Trifluoro-

(280 mg, yield 70%). IR (neat): ν = 2959, 2872, 1731, 1460, 1386,

˜

1367, 1231 cm^{–1 1}H NMR (400 MHz, C₆D₆) the presence of a 2:1 methanesulfonic anhydride (905 mg, 3.2 mmol) was added drop-

mixture of diastereomers induced the splitting of some signals, only

the major isomer is described, δ = 4.13–3.88 (m, 2 H, CH₂OAc),

wise with a syringe to a mixture of 2,6-di-tert-butylpyridine

(612 mg, 3.2 mmol) and keto ester 40c (190 mg, 0.71 mmol) in 1,2-

2.04 [m, 1 H, CH(CH₃)₂], 1.76–1.10 (m, 7 H, 4-H, 5-H, 3-H, dichloroethane (4 mL). The resultant mixture was stirred for 15 h

CH₂CH₂OAc), 1.67 (s, 3 H, CH₃CO₂), 0.85 [d, J = 6.8 Hz, 3 H,

CH(CH₃)₂], 0.71 [s, 3 H, C(CH₃)], 0.70 [d, J = 6.8 Hz, 3 H,

CH(CH₃)₂] ppm. ¹³C NMR (50 MHz, C₆D₆) only the major isomer

is described, δ = 220.7 (C, CO), 169.9. (C, OCOCH₃), 60.9 (CH₂,

CH₂CH₂OAc), 55.1 (CH, C3), 47.1 (C, C1), 36.2 (CH₂,

at 90 °C. After cooling, the mixture was diluted with pentane

(15 mL) and filtered through celite. 2  HCl (2 mL) was added and

the mixture was extracted with dichloromethane (3×10 mL). The

combined organic phases were washed with brine, dried with

MgSO₄and concentrated under reduced pressure. The crude prod-

CH₂CH₂OAc or C5), 33.1 (CH₂, CH₂CH₂OAc or C5) 27.0 [CH, uct was purified by silica gel chromatography (cyclohexane/ethyl

Eur. J. Org. Chem. 2006, 4825–4840

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4835

E. Drège, C. Tominiaux, G. Morgant, D. Desmaële

FULL PAPER

acetate, 4:1) to give triflate 41a as a yellow oil (184 mg, yield 65%). Methyl (1R,3R)- and (1R,3S)-1-[2-(3-Isopropyl-1-methyl-2-oxocy-

[α]²_D⁰= –10.9 (c = 0.9, EtOH). IR (film): ν = 2962, 2872, 1730, 1682

clopentyl)ethyl]cyclohexa-2,5-diene-1-carboxylate (43) and 6-Isopro-

pyl-3a-methyl-3,3a,4,5-tetrahydro-2H-cyclopenta[b]furan (44): To a

˜

(C=C, weak), 1577, 1480, 1455, 1408, 1461, 1211, 1140 cm^–1. ¹H

NMR (400 MHz, CDCl₃): δ = 4.08 (m, 2 H, CH₂OPiv), 2.82 [hept, solution of diisopropylamine (373 mg, 3.7 mmol) in dry THF

J = 6.8 Hz, 1 H, CH(CH₃)₂], 2.30–2.23 (m, 2 H, 4-H), 2.01 (ddd,

J = 13.7, 8.2, 5.6 Hz, 1 H, 5-H), 1.78–1.71 (m, 3 H, CH₂CH₂OPiv

(2 mL) was added at 0 °C a solution of n-butyllithium (2.5  in

hexane, 1.3 mL, 3.25 mmol). The mixture was stirred at 0 °C for

and 5-H), 1.18 [s, 9 H, C(CH₃)₃], 1.17 [s, 3 H, C(CH₃)], 1.03 [d, J 15 min then cooled to –78 °C. A solution of methyl 2,5-cyclohexa-

= 6.8 Hz, 3 H, CH(CH₃)₂], 1.01 [d, J = 6.8 Hz, 3 H, CH(CH₃) dienecarboxylate (23) (422 mg, 3.06 mmol) in THF (3 mL) was

₂] ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 178.4 [C, OCOC(CH₃)₃],

added. The mixture was stirred 20 min at –78 °C and a solution of

144.6 (C, C2), 138.2 (C, C3), 118.6 (q, J = 319 Hz, C, CF₃), 61.2 iodide 39 (300 mg, 1.02 mmol) in DMPU (3 mL) was added drop-

(CH₂, CH₂CH₂OPiv), 45.2 (C, C1), 38.5 [C, OCOC(CH₃)₃], 36.8 wise. The reaction mixture was stirred at –78 °C for 15 min and the

(CH₂, CH₂CH₂OPiv), 33.7 (CH₂, C5), 27.1 [3 CH₃, OCOC- temperature was then gradually raised to 50 °C. After 1 h at 50 °C,

(CH₃)₃], 25.7 [CH, CH(CH₃)₂], 24.5 [CH₃, C(CH₃)], 23.8 (CH₂, the dark-red mixture was cooled to 0 °C and 1  HCl (5 mL) was

C4), 20.3 [CH₃, CH(CH₃)₂], 20.1 [CH₃, CH(CH₃)₂] ppm. ¹⁹F NMR added. The mixture was extracted with diethyl ether (3×20 mL).

(CDCl₃, 188 MHz) δ = –74.2 (s) ppm.

The collected organic phases were washed with brine, dried with

MgSO₄and concentrated in vacuo. Purification by silica gel

chromatography (cyclohexane/ethyl acetate, 4:1) gave ether 44

(15 mg, 10 %) as a volatile colourless oil. ¹H NMR (CDCl₃,

200 MHz): δ = 4.50–4.40 (m, 2 H, =C–OCH₂), 2.74 (dddd, J =

14.2, 10.0, 6.1, 1.0 Hz, 1 H, 5-H), 2.45 [hept, J = 6.8 Hz, 1 H,

CH(CH₃)₂], 2.29 (ddd, J = 14.2, 8.0, 1.5 Hz, 1 H, 5-H), 1.80–1.60

(m, 4 H, 3-H, 4-H), 1.17 [s, 3 H, C(CH₃)], 1.05 [d, J = 6.7 Hz, 3

H, CH(CH₃)₂], 1.01 [d, J = 6.7 Hz, 3 H, CH(CH₃)₂] ppm. Further

elution gave 43 as a pale-yellow oil (186 mg, 60% yield). IR (film):

