Preparation of 9α-fluorinated sesquiterpenic drimanes and evaluation of their antifeedant activities

FULL PAPER

DOI: 10.1002/ejoc.200901499

Preparation of 9α-Fluorinated Sesquiterpenic Drimanes and Evaluation of

Their Antifeedant Activities

Antonio Abad,*^[a]Consuelo Agulló,^[a]Ana C. Cuñat,^[a]Azucena González-Coloma,^[b]and

David Pardo^[a]

Keywords: Natural products / Terpenoids / Fluorine / Total synthesis / Biological activity

The preparation of 9α-fluoro analogues of both natural and

unnatural drimane-type sesquiterpenes is described. Their

synthesis began with the initial preparation of methyl 8-keto-

12-nordriman-11-oate from β-ionone and entailed the elec-

trophilic fluorination of C-9 for the stereoselective introduc-

tion of the fluorine atom. The drimane skeleton was com-

preparation, among others, of 9α-fluorodrimanes, which are

structurally and functionally related to albicanic acid, dri-

menin and olepupuane. Also described are the reactivities

of some of the fluorine-containing systems prepared and a

comparative study of the antifeedant activities of a selection

of 9α-fluorodrimanes and the corresponding hydrogen ana-

pleted from the intermediate 9α-fluoro-8-keto-12-nordrim- logues against several insect species with different feeding

ane system by means of different reactions at the C-8 ketone

carbonyl group, essentially Wittig methylenation, cyano-

hydrin formation or palladium-catalysed carbonylation of the

corresponding enol triflate. Further manipulation of the func-

tionalization derived from these key reactions allowed the

ecologies (Spodoptera littoralis, Myzus persicae and Rhopa-

losiphum padi), which revealed a significant increase in the

antifeedant activities of some of the fluorinated drimane ana-

logues.

stantially alter its physiochemical properties. However, the

analysis and even interpretation of this effect is not easy

because fluorine produces different types of electronic ef-

fects which, depending on the situation, may compensate

or reinforce each other. This situation is aptly described in

an article by Schlosser on the effects of fluorine on OH,

NH and CH acidities: “Fluorine leaves nobody indifferent:

it inflames emotion, be that affections or aversions. As sub-

stituent it is rarely boring, always good for a surprise, but

often completely unpredictable”.^[5]

Over the last few years there has been a growing interest

in the synthesis of fluorine-containing analogues of natural

products and a large number of fluorinated natural prod-

ucts with biological significance such as amino acids,^[6]pep-

tides,^[7]glycosides,^[8]nucleosides,^[9]lipids,^[10]oligosaccha-

rides,^[11]steroids,^[12]prostaglandins,^[13]vitamins,^[14]antibiot-

ics,^[15]pheromones^[16]alkaloids^[17]and others^[18]have been

synthesized and some have subsequently been developed as

pharmaceuticals and are marketed, registered or at the clin-

ical development stage.^[19]Also, a relatively significant

number of fluoro derivatives of bioactive terpene-type com-

pounds have bee reported and in many cases these show

an increase in activity with respect to the corresponding

hydrogen analogue. Although fluoro derivatives of practi-

cally all classes of terpenes, from mono- to triterpenes,^[20]

have been described, most of this research has focused on

the preparation of fluorinated analogues of sesquiterpene-

type compounds such as artemisinin and structurally re-

lated antimalarial compounds.^[21]

Introduction

Fluorinated compounds are very rare in nature and, in

contrast to other halogens found in many products isolated

from natural sources, fewer than 20 naturally occurring flu-

orinated organic compounds have been isolated.^[1]This

contrasts with the very large number of non-natural fluori-

nated compounds that have been synthesized, particularly

in the agrochemical and pharmaceutical fields. In fact, as

many as 30–40% of agrochemicals and 20% of pharmaceu-

ticals on the market are estimated to contain fluorine.^[2]

This growing interest in fluorinated compounds is primarily

motivated by the unique influence of the fluoro substituent

on the chemical, physical and biological properties of these

compounds.^[3]In general, the fluorine atom is considered

bioisosteric with both the hydrogen atom and the hydroxy

group such that their replacement by a fluorine atom does

not change the molecule’s shape very much, exerting only

a minor demand at receptor sites, at least for monofluoro

analogues.^[4]On the other hand, and owing to the peculiar

characteristics of the fluorine atom, fluorine substitution

affects the internal electronics of the molecule and can sub-

[a] Departamento de Química Orgánica, Universitat de Valencia,

Dr. Moliner 50, 46100 Burjassot, Valencia, Spain

Fax: +34-963544328

E-mail: antonio.abad@uv.es

[b] Instituto de Ciencias Agrarias-CCMA, CSIC,

Serrano 115, 28006 Madrid, Spain

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.200901499.

2182

Eur. J. Org. Chem. 2010, 2182–2198

Preparation of 9α-Fluorinated Sesquiterpenic Drimanes

Drimanes are one of the main groups of sesquiterpenes this article, including the change in the reactivity of some

with structures based on the hypothetical drimane skeleton of these systems produced by the presence of the fluorine

1 (Figure 1).^[22]These compounds seem to play an impor- atom. A partial preliminary communication of this work

tant ecological role and some of them exhibit potentially has already been published.^[25]

useful biological activities, including antiviral [influenza A

(H1N1)], anti-inflammatory, cytotoxic and, particularly,

antifeedant properties.^[23]This activity has been associated

in most cases with the presence of a 1,4-dialdehyde moiety

Results and Discussion

at C-11 and C-12, either as an actual aldehyde group or as

a latent aldehyde existing as a γ-butenolide or furan ring.

Representative biologically active examples of this type of

sesquiterpene are albicanic acid (2) and the related al-

bicanol (3), albicanyl acetate (4) and albicanal (5), poly-

godial (6), warburganal (7), cinnamolide (8), drimenin (9)

and olepupuane (10; Figure 2).

Much work has been carried out on the synthesis of dri-

manes.^[26]The most common synthetic strategy for the

preparation of the drimane skeleton is based on the use of

a decalone system as the source of the AB rings into which

the rest of the carbon atoms required to complete the drim-

ane framework are incorporated. We followed the same

strategy for the preparation of the 9α-fluorodrimanes, the

syntheses of which begin with the initial preparation of the

fluorodecalone 11 (Scheme 1). This decalone possesses a

12-nordrimane skeleton and, in principle, an appropriate

functionalization for the ready elaboration of the different

target fluorinated drimanes.

Figure 1. Drimane skeleton.

Scheme 1. 9α-Fluorodrimanes that could potentially be synthesized

from decalone 11.

Figure 2. Representative biologically active natural drimanes.

In this article we describe the preparation of some C-9

fluoro analogues of the above-mentioned drimanes. As is

the case for other closely related systems,^[24]the biological

activity of drimanes is generally enhanced by the presence

Preparation of Fluorodecalone 11

Synthesis of the fluorodecalone 11 started with the initial

of polar groups (i.e., OH, OAc, etc.) in the vicinity of the preparation of non-fluorodecalone analogue 19 (Scheme 2).

dialdehyde or butenolide moieties, a circumstance that may Different synthetic approaches to the preparation of the bi-

perhaps be due to a more favourable interaction with recep- cyclic system of this decalone have been described in the

tors. Therefore, we were interested in investigating how the literature.^[27]In this work we used the procedure based on

modification of the 9-position in the drimane framework the use of β-ionone as the starting material, which is trans-

with a fluorine atom could influence their chemical and formed into decalone 19 through a three-step sequence in-

biological activity. In this work we have prepared C-9 fluoro volving Bu₃SnH regioselective hydrogenation to dihydro-β-

analogues of several natural drimanes and other related ionone followed by methoxycarbonylation and stereoselec-

non-natural ones and evaluated their antifeedant activity. tive stannic chloride catalysed cyclization with an overall

Details of the work are given in the following sections of yield of 60%.^[28]

Eur. J. Org. Chem. 2010, 2182–2198

www.eurjoc.org

2183

A. Abad, C. Agulló, A. C. Cuñat, A. González-Coloma, D. Pardo

FULL PAPER

Elaboration of the Drimane Skeleton: Synthesis of

9α-Fluoroalbicanic Acid (12) and the Related

9α-Fluoroalbicanol (13), 9α-Fluoroalbicanyl Acetate (14)

and 9α-Fluoroalbicanal (15)

With the desired fluorodecalone 11 in hand it was pos-

sible to complete the construction of the drimane frame-

work by introducing the required additional C-12 carbon

atom. One way of doing this was by methylenation of the

carbonyl group of 11 by a Peterson or Wittig olefination

reaction (Scheme 3). Although the reaction of the carbonyl

group of 11 with TMSCH₂MgCl to give the corresponding

β-hydroxysilane was very efficient (99%), we could not find

the conditions to efficiently induce the elimination of tri-

methylsilanol under a variety of both acidic and basic con-

ditions or thermally. However, Wittig methylenation took

place very efficiently when the ketone 11 was treated with

methylidenetriphenylphosphorane in toluene at room temp.

to afford the β,γ-unsaturated ester 21 in 85%yield. The in-

fluence of the fluorine atom on the reactivity of the car-

bonyl group is evidenced by the notable difference in reac-

tivity between the fluorinated and non-fluorinated decalone

systems (i.e., 11 Ǟ 21 vs. 19 Ǟ 22), which may be attrib-

uted, at least partially, to the lowering of the LUMO energy

of the π–CO bond produced by the fluorine atom.^[30,31]

Scheme 2. Reagents and conditions: (a) i. Bu₄SnH, AIBN, 80 °C

(99%); ii. NaH, (MeO)₂C=O, dioxane, 105 °C (86%); iii. SnCl₄,

CH₂Cl₂, 30 °C (71%); (b) i. NaH, NFSI, THF, room temp., (85%

of 11); ii. Selectfluor^®, THF, room temp. (49% of 11 and 16% of

20).

Hydrogen/fluorine interchange at the C-9^[29]position of

the decalone system was effected by electrophilic fluorina-

tion of the sodium enolate of β-keto ester 19 generated by

the treatment of 19 with sodium hydride in THF. The effi-

ciency and stereoselectivity of this electrophilic fluorination

reaction depends on the nature of the electrophilic fluori-

nating agent used.^[3b]The best results were obtained with

N-fluorobenzenesulfonimide (NFSI, Figure 3),^[3c]which

stereoselectively afforded the fluorodecalone 11 in a yield

of 85%. Use of the fluorinating reagent Selectfluor^®[3d]fur-

nished a 3:1 mixture of 9-epimeric fluorodecalones 11 and

20, respectively, in a combined yield of 65% after their

chromatographic separation. The stereochemistry at C-9 in

decalones 11 and 20 was assigned on the basis of their spec-

troscopic data. Of particular relevance were the intense

cross-peaks observed in the ¹H–¹⁹F HOESY (Heteronuclear

Overhauser Enhancement Spectroscopy) spectra of 11 be-

tween the fluorine and the 1α-, 5α- and 7α-hydrogen atoms,

which unequivocally confirmed the α orientation (axial dis-

position) of the fluorine atom. A relatively small but signifi-

cant shielding (ca. 0.5–1.5 ppm) of C-1, C-5 and C-7 is also

observed in the ¹³C NMR spectrum of 11 relative to the

corresponding resonances of 20 due to the syn γ-effect of

the axial fluorine atom.

Scheme 3. Reagents and conditions: (a) Ph₃PCH₃Br, KHMDS,

CH₃Ph, room temp., 2 h (85%); (b) NaH, PrSH, DMF, 80 °C, 2 h

(87%); (c) LiAlH₄·2THF, CH₃Ph, –40 °C (99%); (d) Ac₂O, DMAP,

Py, room temp., 1.5 h, (95%); (e) DMP-py, CH₂Cl₂, room temp.,

4.5 h (95%).

Several reaction conditions were evaluated for the hy-

drolysis of the methyl ester 21 to the corresponding carb-

oxylic acid 12 (Scheme 3), the 9α-fluoro analogue of the

natural drimane albicanic acid (2).^[32]The conditions pre-

viously described for the hydrolysis of albicanic acid methyl

ester (LiI, DMF)^[33]failed and gave a complex reaction mix-

ture, as did some of the other procedures assayed.^[34]How-

ever, the hydrolysis of 21 to 12 was accomplished in good

yield by using NaSPr in DMF, but limiting the heating tem-

perature to 80 °C.

Note that although the acid 12 was relatively stable

towards nucleophilic and basic reagents, it readily un-

dergoes lactonization with elimination of the fluorine atom

Figure 3. Electrophilic fluorinating reagents.

2184

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2182–2198

Preparation of 9α-Fluorinated Sesquiterpenic Drimanes

under certain electrophilic conditions. Thus, treatment of Alternative Elaboration of the Drimane Skeleton:

12 with diborane under the usual hydroboration conditions Preparation of 9α-Fluorodrimenin (17)

afforded the lactone 24 in 74% yield (Scheme 4). This com-

pound is a naturally occurring drimanic sesquiterpenic lac-

In principle, a simple procedure for the elaboration of the

tone known as isodrimenin that was first isolated from the 9α-fluorodrimane skeleton of some of the initial synthetic

stem bark of the South American Drimys species^[35]and targets could imply the preparation of diester 26 from dec-

exhibits significant feeding inhibition activity.^[36]The for- alone 11 (Scheme 5), a strategy that has been used success-

mation of 24 in the above reaction represents an apparently fully for the preparation of functionally related natural

intramolecular S_N2Ј process involving a disfavoured 5-endo- compounds.^[42]Following this approach, the decalone 11

trig cyclization reaction. Although this type of cyclization was converted into the corresponding enol triflate 25 by

is contrary to the generally accepted Baldwin rules, there treatment with potassium hexamethyldisilazane (KHMDS)

are some examples in the literature of somewhat related at –78 °C and trapping of the enolate with N-phenyltrifl-

anti-Baldwin cyclization reactions.^[37]Comparatively, how- amide. The enol triflate 25 was obtained in a yield of 70%

ever, the above-mentioned 5-endo-trig process takes places after chromatography. The use of other bases or triflating

under much milder reaction conditions.

agents such as triflic anhydride or Comins’ reagent^[43]was

either totally unsuccessful or lower-yielding. The triflate

thus obtained underwent palladium-catalysed carbon-

ylation as described by Stille and co-workers^[44]to give the

methyl diester 26 in a yield of about 65%.

With diester 26 in hand we evaluated its transformation

into the fluorinated diol 27 by reduction of the two ester

moieties. This compound may be considered an appropriate

intermediate for the preparation of the 9α-fluoro analogues

of polygodial (16), drimenin (17) and cinnamolide (18). In

fact, these natural compounds have been successfully pre-

pared from the corresponding hydrogen analogue diol.^[45,46]

However, treatment of diester 26 with several reducing

agents under a variety of conditions did not lead to the

desired fluorinated diol 27. Thus, treatment of 26 with Li-

AlH₄at –78 °C exclusively afforded defluorinated diol 28,

a process that probably occurs by the previous reduction of

both methoxycarbonyl groups to the corresponding methyl-

eneoxyaluminium moieties followed by aluminium-assisted

Scheme 4. 5-endo-trig lactonization of 9α-fluoroalbicanic acid (12).