(5R)-5-(2-Hydroxyethyl)-2-isopropyl-5-methylcyclopent-1-en-1-yl

Trifluoromethanesulfonate (41b): To a solution of ester 41a (168 mg,

0.42 mmol) in CH₂Cl₂(6 mL) was added dropwise at –78 °C a tolu-

ene solution of DIBAL-H (1.5 , 0.6 mL, 0.90 mmol). The reaction

was stirred for 4 h at –20 °C and saturated aqueous tartaric acid

(sodium potassium salt) was added. The mixture was vigorously

stirred for 1 h and filtered through celite. The solid was thoroughly

washed with CH₂Cl₂and the aqueous layer was extracted with di-

ethyl ether (3×10 mL). The combined organic layers were washed

with brine, dried with MgSO₄, evaporated and chromatographed

on silica gel (cyclohexane/ethyl acetate, 4:1) to give alcohol 41b

ν = 2955, 2871, 1725 (CO, CO Me), 1637 (C=C, weak), 1453, 1435,

˜

2

1276, 1242 cm^–1. ¹H NMR (CDCl₃, 200 MHz) the presence of a

2:1 mixture of diastereomers induced the splitting of some signals,

only the major isomer is described, δ = 5.84 (dt, J = 11.0, 3.0 Hz,

2 H, HC=CHCH₂CH=CH), 5.62 (br.d, J = 11.0 Hz, 2 H,

HC=CHCH₂CH=CH), 3.62 (s, 3 H, CO₂CH₃), 2.58 (br. s, 2 H,

=CHCH₂CH=), 2.30–1.15 (m, 10 H), 0.92 [d, J = 6.4 Hz, 3 H,

CH(CH₃)₂], 0.83 [s, 3 H, C(CH₃)], 0.74 [d, J = 6.4 Hz, 3 H,

CH(CH₃)₂] ppm. ¹³C NMR (50 MHz, CDCl₃) only the major iso-

mer is described, δ = 218.9 (C, CO), 175.1 (C, CO₂Me), 126.7 (2

CH, C=CHCH₂CH=C), 125.9 (2 CH, C=CHCH₂CH=C), 55.6

(CH, C3), 51.9 (CH₃, OCH₃), 48.2 (C, C1), 47.4 (C, CCO₂Me),

33.9 (CH₂), 33.2 (CH₂), 31.8 (CH₂), 27.0 [CH, CH(CH₃)₂], 26.0

(CH₂, C=CHCH₂CH=C), 21.1 [CH₃, C(CH₃)], 21.0 [CH₃,

CH(CH₃)₂], 20.4 (CH₂, C4), 18.2 [CH₃, CH(CH₃)₂] ppm. MS (ESI,

MeOH): m/z (%): 327 (30) [M + Na]⁺, 305 (25) [M + 1]⁺, 245 (100).

C₁₉H₂₈O₃(304.4): calcd. C 74.96, H 9.27; found C 74.69, H 9.11.

(94 mg, 70%) as an oil. [α]²_D⁰= –12.7 (c = 1.1, EtOH). IR (film): ν

˜

= 3600–3400 (OH), 2966, 1682 (C=C, weak), 1461, 1405, 1206,

1

1138 cm^–1. H NMR (200 MHz, CDCl₃): δ = 3.70 (t, J = 7.2 Hz,

2 H, CH₂OH), 2.82 [hept, J = 6.7 Hz, 1 H, CH(CH₃)₂], 2.27 (t, J

= 6.8 Hz, 2 H, 4-H), 2.06–1.92 (m, 1 H, 5-H), 1.80–1.66 (m, 3 H,

CH₂CH₂OH and 5-H), 1.20 (br. s, OH), 1.16 [s, 3 H, C(CH₃)], 1.03

[d, J = 6.7 Hz, 3 H, CH(CH₃)₂], 1.01 [d, J = 6.7 Hz, 3 H, CH-

(CH₃)₂] ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 144.9 (C, C2), 137.8

(C, C3), 118.5 (q, J = 318 Hz, C, CF₃SO₂), 59.5 (CH₂,

CH₂CH₂OH), 45.0 (C, C1), 41.1 (CH₂, CH₂CH₂OH), 33.8 (CH₂,

C5), 25.6 [CH, CH(CH₃)₂], 24.7 [CH₃, C(CH₃)], 23.8 (CH₂, C4),

20.3 [CH₃, CH(CH₃)₂], 20.0 [CH₃, CH(CH₃)₂] ppm. ¹⁹F NMR

(CDCl₃, 188 MHz): δ = –74.2 (s) ppm. C₁₂H₁₉F₃O₄S (316.4): calcd.

C 45.56, H 6.05; found C 45.84, H 6.22.

(5R)-5-(2-Iodoethyl)-2-isopropyl-5-methylcyclopent-1-en-1-yl Tri-

fluoromethanesulfonate (42): A mixture of 41b (60 mg, 0.19 mmol),

triphenylphosphane (94 mg, 0.36 mmol), imidazole (25 mg,

0.36 mmol) and solid iodine (92 mg, 0.36 mmol) in dry CH₂Cl₂

(2 mL) was stirred at 25 °C for 2 h. An aqueous solution of

Na₂S₂O₃(2 mL) was then added and the mixture was extracted

with dichloromethane (2×10 mL). The combined organic phases

were dried with MgSO₄and concentrated under reduced pressure.

Purification by silica gel chromatography (cyclohexane/ethyl ace-

Methyl (1R)-1-[2-(3-Isopropyl-1-methyl-2-{[(trifluoromethyl)-

sulfonyl]oxy}cyclopent-2-en-1-yl)ethyl]cyclohexa-2,5-diene-1-carbox-

ylate (22): Trifluoromethanesulfonic anhydride (160 mg,

0.57 mmol) was added dropwise with a syringe to a mixture of 2,6-

di-tert-butylpyridine (115 mg, 0.60 mmol) and keto ester 43 (50 mg,

0.16 mmol) in 1,2-dichloroethane (1.5 mL). The resultant mixture

was stirred at 90 °C for 6 h. After cooling, the mixture was diluted

with pentane (15 mL) and filtered through celite. 1  HCl (3 mL)

was added and the mixture was extracted with dichloromethane

(3×10 mL). The combined organic phases were washed with brine,

dried with MgSO₄and concentrated under reduced pressure. The

tate, 10:1) gave 42 as pale yellow oil (56 mg, 70% yield). [α]²_D⁰

=

–34.6 (c = 1.7, EtOH). IR (film): ν = 2966, 2873, 1681 (C=C,

˜

weak), 1460, 1405, 1241, 1207, 1138 cm^–1. ¹H NMR (400 MHz,

CDCl₃): δ = 3.14–3.07 (m, 2 H, CH₂CH₂I), 2.85 [hept, J = 6.8 Hz, crude product was purified by silica gel chromatography (cyclohex-

1 H, CH(CH₃)₂], 2.40–2.20 (m, 2 H, 3-H), 2.15–2.09 (m, 2 H, ane/ethyl acetate, 4:1) to give triflate 22 as a yellow oil (51 mg, yield

CH₂CH₂I), 1.95 (ddd, J = 13.4, 8.4, 4.6 Hz, 1 H, 4-H), 1.75 (ddd, 71%). [α]²_D⁰= –22.4 (c = 2.5, MeOH). IR (film): ν = 3028, 2962,

˜

J = 13.4, 9.3, 6.5 Hz, 1 H, 4-H), 1.17 [s, 3 H, C(CH₃)], 1.05 [d, J 2860, 1730 (CO₂Me), 1683 (C=C, weak), 1454, 1406, 1208,

= 6.7 Hz, 3 H, CH(CH₃)₂], 1.03 [d, J = 6.7 Hz, 3 H, CH-

1139 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 5.90 (dt, J = 10.4,

(CH₃)₂] ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 143.7 (C, C1), 138.8 3.3 Hz, 2 H, HC=CHCH₂CH=CH), 5.69 (dt, J = 10.4, 2.0 Hz, 2

(C, C2), 118.4 (q, J = 318 Hz, C, CF₃SO₂), 48.5 (C, C5), 44.0 (CH₂, H, HC=CHCH₂CH=CH) 3.70 (s, 3 H, OCH₃), 2.85 [hept, J =

CH₂CH₂I), 32.9 (CH₂, C4), 25.8 [CH, (CH₃)₂CH], 24.2 [CH₃, 6.8 Hz, 1 H, CH(CH₃)₂], 2.65 (br. s, 2 H, =CHCH₂CH=), 2.28–

C(CH₃)], 24.0 (CH₂, C3), 20.4 [CH₃, (CH₃)₂CH], 20.1 [CH₃,

(CH₃)₂CH], –1.3 [CH₂, CH₂CH₂I] ppm. ¹⁹F NMR (CDCl₃, 1.59–1.56 [m, 3 H, 5-H, CH₂CH₂C(CO₂Me)], 1.34–1.29 [m, 2 H,

188 MHz): δ = –74.1 (s) ppm. CH₂CH₂C(CO₂Me)], 1.11 [s, 3 H, C(CH₃)], 1.03 [d, J = 6.8 Hz, 6

2.22 (m, 2 H, 4-H), 1.84 (ddd, J = 13.0, 8.2, 5.7 Hz, 1 H, 5-H),

4836

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Eur. J. Org. Chem. 2006, 4825–4840

Synthetic Studies on Cyathin Terpenoids

FULL PAPER

H, CH(CH₃)₂] ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 175.2 (C,

CO₂CH₃), 155.0 (C, C9a), 147.5 (CH, C6), 146.4 (C, C1), 136.5 (C,

C O ₂M e ) , 1 4 5 . 1 ( C , C 2 ) , 1 3 7 . 5 ( C , C 3 ) , 1 2 6 . 7 ( C H , C9b), 129.8 (CH, C7), 126.8 (CH, C9), 54.1 (C, C5a), 52.9 (CH₃,

C=CHCH₂CH=C), 126.1 (CH, C=CHCH₂CH=C), 118.5 (q, J = OCH₃), 49.6 (C, C3a), 39.6 (CH₂, C3), 36.1 (CH₂, C4), 33.6 (CH₂,

319 Hz, C, CF₃SO₂), 52.1 (CH₃, OCH₃), 47.4 (C, CCO₂Me), 45.8 C5), 28.7 (CH₂, C2), 26.7 [CH, (CH₃)₂CH], 23.1 [CH₃, C(CH₃)],

(C, C1), 33.9 (CH₂), 33.1 (CH₂), 32.8 (CH₂), 26.0 (CH₂,

21.5 [CH₃, (CH₃)₂CH], 21.2 [CH₃, (CH₃)₂CH] ppm. C₁₉H₂₄O₃

C=CHCH₂CH=C), 25.7 [CH, (CH₃)₂CH], 24.3 [CH₃, C(CH₃)], (300.4): calcd. C 75.97, H 8.05; found C 75.85, H 7.98.

23.7 (CH₂), 20.4 [CH₃, (CH₃)₂CH], 20.1 [CH₃, (CH₃)₂CH] ppm.

(5S)-5-{2-[1-(Hydroxymethyl)cyclohexa-2,5-dien-1-yl]ethyl}-2-iso-

propyl-5-methylcyclopent-1-en-1-yl Trifluoromethanesulfonate (47):

A 1.5  solution of DIBAL-H in toluene (0.6 mL, 0.90 mmol) was

¹⁹F NMR (CDCl₃, 188 MHz) δ = –74.3 (s) ppm. C₂₀H₂₇F₃O₅S

(436.5): calcd. C 55.03, H 6.23; found C 55.23, H 6.34.