The 9α-fluoro analogues of other biologically active dri- S_N2Ј elimination of the fluoride ion by inter- or, most prob-

manes structurally related to albicanic acid were readily ably, intramolecular hydride transfer (see Scheme 5).^[47]The

prepared from the ester 21 (Scheme 3). Thus, LiAlH₄re- course of this reduction reaction contrasts with the result

duction of the ester moiety of 21 took place readily at low obtained in the above-mentioned reduction of ester 21 to

temperature to afford 13, the 9α-fluoro analogue of the alcohol 13 (see Scheme 3), which proceeded without detect-

cytotoxic and potent fish antifeedant albicanol (3).^[38]This able elimination of fluorine. On the other hand, reduction

latter compound can also be prepared by LiAlH₄reduction of the C-12 methoxycarbonyl moiety could only be

of methyl albicanate (22), although higher temperatures achieved, albeit in low yield (30%), by treatment of 26 with

were required in this case due to the significantly decreased 3–5 equiv of DIBAL-H in THF/cyclohexane at –78 °C for

reactivity of the ester moiety of this compound with respect 4 h. In addition to the hydroxy ester 29, the reaction also

to 21. Acetylation of 13 under standard conditions gave 14, produced the diol 28 and recovered the starting diester, each

the 9α-fluoro analogue of the also natural albicanyl acetate one in a yield of around 30%. All attempts to improve the

(4).^[39]On the other hand, several conditions were examined conversion of diester 26 to the hydroxy ester 29 under vari-

for the conversion of 9α-fluoroalbicanol (13) to the corre- ous conditions were unsuccessful. Longer reaction times or

sponding aldehyde. The best results were obtained with the higher temperatures reduced the yield of 29 and gave larger

Dess–Martin periodinane reagent or tetrapropylammonium amounts of diol 28.

perruthenate (TPAP), which afforded an excellent yield of

Not surprisingly, all attempts to reduce the methoxycarb-

the relatively unstable drimanic aldehyde 15, the 9α-fluoro onyl group of 29 to 27 were also unsuccessful. For example,

analogue of albicanal (5).^[40]The oxidation of 13 was signif- reduction with LiAlH₄under several conditions gave only

icantly slower in comparison with the oxidation of al- diol 28, whereas reduction with LiBH₄in MeOH^[48]af-

bicanol (3) to albicanal (5). This is consistent with the forded the methoxy diol 30, a result that clearly shows the

mechanism suggested for this oxidation reaction and the propensity of the allyl fluoride moiety of this system to par-

slower formation rate of the perruthenate ester intermediate ticipate in a S_N2Ј process. Similar results were obtained af-

due to the lower nucleophilicity of the fluorinated ter derivatization of the hydroxy group of 29 to a meth-

alcohol.^[41]

oxymethyl or a trialkylsilyl ether.^[49]

Eur. J. Org. Chem. 2010, 2182–2198

www.eurjoc.org

2185

A. Abad, C. Agulló, A. C. Cuñat, A. González-Coloma, D. Pardo

FULL PAPER

Scheme 5. Reagents and conditions: (a) KHMDS, PhNTf₂, THF, –78 °C (70%); (b) Pd(OAc)₂, PPh₃, iPr₂NEt, CO, CH₃OH, DMF, 65 °C

(65%); (c) LiAlH₄, THF, –78 °C (90%); (d) DIBAL-H, THF/C₆H₁₂, –78 °C, (30% of 29 + 30% of 28 + 30% of 26); (e) for 28: LiAlH₄,

CH₃Ph, –40 °C (83%); for 30: LiBH₄, THF, MeOH, 65 °C, 1 h (65%); (f) DBU, 3 Á MS, C₆H₆, room temp. (85%).

Although obtained in low yield, the availability of the ation reaction of 21 took place stereoselectively from the

hydroxy ester 29 allowed the ready preparation of 9α- less hindered α face of the exo-methylene double bond to

fluorodrimenin (17; Scheme 5), the 9α-fluoro analogue of give the epoxide 31 in high yield (Scheme 6). The stereo-

the bioactive drimane sesquiterpene drimenin (9).^[36,50]chemistry of epoxide 31 was confirmed by NOE experi-

Thus, base-promoted lactonization of hydroxy ester 29 by ments in which irradiation of the signal at δ = 3.41 ppm

treatment with 8-diazabicyclo[5.4.0]undec-7-ene (DBU) in (12-H) gave enhancement of the signal at δ = 1.12 ppm,

benzene at room temp. in the presence of 3 Å molecular which corresponds to the axially disposed methyl group at

sieves afforded 9α-fluorodrimenin (17) in a yield of 85%.

The low yield obtained for allylic alcohol 29 prompted

C-10.

However, this epoxide proved to be thermally and chemi-

us to investigate an alternative route to improve the overall cally very stable and all attempts to promote the opening of

yield of 9α-fluorodrimenin from decalone 11. We first tried the epoxide moiety to the allylic alcohol under acid (PTSA,

to transform the exo-methylene compound 21 into 29 by toluene, reflux), basic (R₂NAlEt₂, benzene, room temp.) or

epoxidation/epoxide ring-opening reactions (Scheme 6) as even radical (Cp₂TiCl, benzene, room temp.) reaction con-

the same transformation has been described in the literature ditions failed, the starting material being recovered unal-

for the non-fluorinated analogue.^[51]Epoxidation of the tered under all the conditions assayed.^[49]After these unsuc-

double bond of 21 was effected with m-chloroperbenzoic cessful attempts to transform the exo-methylenic compound

acid (MCPBA) under standard conditions, although due to 21 into allylic alcohol 29, this conversion was achieved quite

the withdrawing effect of the allylic fluorine atom the reac- efficiently by the sequence of allylic bromination/bromine

tion was considerably slower than the epoxidation of the substitution reactions. Thus, reaction of olefin 21 with N-

corresponding non-fluorinate olefin. The smooth epoxid- bromosuccinimide (NBS) in a MeOH/CH₂Cl₂medium re-

Scheme 6. Reagents and conditions: (a) as shown in Scheme 3, step a; (b) MCPBA, CH₂Cl₂, room temp., 20 h (82%); (c) NBS, CH₂Cl₂/

CH₃OH, room temp. (75%); (d) AgBF₄, 2,6-lutidine, acetone/H₂O, 60 °C (85%).

2186

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2182–2198

Preparation of 9α-Fluorinated Sesquiterpenic Drimanes

gioselectively afforded the allyl bromide 32 in a yield of to transform 34 into hydroxy dialdehyde 35, a potential in-

75%. The required substitution of the bromine atom by a termediate for 9α-fluoropolygodial, using several Swern oxi-

hydroxy group was not as easy as initially thought and most dation conditions^[53]only afforded complex reaction mix-

of the usual procedures used for the halogen/hydroxy ex- tures. Likewise, oxidation with some of the oxidizing rea-

change afforded only low yields of the allylic alcohol. For- gents used for the oxidation of 1,4-diols to lactones did not

tunately, treatment of allyl bromide 32 with silver tetra- give the hydroxy lactone 36, the 9α-fluoro analogue of the

fluoroborate (AgBF₄) and 2,6-lutidine in a mixture of acet- antifungal drimane peniopholide^[54]and a potential inter-

one/water at 65 °C satisfactorily furnished the desired allyl mediate for 9α-fluorocinnamolide, but instead afforded the

alcohol 29 in an excellent yield of 85%.^[52]The preparation regioisomeric lactone 37. Thus, oxidation with the Dess–

of 29 from decalone 11 by this route is considerably more Martin periodinane reagent (DMP) in pyridine at room

efficient than the former, with an overall yield of 45% com- temperature afforded 37 in a yield of 90%. The tertiary hy-

pared with about 15% for the former route.

droxy group 37 was dehydrated regioselectively to the C8–

C12 position by treatment with thionyl chloride in pyridine

to give in nearly quantitative yield compound 38, a 9α-

fluorodrimane closely related to several naturally occurring

olepupuane-type drimanes.^[55]

Preparation of Other 9α-Fluorodrimanes

We also undertook some additional transformations fo-

cusing on the preparation of other fluorinated drimanes in-

cluding two of the initial targets, 9α-fluoropolygodial (16)

and 9α-fluorocinnamolide (18; see Scheme 1). Unfortu-

nately, the synthesis of these latter compounds could not

be completed satisfactorily due to the “unexpected” effect

produced by the fluorine atom on the reactivity of some

key intermediates of their synthesis. This section briefly de-

scribes several of these transformations, some of which il-

lustrate the difficulty of predicting the precise influence of

fluorine on the reactivity of neighbouring functional

groups.

One of these approaches begins with the hydroxylation

of the previously obtained 9α-fluoroalbicanol (13;

Scheme 7). The cis-hydroxylation of the double bond of 13

with a catalytic amount of osmium tetroxide and N-methyl-

morpholine N-oxide (NMO) as co-oxidant proceeded

stereoselectively from the less hindered side to afford the

triol 34 in a yield of 85%. The stereochemistry of 34 was

On the other hand, hydroxylation of 9α-fluoroalbicanol

acetate (14) under the same conditions as described above

for 13 gave the corresponding diol 39. Initial attempts to

oxidize the hydroxymethyl group (using, for example, NaO-

ClO, Me₂CH=CHMe₂, tBuOH) to the corresponding car-

boxylic acid group failed. However, the diol 39 was readily

transformed into the hydroxy lactol 40, structurally and

functionally related to some natural drimanes,^[56]by oxi-

dation of the hydroxymethyl group to the aldehyde followed

by hydrolysis of the acetate group (Scheme 7). Nevertheless,

all attempts to oxidize the lactol to the corresponding lac-

tone (i.e., 36) were unsuccessful. Swern reagent, N-iodosuc-

cinimide^[57]or silver carbonate/Celite^[58]led only to the re-

covery of the starting material, whereas oxidation with

DMP, PCC, JonesЈ reagent or TPAP led to cleavage of the

glycol moiety to give only the corresponding 11-formyloxy-

8-keto derivative (see the Supporting Information).

An alternative approach to 9α-fluorocinnamolide (18)

confirmed by the NOE enhancements observed between based on the method previously described in Scheme 5 for

protons 12-H (irradiated) and CH₃-10 and 7β-H. Attempts the preparation of 9α-fluorodrimenin (17) was also ex-

Scheme 7. Reagents and conditions: (a) OsO₄, NMO, acetone/H₂O, 3 d, room temp. (85% for 34 and 50% for 39); (b) DMP, Py, room

temp., 5 h (90%); (c) SOCl₂, Py, CH₂Cl₂, 20 h, room temp. (quantitative yield); (d) i. (COCl)₂, DMSO, Et₃N, CH₂Cl₂, –60 °C; ii. KOH,

CH₃OH/H₂O, 0.5 h, room temp. (60%).

Eur. J. Org. Chem. 2010, 2182–2198

www.eurjoc.org

2187

A. Abad, C. Agulló, A. C. Cuñat, A. González-Coloma, D. Pardo

FULL PAPER

plored. This approach was initiated with the preparation cyanohydrin, which cyclized in situ to give the drimanic hy-

of enol triflate 25 (Scheme 8), which was transformed into droxy butyrolactone 9α-fluoro-8-epi-peniopholide (45)^[54]in

compound 41 by reduction of the ester to a primary alcohol an overall yield of 85%.

group by treatment with LiAlH₄at low temperature. No

With this compound in hand we then focused on the eli-

S_N2Ј elimination of fluoride was detected in this case, which mination of the tertiary hydroxy group. We were unable to

is in direct contrast to what was observed in the related obtain the elimination product 18 despite trying many dif-

reductions of esters 26 or 29. However, the palladium-medi- ferent basic dehydration conditions such as SOCl₂/Py and

ated carbonylation of enol triflate 41 led to the formation DMAP or DBU, POC1₃/Py and DBU, MsCl/Et₃N in

of the expected γ-butyrolactone moiety and also to S_N2Ј ClCH₂CH₂Cl, Martin’s reagent and Burgess’s reagent at

displacement of fluoride by methoxide to afford the meth- temperatures that ranged from room temperature to 120 °C.

oxy lactone 42, the methyl ether of 7α-hydroxyconfertifolin, Dehydration under acidic conditions, for example, PTSA/

a

drimanic lactone isolated from diverse natural toluene or HCl/AcOH at reflux, also produced disappoint-

sources.^[54,59]Derivatization of the hydroxy group in 41 to ing results. In all cases, the starting material was recovered

a methoxymethyl (R = MOM) or triflate group (R = nearly unaltered even after prolonged reaction times. Al-

SO₂CF₃) did not circumvent the S_N2Ј reaction.^[49]It is though the difficulty in promoting the elimination in acidic

interesting to note that this reaction might involve a pre- media could be accounted for on the basis of the strong

vious oxidative addition of the allyl fluoride moiety to Pd⁰, electron-withdrawing nature of fluorine which destabilizes

a reaction that has yet to be thoroughly studied.^[60]It is the partial positive charge generated at C-8, the unusual

likely in this case that the intermediate η³-allylpalladium(II) resistance to dehydration of the axial hydroxy group at C-

complex formed is stabilized by the oxygenated function at 8 under basic conditions is more difficult to understand.

C-11, which favours the observed reaction. Although use- Treatment of 45 with Deoxo-fluor^®, a nucleophilic fluori-

less for the main objective of this work, the approach de- nating reagent, in pyridine at room temperature surprisingly

tailed in Scheme 8 could be of interest to elaborate the type caused the rapid dehydration of the tertiary hydroxy group

of functionalization present in 42, which is not only a char- and the elimination of HF to form 7,9(11)-dien-11,12-drim-

acteristic of some drimanes but also of other polycyclic ter- anolide after 2 h in a yield of 70% (see the Supporting In-

penes.

formation). Although Deoxo-fluor^®and other related N,N-

dialkylaminosulfur trifluoride reagents are well known as

powerful dehydrating agents,^[3b]to the best of our knowl-

edge no example of this type of dehydrofluorination reac-

tion has been described in the literature. Attempts to dehy-

drate the tertiary alcohol by pyrolytic elimination of the

corresponding acetate, that is, 46, were also unsuccessful.

Heating the acetate 46 in bulk up to 250 °C did not cause

any reaction, but decomposition was observed upon heating

at higher temperatures (approximately 270 °C).

In view of the difficulties encountered in the dehydration

of hydroxy lactone 45, we decided to invert the order of the

last two steps by first dehydrating the hydroxy group and

then subjecting the resulting unsaturated nitrile to lactoniz-

ation (Scheme 9). Acetylation of the hydroxy group of 43

under standard conditions gave the β-acetoxydecalone 47,

which was converted into cyanohydrin 48 in an overall yield

of about 83% by successive treatment with TMSCN/ZnI₂

Scheme 8. Reagents and conditions: (a) as shown in Scheme 5,

step a; (b) LiAlH₄, PhCH₃, –50 °C, 1 h (70%); (c) Pd(OAc)₂, PPh₃,

iPr₂NEt, CO, CH₃OH, DMF, 65 °C, 20 h (75%).

Finally, another approach to the elaboration of the drim- and the HF/pyridine complex (Olah’s reagent). Although

ane framework was based on the cyanohydrin formation of initial experiments focusing on the elimination of the hy-

β-hydroxydecalone 43 (Scheme 9). This decalone has al- droxy group failed, it was eventually found that treatment

ready been prepared from β-keto ester 11 in three steps: of 48 with thionyl chloride in pyridine at room temperature

formation of the ethylene ketal, reduction of the ester to the for 4–5 h followed by very slow heating to 80 °C (ca. 4 h)

primary alcohol and regeneration of the carbonyl group. and maintaining that temperature for a period of about

Treatment of 43 with excess trimethylsilyl cyanide 15 h provided the desired unsaturated nitrile 49 in an iso-

(TMSCN) in the presence of ZnI₂as catalyst provided the lated yield of 90%. Hydrolysis of the acetate moiety of 49,

cyanohydrin trimethylsilyl ether 44. The stereochemistry of required for the subsequent lactonization step, was also

the new stereogenic centre generated at C-8 was determined more difficult than expected. Typical hydrolysis conditions,

by a NOESY experiment. Significant NOE interactions either acidic or basic, were unsuccessful leading to intracta-

were observed between the protons of the axially disposed ble mixtures. Even conditions that usually afford very easy

trimethylsilyloxy group at C-8 and protons 11-H and CH₃- hydrolysis, such as those involving the treatment of 49 with

10. The trimethylsilyl ether groups of 44 were hydrolysed 3 equiv. of K₂CO₃in MeOH/H₂O (3:2) at room tempera-

by mild acid treatment to give an intermediate β-hydroxy ture for 20 min or 3 equiv. of LiOH in THF/H₂O (2:1) at

2188

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2182–2198

Preparation of 9α-Fluorinated Sesquiterpenic Drimanes

Scheme 9. Reagents and conditions: (a) (CH₂OH)₂, PTSA, PhCH₃, reflux, 24 h (90%); (b) LiAlH₄, PhCH₃, –40 °C, 1 h (92%); (c) PTSA,

acetone/H₂O, 55 °C, 4 h (89%); (d) TMSCN, ZnI₂, CH₂Cl₂, room temp., 15 h (76%); (e) PTSA, THF/H₂O, 55 °C, 20 h (85%); (f) Ac₂O,

Py, 80 °C, 3 d (55%); (g) Ac₂O, Py, room temp., 2.5 h (99%); (h) i. TMSCN, ZnI₂, CH₂Cl₂, room temp., 5 h; ii. HF–Py, THF, room

temp., 18 h (83% overall yield for the two steps); (i) SOCl₂, Py, see text, (90%); (j) DIBAL-H (2 equiv.), THF, –78 °C, 30 min then

DIBAL-H (2 equiv.), THF, –78 °C, 1 h (97%).

room temperature overnight, led to a complex mixture in active compounds than M. persicae. These three fluorinated

which only traces of the corresponding alcohol could be compounds had similar or better antisettling activity

detected by TLC. Finally, and after much experimentation, towards R. Padi than polygodial, but with significantly nar-

we found that the transformation of 49 into hydroxy nitrile rower confidence levels.^[62]Furthermore, none of these com-

50 could be achieved satisfactorily by reduction of the ace- pounds exhibited phytotoxic effects when applied to the leaf

tate moiety with DIBAL-H under quite specific, very mild surface.

conditions (see the Exptl. Sect.).

The activities of these sesquiterpenes was species-de-

pendent, as previously shown for other drimane-type com-

pounds, including polygodial.^[62]Family- and/or species-re-

lated differences in the drimane molecular target have been

suggested.^[63]

Having prepared 50, its transformation to target 9α-fluo-

rocinnamolide (18) seemed simple because, in addition to

the related transformation of 44 into 45 described above,

this type of lactonization has been described in the litera-

ture for non-fluorinated β-hydroxy nitriles.^[61]However, all

attempts to lactonize 50 failed. Reaction in neither acidic

nor basic media produced any satisfactory results.

Several structure–activity trends can be deduced from the

antifeedant effect of the test compounds on R. Padi. In ge-

neral, fluorination of the C-9 position decreased the activity

of compounds with an 8(12)-exo-methylene double bond

(13, 14 and 21 vs. 3, 4 and 22, respectively) and increased

the activity of compounds with a carbonyl group at C-11

(11, 17 and 31 vs. 19, 9 and 51, respectively), especially for

9α-fluorodrimenin (17) and epoxide 31. The strong antiset-

tling activity of 49 could be related to the Michael-type ad-

dition reactivity of the α,β-unsaturated nitrile moiety. A

similar positive effect produced by the fluorine atom could

be observed for the activity of the fluorinated analogues of

albicanol and drimenin (13 and 17 vs. 3 and 9, respectively)

on M. persicae. In contrast, S. littoralis was generally more

sensitive to the non-fluorinated analogues. Similarly, pre-

vious results have shown the importance of the C-9 substit-

uents on the antifeedant effects of drimanes.^[62,63]

Evaluation of Antifeedant Activity

A comparative study of the antifeedant activities of a

selection of the fluorinated compounds prepared above and

the corresponding hydrogen analogues against several insect

species with different feeding ecologies (Spodoptera litto-

ralis, Myzus persicae and Rhopalosiphum padi) was carried

out and the results are shown in Table 1. The fluorinated

12-nordrimane 11 and the non-fluorinated drimane 22 (see

Scheme 3) showed sufficient antifeedant activity against S.

littoralis to carry out dose-response experiments [percent

feeding reduction (%FR) Ͼ 65], whereas 19 and 51 (the

epoxidation product of methyl albicanate) had significant

moderate effects, with activity levels similar to polygodial

Oral cannulation of S. littoralis L6 larvae showed that

(6).^[62]The effective antifeedant doses calculated for the the non-fluorinated derivatives 19 and 51 were moderate

four compounds were quite similar (EC₅₀values between post-ingestive antifeedants whereas the fluorinated deriva-

3.6 and 4.0 µg/cm²). Most of the compounds tested had sig- tive of 19 (i.e., 11) was toxic (pANCOVA2 Ͻ 0.05, see the

nificant effects (p Ͻ 0.05, Wilcoxon signed rank test) on Supporting Information). Post-ingestive effects against this

the settling behaviour of both aphid species. Fluorinated insect have been reported for 3β-hydroxycinnamolide and

compounds 17 and 49 were very active against both aphid 3β-acetoxydrimenin^[64]and suggested for synthetic ana-

species, 31 only acted on R. padi [percent settling inhibition logues (lactones) of polygodial (6) and warburganal (7) on

(%SI) Ն 80], whereas 4 was moderately active on M. per- Pieris brassicae and L. decemlineata larvae.^[63]However, 6

sicae (%SI = 74). Overall, R. padi was more sensitive to the did not affect orally injected S. littoralis.^[62]

Eur. J. Org. Chem. 2010, 2182–2198

www.eurjoc.org

2189

A. Abad, C. Agulló, A. C. Cuñat, A. González-Coloma, D. Pardo

FULL PAPER

Table 1. Antifeedant activity [expressed as meanϮSE values of % feeding reduction (FR) and % settling inhibition (SI)] of 9α-fluoro

compounds 11, 13, 14, 17, 21, 31, 45, 47 and 49 and the corresponding 9α-hydrogen analogues on S. littoralis larvae and R. padi and M.

persicae adults.

Spodoptera littoralis (%FR)^[a]

Rhopalosiphum padi (%SI)^[b]

9αF compound 9αH analogue

60.7Ϯ5.5^[c]

Myzus persicae (%SI)^[b]

9αF compound 9αH analogue

51.8Ϯ10.7^[c]

9αF compound 9αH analogue

66.8Ϯ8.9,^[c]

(3.6Ϯ1.2)^[d]

14.2Ϯ5.3

11

19

63.6Ϯ10.4^[c]

11

19

54.2Ϯ7.0^[c]

11

19

63.6Ϯ7.0^[c]

13

14

3

4

40.4Ϯ10.8

63.5Ϯ4.2^[c]

13

14

61.5Ϯ9.7^[c]

56.9Ϯ7.3^[c]

90.0Ϯ1.9,^[c]

(1.8Ϯ0.4)^[d]

3

4

63.8Ϯ8.2^[c]

13

14

63.2Ϯ5.5^[c]

37.0Ϯ9.1

3

4

52.3Ϯ11.0^[c]

33.9Ϯ12.2

74.0Ϯ7.1^[c]

54.7Ϯ6.9^[c]

17

21

31

52.4Ϯ17.4

37.2Ϯ11.8

41.61Ϯ1.8

9

53.9Ϯ8.3

17

21

31

9

59.3Ϯ9.7^[c]

51.7Ϯ8.^[c]

39.7Ϯ8.7

17

21

31

73.2Ϯ9.3^[c]

9

37.4Ϯ6.9

56.7Ϯ7.9^[c]

41.6Ϯ9.5

73.7Ϯ8.8,^[c]

22

30.9Ϯ10.0

22

41.7Ϯ9.1

22

(3.9Ϯ1.3)^[d]

89.3Ϯ2.9,^[c]

(2.3Ϯ0.3)^[d]

51.2Ϯ8.7^[c]

40.7Ϯ8.3^[c]

79.9Ϯ4.6,^[c]

(2.9Ϯ0.5)^[d]

51^[e]

63.2Ϯ10.2^[c]

51^[e]

47.3Ϯ8.9^[c]51^[e]

45

47

38.9Ϯ13.6

32.8Ϯ11.8

–

45

47

–

45

47

47.0Ϯ8.7^[c]

40.8Ϯ9.2

–

49

39.1Ϯ7.7

–

49

–

49

71.5Ϯ7^[c]

–

[a] Feeding reduction as a percentage (FR) = [1 – (T/C)]ϫ100^[65]in which T = consumption of treated discs and C = consumption of

control discs (n = 10 replicates). 100% indicates no consumption on treated leaf discs.^[66][b] Settling inhibition as a percentage (SI) =

[1 – %T/%C]ϫ100^[67]in which %T = aphids settled on treated leaves and %C = aphids settled on control leaves (n = 20 replicates). [c] p

Ͻ 0.05 (Wilcoxon signed rank test). [d] EC₅₀= effective dose (µg/cm²) required to give a 50% feeding or settling inhibition (given at a

95% confidence level). [e] 51: Methyl 8α(12)-epoxyalbicanate (see ref.^[68]).

In the light of the above results it is safe to conclude corresponding hydrogen analogues against several insect

that, in general, fluorination of the 9α-position produces a species has shown that fluorination of the 9α-position pro-

positive effect on the antifeedant activity of the drimane duces a positive effect on the antifeedant activity of the dri-

compounds against aphids. The presence of the fluorine mane-type compounds against aphids, particularly in the

atom at C-9 together with a double bond at C7–C8, either case of a double bond at C7–C8 conjugated with an elec-

as such, as in 17 and 49, or in a latent form, as in epoxide tron-withdrawing group at C-12 (compound 49), probably

31, confers a considerable antifeedant activity on these mo- as a result of the enhanced Michael-type addition reactivity

lecules against both aphid species. On the other hand, com- of the conjugate moiety.

pounds with a double bond between C-8 and C-12 also ex-

These results also suggest that an increase in biological

hibit good activity, although in this case the presence of the activity, particularly but not exclusively antifeedant, might

fluorine atom has a detrimental effect on the antifeedant occur with the fluorination of other higher terpenic systems

activity. In contrast, the antifeedant response of polypha- structurally and functionally related to drimanes such as

gous S. littoralis larvae to these compounds indicates that spongianes and scalaranes. This will be the subject of a fur-

the introduction of the fluorine atom on the drimane sys- ther investigation in our laboratory.

tem resulted in a decrease in activity.

Experimental Section

Conclusions

General: Except when specified otherwise, the TLC R_fvalues are

A synthetic approach for the elaboration of the 9α-

fluorodrimane framework has been developed. This ap-

proach is based on the previous preparation of methyl 8-

keto-12-nordriman-11-oate from β-ionone and involves the

electrophilic fluorination of C-9 to stereoselectively intro-

duce the fluorine atom. The drimane skeleton is completed

given for a hexane/ethyl acetate (8:2) system. General experimental

procedures and the details of the preparation and characterization

of compounds 3, 4, 9, 19, 20, 22, 24, 28, 30, 41–43, 46, 51 and the

product formed from the reaction of 45 with Deoxo-fluor^®are

given in the Supporting Information.

(؎)-Methyl 9α-Fluoro-8-oxo-12-nordriman-11-oate (11): A solution

from the intermediate 9α-fluoro-8-keto-12-nordrimane sys- of β-keto ester 19 (2.56 g, 10.16 mmol) in anhydrous THF (10 mL)

was added dropwise into a suspension of NaH (60% dispersion in

mineral oil, 447 mg, 11.17 mmol, 1.1 equiv., prewashed with pen-

tane) at 0 °C under argon. After 30 min of stirring at this tempera-

ture the reaction mixture was warmed to room temp. and stirred

for 2 h. Then, a solution of NFSI (3.96 g, 12.19 mmol, 1.2 equiv.)

in THF (20 mL) was added through a syringe.^[3c]After stirring for

2 h at room temp., the reaction was quenched with water and

worked up as usual using Et₂O to extract. The product was purified

by chromatography (hexane/Et₂O, 8:2, as eluent) to give the 9α-

fluoro-β-keto ester 11 (2.33 g, 85%) as a white solid. TLC: R_f=

tem by different reactions at the C-8 ketone carbonyl group,

essentially Wittig methylenation, cyanohydrin formation or

palladium-catalysed carbonylation of the corresponding

enol triflate. Appropriate manipulation of the functionaliza-

tion of the systems derived from these key reactions has

allowed the preparation of 9α-fluorodrimanes structurally

and functionally related to natural albicanic acid, drimenin,

olepupuane and other 9α-fluorodrimane-type compounds.

A comparative study of the antifeedant activities of a

selection of the fluorinated compounds prepared and the 0.44; m.p. 82–83 °C (hexane/EtOAc). IR (KBr): ν_max= 2950, 2927,

˜

2190

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2182–2198

Preparation of 9α-Fluorinated Sesquiterpenic Drimanes

2867, 2848, 1751, 1716, 1633, 1600, 1459, 1434, 1380, 1348, 1195,

3), 42.2 (d, J = 18.9 Hz, C-10), 45.9 (d, J = 4.0 Hz, C-5), 60.3 (d,

J = 23.5 Hz, C-11), 101.7 (d, J = 171.1 Hz, C-9), 112.8 (d, J =

1166, 1112 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.79 (s, 3 H,

CO₂CH₃), 2.80 (dddd, J = 10.8, 10.8, 5.4, 5.4 Hz, 1 H, 7α-H), 2.47 7.5 Hz, C-12), 143.8 (d, J = 22.4 Hz, C-8) ppm. ¹⁹F NMR

(dddd, J = 10.8, 3.6, 1.8, 1.8 Hz, 1 H, 7β-H), 1.98 (m, 1 H, 6-H), (282 MHz, CDCl3): δ = –171.4 (s) ppm. MS (EI): m/z (%) = 240

1.94 (m, 1 H, 5-H), 1.68 (m, 1 H, 6-HЈ), 1.64 (m, 1 H, 1-H), 1.60 (15) [M]⁺, 225 (11), 137 (100), 123 (46), 109 (16), 95 (32), 81 (34),

(m, 1 H, 2-H), 1.52 (m, 1 H, 2-HЈ), 1.42 (m, 1 H, 3-H), 1.30 (m, 1

H, 3-HЈ), 1.22 (m, 1 H, 1-HЈ), 1.17 (s, 3 H, 15-H), 0.98 (s, 3 H, 13-

H), 0.90 (s, 3 H, 14-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

14.5 (d, J = 3.5 Hz, C-15), 18.1 (C-2), 21.9 (C-14), 22.3 (C-6), 32.6

(C-1), 33.5 (d, J = 5.4 Hz, C-13), 34.4 (C-4), 37.9 (d, J = 2.7 Hz,

C-7), 41.1 (C-3), 44.4 (d, J = 5.6 Hz, C-5), 45.0 (d, J = 18.4 Hz, C-

10), 52.3 (CO₂CH₃), 100.4 (d, J = 196.7 Hz, C-9), 165.7 (d, J =

25.6 Hz, C-11), 202.3 (d, J = 25.3 Hz, C-8) ppm. ¹⁹F NMR

(282 MHz, CDCl₃): δ = –162.0 (s) ppm. MS (EI): m/z (%) = 270

(12) [M]⁺, 252 (16), 237 (7), 217 (2), 203 (6), 179 (4), 163 (6), 137

(100), 123 (36), 109 (14), 95 (24), 69 (39), 55 (26). HRMS: calcd.

for C₁₅H₂₃FO₃270.163123; found 270.162143.

69 (34), 55 (22). HRMS: calcd. for C₁₅H₂₅FO 240.188944; found

240.189570.

(؎)-9α-Fluoro-8(12)-drimen-11-ol Acetate (9α-Fluoroalbicanyl Acet-

ate, 14): A mixture of albicanol (13; 210 mg, 0.87 mmol), DMAP

(53 mg, 0.44 mmol, 0.5 equiv.) and Ac₂O (390 µL, 3.50 mmol,

4 equiv.) in anhydrous pyridine (1.6 mL) was stirred at room temp.

for 1 h. Work-up as usual using CH₂Cl₂to extract and column

chromatography of the crude product (hexane/Et₂O, 8:2, as eluent)

afforded 9α-fluoroalbicanyl acetate (14; 234 mg, 95%) as an oil.

TLC: R = 0.54. IR (KBr): ν

= 2941, 2869, 1743, 1650, 1558,

˜

f

max

1457, 1386, 1367, 1240, 1047 cm^–1. ¹H NMR (400 MHz, CDCl₃):

δ = 5.05 (s, 1 H, 12-H), 4.73 (d, J = 3.8 Hz, 1 H, 12-HЈ), 4.57–4.36

(m, 2 H, 11-H), 2.37 (m, 1 H, 7-H), 2.20 (m, 1 H, 7-HЈ), 2.08 (s, 3

H, COCH₃), 1.80 (m, 1 H, 6-H), 1.74 (m, 1 H, 5-H), 1.60 (m, 1 H,

6-HЈ), 1.60 (m, 1 H, 2-H), 1.60 (m, 1 H, 1-H), 1.50 (m, 1 H, 2-HЈ),

1.42 (m, 1 H, 1-HЈ), 1.27 (m, 1 H, 3-H), 1.25 (m, 1 H, 3-HЈ), 0.90

(s, 3 H, 13-H), 0.89 (s, 3 H, 15-H), 0.83 (s, 3 H, 14-H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 16.7 (d, J = 3.4 Hz, C-15), 18.8 (C-

2), 21.0 (COCH₃), 21.8 (C-14), 23.1 (d, J = 1.1 Hz, C-6), 32.5 (C-

1), 32.9 (C-7), 33.4 (C-4), 33.7 (C-13), 41.1 (C-3), 42.5 (d, J =

18.9 Hz, C-10), 45.6 (d, J = 4.4 Hz, C-5), 61.9 (d, J = 22.4 Hz, C-

11), 99.4 (d, J = 176.3 Hz, C-9), 112.0 (d, J = 6.3 Hz, C-8), 143.8

(d, J = 22.4 Hz, C-12), 171.2 (COCH₃) ppm. ¹⁹F NMR (282 MHz,

CDCl₃): δ = –168.1 (s) ppm. MS (EI): m/z (%) = 282 (10) [M]⁺,

222 (60), 207 (17), 189 (15), 137 (100), 123 (43), 109 (20), 95 (28),

81 (28), 69 (39), 55 (19). HRMS: calcd. for C₁₇H₂₇FO₂282.199509;

found 282.199291.