Methyl (1R)-1-[2-(3-Isopropyl-1-methyl-2-{[(trifluoromethyl)- added dropwise at –78 °C to a stirred solution of compound 22

sulfonyl]oxy}cyclopent-2-en-1-yl)ethyl]-4-oxocyclohexa-2,5-diene-1- (130 mg, 0.30 mmol) in CH₂Cl₂(4 mL). The mixture was stirred

carboxylate (45): 3,5-Dimethypyrazole (670 mg, 7.0 mmol) was at –78 °C for 1 h and then treated with saturated aqueous ammo-

added to a suspension of anhydrous chromium trioxide (700 mg,

7.0 mmol) in CH₂Cl₂(6 mL), and the mixture was stirred at 0 °C

for 20 min. Triflate 22 (300 mg, 0.7 mmol) in CH₂Cl₂(6 mL) was

added in one portion to the dark-red solution and the reaction

mixture was stirred at 20 °C for 4 h. Diethyl ether (10 mL) and

celite (500 mg) were added and the mixture was stirred for a further

1 h. The mixture was filtered through a short column packed with

florisil and the filtrate was concentrated in vacuo. The crude prod-

uct was purified by silica gel chromatography (cyclohexane/ethyl

acetate, 4:1) to give 45 as a pale-yellow oil (126 mg, 40% yield).

nium chloride (1 mL). The mixture was warmed to 0 °C and a satu-

rated aqueous solution of sodium and potassium tartaric acid salt

(4 mL) was added. The mixture was vigorously stirred at room tem-

perature for 1 h, diluted with CH₂Cl₂(10 mL) and filtered. The

solid was abundantly washed with CH₂Cl₂. The phases of the fil-

trate were separated and the aqueous layer extracted with CH₂Cl₂

(3×10 mL). The combined organic phases were dried with anhy-

drous MgSO₄and concentrated in vacuo. The crude product was

purified by silica gel chromatography (cyclohexane/ethyl acetate,

5:1) to give alcohol 47 as a yellow oil (110 mg, 90% yield). [α]²_D⁰

[α]²_D⁰= –34.6 (c = 0.6, EtOH). IR (neat): ν = 2964, 1736 cm^–1

= –31.1 (c = 2.3, EtOH). IR (neat): ν = 3600–3200 (OH), 1683,

˜

(CO₂Me), 1669 (C=O), 1631 (C=C), 1475, 1403, 1207, 1138 cm^–1. 1460, 1405, 1207, 1139 cm^–1. ¹H NMR (400 MHz, CDCl₃), δ =

¹H NMR (400 MHz, CDCl₃): δ = 6.96 (d, J = 10.3 Hz, 2 H, 6.01 (dt, J = 10.6, 3.2 Hz, 2 H, HC=CHCH₂CH=CH), 5.34 (dt, J

H C = C H C O C H = C H ) , 6 . 3 4 ( d , J = 1 0 . 3 H z , 2 H ,

C=CHCOCH=C), 3.72 (s, 3 H, CO₂CH₃), 2.84 [hept, J = 6.7 Hz,

1 H, CH(CH₃)₂], 2.34–2.20 (m, 2 H, 4-H), 1.94–1.85 [m, 2 H,

= 10.6, 2.1 Hz, 2 H, HC=CHCH₂CH=CH), 3.34 (s, 2 H, CH₂OH),

2.83 [hept, J = 6.8 Hz, 1 H, CH(CH₃)₂], 2.66 (br. s, 2 H,

=CHCH₂CH=), 2.30–2.10 (m, 2 H, 3-H), 1.82 (ddd, J = 12.8, 8.6,

CH₂C(CO₂Me)], 1.81–1.75 (m, 1 H, 5-H), 1.71–1.66 (m, 1 H, 5-H), 5.6 Hz, 1 H, 4-Hα), 1.70–1.63 (m, 1 H, 4-Hβ), 1.47 (br. s, 1 H, OH),

1.30–1.21 [m, 2 H, CH₂CH₂C(CO₂Me)], 1.08 [s, 3 H C(CH₃)], 0.99 1.27–1.00 [m, 4 H, CH₂CH₂(C)CH₂OH], 1.10 [s, 3 H, C(CH₃)], 1.03

[d, J = 6.8 Hz, 6 H, CH(CH₃)₂] ppm. ¹³C NMR (50 MHz, CDCl₃): [d, J = 6.8 Hz, 3 H, CH(CH₃)₂], 1.02 [d, J = 6.8 Hz, 3 H, CH(CH₃)

δ = 184.9 (C, C=CHCOCH=C), 170.7 (C, CO₂CH₃), 147.4 (2 CH, ₂] ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 145.4 (C, C1), 137.4 (C,

C=CHCOCH=C), 144.1 (C, C2), 138.5 (C, C3), 130.4 (2 CH, C 2 ) , 1 2 9 . 5 ( 2 C H , C = C H C H ₂C H = C ) , 1 2 7 . 9 ( 2 C H ,

C=CHCOCH=C), 118.5 (q, J = 320 Hz, C, CF₃SO₂), 53.0 (CH₃, C=CHCH₂CH=C), 118.5 (q, J = 320 Hz, C, CF₃SO₂), 70.6 (CH₂,

CO₂CH₃), 51.8 [C, C(CO₂Me)], 45.9 (C, C1), 33.1 [2 CH₂,

CH₂OH), 46.1 [C, C(CH₃)], 43.1 (C, CCH₂OH), 33.3 (CH₂), 33.2

CH₂C(CO₂Me) and C5], 32.6 [CH₂, CH₂CH₂C(CO₂Me)], 25.7 (CH₂), 31.4 (CH₂), 26.6 (CH₂), 25.7 [CH, (CH₃)₂CH], 24.6 [CH₃,

[CH, (CH₃)₂CH], 24.6 [CH₃, (CH₃)C], 23.9 (CH₂, C4), 20.4 [CH₃, C(CH₃)], 23.8 (CH₂, C3), 20.5 [CH₃, (CH₃)₂CH], 20.1 [CH₃,

(CH₃)₂CH], 20.1 [CH₃, (CH₃)₂CH] ppm. ¹⁹F NMR (CDCl₃, (CH₃)₂CH] ppm. ¹⁹F NMR (CDCl₃, 188 MHz) δ = –74.3 (s) ppm.

188 MHz): δ = –74.2 (s) ppm. C₂₀H₂₅F₃O₆S (450.4): calcd. C 53.33,

H 5.59; found C 53.54, H 5.75.

C₁₉H₂₇F₃O₄S (408.5): calcd. C 56.14, H 6.20; found C 56.17, H

6.31.