(؎)-9α-Fluoro-8(12)-drimen-11-oic Acid (9α-Fluoroalbicanic Acid,

12): A solution of ester 21 (40 mg, 0.15 mmol) in anhydrous DMF

(1 mL) was added to a solution of sodium propanethiolate in DMF,

generated by reaction of NaH (60% dispersion in mineral oil,

53 mg, 1.32 mmol, 9 equiv., prewashed with pentane) and pro-

panethiol (135 µL, 1.48 mmol, 10 equiv.) in DMF (3 mL), at room

temp. under argon.^[69]The mixture was stirred at 80 °C for 2 h,

cooled to 0 °C and treated with dilute aqueous HCl. Work-up as

usual using EtOAc to extract followed by evaporation of the sol-

vent afforded nearly pure 9α-fluoroalbicanic acid (12;33 mg, 87%)

as an amorphous solid. TLC: R = 0.04. IR (NaCl): ν

= 3113,

˜

f

max

2934, 2864, 1719, 1630, 1455, 1431, 1386, 1117, 1062 cm^–1. ¹H

NMR (300 MHz, CDCl₃): δ = 9.08 (s, 1 H, COOH), 5.10 (dd, J =

4.2, 1.6 Hz, 1 H, 12-H), 5.04 (br. s, 1 H, 12-HЈ), 2.42 (m, 1 H, 7-

H), 2.33 (m, 1 H, 7-HЈ), 1.72 (m, 1 H, 5-H), 1.65 (m, 1 H, 6-H),

1.60 (m, 1 H, 1-H), 1.60–1.47 (m, 2 H, 2-H), 1.41 (m, 1 H, 6-HЈ),

1.37 (m, 1 H, 3-H), 1.31 (m, 1 H, 1-HЈ), 1.18 (m, 1 H, 3-HЈ), 1.14

(s, 3 H, 15-H), 0.90 (s, 3 H, 13-H), 0.86 (s, 3 H, 14-H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 15.5 (d, J = 2.8 Hz, C-15), 18.4 (C-

2), 21.9 (C-14), 22.0 (C-6), 31.9 (C-7), 32.9 (C-1), 33.3 (C-4), 33.6

(C-13), 41.3 (C-3), 42.5 (d, J = 19.3 Hz, C-10), 45.4 (d, J = 4.8 Hz,

C-5), 101.5 (d, J = 184.2 Hz, C-9), 113.3 (d, J = 7.5 Hz, C-12),

141.5 (d, J = 20.8 Hz, C-8), 170.1 (d, J = 27.8 Hz, C-11) ppm. ¹⁹F

NMR (282 MHz, CDCl₃): δ = –153.7 (s) ppm. MS (EI): m/z (%) =

254 (7) [M]⁺, 234 (23), 219 (46), 189 (26), 151 (25), 137 (85), 123

(63), 105 (40), 81 (44), 69 (100). HRMS: calcd. for C₁₅H₂₃FO₂

254.168208; found 254.164104.

(؎)-9α-Fluoro-8(12)-drimen-11-al (9α-Fluoroalbicanal, 15): Dess–

Martin periodinane (67 mg, 0.16 mmol, 1.5 equiv.) was added to a

solution of alcohol 13 (25 mg, 0.10 mmol) in CH₂Cl₂(0.3 mL) un-

der argon. The flask was wrapped in aluminium foil to protect it

from light, then cooled to 0 °C and dry pyridine (26 µL, 0.32 mmol,

3.1 equiv.) was added. The mixture was warmed up to room temp.

and then stirred for 4.5 h. Work-up using CH₂Cl₂to extract fol-

lowed by purification by chromatography (hexane/Et₂O, 8:2, as elu-

ent) gave 9α-fluoroalbicanal (15; 226 mg, 95%) as a colourless oil.

TLC: R = 0.57. IR (KBr): ν

= 2944, 2869, 2846, 2717, 1741,

˜

f

max

1648, 1459, 1390, 1367, 1024, 916 cm^–1. ¹H NMR (500 MHz,

CDCl₃): δ = 9.83 (d, J = 9.0 Hz, 1 H, 11-H), 5.07 (d, J = 1.8 Hz,

1 H, 12-H), 4.84 (dd, J = 4.3, 1.8 Hz, 1 H, 12-HЈ), 2.43 (ddddd, J

= 13.7, 13.7, 5.3, 1.7, 1.7 Hz, 1 H, 7α-H), 2.33 (ddd, J = 13.7, 5.1,

2.2 Hz, 1 H, 7β-H), 1.73 (m, 1 H, 1-H), 1.72 (m, 1 H, 5-H), 1.69

(m, 1 H, 6-H), 1.62–1.43 (m, 2 H, 2-H), 1.42 (m, 1 H, 6-HЈ), 1.40

(m, 1 H, 3-H), 1.22 (m, 1 H, 1-HЈ), 1.22 (m, 1 H, 3-HЈ), 1.13 (s, 3

H, 15-H), 0.91 (s, 3 H, 13-H), 0.86 (s, 3 H, 14-H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 15.5 (d, J = 3.4 Hz, C-15), 18.3 (C-2), 22.0

(C-14), 22.1 (C-6), 32.3 (C-1), 32.8 (d, J = 2.3 Hz, C-7), 33.4 (C-

4), 33.5 (C-13), 41.3 (C-3), 43.2 (d, J = 16.9 Hz, C-10), 45.4 (d, J

= 2.9 Hz, C-5), 101.4 (d, J = 178.0 Hz, C-9), 113.6 (d, J = 7.5 Hz,

C-12), 141.8 (d, J = 20.6 Hz, C-8), 201.0 (d, J = 40.7 Hz, C-

11) ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = –164.1 (s) ppm. MS

(EI): m/z (%) = 238 (60) [M]⁺, 223 (28), 203 (9), 189 (12), 167 (28),

154 (20), 141 (26), 123 (86), 121 (25), 109 (31), 81 (46), 69 (100), 55

(42). HRMS: calcd. for C₁₅H₂₃FO 238.173294; found 238.170834.

(؎)-9α-Fluoro-8(12)-drimen-11-ol (9α-Fluoroalbicanol, 13): A 1 

solution of LiAlH₄in toluene (820 µL, 0.82 mmol, 2 equiv.) was

added dropwise into a solution of ester 21 (110 mg, 0.41 mmol) in

anhydrous toluene (2 mL) at –40 °C under argon. After stirring for

30 min at this temperature, the mixture was carefully quenched

with water and worked up using CH₂Cl₂to extract. Chromatog-

raphy of the crude product (hexane/EtOAc, 8:2, as eluent) afforded

pure 9α-fluoroalbicanol (13; 98 mg, 99%) as a white solid. TLC:

R = 0.24; m.p. 96–98 °C (benzene). IR (KBr): ν

= 3371, 2975,

˜

f

max

2931, 2865, 1650, 1631, 1456, 1444, 1384, 1085, 1062, 975,

892 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.12 (s, 1 H, 12-H),

4.99 (d, J = 3.7 Hz, 1 H, 12-HЈ), 4.08–3.85 (m, 2 H, 11-H), 2.40

(ddddd, J = 13.2, 13.2, 5.3, 1.5, 1.5 Hz, 1 H, 7α-H), 2.24 (m, 1 H,

7β-H), 1.74 (m, 1 H, 5-H), 1.74 (m, 1 H, 6-H), 1.62 (m, 1 H, 1-H),

1.56–1.46 (m, 2 H, 2-H), 1.42 (m, 1 H, 1-HЈ), 1.36 (m, 1 H, 3-H),

1.32 (m, 1 H, 6-HЈ), 1.20 (m, 1 H, 3-HЈ), 0.91 (s, 3 H, 13-H), 0.85

(s, 3 H, 15-H), 0.83 (s, 3 H, 14-H) ppm. ¹³C NMR (75 MHz, (؎)-9α-Fluoro-7-drimen-11,12-olide (9α-Fluorodrimenin, 17): DBU

CDCl₃): δ = 16.6 (d, J = 4.0 Hz, C-15), 18.8 (C-2), 21.9 (C-14), (9 µL, 0.06 mmol, 1 equiv.) and a few grains of recently activated

23.2 (C-6), 32.4 (C-1), 33.0 (C-7), 33.5 (C-4), 33.7 (C-13), 41.2 (C- 3 Å molecular sieves (MS) were added to a solution of hydroxy

Eur. J. Org. Chem. 2010, 2182–2198

www.eurjoc.org

2191

A. Abad, C. Agulló, A. C. Cuñat, A. González-Coloma, D. Pardo

FULL PAPER

ester 29 (17 mg, 0.06 mmol) in anhydrous benzene (1.8 mL) under

argon at room temp. The mixture was stirred for 3 h, filtered to

separate the MS and worked up as usual using CH₂Cl₂to extract.

Purification of the crude product by chromatography (hexane/

EtOAc, 8:2, as eluent) afforded 9α-fluorodrimenin (17; 12 mg,

2.21 (m, 1 H, 6-HЈ), 1.85 (m, 1 H, 1-H), 1.73 (m, 1 H, 5-H), 1.63-

1.49 (m, 2 H, 2-H), 1.47 (m, 1 H, 3-H), 1.36 (m, 1 H, 1-HЈ), 1.25

(m, 1 H, 3-HЈ), 1.05 (s, 3 H, 15-H), 0.97 (s, 3 H, 14-H), 0.96 (s, 3

H, 13-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 16.1 (d, J =

1.7 Hz, C-15), 17.8 (C-2), 22.3 (C-14), 23.0 (d, J = 2.3 Hz, C-6),

31.6 (d, J = 7.5 Hz, C-1), 32.9 (C-4), 33.1 (C-13), 41.0 (C-3), 41.9

(C-5), 42.2 (d, J = 18.4 Hz, C-10), 52.5 (CO₂CH₃), 96.7 (d, J =

193.2 Hz, C-9), 118.3 (q, J = 320.2 Hz, CF₃), 126.3 (d, J = 7.5 Hz,

C-7), 142.9 (d, J = 20.7 Hz, C-8), 166.3 (d, J = 29.9 Hz, C-11) ppm.

85%) as an amorphous solid. TLC: R = 0.35. IR (KBr): ν

=

˜

f

max

2948, 2925, 2871, 1787, 1731, 1463, 1459, 1340, 1164, 1018 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 6.18 (s, 1 H, 7-H), 4.91 (d, J =

11.8 Hz, 1 H, 12-H), 4.70 (d, J = 11.8 Hz, 1 H, 12-HЈ), 2.33 (m, 1

H, 6-H), 2.17 (m, 1 H, 1-H), 2.08 (m, 1 H, 6-HЈ), 1.85 (m, 1 H, 5- ¹⁹F NMR (282 MHz, CDCl₃): δ = –74.8 (d, J = 4.1 Hz), –149.5 (q,

H), 1.81 (m, 1 H, 1-HЈ), 1.68–1.54 (m, 2 H, 2-H), 1.48 (m, 1 H, 3- J = 4.1 Hz) ppm. MS (EI): m/z (%) = 402 (4) [M]⁺, 335 (1), 307

H), 1.34 (m, 1 H, 3-HЈ), 0.96 (s, 3 H, 14-H), 0.93 (s, 3 H, 13-H), (2), 267 (2), 252 (5), 217 (3), 124 (100), 109 (72), 69 (23), 55 (10).

0.88 (s, 3 H, 15-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.5 (d,

J = 2.3 Hz, C-15), 17.6 (C-2), 21.7 (C-14), 24.3 (d, J = 3.4 Hz, C-

6), 28.9 (d, J = 6.3 Hz, C-1), 32.9 (C-4), 33.1 (C-13), 37.0 (d, J =

19.5 Hz, C-10), 41.6 (C-3), 42.2 (C-5), 69.2 (C-12), 91.4 (d, J =

178.7 Hz, C-9), 128.3 (d, J = 16.1 Hz, C-8), 131.2 (d, J = 9.2 Hz,

C-7), 170.9 (d, J = 27.6 Hz, C-11) ppm. ¹⁹F NMR (282 MHz,

CDCl₃): δ = –145.3 (s) ppm. MS (EI): m/z (%) = 252 (2) [M]⁺, 234

(100), 217 (20), 187 (20), 173 (12), 163 (12), 133 (13), 119 (50),

109 (38), 105 (27), 91 (20), 69 (33). HRMS: calcd. for C₁₅H₂₁FO₂

252.152558; found 252.153496.

HRMS: calcd. for C₁₆H₂₂F₄O₅S 402.112409; found 402.111205.

(؎)-Dimethyl 9α-fluoro-7-drimen-11,12-dioate (26): Pd(OAc)₂

(22 mg, 0.09 mmol, 0.25 equiv.), Ph₃P (52 mg, 0.19 mmol,

0.5 equiv.) and iPr₂NEt (140 µL, 0.79 mmol, 2 equiv.) were added

to a stirred solution of the enol triflate 25 (156 mg, 0.39 mmol) in

a 1:1 mixture of DMF/MeOH (2.4 mL) and the resulting solution

was stirred at 65 °C under CO balloon pressure for 20 h. The usual

work-up using CH₂Cl₂to extract and chromatography (hexane/

EtOAc, 8:2, as eluent) afforded the diester 26 (80 mg, 65%) as a

semi-solid. TLC: R = 0.27. IR (KBr): ν

= 2950, 2927, 2871,

˜

f

max

(؎)-Methyl 9α-fluoro-8(12)-drimen-11-oate (21): A 0.5  solution

of KHMDS in toluene (13.5 mL, 6.75 mmol, 2.7 equiv.) was added

dropwise into a suspension of Ph₃PCH₃Br (2.68 g, 7.50 mmol,

3 equiv.) in anhydrous toluene (15 mL) at room temp. under argon.

After stirring for 30 min, a solution of decalone 11 (675 mg,

2.5 mmol) in toluene (10 mL) was added and stirring was continued

for another 2 h. Work-up as usual using Et₂O to extract yielded an

oily residue which was purified by column chromatography (hex-

ane/Et₂O, 8:2, as eluent) to yield methyl 9α-fluoroalbicanate (21;

2846, 1760, 1724, 1656, 1436, 1272, 1255, 1137 cm^–1. ¹H NMR

(300 MHz, CDCl₃): δ = 7.38 (ddd, J = 4.8, 2.4, 2.4 Hz, 1 H, 7-H),

3.76 (s, 3 H, CO₂CH₃), 3.72 (s, 3 H, CO₂CH₃), 2.33 (m, 1 H, 6-H),

2.16 (m, 1 H, 6-HЈ), 1.85 (m, 1 H, 1-H), 1.78 (m, 1 H, 5-H), 1.51

(m, 2 H, 2-H), 1.43 (m, 1 H, 3-H), 1.28 (m, 1 H, 1-HЈ), 1.25 (m, 1

H, 3-HЈ), 0.97 (s, 3 H, 14-H), 0.96 (s, 3 H, 15-H), 0.92 (s, 3 H, 13-

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.9 (d, J = 2.3 Hz, C-

15), 18.0 (C-2), 22.1 (C-14), 24.6 (d, J = 2.3 Hz, C-6), 31.8 (d, J =

6.9 Hz, C-1), 32.8 (C-4), 33.1 (C-13), 40.3 (d, J = 19.0 Hz, C-10),

41.1 (C-5), 41.5 (C-3), 51.9 and 52.1 (2ϫCO₂CH₃), 94.8 (d, J =

193.8 Hz, C-9), 128.2 (d, J = 17.2 Hz, C-8), 147.8 (d, J = 6.3 Hz,

C-7), 165.8 (C-12), 169.6 (d, J = 28.1 Hz, C-11) ppm. ¹⁹F NMR

569 mg, 85%) as an oil. TLC: R = 0.54. IR (KBr): ν

= 2989,

˜

f

max

2948, 2869, 2846, 1739, 1650, 1459, 1434, 1390, 1288, 1263, 1068,

916 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.03 (dd, J = 4.2,

1.8 Hz, 1 H, 12-H), 4.95 (d, J = 1.8 Hz, 1 H, 12-HЈ), 3.78 (s, 3 H, (282 MHz, CDCl₃): δ = –143.8 (s) ppm. MS (EI): m/z (%) = 312

CO₂CH₃), 2.45 (ddddd, J = 13.7, 13.7, 5.7, 2.6, 2.6 Hz, 1 H, 7α-

H), 2.31 (dddd, J = 13.7, 4.7, 2.6, 2.6 Hz, 1 H, 7β-H), 1.78–1.56

(2) [M]⁺, 280 (7), 260 (13), 242 (100), 227 (64), 212 (47), 196 (11),

169 (6), 153 (4), 124 (52), 109 (62), 92 (8), 69 (11). HRMS: calcd.

(m, 2 H, 6-H), 1.75 (ddd, J = 12.5, 2.8, 2.6 Hz, 1 H, 5-H), 1.65 (m, for C₁₇H₂₅FO₄312.173688; found 312.173439.

1 H, 1-H), 1.61 (m, 1 H, 2-H), 1.48 (m, 1 H, 2-HЈ), 1.39 (m, 1 H,

(؎)-Methyl 9α-Fluoro-12-hydroxy-7-drimen-11-oate (29): 2,6-Lut-

3-H), 1.21 (m, 1 H, 1-HЈ), 1.17 (m, 1 H, 3-HЈ), 1.15 (s, 3 H, 15-H),

0.92 (s, 3 H, 13-H), 0.88 (s, 3 H, 14-H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 15.6 (d, J = 2.8 Hz, C-15), 18.5 (C-2), 22.0 (C-6), 21.9

(C-14), 31.9 (C-7), 32.9 (C-1), 33.3 (C-4), 33.6 (C-13), 41.3 (C-3),

42.8 (d, J = 19.5 Hz, C-10), 45.3 (d, J = 5.2 Hz, C-5), 51.8 (d, J =

1.1 Hz, CO₂CH₃), 101.1 (d, J = 187.8 Hz, C-9), 112.8 (d, J =

6.9 Hz, C-12), 142.1 (d, J = 21.2 Hz, C-8), 168.6 (d, J = 25.8 Hz,

C-11) ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = –158.2 (s) ppm. MS

(EI): m/z (%) = 268 (26) [M]⁺, 253 (8), 233 (5), 137 (100), 123 (46),

109 (11), 95 (21), 69 (38), 55 (19). HRMS: calcd. for C₁₆H₂₅FO₂

268.183859; found 268.183794.

idine (580 µL, 5.0 mmol, 4 equiv.) was added to a solution of bro-

mide 32 (434 mg, 1.25 mmol) and AgBF₄(730 mg, 3.75 mmol,

3 equiv.) in acetone (12 mL) and water (24 mL) under argon. The

resulting mixture was stirred at 60 °C for 3 h, then cooled to room

temp., diluted with water and extracted with CH₂Cl₂. The extracts

were washed with dilute HCl, 5% NaHCO₃and brine and dried

with anhydrous Na₂SO₄. Evaporation of the solvent and

chromatography (hexane/EtOAc, 8:2, as eluent) gave the hydroxy

ester 29 (301 mg, 85%) as a solid. TLC: R_f= 0.12; m.p. 98–99 °C

(hexane). IR (KBr): ν

= 3434, 2987, 2950, 2923, 2869, 1737,

˜

max

1681, 1461, 1434, 1390, 1274, 1207, 1076, 1056, 1037 cm^–1. ¹H

(؎)-Methyl 9α-Fluoro-8-trifluoromethanesulfonyloxy-7-drimen-11- NMR (300 MHz, CDCl₃): δ = 6.20 (br. s, 1 H, 7-H), 4.14 (d, J =

oate (25): A solution of decalone 11 (107 mg, 0.39 mmol) in THF

(2.5 mL) was slowly added dropwise to a 0.5  solution of

KHMDS in toluene (1.03 mL, 0.51 mmol, 1.3 equiv.) at –78 °C un-

der argon. After stirring for 2 h at this temperature, a solution of

PhNTf₂(233 mg, 0.59 mmol, 1.5 equiv.) in THF (2.5 mL) was

added and the stirring was continued for an additional 2 h. Work-

up as usual using CH₂Cl₂to extract and purification by column

chromatography (hexane/EtOAc, 9:1, as eluent) gave the enol trifl-

ate 25 (110 mg, 70%) as a colourless oil. TLC: R_f= 0.47. IR (KBr):

12.9 Hz, 1 H, 12-H), 4.03 (d, J = 12.9 Hz, 1 H, 12-HЈ), 3.79 (s, 3

H, CO₂CH₃), 2.18 (m, 1 H, 6-H), 2.02 (m, 1 H, 6-HЈ), 1.78 (m, 1

H, 1-H), 1.77 (m, 1 H, 5-H), 1.51 (m, 2 H, 2-H), 1.42 (m, 1 H, 3-

H), 1.23 (m, 1 H, 3-HЈ), 1.22 (m, 1 H, 1-HЈ), 0.98 (s, 3 H, 15-H),

0.95 (s, 3 H, 14-H), 0.91 (s, 3 H, 13-H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 15.7 (d, J = 2.3 Hz, C-15), 18.2 (C-2), 22.0 (C-14),

23.7 (d, J = 2.8 Hz, C-6), 32.0 (d, J = 5.7 Hz, C-1), 32.9 (C-4), 33.0

(C-13), 40.3 (d, J = 18.9 Hz, C-10), 41.3 (C-3), 41.9 (C-5), 52.1

(CO₂CH₃), 64.2 (C-12), 98.0 (d, J = 190.0 Hz, C-9), 133.3 (d, J =

14.9 Hz, C-8), 134.3 (d, J = 8.6 Hz, C-7), 170.4 (d, J = 28.1 Hz, C-

11) ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = –140.0 (s) ppm. MS

ν

= 2956, 2933, 2875, 2850, 1762, 1753, 1681, 1421, 1213,

˜

max

1143 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.23 (ddd, J = 5.8,

2.9, 2.9 Hz, 1 H, 7-H), 3.82 (s, 3 H, CO₂CH₃), 2.39 (m, 1 H, 6-H), (EI): m/z (%) = 284 (5) [M]⁺, 266 (5), 232 (28), 187 (6), 124 (62),

2192

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2182–2198

Preparation of 9α-Fluorinated Sesquiterpenic Drimanes

109 (100), 91 (15), 69 (28). HRMS: calcd. for C₁₆H₂₅FO₃

284.178773; found 284.178636.

triol 34 (37 mg, 85%) as an amorphous solid. TLC: R_f= 0.14 (hex-

ane/EtOAc, 1:1). IR (KBr): ν = 3396, 2981, 2942, 2869, 1648,

˜

max

1637, 1456, 1388, 1375, 1363, 1265, 1025, 989, 742 cm^–1. H NMR

(300 MHz, CDCl₃): δ = 4.03–4.18 (m, 2 H, 11-H), 3.86 (d, J =

11.5 Hz, 1 H, 12-H), 3.76 (dd, J = 11.5, 1.7 Hz, 1 H, 12-HЈ), 1.88

(m, 1 H, 7-H), 1.62 (m, 2 H, 1-H, 2-H), 1.58 (m, 1 H, 7-HЈ), 1.56

(m, 1 H, 5-H), 1.54 (m, 1 H, 6-H), 1.46 (m, 1 H, 1-HЈ), 1.45 (m, 1

H, 2-HЈ), 1.34 (m, 1 H, 3-H), 1.29 (m, 1 H, 6-HЈ), 1.17 (m, 1 H,

3-HЈ), 1.05 (s, 3 H, 15-H), 0.88 (s, 3 H, 13-H), 0.83 (s, 3 H, 14-

H) ppm. ¹³C NMR (75 MHz, CD₃COCD₃): δ = 17.8 (d, J =

5.1 Hz, C-15), 19.8 (C-2), 20.7 (C-6), 22.8 (C-14), 34.4 (d, J =

3.4 Hz, C-1), 34.6 (C-7), 34.7 (C-4), 34.8 (C-13), 42.9 (C-3), 43.4

(d, J = 18.4 Hz, C-10), 46.5 (d, J = 3.3 Hz, C-5), 48.5 (d, J =

3.3 Hz, C-5), 64.0 (d, J = 27.9 Hz, C-11), 66.6 (d, J = 5.5 Hz, C-

12), 79.0 (d, J = 20.6 Hz, C-8), 102.9 (d, J = 182.0 Hz, C-9) ppm.

¹⁹F NMR (282 MHz, CDCl₃): δ = –173.1 (s) ppm. MS (EI): m/z

(%) = 256 (54) [M – 18]⁺, 243 (60), 225 (38), 203 (54), 163 (17),

123 (45), 95 (76), 81 (66), 69 (100), 55 (60). HRMS: calcd. for

C₁₅H₂₅FO₂[M – H₂O]⁺256.183859; found 256.184792.

1

(؎)-Methyl 8α,12-Epoxy-9α-fluorodriman-11-oate (31): MCPBA

(120 mg, 0.53 mmol, 2.3 equiv.) was added to a solution of 21

(63 mg, 0.23 mmol) in CH₂Cl₂(7 mL) cooled in an ice–water bath.

The reaction mixture was warmed up to room temp. and then

stirred for 20 h, diluted with CH₂Cl₂and successively washed with

5% aqueous solutions of KI, Na₂S₂O₃and NaHCO₃and then with

brine. Drying over anhydrous MgSO₄and evaporation of the sol-

vent gave a residue that was purified by chromatography (hexane/

EtOAc, 8:2, as eluent) to yield the epoxy ester 31 (55 mg, 82%).

TLC: R = 0.45. IR (NaCl): ν

= 3054, 2984, 2954, 1734, 1445,

˜

f

max

1416, 1271, 1062, 898 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 3.71

(s, 3 H, CO₂CH₃), 3.41 (ddd, J = 4.5, 2.0, 2.0 Hz, 1 H, 12-H), 2.67

(dd, J = 4.5, 4.5 Hz, 1 H, 12-HЈ), 2.32 (ddddd, J = 13.2, 13.2, 5.1,

2.4, 2.4 Hz, 1 H, 7α-H), 1.76 (m, 1 H, 6-H), 1.68 (m, 1 H, 5-H),

1.61 (m, 1 H, 1-H), 1.57 (m, 1 H, 2-H), 1.53 (m, 1 H, 6-HЈ), 1.47

(m, 1 H, 2-HЈ), 1.39 (m, 1 H, 3-H), 1.26 (m, 1 H, 7β-H), 1.21 (s, 3

H, 15-H), 1.19 (m, 1 H, 3-HЈ), 1.05 (m, 1 H, 1-HЈ), 0.93 (s, 3 H,

13-H), 0.88 (s, 3 H, 14-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

14.8 (d, J = 3.2 Hz, C-15), 18.0 (C-2), 20.4 (C-6), 21.8 (C-14), 30.3

(d, J = 1.6 Hz, C-7), 32.7 (C-1), 33.2 (C-4), 33.7 (C-13), 41.1 (C-

3), 44.1 (d, J = 18.4 Hz, C-10), 45.0 (d, J = 4.7 Hz, C-5), 52.2 (d,

J = 0.9 Hz, CO₂CH₃), 53.4 (d, J = 4.6 Hz, C-12), 58.0 (d, J =

25.9 Hz, C-8), 101.5 (d, J = 195.4 Hz, C-9), 167.7 (d, J = 26.1 Hz,

C-11) ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = –169.4 (s) ppm. MS

(EI): m/z (%) = 284 (1) [M]⁺, 269 (3), 239 (6), 193 (41), 178 (30),

161 (17), 137 (52), 123 (22), 109 (18), 95 (34), 73 (100). HRMS:

calcd. for C₁₆H₂₅FO₃284.178773; found 284.180046.

(؎)-9α-Fluoro-8α-hydroxydriman-11,12-olide (37): Dess–Martin

periodinane (154 mg, 0.36 mmol, 3.1 equiv.) was added to a solu-

tion of triol 34 (32 mg, 0.12 mmol) in CH₂Cl₂(0.3 mL) under ar-

gon. The flask was wrapped in aluminium foil to protect it from

light, then cooled to 0 °C and dry pyridine (60 µL, 0.73 mmol,

6.2 equiv.) was added. The mixture was warmed up to room temp.

and stirred for 5 h, then diluted with CH₂Cl₂, washed successively

with saturated aqueous solutions of NaHCO₃and Na₂S₂O₃fol-

lowed by brine and dried with anhydrous MgSO₄. Elimination of

the solvent and purification by chromatography (hexane/Et₂O, 8:2,

as eluent) gave hydroxy lactone 37 (28 mg, 90%). TLC: R_f= 0.39.

(؎)-Methyl 12-Bromo-9α-fluoro-7-drimen-11-oate (32): MeOH

(10 mL) was added to a solution of compound 21 (447 mg,

1.67 mmol) and NBS (446 mg, 2.50 mmol, 1.5 equiv.) in CH₂Cl₂

(30 mL) and the resulting mixture was stirred at room temp. for

3 h.^[70]The mixture was diluted with CH₂Cl₂and worked up as

usual. The crude product was purified by column chromatography

(hexane/Et₂O, 8:2, as eluent) to give the bromo ester 32 (434 mg,

IR (KBr): ν

= 3479, 2954, 2925, 2871, 1787, 1461, 1390, 1149,

˜

max

1143, 1095, 1027, 1004 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ =

4.18 (app. AB system, J = 10.5 Hz, 2 H, 12-H), 2.12 (m, 1 H, 7-

H), 1.79 (m, 1 H, 1-H), 1.70 (m, 1 H, 2-H), 1.65 (m, 1 H, 1-HЈ),

1.56 (m, 1 H, 7-HЈ), 1.53 (m, 2 H, 6-H), 1.43 (m, 1 H, 3-H), 1.29

(m, 1 H, 2-HЈ), 1.28 (m, 1 H, 5-H), 1.20 (m, 1 H, 3-HЈ), 1.09 (s, 3

H, 15-H), 0.94 (s, 3 H, 13-H), 0.85 (s, 3 H, 14-H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 15.9 (d, J = 4.0 Hz, C-15), 17.6 (d, J =

1.7 Hz, C-6), 19.1 (C-2), 22.1 (C-14), 31.3 (d, J = 12.1 Hz, C-1),

33.1 (C-7), 33.3 (C-4), 33.4 (C-13), 40.8 (d, J = 20.7 Hz, C-10), 41.0

(C-3), 45.8 (C-5), 73.1 (d, J = 4.4 Hz, C-12), 75.0 (d, J = 18.9 Hz,

C-8), 98.4 (d, J = 200.1 Hz, C-9), 171.8 (d, J = 26.4 Hz, C-11) ppm.

¹⁹F NMR (282 MHz, CDCl₃): δ = –184.8 (s) ppm. MS (EI): m/z

(%) = 270 (76) [M]⁺, 255 (100), 237 (49), 196 (71), 137 (75), 123

(91), 83 (36), 69 (98), 55 (56). HRMS: calcd. for C₁₅H₂₃FO₃

270.163123; found 270.162215.

75%). IR (KBr): ν

= 3450, 2950, 2927, 2869, 1733, 1654, 1457,

˜

max

1440, 1390, 1280, 1074, 1058 cm^–1. ¹H NMR (400 MHz, CDCl₃):

δ = 6.33 (s, 1 H, 7-H), 4.15 (d, J = 10.8 Hz, 1 H, 12-H), 3.91 (d, J

= 10.8 Hz, 1 H, 12-HЈ), 3.82 (s, 3 H, CO₂CH₃), 2.28 (m, 1 H, 6-

H), 2.06 (m, 1 H, 6-HЈ), 1.89 (m, 1 H, 5-H), 1.82 (m, 1 H, 1-H),

1.71–1.39 (m, 2 H, 2-H), 1.36 (m, 1 H, 3-H), 1.21 (m, 1 H, 1-HЈ),

1.18 (m, 1 H, 3-HЈ), 0.96 (s, 3 H, 15-H), 0.94 (s, 3 H, 14-H), 0.91

(s, 3 H, 13-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.4 (d, J =

1.7 Hz, C-15), 18.1 (C-2), 21.9 (C-14), 24.4 (d, J = 2.9 Hz, C-6),

32.0 (d, J = 5.2 Hz, C-1), 32.9 (C-4), 33.0 (C-13), 33.0 (C-12), 40.6

(d, J = 19.5 Hz, C-10), 41.1 (d, J = 2.3 Hz, C-5), 41.2 (C-3), 52.2

(CO₂CH₃), 97.5 (d, J = 194.2 Hz, C-9), 129.9 (d, J = 15.9 Hz, C-

8), 138.1 (d, J = 7.5 Hz, C-7), 169.6 (d, J = 27.2 Hz, C-11) ppm.

¹⁹F NMR (282 MHz, CDCl₃): δ = –140.5 (s) ppm. MS (EI): m/z

(%) = 349 (7) [M + 1]⁺(⁸¹Br), 347 (8) [M + 1]⁺(⁷⁹Br), 267 (18),

247 (15), 245 (8), 215 (8), 207 (5), 187 (17), 177 (11), 145 (6), 137

(8), 131 (5), 124 (100). HRMS: calcd. for C₁₆H₂₅⁷⁹BrFO₂[M +

H]⁺347.102195; found 347.100912.

(؎)-9α-Fluoro-8(12)-drimen-11,12-olide (38): A solution of hydroxy

lactone 37 (69 mg, 0.25 mmol) in CH₂Cl₂(5 mL) was cooled to

0 °C and treated sequentially with anhydrous pyridine (31 µL,

0.38 mmol, 1.5 equiv.) and SOCl₂(28 µL, 0.38 mmol, 1.5 equiv.).

The reaction mixture was warmed to room temp. and stirred for

15 h, then diluted with CH₂Cl₂, washed with 5% NaHCO₃and

brine and dried with anhydrous MgSO₄. Evaporation of the solvent

and chromatographic purification (hexane/EtOAc, 9:1, as eluent)

gave the lactone 38 (65 mg, 100%) as a viscous oil. TLC: R_f= 0.54.