Methyl (3aR,5aR)-1-Isopropyl-3a-methyl-8-oxo-2,3,3a,4,5,8-hexa- (1S)-{1-[2-(3-Isopropyl-1-methyl-2-{[(trifluoromethyl)sulfonyl]-

hydro-5aH-cyclopenta[a]naphthalene-5a-carboxylate (46a): To a

mixture of triflate 45 (163 mg, 0.36 mmol), triphenylphosphane

oxy}cyclopent-2-en-1-yl)ethyl]cyclohexa-2,5-dien-1-yl}methyl 2,2-

Dimethylpropanoate (48): To a solution of alcohol 47 (120 mg,

(37 mg, 0.14 mmol), potassium carbonate (100 mg, 0.72 mmol) and 0.29 mmol) in CH₂Cl₂(3 mL) was sequentially added at 0 °C, tri-

n-tetrabutylammonium bromide (210 mg, 0.65 mmol) in toluene ethylamine (52 mg, 0.51 mmol), DMAP (10 mg, 0.09 mmol) and

(10 mL) was added palladium acetate (16 mg, 20 mol-%, pivaloyl chloride (40 mg, 0.33 mmol). After stirring for 4 h at

0.07 mmol). The mixture was carefully degassed through two

freeze-pump-thaw cycles and stirred at 120 °C (oil bath) for 1 h.

After cooling, the reaction mixture was filtered through celite and

the solid was thoroughly washed with diethyl ether. The combined

organic phases were dried and concentrated under reduced pressure

to give a yellow oil which was purified by flash chromatography to

yield a 4:1 mixture of esters 46a and 46b (80 mg, 74% yield). An

analytical sample of 46a (64 mg, 65% yield) was obtained by care-

ful chromatography on silica gel (cyclohexane/ethyl acetate, 4:1).

20 °C, 1  HCl (2 mL) was added. The organic phase was separated

and the aqueous phase extracted with CH₂Cl₂(3×10 mL). The

combined organic phases were washed with brine, dried with anhy-

drous MgSO₄and concentrated in vacuo. The crude product was

purified by silica gel chromatography (cyclohexane/ethyl acetate,

4:1) to give 48 as a colourless oil (102 mg, 71% yield). [α]²_D⁰= –25.4

(c = 0.6, EtOH). IR (neat): ν = 2962, 2929, 2872, 1732, 1460, 1407,

˜

1

1365, 1211, 1140 cm^–1. H NMR (400 MHz, CDCl₃): δ = 5.84 (dt,

J = 10.8, 3.1 Hz, 2 H, HC=CHCH₂CH=CH), 5.35 (tt, J = 10.8,

1.9 Hz, 2 H, HC=CHCH₂CH=CH), 3.83 (s, 2 H, CH₂OCOtBu),

[α]²_D⁰= +118 (c = 0.6, EtOH). IR (neat): ν = 1732, 1660, 1452 cm^–1.

˜

¹H NMR (400 MHz, CDCl₃): δ = 6.74 (d, J = 10.0 Hz, 1 H, 6-H), 2.81 [hept, J = 6.8 Hz, 1 H, CH(CH₃)₂], 2.60 (br. s, 2 H,

6.34 (dd, J = 10.0, 1.6 Hz, 1 H, 7-H), 6.14 (d, J = 1.6 Hz, 1 H, 9-

H), 3.62 (s, 3 H, CO₂CH₃), 2.92 [hept, J = 6.8 Hz, 1 H, CH(CH₃)

=CHCH₂CH=), 2.30–2.15 (m, 2 H, 4-H), 1.81 (ddd, J = 12.7, 8.6,

5.3 Hz, 1 H, 5-Hα), 1.68–1.63 (m, 1 H, 5-Hβ), 1.35–1.25 [m, 4 H,

₂], 2.55–2.42 (m, 1 H, 5-H_eq), 2.39–2.34 (m, 2 H, 2-H), 1.84–1.67 CH₂CH₂(C)CH₂OPiv], 1.16 [s, 9 H, OCOC(CH₃)₃], 1.09 [s, 3 H,

(m, 5 H, 5-H_ax, 3-H, 4-H), 1.04 [d, J = 6.8 Hz, 3 H, CH(CH₃)₂], C(CH₃)], 1.01 [d, J = 6.7 Hz, 3 H, CH(CH₃)₂], 0.99 [d, J = 6.7 Hz,

0.97 [d, J = 6.8 Hz, 3 H, CH(CH₃)₂], 0.94 [s, 3 H, C(CH₃)] ppm. 3 H, CH(CH₃)₂] ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 178.1 [C,

¹³C NMR (50 MHz, CDCl₃): δ = 186.4 (C, CO), 170.1 (C,

CO₂C(CH₃)₃], 145.2 (C, C2), 137.4 (C, C3), 128.9 (1 CH,

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4837

E. Drège, C. Tominiaux, G. Morgant, D. Desmaële

FULL PAPER

C=CHCH₂CH=C), 128.8 (1 CH, C=CHCH₂CH=C), 126.4 (1 CH,

(CH₃)₃], 1.05 [d, J = 6.8 Hz, 3 H, CH(CH₃)₂], 0.96 [d, J = 6.8 Hz,

C=CHCH₂CH=C), 126.2 (1 CH, C=CHCH₂CH=C), 118.5 (q, J = 3 H, CH(CH₃)₂], 0.96 [s, 3 H, C(CH₃)] ppm. ¹³C NMR (100 MHz,

320 Hz, C, CF₃SO₂), 70.8 (CH₂, CH₂OCOtBu), 46.0 [C, C(CH₃)], CDCl₃): δ = 186.9 (C, CO), 177.9 [C, OCOC(CH₃)₃], 157.5 (C,

40.5 [C, CCH₂OCOC(CH₃)₃], 38.7 [C, OCOC(CH₃)₃], 33.2 (CH₂, C9a), 152.2 (CH, C6), 147.2 (C, C1), 136.5 (C, C9b), 129.7 (CH,

C5), 33.1 (CH₂), 31.4 (CH₂), 26.7 (CH₂, C=CHCH₂CH=C), 26.5

C7), 127.6 (CH, C9), 66.2 (CH₂, CH₂OCOtBu), 49.9 (C, C3a), 45.3

[3 CH₃, OCOC(CH₃)₃], 25.5 [CH₃, C(CH₃)], 24.6 [CH, (CH₃)₂CH], (C, C5a), 39.6 (CH₂, C3), 38.7 [C, OCOC(CH₃)₃], 36.1 (CH₂, C4),

23.7 (CH₂, C4), 20.3 [CH₃, (CH₃)₂CH], 19.9 [CH₃, (CH₃)₂- 31.8 (CH₂, C5), 29.0 (CH₂, C2), 27.1 [CH, (CH₃)₂CH], 26.9 [3 CH₃,

CH] ppm. ¹⁹F NMR (CDCl₃, 188 MHz) δ = –74.2 (s) ppm. OCOC(CH₃)₃], 23.5 [CH₃, C(CH₃)], 21.5 [CH₃, (CH₃)₂CH], 21.4

C₂₄H₃₅F₃O₅S (492.6): calcd. C 58.52, H 7.16; found C 58.74, H

7.35.