(؎)-9α-Fluorodrimane-8α,11,12-triol

(34):

NMO

(24 mg,

IR (KBr): ν

= 2946, 2871, 1810, 1677, 1461, 1386, 1274, 1263,

˜

max

1

0.21 mmol, 1.2 equiv.) and a catalytic amount of OsO₄were added

to a solution of fluorinated albicanol 13 (41 mg, 0.17 mmol) in a

4:1 mixture of acetone/water (1.9 mL) cooled to 0 °C. The flask

was wrapped in aluminium foil to protect it from light and stirred

at room temp. for about 3 d. The reaction mixture was worked up

as usual using CH₂Cl₂to extract and the crude product was puri-

fied by chromatography (hexane/EtOAc, 7:3, as eluent) to give the

1054, 1014, 995, 948 cm^–1. H NMR (300 MHz, CDCl₃): δ = 6.65

(t, J = 2.0 Hz, 1 H, 12-H), 2.45 (dddd, J = 15.6, 4.9, 1.3, 1.3 Hz, 1

H, 7β-H), 2.18 (m, 1 H, 7α-H), 1.85 (m, 1 H, 1-H), 1.77 (m, 1 H,

6-H), 1.77 (m, 1 H, 1-HЈ), 1.59 (m, 1 H, 5-H), 1.55 (m, 2 H, 2-H),

1.42 (m, 1 H, 3-H), 1.35 (m, 1 H, 6-HЈ), 1.26 (m, 1 H, 3-HЈ), 0.94

(s, 3 H, 13-H), 0.93 (s, 3 H, 15-H), 0.86 (s, 3 H, 14-H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 15.2 (d, J = 2.9 Hz, C-15), 17.8 (C-

Eur. J. Org. Chem. 2010, 2182–2198

www.eurjoc.org

2193

A. Abad, C. Agulló, A. C. Cuñat, A. González-Coloma, D. Pardo

FULL PAPER

2), 21.8 (C-6), 21.9 (C-7), 21.9 (C-14), 29.4 (d, J = 5.5 Hz, C-1),

109 (60), 95 (39), 69 (33). HRMS: calcd. for C₁₅H₂₅FO₃

33.5 (C-13), 33.6 (C-4), 41.5 (C-3), 41.5 (d, J = 21.2 Hz, C-10), 45.6 272.178773; found 272.177032.

(C-5), 95.4 (d, J = 192.3 Hz, C-9), 119.3 (d, J = 18.9 Hz, C-8),

(؎)-9α-Fluoro-8β,11-bis(trimethylsilyloxy)drimane-12-carbonitrile

(44): A mixture of hydroxy ketone 43 (129 mg, 0.53 mmol) and

ZnI₂(102 mg, 0.32 mmol, 0.6 equiv.) in CH₂Cl₂(5.3 mL) was

treated with trimethylsilyl cyanide (710 µL 5.33 mmol, 10 equiv.) at

0 °C under argon.^[71]The reaction was allowed to slowly warm to

room temp. and stirred for 15 h. The reaction mixture was diluted

with CH₂Cl₂and worked up as usual. Purification by column

chromatography (hexane/Et₂O, 8:2, as eluent) afforded nitrile 44

137.6 (d, J = 12.1 Hz, C-12), 172.2 (d, J = 25.3 Hz, C-11) ppm. ¹⁹

F

NMR (282 MHz, CDCl₃): δ = –170.1 (s) ppm. MS (EI): m/z (%) =

252 (11) [M]⁺, 237 (11), 142 (15), 137 (20), 124 (15), 123 (63), 109

(14), 95 (14), 81 (19), 69 (100). HRMS: calcd. for C₁₅H₂₁FO₂

252.152558; found 252.148304.

(؎)-11-Acetoxy-9α-fluorodrimane-8α,12-diol (39): Prepared by

hydroxylation of albicanyl acetate (14; 124 mg, 0.44 mmol) with

NMO (62 mg, 0.53 mmol, 1.2 equiv.) and catalytic OsO₄in a 4:1

mixture of acetone/water (5 mL) as described above for 34. The

diol 39 was obtained in 50% yield (70 mg) after purification by

column chromatography (hexane/EtOAc, 8:2, as eluent). TLC: R_f

(168 mg, 76%). IR (KBr): ν

= 2956, 2902, 2871, 1459, 1444,

˜

max

1

1251, 1126, 873, 844 cm^–1. H NMR (300 MHz, CDCl₃): δ = 4.07

(dd, J = 29.0, 12.0 Hz, 1 H, 11-H), 3.91 (dd, J = 15.0, 12.0 Hz, 1

H, 11-HЈ), 2.15 (m, 2 H, 7-H), 1.58 (m, 1 H, 2-H), 1.57 (m, 1 H,

1-H), 1.48 (m, 2 H, 6-H), 1.48 (m, 1 H, 5-H), 1.46 (m, 1 H, 1-HЈ),

1.43 (m, 1 H, 2-HЈ), 1.35 (m, 1 H, 3-H), 1.18 (m, 1 H, 3-HЈ), 1.07

(s, 3 H, 15-H), 0.89 (s, 3 H, 13-H), 0.84 (s, 3 H, 14-H), 0.28 [s, 9

H, C8-OSi(CH₃)₃], 0.15 [s, 9 H, C11-OSi(CH₃)₃] ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = –0.6 [C11-OSi(CH₃)₃], 1.1 [C8-OSi(CH₃)₃],

16.4 (d, J = 4.0 Hz, C-15), 16.8 (C-6), 17.9 (C-2), 21.9 (C-14), 33.0

(C-13), 33.1 (d, J = 4.0 Hz, C-1), 33.7 (C-4), 38.6 (d, J = 1.4 Hz,

C-7), 40.8 (C-3), 41.5 (d, J = 17.5 Hz, C-10), 46.2 (d, J = 1.9 Hz,

C-5), 60.5 (d, J = 33.9 Hz, C-11), 71.5 (d, J = 20.1 Hz, C-8), 97.9

(d, J = 189.4 Hz, C-9), 121.4 (CN) ppm. ¹⁹F NMR (282 MHz,

CDCl₃): δ = –172.7 (s) ppm. MS (EI): m/z (%) = 413 (25) [M]⁺,

399 (32), 398 (100), 371 (33), 279 (16), 269 (14), 149 (84). HRMS:

calcd. for C₂₁H₄₀FNO₂Si₂413.258165; found 413.259590.

= 0.08. IR (KBr): ν_max= 3438, 2945, 2863, 2844, 1731, 1456, 1388,

˜

1368, 1233, 1044, 1025 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ =

4.74 (dd, J = 15.2, 12.6 Hz, 1 H, 11-H), 4.38 (dd, J = 17.9, 12.6 Hz,

1 H, 11-HЈ), 3.64 (s, 2 H, 12-H), 2.075 (s, 3 H, COCH₃), 2.07 (m,

1 H, 7-H), 1.64 (m, 1 H, 6-H), 1.63 (m, 1 H, 7-HЈ), 1.63 (m, 1 H,

2-H), 1.63 (m, 1 H, 1-H), 1.52 (m, 1 H, 5-H), 1.49 (m, 1 H, 2-HЈ),

1.47 (m, 1 H, 1-HЈ), 1.34 (m, 1 H, 3-H), 1.24 (m, 1 H, 6-HЈ), 1.16

(m, 1 H, 3-HЈ), 0.98 (s, 3 H, 15-H), 0.89 (s, 3 H, 13-H), 0.81 (s, 3

H, 14-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 16.3 (d, J =

5.2 Hz, C-15), 18.0 (C-2), 19.2 (C-6), 21.0 (COCH₃), 21.6 (C-14),

33.0 (d, J = 3.4 Hz, C-7), 33.2 (C-1), 33.2 (C-4), 33.4 (C-13), 40.9

(C-3), 42.4 (d, J = 18.9 Hz, C-10), 46.4 (d, J = 2.9 Hz, C-5), 61.5

(d, J = 23.5 Hz, C-11), 64.0 (d, J = 5.1 Hz, C-12), 76.7 (d, J =

21.8 Hz, C-8), 100.2 (d, J = 183.7 Hz, C-9), 170.5 (COCH₃) ppm.

¹⁹F NMR (282 MHz, CDCl₃): δ = –174.1 (s) ppm. MS (FAB): m/z

(%) = 317 (100) [M + 1]⁺, 298 (56), 281 (32), 221 (74), 201 (22), 109

(33). HRMS: calcd. for C₁₇H₃₀FO₄[M + H]⁺317.212813; found

317.213550.

(؎)-9α-Fluoro-8β-hydroxydriman-12,11-olide (45): A mixture of bis-

(trimethylsilyloxy)nitrile 44 (239 mg, 0.57 mmol) and a catalytic

amount of PTSA in 4% aqueous THF (5 mL) was heated at 55 °C

for 20 h. Work-up of the reaction mixture as usual using CH₂Cl₂

to extract and chromatographic purification of the crude reaction

product (hexane/EtOAc, 8:2, as eluent) afforded hydroxy lactone

45 (133 mg, 85%) as a white solid. TLC: R_f= 0.24; m.p. 146–147 °C

(؎)-11,12-Epoxy-9α-fluorodrimane-8α,12α-diol

(40):

DMSO

(53 µL, 0.75 mmol, 5 equiv.) was added to a solution of oxalyl chlo-

ride (150 µL of a 2  solution in CH₂Cl₂, 0.30 mmol, 2 equiv.) in

anhydrous CH₂Cl₂(0.5 mL) at –60 °C. After 10 min of stirring at

this temperature, a solution of glycol 39 (47 mg, 0.15 mmol) in

CH₂Cl₂(0.5 mL) was added and the reaction mixture was stirred

for 30 min during which time the temperature of the reaction mix-

ture was raised to –20 °C. Then the reaction mixture was cooled

again to –60 °C and Et₃N (210 µL, 1.50 mmol, 10 equiv.) was

added. After 1 h the reaction was worked up as usual using CH₂Cl₂

to extract to give an oily residue (44 mg), which was dissolved in a

1:1 mixture of MeOH/H₂O (3 mL) containing a catalytic amount

of KOH. The mixture was stirred at room temp. for 30 min, diluted

with water and worked up using CH₂Cl₂to extract. Purification by

chromatography (hexane/EtOAc, 8:2, as eluent) afforded the hy-

(Et O). IR (NaCl): ν_max= 3444, 2950, 2871, 1778, 1712, 1461, 1392,

˜

2

1365, 1261, 1184, 1051, 977 cm^–1. H NMR (300 MHz, CDCl₃): δ

1

= 4.69 (dd, J = 35.8, 9.5 Hz, 1 H, 11-H), 4.25 (dd, J = 15.8, 9.5 Hz,

1 H, 11-HЈ), 3.19 (br. d, J = 1.5 Hz, 1 H, OH), 1.88 (m, 2 H, 7-H),

1.68 (m, 2 H, 6-H), 1.68 (m, 1 H, 1-H), 1.67 (m, 1 H, 2-H), 1.58

(m, 1 H, 5-H), 1.48 (m, 1 H, 2-HЈ), 1.41 (m, 1 H, 3-H), 1.22 (s, 3

H, 15-H), 1.21 (m, 1 H, 3-HЈ), 1.20 (m, 1 H, 1-HЈ), 0.91 (s, 3 H,

13-H), 0.89 (s, 3 H, 14-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

16.4 (d, J = 5.2 Hz, C-15), 16.7 (C-6), 17.4 (C-2), 21.4 (C-14), 27.6

(C-7), 32.0 (d, J = 3.4 Hz, C-1), 33.0 (C-4), 33.7 (C-13), 39.6 (d, J

= 17.2 Hz, C-10), 41.5 (C-3), 46.6 (d, J = 3.4 Hz, C-5), 71.0 (d, J

= 25.3 Hz, C-11), 74.6 (d, J = 32.7 Hz, C-8), 102.5 (d, J = 170.7 Hz,

C-9), 176.1 (C-12) ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = –161.5

(s) ppm. MS (EI): m/z (%) = 270 (2) [M]⁺, 238 (3), 209 (5), 160

(15), 137 (53), 136 (17), 125 (22), 123 (65), 95 (50), 81 (57), 73

(46), 69 (100). HRMS: calcd. for C₁₅H₂₃FO₃270.163123; found

270.162354.

droxy lactol 40 (27 mg, 60%). TLC: R = 0.12. IR (NaCl): ν

=

˜

f

max

3405, 2950, 2919, 2863, 1726, 1454, 1393, 1091, 1024 cm^–1. ¹H

NMR (300 MHz, CDCl₃): δ = 5.11 (s, 1 H, 12-H), 3.99 (dd, J =

14.4, 9.0 Hz, 1 H, 11-H), 3.88 (dd, J = 9.0, 2.7 Hz, 1 H, 11-HЈ),

2.10 (m, 1 H, 7-H), 1.63 (m, 1 H, 2-H), 1.61 (m, 1 H, 1-H), 1.60 (؎)-11-Acetoxy-9α-fluoro-12-nordriman-8-one (47): A solution of

(m, 1 H, 6-H), 1.48 (m, 1 H, 6-HЈ), 1.45 (m, 1 H, 7-HЈ), 1.41 (m, hydroxy ketone 43 (165 mg, 0.68 mmol) and Ac₂O (300 µL,

1 H, 3-H), 1.34 (m, 1 H, 1-HЈ), 1.32 (m, 1 H, 2-HЈ), 1.32 (m, 1 H, 2.72 mmol, 4 equiv.) in pyridine (1.2 mL) was stirred at room temp.

5-H), 1.17 (m, 1 H, 3-HЈ), 1.06 (s, 3 H, 15-H), 0.92 (s, 3 H, 13-H),

for 2 h. The mixture was diluted with water and extracted with

CH₂Cl₂. The combined extracts were washed with dilute aqueous

0.86 (s, 3 H, 14-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.4 (d,

J = 5.8 Hz, C-15), 17.7 (C-6), 18.5 (C-2), 22.0 (C-14), 30.9 (C-7), HCl, 5% aqueous NaHCO₃and brine, dried with anhydrous

31.5 (C-1), 33.0 (C-4), 33.2 (C-13), 39.7 (d, J = 20.9 Hz, C-10), 41.3 Na₂SO₄and concentrated. Chromatographic purification (hexane/

(C-3), 45.3 (C-5), 68.3 (d, J = 29.8 Hz, C-11), 76.1 (d, J = 17.2 Hz,

C-8), 99.7 (d, J = 5.7 Hz, C-12), 102.0 (d, J = 193.0 Hz, C-9) ppm.

¹⁹F NMR (282 MHz, CDCl₃): δ = –176.2 (s) ppm. MS (EI): m/z

(%) = 272 (1) [M]⁺, 206 (59), 191 (99), 163 (36), 137 (38), 123 (100),

Et₂O, 8:2, as eluent) gave the keto acetate 47 (194 mg, 99%). TLC:

R = 0.42. IR (KBr): ν

= 2948, 2881, 1747, 1731, 1461, 1434,

˜

f

max

1386, 1367, 1236, 1054 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ =

4.54 (dd, J = 32.0, 12.1 Hz, 1 H, 11-H), 4.30 (dd, J = 12.1, 10.6 Hz,

2194

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2182–2198

Preparation of 9α-Fluorinated Sesquiterpenic Drimanes

1 H, 11-HЈ), 2.90 (m, 1 H, 7-H), 2.36 (m, 1 H, 7-HЈ), 2.04 (s, 3 H, (COCH₃), 22.0 (C-14), 25.3 (d, J = 2.6 Hz, C-6), 31.1 (d, J =

COCH₃), 2.02 (m, 1 H, 6-H), 1.99 (m, 1 H, 5-H), 1.75 (m, 1 H, 1- 6.4 Hz, C-1), 32.7 (C-4), 32.9 (C-15), 40.0 (d, J = 18.0 Hz, C-10),

H), 1.59 (m, 1 H, 6-HЈ), 1.57 (m, 2 H, 2-H), 1.43 (m, 1 H, 1-HЈ),

40.8 (C-3), 41.3 (C-5), 62.2 (d, J = 33.5 Hz, C-11), 92.7 (d, J =

1.40 (m, 1 H, 3-H), 1.24 (m, 1 H, 3-HЈ), 0.97 (s, 3 H, 13-H), 0.86 183.9 Hz, C-9), 112.4 (d, J = 20.3 Hz, C-8), 117.2 (CN), 153.9 (d,

(s, 3 H, 15-H), 0.85 (s, 3 H, 14-H) ppm. ¹³C NMR (75 MHz, J = 6.3 Hz, C-7), 170.3 (COCH₃) ppm. ¹⁹F NMR (282 MHz,

CDCl₃): δ = 15.0 (d, J = 4.3 Hz, C-15), 18.4 (C-2), 20.8 (COCH₃), CDCl₃): δ = –145.4 (s) ppm. MS (EI): m/z (%) = 293 (1) [M]⁺, 231

21.7 (C-14), 23.9 (C-6), 32.4 (C-1), 33.6 (C-4), 33.6 (C-13), 38.6 (d,

(10), 221 (15), 156 (6), 130 (12), 124 (91), 109 (100), 81 (12), 69

J = 2.7 Hz, C-7), 41.0 (C-3), 44.8 (d, J = 4.6 Hz, C-5), 45.1 (d, J (24). HRMS: calcd. for C₁₇H₂₄FNO₂293.179107; found

= 18.8 Hz, C-10), 59.9 (d, J = 20.2 Hz, C-11), 100.5 (d, J =

188.5 Hz, C-9), 170.8 (COCH₃), 206.7 (d, J = 27.0 Hz, C-8) ppm.

¹⁹F NMR (282 MHz, CDCl₃): δ = –173.3 (s) ppm. MS (EI): m/z

(%) = 284 (10) [M]⁺, 224 (46), 209 (15), 191 (9), 163 (12), 137 (57),

136 (42), 123 (100), 109 (38), 95 (61), 69 (90). HRMS: calcd. for

C₁₆H₂₅FO₃284.178773; found 284.170853.

293.174743.

(؎)-9α-Fluoro-11-hydroxy-7-drimene-12-carbonitrile (50): A solu-

tion of acetoxy nitrile 49 (27 mg, 0.09 mmol) in anhydrous THF

(1 mL) was treated with a 1  solution of DIBAL-H in cyclohexane

(190 µL, 0.19 mmol, 2 equiv.) at –78 °C under argon. The mixture

was stirred at this temperature for 30 min, treated again with an-

other identical portion of the DIBAL-H solution (190 µL) and then

stirred under the same conditions for an additional 30 min. The

reaction was quenched by the addition of acetone (1 mL), stirred

for 15 min, diluted with CH₂Cl₂, washed with brine and dried with

anhydrous Na₂SO₄. After evaporation of the solvent chromato-

graphic purification (hexane/Et₂O from 8:2 to 6:4) gave the hydroxy

nitrile 50 (23 mg, 97%) as a white solid. TLC: R_f= 0.16; m.p. 137–

(؎)-11-Acetoxy-9α-fluoro-8β-hydroxydrimane-12-carbonitrile (48):

A mixture of keto acetate 47 (166 mg, 0.58 mmol) and ZnI₂

(111 mg, 0.35 mmol, 0.6 equiv.) in dry CH₂Cl₂(5.5 mL) was treated

with trimethylsilyl cyanide (385 µL, 3.0 mmol, 10 equiv.) at 0 °C

under argon. The reaction mixture was stirred at room temp. for

5 h and then worked up as usual using CH₂Cl₂to extract. The

residue left after evaporation of the solvent (ca. 197 mg) was trans-

ferred to a Teflon tube, dissolved in anhydrous THF (2 mL) and

treated with the HF/pyridine complex (ca. 500 µL). The mixture

was stirred at room temp. until complete consumption of the silyl

ether intermediate was observed by TLC analysis (ca. 18 h), then

diluted with CH₂Cl₂, washed with dilute aqueous HCl, 5%

NaHCO₃and brine, and dried with anhydrous Na₂SO₄. Evapora-

tion of the solvent and chromatographic purification (hexane/

EtOAc, 8:2, as eluent) gave the acetoxy nitrile 48 (150 mg, 83%

138 °C (hexane). IR (NaCl): ν

= 3484, 2948, 2916, 2868, 2220,

˜

max

1742, 1641, 1471, 1392, 1073 cm^–1. ¹H NMR (300 MHz, CDCl₃):

δ = 7.09 (quint., J = 2.7 Hz, 1 H, 7-H), 4.00 (app. d, J = 13.2 Hz,

2 H, 11-H), 2.39 (m, 1 H, 6-H), 2.13 (m, 1 H, 6-HЈ), 1.90 (br. s, 1

H, OH), 1.77 (ddd, J = 12.0, 4.7, 1.5 Hz, 1 H, 5-H), 1.71–1.54 (m,

2 H, 1-H), 1.68–1.45 (m, 2 H, 2-H), 1.43 (m, 1 H, 3-H), 1.22 (m, 1

H, 3-HЈ), 0.96 (s, 3 H, 15-H), 0.95 (s, 3 H, 14-H), 0.92 (s, 3 H, 13-

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.2 (d, J = 3.3 Hz, C-

15), 17.9 (C-2), 22.0 (C-14), 25.4 (d, J = 2.7 Hz, C-6), 31.2 (d, J =

6.6 Hz, C-1), 32.8 (C-4), 33.0 (C-13), 39.9 (d, J = 18.0 Hz, C-10),

41.0 (C-3), 41.7 (C-5), 62.4 (d, J = 31.7 Hz, C-11), 94.2 (d, J =

181.3 Hz, C-9), 112.7 (d, J = 20.2 Hz, C-8), 117.2 (CN), 154.1 (d,

J = 6.5 Hz, C-7) ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = –148.0

(s) ppm. MS (EI): m/z (%) = 251 (1) [M]⁺, 221 (36), 206 (11), 186

(6), 130 (11), 124 (84), 109 (100), 69 (24). HRMS: calcd. for

C₁₅H₂₂FNO 251.168543; found 251.166264.

overall yield from 47). TLC: R = 0.16. IR (NaCl): ν

= 3390,

˜

f

max

2952, 2871, 1751, 1727, 1461, 1378, 1240, 1103, 1056 cm^–1. ¹H

NMR (300 MHz, CDCl₃): δ = 4.87 (dd, J = 31.3, 13.0 Hz, 1 H,

11-H), 4.41 (dd, J = 13.0, 11.6 Hz, 1 H, 11-HЈ), 2.30–2.09 (m, 2 H,

7-H), 2.21 (s, 3 H, COCH₃), 1.61–1.41 (m, 4 H, 2-H, 6-H), 1.61

(m, 1 H, 1-H), 1.44 (m, 1 H, 5-H), 1.44 (m, 1 H, 1-HЈ), 1.35 (m, 1

H, 3-H), 1.18 (s, 3 H, 15-H), 1.14 (m, 1 H, 3-HЈ), 0.91 (s, 3 H, 13-

H), 0.85 (s, 3 H, 14-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 16.1

(d, J = 4.2 Hz, C-15), 16.5 (C-6), 17.7 (C-2), 21.2 (COCH₃), 21.9

(C-14), 33.0 (d, J = 4.5 Hz, C-1), 33.1 (C-4), 33.7 (C-13), 37.3 (C-

7), 40.6 (C-3), 41.7 (d, J = 17.1 Hz, C-10), 45.9 (C-5), 61.7 (d, J =

21.6 Hz, C-11), 70.0 (d, J = 31.8 Hz, C-8), 96.5 (d, J = 190.7 Hz,

C-9), 121.1 (CN), 173.1 (COCH₃) ppm. ¹⁹F NMR (282 MHz,

CDCl₃): δ = –168.3 (s) ppm. MS (EI): m/z (%) = 311 (10) [M]⁺,

306 (100), 285 (98), 225 (24), 219 (30), 207 (15), 167 (23), 165 (21).

HRMS: calcd. for C₁₇H₂₆FNO₃311.189672; found 311.195612.

Bioassays: Selected compounds were evaluated in independent bio-

assays against three important agricultural insect pests. The anti-

feedant activity was tested with larvae of the generalist Spodoptera

littoralis (Lepidoptera: Noctuidae). Aphid settling inhibition was

evaluated with a grass specialist, Rhopalosiphum padi, and a feeding

generalist, Myzus persicae (both Hemiptera: Aphididae). Com-

pounds were assayed at an initial dose of 50 µg/cm²and those with

higher deterrent activities were used to calculate EC₅₀values. Insect

rearing, choice feeding assays and oral cannulations were con-

ducted as described previously.^[72]

(؎)-11-Acetoxy-9α-fluoro-7-drimene-12-carbonitrile (49): Anhy-

drous pyridine (122 µL, 1.51 mmol, 3.1 equiv.) and thionyl chloride

(53 µL, 0.73 mmol, 1.5 equiv.) were added to a solution of hydroxy

nitrile 48 (152 mg, 0.49 mmol) in dry toluene (5 mL). The mixture

was stirred at room temp. for 4 h, heated progressively from room

temp. to 80 °C over 4 h and then stirred at this temperature for

15 h. After work-up as described for 47, the residue obtained was

purified by column chromatography (hexane/EtOAc, 7:3, as eluent)

to give the unsaturated nitrile 49 (130 mg, 90%) as a solid. TLC:

Supporting Information (see also the footnote on the first page of

this article): General experimental, details of the preparation of

compounds 3, 4, 9, 19, 20, 22, 24, 28, 30, 41–43, 46 and 51, re-

duction of diester 26 with DIBAL-H, dehydration of 45 with De-

oxo-fluor^®, oxidative fragmentation of 40, oral cannulation data

1

and characterization H NMR spectra for compounds 11–15, 17,

21, 31, 37, 38, 45–47, 49 and 50.

R = 0.20; m.p. 72–73 °C (Benzene). IR (NaCl): ν_max= 2950, 2871,

˜

f

2221, 1751, 1637, 1463, 1390, 1367, 1236, 1052, 981, 908 cm^–1. H

1

NMR (300 MHz, CDCl₃): δ = 7.08 (quint., J = 2.7 Hz, 1 H, 7-H),

4.43 (dd, J = 30.2, 12.3 Hz, 1 H, 11-H), 4.38 (dd, J = 27.9, 12.3 Hz,

1 H, 11-HЈ), 2.37 (m, 1 H, 6-H), 2.13 (s, 3 H, COCH₃), 2.13 (m, 1

H, 6-HЈ), 1.79 (ddd, J = 11.9, 4.6, 1.5 Hz, 1 H, 5-H), 1.58 (m, 2 H,

1-H), 1.58–1.47 (m, 2 H, 2-H), 1.43 (m, 1 H, 3-H), 1.22 (m, 1 H,

Acknowledgments

This work was partially supported by grants from the Spanish Gov-

3-HЈ), 0.95 (s, 3 H, 14-H), 0.93 (s, 6 H, 13-H, 15-H) ppm. ¹³C NMR ernment (Grants 1FD-97-0705, BQU2002-00272 and CTQ2006-

(75 MHz, CDCl₃): δ = 15.4 (d, J = 2.9 Hz, C-15), 17.9 (C-2), 20.8

15597-C02-01/PPQ).

Eur. J. Org. Chem. 2010, 2182–2198

www.eurjoc.org

2195

A. Abad, C. Agulló, A. C. Cuñat, A. González-Coloma, D. Pardo

FULL PAPER

[18]

a) K. L. Kirk, Org. Process Res. Dev. 2008, 12, 305–321; b)

L. Begum, M. G. B. Drew, J. L. Humphreys, D. J. Lowes, P. R.

Russi, H. L. Whitby, R. C. Whitehead, Tetrahedron Lett. 2004,

45, 6249–6253; c) G. Koch, O. Loiseleur, K. H. Altmann, Syn-

lett 2004, 693–697.

[1]

a) D. B. Harper, D. O’Hagan, Nat. Prod. Rep. 1994, 11, 123–

133; b) D. O’Hagan, D. B. Harper, J. Fluorine Chem. 1999, 100,

127–133; c) D. B. Harper, D. O’Hagan, C. D. Murphy, “Fluori-

nated Natural Products: Occurrence and Biosynthesis” in Nat-

ural Production of Organohalogen Compounds (Handbook of

Environmental Chemistry) (Ed.: G. W. Gribble), Springer,

Berlin, 2003, vol. 3P, pp. 141–169.

[19]

[20]

a) J. P. Begue, D. Bonnet-Delpon, J. Fluorine Chem. 2006, 127,

992–1012; b) C. J. Thomas, Curr. Top. Med. Chem. 2006, 6,

1529–1543.

For more recent examples, see: a) Y. Aoyagi, Y. Hitotsuyanagi,

T. Hasuda, S. Matsuyama, H. Fukaya, K. Takeya, R. Aiyama,

T. Matsuzaki, S. Hashimoto, Bioorg. Med. Chem. Lett. 2008,

18, 2459–2463; b) D. Biedermann, J. Sarek, J. Klinot, M.

Hajduch, P. Dzubak, Synthesis 2005, 1157–1163; c) D. Bieder-

mann, J. Sarek, J. Klinot, M. Hajduch, P. Dzubak, Synthesis

2005, 1157–1163; d) Y. H. Jin, D. C. Williams, R. Croteau,

R. M. Coates, J. Am. Chem. Soc. 2005, 127, 7834–7842; e) M.

Suehiro, N. R. Simpson, R. van Heertum, J. Labelled Compd.

Radioph. 2004, 47, 485–491; f) D. O. Kiesewetter, E. M. Jagoda,

C. H. K. Kao, Y. Ma, L. Ravasi, K. Shimoji, L. P. Szajek, W. C.

Eckelman, Nucl. Med. Biol. 2003, 30, 11–24; g) W. Dmowski,

J. Fluorine Chem. 2001, 109, 33–37; h) M. Wust, D. B. Little,

M. Schalk, R. Croteau, Arch. Biochem. Biophys. 2001, 387,

125–136; i) O. Lefebvre, T. Brigaud, C. Portella, J. Org. Chem.

2001, 66, 4348–4351; j) W. Dmowski, K. Piasecka-Maciejew-

ska, J. Fluorine Chem. 2000, 105, 77–82; k) C. Portella, T. Bri-

gaud, O. Lefebvre, R. Plantier-Royon, J. Fluorine Chem. 2000,

101, 193–198; l) W. Dmowski, K. Piasecka-Maciejewska, J.

Fluorine Chem. 2000, 104, 273–276; m) Y. Komatsu, T. Kita-

zume, J. Fluorine Chem. 2000, 102, 61–67; n) O. Lefebvre, T.

Brigaud, C. Portella, Tetrahedron 1999, 55, 7233–7242; o) G.

Appendino, G. C. Tron, G. Cravotto, G. Palmisano, R. Annun-

ziata, R. Baj, G. N. Surico, Eur. J. Org. Chem. 1999, 3413–3420;

p) J. Anaya, M. C. Grande, M. Grande, A. I. Patino, P. Torres,

Synlett 1999, 1429–1431; q) W. Dmowski, K. Piasecka-Macie-

jewskak, J. Fluorine Chem. 1999, 97, 97–100; r) W. Dmowski,

K. Piasecka-Maciejewska, Org. Prep. Proc. Int. 1999, 31, 207–

211.

For more recent examples, see: a) G. H. Posner, W. A. Maio,

A. S. Kalinda, Bioorg. Med. Chem. 2008, 16, 5247–5253; b) C.

Chollet, B. Crousse, M. Ourevitch, D. Bonnet-Delpon, J. Org.

Chem. 2006, 71, 3082–3085; c) F. Grellepois, P. Grellier, D.

Bonnet-Delpon, J. P. Bégué, Org. Lett. 2005, 7, 5219–5222; d)

F. Grellepois, P. Grellier, D. Bonnet-Delpon, J. P. Bégué, Chem-

BioChem 2005, 6, 648–652; e) G. Magueur, B. Crousse, S. Char-

neau, P. Grellier, J. P. Bégué, D. Bonnet-Delpon, J. Med. Chem.

2004, 47, 2694–2699; f) F. Grellepois, F. Chorki, M. Ourevitch,

S. Charneau, P. Grellier, K. A. McIntosh, W. N. Charman, B.

Pradines, B. Crousse, D. Bonnet-Delpon, J. P. Bégué, J. Med.

Chem. 2004, 47, 1423–1433; g) M. Rodríguez, D. Bonnet-

Delpon, J. P. Bégué, A. Robert, B. Meunier, Bioorg. Med.

Chem. Lett. 2003, 13, 1059–1062; h) G. Magueur, B. Crousse,

M. Ourevitch, J. P. Begue, D. Bonnet-Delpon, J. Org. Chem.

2003, 68, 9763–9766; i) F. Chorki, F. Grellepois, B. Crousse,

V. D. Hoang, N. Van Hung, D. Bonnet-Delpon, J. P. Bégué,

Org. Lett. 2002, 4, 757–759; j) F. Grellepois, F. Chorki, B.

Crousse, M. Ourevitch, D. Bonnet-Delpon, J. P. Bégué, J. Org.

Chem. 2002, 67, 1253–1260; k) F. Chorki, F. Grellepois, B.

Crousse, M. Ourevitch, D. Bonnet-Delpon, J. P. Bégué, J. Org.

Chem. 2001, 66, 7858–7863.

[2]

a) A. M. Thayer, Chem. Eng. News 2006, 84, 15–24; b) F.

Cottet, M. Marull, O. Lefebvre, M. Schlosser, Eur. J. Org.

Chem. 2003, 1559–1568; c) V. A. Soloshonok, H. Ohkura, M.

Yasumoto, J. Fluorine Chem. 2006, 127, 707–711; d) S. Purser,

P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008,

37, 320–330, and references cited therein.

a) T. Hiyama, Organofluorine Compounds, Chemistry and Appli-

cations, Springer, Berlin, 2000; b) P. Kirsch, Modern Fluoroor-

ganic Chemistry, Synthesis, Reactivity, Applications, Wiley-

VCH, Weinheim, 2004; c) E. Differding, H. Ofner, Synlett

1991, 187–189; d) G. S. Lal, J. Org. Chem. 1993, 58, 2791–2796.

K. B. Park, N. R. Kitteringham, P. M. O’Neill, Annu. Rev.

Pharmacol. Toxicol. 2001, 41, 443–470.