[CH₃, (CH₃)₂CH] ppm. MS (ESI, MeOH): m/z (%): 379 (100) [M

+ Na]⁺. C₂₃H₃₂O₃·½H₂O (365.5): calcd. C 75.58, H 9.10; found C

75.25, H 9.37.

(1S)-{1-[2-(3-Isopropyl-1-methyl-2-{[(trifluoromethyl)sulfonyl]-

oxy}cyclopent-2-en-1-yl)ethyl]-4-oxocyclohexa-2,5-dien-1-yl}methyl

2,2-Dimethylpropaonate (49): 3,5-Dimethypyrazole (220 mg,

2.3 mmol) was added to a suspension of anhydrous chromium tri-

oxide (230 mg, 2.3 mmol) in CH₂Cl₂(3 mL) and the mixture was

stirred at room temperature for 20 min. To the dark-red solution,

triflate 48 (113 mg, 0.23 mmol) in CH₂Cl₂(2 mL) was added in one

portion and the reaction mixture was stirred at 20 °C for 4 h. Di-

ethyl ether (5 mL) and celite (200 mg) were added and the mixture

was stirred for one more hour. The mixture was filtered through a

short column packed with florisil and the filtrate was concentrated

in vacuo. The crude product was purified by silica gel chromatog-

raphy (cyclohexane/ethyl acetate, 4:1) to give 49 a pale-yellow oil

(1aR,1bR,3aR,8aR)-[6-Isopropyl-3a-methyl-8-oxo-1a,2,3,3a,4,5,

8,8a-octahydro-1bH-cyclopenta[5,6]naphtho[1,2-b]oxiren-1b-yl]-

methyl 2,2-Dimethylpropanoate (51): To a mixture of trienone 50a

(94 mg, 0.26 mmol) in methanol (0.4 mL) was added a solution of

50% hydrogen peroxide (0.15 mL, 0.78 mmol) in 5% aqueous so-

dium hydroxide (0.22 mL, 0.13 mmol). The reaction mixture was

stirred for 24 h at 25 °C. Brine (2 mL) was added and the mixture

was extracted with diethyl ether (3×20 mL). The combined organic

phases were washed with saturated aqueous sodium bisulfite, brine,

dried with MgSO₄and concentrated under reduced pressure. Puri-

fication by silica gel chromatography (cyclohexane/ethyl acetate,

1:4) gave epoxide 51 as colourless crystals (50 mg, 50% yield), m.p.

(70 mg, 60% yield). [α]²_D⁰= –29.2 (c = 1.0, EtOH). IR (neat): ν =

159 °C (iPrOH). [α]²_D⁰= +47 (c = 5.1, EtOH). IR (film): ν = 2958,

˜

2962, 2860, 1732, 1667 (C=O), 1635 (C=C), 1475, 1460, 1407 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 6.71 (ddd, J = 10.2, 7.0, 3.2 Hz,

2 H, HC=CHCOCH=C H) , 6 . 3 8 ( d, J = 10 . 2 Hz , 2 H,

HC=CHCOCH=CH), 4.12 (s, 2 H, CH₂OCOtBu), 2.82 [hept, J =

6.8 Hz, 1 H, CH(CH₃)₂], 2.36–2.12 (m, 2 H, 4-H), 1.83–1.56 (m, 4

H), 1.30–1.17 (m, 2 H), 1.12 [s, 9 H, OCOC(CH₃)₃], 1.08 [s, 3 H,

C(CH₃)], 1.09 [d, J = 6.8 Hz, 6 H, CH(CH₃)₂] ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 185.8 (C, CO), 177.7 (C, OCOtBu), 150.7

(CH, C=CHCOCH=C), 150.5 (CH, C=CHCOCH=C), 144.1 (C,

C2), 138.4 (C, C3), 131.5 (CH, C=CHCOCH=C), 131.4 (CH,

C=CHCOCH=C), 118.5 (q, J = 320 Hz, C, CF₃SO₂), 67.5 (CH₂,

CH₂OCOtBu), 46.0 [C, C1 or CCH₂OCOC(CH₃)₃], 45.9 [C, C1 or

CCH₂OCOC(CH₃)₃], 38.7 [C, CO₂C(CH₃)₃], 33.2 (CH₂), 32.6

(CH₂), 29.8 (CH₂), 26.9 [3 CH₃, OCOC(CH₃)₃], 25.6 [CH₃,

C(CH₃)], 24.9 [CH, (CH₃)₂CH], 23.9 (CH₂, C4), 20.4 [CH₃,

(CH₃)₂CH], 20.1 [CH₃, (CH₃)₂CH] ppm. ¹⁹F NMR (CDCl₃,

188 MHz) δ = –74.2 (s) ppm.

2927, 2856, 1727 (OCOtBu), 1668, 1461, 1410, 1280, 1261, 1215,

1140 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.86 (s, 1 H, 7-H),

4.22 (d, J = 11.2 Hz, 1 H, CH₂OCOtBu), 4.06 (d, J = 11.2 Hz, 1

H, CH₂OCOtBu), 3.50–3.45 (m, 2 H, 1a-H and 8a-H), 2.76 [hept,

J = 6.8 Hz, 1 H, CH(CH₃)₂], 2.45–2.40 (m, 2 H, 5-H), 2.29 (td, J

= 13.8, 4.8 Hz, 1 H, 2-Hβ), 1.91 (dt, J = 13.8, 2.7 Hz, 1 H, 2-Hα),

1.86–1.60 (m, 4 H, 3-H, 4-H), 1.13 [s, 9 H, OCOC(CH₃)₃], 1.03 [d,

J = 6.8 Hz, 3 H, CH(CH₃)₂], 1.02 [s, 3 H, C(CH₃)], 0.92 [d, J =

6.8 Hz, 3 H, CH(CH₃)₂] ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

187.5 (C, CO), 180.8 [C, OCOC(CH₃)₃], 159.6 (C, C6 or C6b),

159.2 (C, C6 or C6b), 145.8 (C, C6a), 123.9 (CH, C7), 66.8 (CH₂,

CH₂OCO), 60.7 (CH, C1a), 55.3 (CH, C8a), 48.6 (CH, C3a), 46.2

(C, C1b), 39.0 (CH₂, C4), 38.9 [C, OCOC(CH₃)₃], 36.1 (CH₂, C3),

29.7 (CH₂, C2), 29.2 (CH₂, C5), 27.0 [3 CH₃, OCOC(CH₃)], 26.7

[CH, (CH₃)₂CH], 23.5 [CH₃, C(CH₃)], 21.5 [2 CH₃, (CH₃)₂-

CH] ppm. MS (ESI, MeOH), m/z (%): 395 (6) [M + Na]⁺, 379

(100), 357 (17).

(3aR,5aR)-[1-Isopropyl-3a-methyl-8-oxo-2,3,3a,4,5,8-hexahydro-

5aH-cyclopenta[a]naphthalen-5a-yl]methyl 2,2-Dimethylpropanoate

(50a): A mixture of triflate 49 (300 mg, 0.59 mmol), triphenylphos-

phane (62 mg, 0.23 mmol), potassium carbonate (205 mg,

1.48 mmol) and n-tetrabutylammonium bromide (380 mg,

1.18 mmol) in toluene (10 mL) was added palladium acetate

(26 mg, 20 mol-%, 0.11 mmol). The mixture was carefully degassed

through two freeze-pump-thaw cycles and stirred at 120 °C (oil

bath) for 2 h. After cooling, the reaction mixture was filtered

through celite and the solid was thoroughly washed with diethyl

ether. The combined organic phases were dried and concentrated

under reduced pressure. Chromatography on silica gel (cyclohex-

ane/ethyl acetate, 5:1) afforded ester 50a (153 mg, 73 % yield).

Crystallographic Data: Crystal size 0.23×0.25 ×0.29 mm, ortho-

rhombic, space group P2₁2₁2₁(no. 19), Z = 4, a = 10.511(5), b =

12.617(5), c = 15.818(5) Å, α = β = γ = 90°, V = 2097.9(15) Å³, d

= 1.179 g cm^–3, F(000) = 808, λ = 0.710693 Å (Mo-K_α), µ =

0.079 mm^–1; 5788 reflections measured (0 Յ h Յ 14, 0 Յ k Յ 17,

0 Յ l Յ 22) on a Nonius CAD4 diffractometer. The structure was

solved with SIR92 and refined with CRYSTALS. Hydrogen atoms

riding refinement converged to R(gt) = 0.0493 for the 1716 reflec-

tions having I Ն 2σ(I), and wR(gt) = 0.1041, goodness-of-fit S

= 0.9117, residual electron density –0.25 and 0.29 eÅ^–3, CCDC-

267231.^[35]

(3aR, 5aR)-[1-Isopropyl-3a-methyl-8-oxo-2,3,3a,4,6,7,8-octahydro-

5aH-cyclopenta[a]naphthalene-5a-yl]methyl 2,2-Dimethylpropanoate

[α]²_D⁰= +82.5 (c = 1.9, EtOH). IR (neat): ν = 2956, 2630, 2870,

˜

1734 (OCOtBu), 1684 (weak, CO), 1658, 1624, 1450 1405, 1239, (52): A solution of trienone 50a (206 mg, 0.58 mmol) in EtOH

1209 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.79 (d, J = 10.1 Hz, (10 mL) was hydrogenated over chlorotris(triphenylphosphane)rho-

1 H, 6-H), 6.34 (dd, J = 10.1, 1.3 Hz, 1 H,7-H), 6.18 (d, J = 1.3 Hz,

dium() (100 mg, 0.11 mmol) at atmospheric pressure for 60 h at

1 H, 9-H), 4.27 (d, J = 10.5 Hz, 1 H, CH₂OCOtBu), 4.05 (d, J = 25 °C. The mixture was filtered through celite and the filtrate was

10.5 Hz, 1 H, CH₂OCOtBu), 2.85 [hept, J = 6.8 Hz, 1 H, CH-

(CH₃)₂], 2.50–2.40 (m, 2 H, 2-H), 1.94 (dt, J = 12.8, 2.7 Hz, 1 H,

5-H_eq), 1.88 (ddd, J = 11.7, 6.8, 2.7 Hz, 1 H, 3-Hβ), 1.80 (m, 1 H,

concentrated in vacuo. Chromatography of the crude residue (cy-

clohexane/ethyl acetate, 4:1) gave dienone 52 (155 mg, 75%) as a

yellow oil. [α]²_D⁰= +448 (c = 0.7, EtOH). IR (film): ν = 2961, 2931,

˜

5-H_ax), 1.76–1.67 (m, 3 H, 3-Hα, 4-H), 1.11 [s, 9 H, OCOC- 1729 (OCOtBu), 1707 (C=O), 1673 (C=C), 1459, 1281, 1146,

4838

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Eur. J. Org. Chem. 2006, 4825–4840

Synthetic Studies on Cyathin Terpenoids

FULL PAPER

1034 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.89 (s, 1 H, 9-H),

for the MS spectra and Mrs. S. Mairesse-Lebrun for the elemental

4.17 (d, J = 11.5 Hz, 1 H, CH₂OCOtBu), 4.01 (d, J = 11.5 Hz, 1 analyses.