M. Schlosser, Angew. Chem. Int. Ed. 1998, 37, 1496–1513.

a) N. C. Yoder, K. Kumar, Chem. Soc. Rev. 2002, 31, 335–341;

b) X.-L. Qiu, W.-D. Mengb, F.-L. Qing, Tetrahedron 2004, 60,

6711–6745; c) R. Smits, C. D. Cadicamo, K. Burger, B. Koksch,

Chem. Soc. Rev. 2008, 37, 1727–1739.

a) M. Sani, M. Molteni, L. Bruche, A. Volonterio, M. Zanda,

Synthesis and properties of new fluorinated peptidomimetics, in:

Fluorine-Containing Synthons (Ed.: V. A. Soloshonok), Ameri-

can Chemical Society, Washington, 2005, ACS Symposium

Series No. 911, pp. 572–592; b) C. Jaeckel, B. Koksch, Using

the potential of fluorine for peptide and protein modification, in:

Fluorine-Containing Synthons (Ed.: V. A. Soloshonok), Ameri-

can Chemical Society, Washington, 2005, ACS Symposium

Series No. 911, pp. 611–635.

a) K. Dax, M. Albert, J. Ortner, B. J. Paul, Carbohydr. Res.

2000, 327, 47–86; b) K. W. Pankiewicz, Carbohydr. Res. 2000,

327, 87–105; c) R. Plantier-Royon, C. Portella, Carbohydr. Res.

2000, 327, 119–146; d) M. Hein, R. Miethchen, Adv. Org.

Synth. 2006, 2, 381–429.

a) K. W. Pankiewicz, Carbohydr. Res. 2000, 327, 87–105; b) W.-

D. Meng, F.-L. Qing, Curr. Top. Med. Chem. 2006, 6, 1499–

1528.

a) M. Prakesch, D. Gree, S. Chandrasekhar, R. Gree, Eur. J.

Org. Chem. 2005, 1221–1232; b) E. Kerouredan, M. Prakesch,

D. Gree, R. Gree, Lett. Org. Chem. 2004, 1, 78–80; c) V. M.

Dembitsky, M. Srebnik, Prog. Lipid Res. 2002, 41, 315–367.

a) Y. Ito, S. Hagihara, M. A. Arai, I. Matsuo, M. Takatani,

Glycoconjugate J. 2004, 21, 257–266; b) J. Xia, J. Xue, R. D.

Locke, E. V. Chandrasekaran, T. Srikrishnan, K. L. Matta, J.

Org. Chem. 2006, 71, 3696–3706.

a) R. D. Chambers, T. Nakano, M. Parsons, G. Sandford, A. S.

Batsanov, J. A. K. Howard, J. Fluorine Chem. 2008, 129, 811–

816; b) S. Diederich, B. Hanke, P. Burkhardt, M. Müller, M.

Schöneshöfer, V. Bähr, W. Oelkers, Steroids 1998, 63, 271–277;

c) D. Alker, D. H. R. Barton, R. H. Hesse, J. Lister-James,

R. E. Markwell, M. M. Pechet, S. Rozen, T. Takashita, H. T.

Toh, Nouv. J. Chem. 1980, 4, 239–258.

[3]

[4]

[5]

[6]

[7]

[8]

[21]

[9]

[10]

[11]

[12]

[13]

[14]

Y. Matsumura, Synthesis and pharmacological properties of flu-

orinated prostanoids, in: Fluorine and Health: Molecular Im-

aging, Biomedical Materials and Pharmaceuticals (Eds.: A.

Tressaud, G. Haufe), Elsevier, New York, 2008, pp. 623–659.

A. Ohno, M. Shimizu, S. Yamada, Chem. Pharm. Bull. 2002,

50, 475–483.

R. J. M. Goss, H. Hong, Chem. Commun. 2005, 3983–3985.

C. Pesenti, F. Viani, ChemBioChem 2004, 5, 590–613.

a) J. Bennouna, J.-P. Delord, M. Campone, L. Nguyen, Clin.

Cancer Res. 2008, 14, 1625–1632; b) X. Wang, Y. Yu, R. Song,

Heilongjiang Yiyao 2007, 20, 341–342.

[22]

[23]

J. D. Connolly, R. A. Hill, Dictionary of Terpenoids, 1st ed.,

Chapman and Hall, London, 1991, vol. 1, p. 453.

a) B. J. M. Jansen, A. de Groot, Nat. Prod. Rep. 1991, 8, 309–

318; b) B. J. M. Jansen, A. de Groot, Nat. Prod. Rep. 2004, 21,

449–477; c) C.-L. Lee, .-C. Chiang, .-H. Cheng, C-C. Liaw,

M. H. Abd El-Razek, F.-R. Chang, Y.-C. Wu, J. Nat. Prod.

2009, 72, 1568–1572.

a) S. M. Kupchan, M. A. Eakin, A. M. Thomas, J. Med. Chem.

1971, 14, 1147–1152; b) J. J. La Clair, P. T. Lansbury, B. Zhi,

K. Hoogsteen, J. Org. Chem. 1995, 60, 4822–4833, and refer-

ences cited therein; c) G. Wang, W. Tang, R. R. Bidigare, Terpe-

[15]

[16]

[17]

[24]

2196

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2182–2198

Preparation of 9α-Fluorinated Sesquiterpenic Drimanes

noids as Therapeutic Drugs and Pharmaceutical Agents, in: Nat-

ural products. Drug Discovery and Therapeutic Medicine (Eds.:

L. Zhang, A. L. Demain), Humana Press, Totowa, 2005, pp.

197–228; d) N. Ungur, V. Kulcitxki, Tetrahedron 2009, 65,

3815–3828.

A. Abad, C. Agulló, A. C. Cuñat, D. Pardo, Tetrahedron Lett.

2003, 44, 1899–1902.

a) M. A. González, Tetrahedron 2008, 64, 445–467; b) B. J. M.

Jansen, A. de Groot, Nat. Prod. Rep. 1991, 8, 319–337; c) P. F.

Vlad, “Synthetic Investigations in the Field of Drimane Sesqui-

terpoids”, in: Studies in Natural Products Chemistry, vol. 33

[Bioactive Natural Products (Part M)] (Ed.: Atta-ur-Rahman),

Elsevier Science, Amsterdam, 2006, pp. 393–432; d) J. R. Hen-

derson, B. Parvez, B. A. Keay, Org. Lett. 2009, 11, 3178–3181,

and references cited therein.

1973–1984; c) A. Abad, C. Agulló, M. Arnó, M. L. Marín,

R. J. Zaragoza, J. Chem. Soc., Perkin Trans. 1 1996, 2193–2199;

d) F. Rivas, S. Ghosh, E. A. Theodorakis, Tetrahedron Lett.

2005, 46, 5281–5284.

D. L. Comins, A. Dehghani, Tetrahedron Lett. 1992, 33, 6299–

6302.

[43]

[25]

[26]

[44] W. J. Scott, G. T. Crisp, J. K. Stille, J. Am. Chem. Soc. 1984,

106, 4630–4632.

[45] S. P. Tanis, K. Nakanishi, J. Am. Chem. Soc. 1979, 101, 4398–

4400.

[46] D. M. Hollinshead, S. C. Howell, S. V. Ley, M. Mahon, N. M.

Ratcliffe, P. A. Worthington, J. Chem. Soc., Perkin Trans. 1

1983, 1579–1589.

[47]

Y. Nakamura, M. Okada, H. Horikawa, T. Taguchi, J. Fluorine

Chem. 2002, 117, 143–148.

[27]

[28]

[48]

[49]

For recent examples, see: a) S. N. Suryawanshi, N. Chandra,

Ind. J. Chem., Sect. B 2004, 43, 992–995; b) Y. Tanada, K.

Mori, Eur. J. Org. Chem. 2003, 848–854; c) N. Furuichi, T.

Hata, H. Soetjipto, M. Kato, S. Katsumura, Tetrahedron 2001,

57, 8425–8442; d) M. Nozawa, Y. Murakami, K. Noda, R. Ta-

matsukuri, K. Kato, H. Akita, Chem. Pharm. Bull. 2000, 48,

1176–1186.

a) T. Laube, J. Schröder, R. Stehle, K. Seifert, Tetrahedron

2002, 58, 4299–4309; b) D. Herlem, J. Kervagoret, D. H. Yu,

F. Khuonghuu, A. S. Kende, Tetrahedron 1993, 49, 607–618; c)

J. D. White, R. W. Skeean, G. L. Trammell, J. Org. Chem. 1985,

50, 1939–1948.

K. Soai, A. Ookawa, J. Org. Chem. 1986, 51, 4000–4005.

D. Pardo, Synthesis of fluorinated analogues of bioactive ter-

penes. Preparation of fluorinated drimanes, Ph. D. Thesis, Uni-

versity of Valencia, 2006.

[50] a) G. G. Harrigan, A. Ahmad, N. Baj, T. E. Glass, A. A. L.

Gunatilaka, D. G. I. Kingston, J. Nat. Prod. 1993, 56, 921–925;

b) G. L. Fritz, G. D. Mills Jr., J. D. Warthen Jr., R. M. Waters,

J. Chem. Ecol. 1989, 15, 2607–2623.

[51]

a) H. Akita, M. Nozawa, A. Mitsuda, H. Ohsawa, Tetrahedron:

Asymmetry 2000, 11, 1375–1388; b) J. Justicia, J. E. Oltra, A. F.

Barrero, A. Guadano, A. González-Coloma, J. M. Cuerva, Eur.

J. Org. Chem. 2005, 712–718.

T. Shimizu, S. Hiranuma, T. Watanabe, M. Kirihara, Heterocy-

cles 1994, 38, 243–248.

[29]

[30]

[31]

[52]

For simplicity, the usual drimane nomenclature and numbering

is used for all bicyclic compounds.

R. J. Linderman, E. A. Jamois, J. Fluorine Chem. 1991, 53, 79–

91.

[53] J. G. Urones, I. S. Marcos, B. G. Perez, A. M. Lithgow, D.

Diez, P. Basabe, P. M. Gomez, Tetrahedron Lett. 1994, 35,

3781–3784.

[54] W. A. Ayer, L. S. Trifonov, J. Nat. Prod. 1992, 55, 1454–1461.

[55] H. Gaspar, A. Cutignano, T. Ferreira, G. Calado, G. Cimino,

A. Fontana, J. Nat. Prod. 2008, 71, 2053–2056.

[56] V. J. Paul, Y. Seo, K. W. Cho, J. R. Rho, J. Shin, P. R. Berg-

quist, J. Nat. Prod. 1997, 60, 1115–1120.

[57]

According to the LUMO energy calculations, the LUMO en-

ergy of the π–CO bond is lowered by ca. 6.5 kcal/mol by the

effect of the fluorine atom. LUMO energies were determined

after optimizing the molecular geometry for 11 and 19, first,

by using the MM3 force-field and then by using MOPAC with

the standard PM3 parameter set (CAChe WorkSystem Pro

Version 7.5.0.85, Fujitsu Ltd., Tokyo, Japan). Most probably,

the long reaction time required for the complete conversion of

19 to 22 (see the Supporting Information) must also be due to

the acid–basic equilibrium that exists between the β-keto ester

moiety and the phosphorus ylide.

G. A. Kraus, X. Wang, Bioorg. Med. Chem. Lett. 2000, 10,

895–897.

[58] S. Yamauchi, Y. Kinoshita, Biosci. Biotechnol. Biochem. 1998,

62, 521–525.

[59] A. A. Wube, F. Bucar, S. Gibbons, K. Asres, Phytochemistry

2005, 66, 2309–2315.

[60] L. Hintermann, F. Lang, P. Maire, A. Togni, Eur. J. Inorg.

Chem. 2006, 7, 1397–1412.

[61]

[32]

[33]

[34]

M. Toyota, Y. Asakawa, T. Takemoto, Phytochemistry 1981, 20,

2359–2366.

V. Ragoussis, M. Liapis, N. Ragoussis, J. Chem. Soc., Perkin

Trans. 1 1987, 987–992.

a) C. J. Salomon, E. G. Mata, O. A. Mascaretti, J. Org. Chem.

1994, 59, 7259–7266; b) F. Fulop, M. Palko, E. Forro, M.

Dervarics, T. A. Martinek, R. Sillanpaa, Eur. J. Org. Chem.

2005, 3214–3220.

a) F. T. Luo, A. Jeevanandam, Tetrahedron Lett. 1998, 39,

9455–9456; b) P. Gmeiner, E. Hummel, C. Haubmann, Liebigs

Ann. 1995, 1987–1992.

[62] L. Moreno-Osorio, M. Cortes, V. Armstrong, M. Bailen, A.

Gonzalez-Coloma, Z. Naturforsch., Teil C, 2008, 63, 215–220.

[35]

[36]

[37]

[63]

[64]

[65]

[66]

[67]

[68]

H. H. Appel, J. D. Connolly, K. H. Overton, R. P. M. Bond, J.

Chem. Soc. 1960, 4685–4692.

G. J. Z. Gols, J. J. A. van Loon, L. Messchendorp, Entomol.

Exp. Appl. 1996, 79, 69–76.

a) J. Ichikawa, T. Mori, Y. Iwai, Chem. Lett. 2004, 33, 1354–

1355; b) J. Ichikawa, R. Nadano, N. Ito, Chem. Commun. 2006,

4425–4427; c) J. Ichikawa, G. Lapointe, Y. Iwai, Chem. Com-

mun. 2007, 2698–2700.

H. Ito, T. Muranaka, K. Mori, Z. X. Jin, H. Tokuda, H. Nish-

ino, T. Yoshida, Chem. Pharm. Bull. 2000, 48, 1190–1195, and

references cited therein.

J. Hellou, R. J. Andersen, J. E. Thompson, Tetrahedron 1982,

38, 1875–1879.

M. Toyota, Y. Ooiso, T. Kusuyama, Y. Asakawa, Phytochemis-

try 1994, 35, 1263–1965.

W. D. Chandler, Z. Wang, D. G. Lee, Can. J. Chem. 2005, 83,

1212–1221.

L. Messchendorp, G. J. Z. Gols, J. J. A. van Loon, Entomol.

Exp. Appl. 2000, 95, 217–227.

J. Justicia, E. Oltra, A. F. Barrero, A. Guadaño, A. Gonzalez-

Coloma, J. M. Cuerva, Eur. J. Org. Chem. 2005, 712–718.

M. D. Bentley, D. E. Leonard, W. F. Stoddard, L. H. Zalkow,

Ann. Entomol. Soc. Am. 1984, 77, 393–397.

P. Escoubas, L. Lajide, J. Mitzutani, Entom. Exp. Appl. 1993,

66, 99–107.

[38]

C. Gutierrez, A. Fereres, M. Reina, R. Cabrera, A. González-

Coloma, J. Chem. Ecol. 1997, 23, 1641–1650.

A. J. Sánchez, J. P. Konopelski, J. Org. Chem. 1994, 59, 5445–

5452.

L. N. Mander, R. J. Thomson, Org. Lett. 2003, 5, 1321–1324.

A. Abad, C. Agulló, A. C. Cuñat, I. A. Marzal, A. Gris, I.

Navarro, C. Ramírez de Arellano, Tetrahedron 2007, 63, 1664–

1679.

D. A. Evans, G. L. Carroll, L. K. Truesdale, J. Org. Chem.

1974, 39, 914–917.

a) M. Reina, A. González-Coloma, C. Gutiérrez, R. Cabrera,

M. L. Rodríguez, V. Fajardo, L. Villarroel, J. Nat. Prod. 2001,

[39]

[40]

[41]

[42]

[69]

[70]

[71]

[72]

For example, see: a) E. J. Corey, G. Luo, L. S. Lin, J. Am.

Chem. Soc. 1997, 119, 9927–9928; b) J. A. Bacigaluppo, M. I.

Colombo, J. Zinczuk, E. A. Ruveda, Synth. Commun. 1992, 22,

Eur. J. Org. Chem. 2010, 2182–2198

www.eurjoc.org

2197

A. Abad, C. Agulló, A. C. Cuñat, A. González-Coloma, D. Pardo

FULL PAPER

64, 6–11; b) A. González-Coloma, D. Terrero, A. Perales, P.

Escoubas, B. M. Fraga, J. Agric. Food Chem. 1996, 44, 296–

300; c) A. González-Coloma, C. Gutiérrez, J. M. M del Corral,

M. Gordaliza, M. L. de la Puente, A. San Feliciano, J. Agric.

Food Chem. 2000, 48, 3677–3681; d) A. González-Coloma, M.

Reina, R. Cabrera, P. Castañera, C. Gutiérrez, J. Chem. Ecol.

1995, 21, 1255–1270.

Received: December 23, 2009

Published Online: February 24, 2010

2198

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2182–2198

Article Doi

Preparation of 9α-fluorinated sesquiterpenic drimanes and evaluation of their antifeedant activities

DOI: 10.1002/ejoc.200901499

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.200901499

Full text of DOI:10.1002/ejoc.200901499

Products guided by the article

R&D Labs maybe for 112709-41-8

Relevant to this article

Hot Product