H, CH₂OCOtBu), 2.81 [hept, J = 6.8 Hz, 1 H, CH(CH₃)₂], 2.64

(ddd, J = 11.8, 5.6, 2.1 Hz, 1 H, 7-Hβ), 2.45–2.30 (m, 3 H, 2-H, 7-

Hα), 2.10 (ddd, J = 11.8, 5.4, 2.1 Hz, 1 H, 6-Hβ), 1.85–1.78 (m, 3

H, 6-Hα, 5-H, 3-H), 1.75–1.60 (m, 4 H, 4-H, 5-H, 3-H), 1.21 [s, 9

H, OCOC(CH₃)₃], 1.03 [d, J = 6.8 Hz, 3 H, CH(CH₃)₂], 1.01 [s, 3

H, C(CH₃)], 0.96 [d, J = 6.8 Hz, 3 H, CH(CH₃)₂] ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 199.1 (C, CO), 178.0 [C, OCOC(CH₃)₃],

157.9 (C, C9a), 149.2 (C, C1), 136.8 (C, C9b), 127.2 (CH, C9), 64.0

(CH₂, CH₂OCOtBu), 49.5 (C, C3a), 40.3 (C, C5a), 39.2 (CH₂, C3),

38.8 [C, OCOC(CH₃)₃], 36.1 (CH₂, C4), 34.0 (CH₂, C7), 33.4 (CH₂,

C6), 32.6 (CH₂, C5), 29.2 (CH₂, C2), 27.2 [3 CH₃, OCOC(CH₃)₃],

26.9 [CH, (CH₃)₂CH], 23.8 [CH₃, C(CH₃)], 21.3 [CH₃, (CH₃)₂CH],

21.2 [CH₃, (CH₃)₂CH] ppm. MS (EI = 70 eV), m/z (%): 358 (49)

[M^·+], 343 (17), 271 (14), 259 (43), 257 (100). C₂₃H₃₄O₃(358.5):

calcd. C 77.05, H 9.56; found C 76.71, H 9.79.

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(3aR,5aR)-[1-Isopropyl-3a-methyl-8-oxo-3,3a,4,5,6,7,8,9-octahydro-

cyclohepta[e]inden-5a(2H)-yl]methyl 2,2-Dimethylpropanoate (5): A

solution of Me₃Al (2  in heptane, 0.5 mL, 1 mmol) was added to

dry CH₂Cl₂(6 mL). The mixture was cooled to –78 °C and a solu-

tion of dienone 52 (80 mg, 0.22 mmol) in dry CH₂Cl₂(2 mL) was

added followed by a solution of TMSCHN₂(2  in hexane, 0.5 mL,

1 mmol). The reaction mixture was warmed to room temperature

for 4 h. After diluting with CH₂Cl₂(20 mL), an ice-cooled aqueous

solution of NaHCO₃(3 mL) was slowly added at 0 °C and stirring

was continued for 5 min. The organic layer was separated and the

aqueous phase extracted with diethyl ether (2×10 mL). The com-

bined organic phases were dried with MgSO₄and concentrated in

vacuo. The residue was dissolved in acetone (3 mL) and 3  HCl

(1.5 mL) was added. The mixture was stirred for 2 h at room tem-

perature. Solid K₂CO₃(330 mg, 2.4 mmol) was then added and the

mixture was concentrated under reduce pressure. The residue was

extracted with diethyl ether (2×10 mL). The combined organic

phases were dried with MgSO₄and concentrated in vacuo. Purifica-

tion by silica gel chromatography (cyclohexane/ethyl acetate, 10:1)

gave ketone 5 as colourless oil (50 mg, 60% yield) and 54 (8 mg,

10% yield). Only the major isomer 5 is described. [α]²_D⁰= +225 (c

= 0.8, EtOH). IR (film): ν = 2957, 2934, 2865, 1727 (C=O, OC-

˜

1

OtBu), 1667 (C=C), 1479, 1458, 1397, 1281, 1150 cm^–1. H NMR

[8] a) B. B. Snider, N. H. Vo, S. V. O’Neil, B. M. Foxman, J. Am.

Chem. Soc. 1996, 118, 7644–7645; b) B. B. Snider, N. H. Vo,

S. V. O’Neil, J. Org. Chem. 1998, 63, 4732–4740.

(400 MHz, CDCl₃) δ = 5.30 (t, J = 6.5 Hz, 1 H, 10-H), 3.97 (d, J

= 11.2 Hz, 1 H, CH₂OCOtBu), 3.93 (d, J = 11.2 Hz, 1 H, CH₂OC-

OtBu), 3.48 (dd, J = 14.4, 6.2 Hz, 1 H, 9-H), 3.18 (dd, J = 14.4,

6.7 Hz, 1 H, 9-H), 2.73 [hept, J = 6.8 Hz, 1 H, CH(CH₃)₂], 2.69

(ddd, J = 18.8, 9.8, 2.7 Hz, 1 H, 7-H), 2.52 (ddd, J = 18.8, 8.9,

2.3 Hz, 1 H, 7-H), 2.35–2.25 (m, 3 H, 2-H, 6-H), 1.95–1.85 (m, 1

H, 4-Hax), 1.80–1.50 (m, 5 H, 6-H, 3-H, 5-H), 1.38 (dt, J = 13.8,

3.3 Hz, 1 H, 4-Heq), 1.19 [s, 9 H, OCOC(CH₃)₃], 0.94 [d, J =

6.8 Hz, 3 H, CH(CH₃)₂], 0.92 [s, 3 H, C(CH₃)], 0.90 [d, J = 6.8 Hz,

3 H, CH(CH₃)₂] ppm. ¹³C NMR (100 MHz, CDCl₃) δ = 209.2 (C,

CO), 178.2 [C, OCOC(CH₃)₃], 142.3 (C, C10b), 139.9 (C, C1 or

C10a), 139.7 (C, C1 or C10a), 117.8 (CH, C10), 66.8 (CH₂, CH₂O-

COtBu), 48.7 (C, C3a), 44.8 (C, C5a), 41.6 (CH₂, C9), 38.9 [C,

OCOC(CH₃)₃], 38.7 (CH₂, C3), 37.9 (CH₂, C7), 36.4 (CH₂, C5),

31.7 (CH₂, C4), 30.6 (CH₂, C6), 28.4 (CH₂, C2), 27.2 [3 CH₃, OC-

OC(CH₃)₃], 26.4 [CH, (CH₃)₂CH], 23.4 [CH₃, C(CH₃)], 21.6 [CH₃,

(CH₃)₂CH], 21.3 [CH₃, (CH₃)₂CH] ppm. C₂₄H₃₆O₃(372.5): calcd.

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Acknowledgments

We gratefully acknowledge Dr. Jacqueline Mahuteau and Dr.

Michèle Ourevitch for the NMR experiments, Mrs Michèle Danet

Eur. J. Org. Chem. 2006, 4825–4840

www.eurjoc.org

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Published Online: September 5, 2006

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Article Doi

Synthetic studies on cyathin terpenoids: Enantioselective synthesis of the tricyclic core of cyathin through intramolecular Heck cyclisation

DOI: 10.1002/ejoc.200600429

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