New route to herbertanes via a Suzuki cross-coupling reaction: Synthesis of herbertenediol

Article abstract of DOI:10.1016/S0040-4020(01)00987-5

The synthesis of herbertenediol, a relevant member of the herbertane-type sesquiterpene family, is described. The synthesis is based on a new general approach to this group of sesquiterpenes where the herbertane skeleton is constructed using a Suzuki cross-coupling reaction and a [2,3]-sigmatropic Still-Wittig rearrangement as key synthetic steps.

Full text of DOI:10.1016/S0040-4020(01)00987-5

TETRAHEDRON
Pergamon
Tetrahedron 57 52001) 9727±9735
New route to herbertanes via a Suzuki cross-coupling reaction:
synthesis of herbertenediol
p
Antonio Abad, Consuelo Agullo, Ana C. CunÄat, Diego Jimenez and Remedios H. Perni
Â
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Departamento de Quõmica Organica, Facultad de Quõmicas, Universidad de Valencia, C/Dr Moliner 50, E-46100 Burjassot, Valencia, Spain
Received 13 July 2001; revised 17 September 2001; accepted 10 October 2001
AbstractÐThe synthesis of herbertenediol, a relevant member of the herbertane-type sesquiterpene family, is described. The synthesis is
based on a new general approach to this group of sesquiterpenes where the herbertane skeleton is constructed using a Suzuki cross-coupling
reaction and a [2,3]-sigmatropic Still±Wittig rearrangement as key synthetic steps. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
sesquiterpenes based on a Suzuki reaction for the coupling
of the aryl and cyclopentane moieties. In this paper, we
describe the application of this approach to the synthesis
of herbertenediol 52).7
A family of sesquiterpenes sharing the hypothetical herber-
tane skeleton 51) has been isolated from several Herbertus
species and other liverworts.1,2 The synthesis of these
compounds has attracted the attention of numerous research
groups due to the signi®cant biological properties shown by
most of them and the dif®culties associated with the
construction of the vicinal quaternary centres on the ®ve-
membered ring.3 Surely, herbertenediol 52), isolated from
the liverwort Herbertus adunca,4 is the most relevant
member of this group of natural products. Herbertenediol
possesses signi®cant anti-fungal properties and exhibits a
potent anti-lipid peroxidation activity5 and may be con-
sidered as both the biosynthetic and chemical monomer
precursor of the also natural dimeric sesquiterpenes
known as mastigophorenes, a small group of compounds
that show interesting neurotro®c properties.6
2. Results and discussion
As shown in Scheme 1, the synthesis of the herbertane
framework is based on the preparation of key intermediate
allylic alcohol 3, which is obtained from readily available
materials using an intermolecular Suzuki cross-coupling
reaction.8 The allylic hydroxyl group of 3 is used to direct
the construction of the benzylic chiral carbon centre, thus
facilitating the stereoselective elaboration of the trimethyl-
cyclopentane nucleus of the target herbertane system.
The synthesis of intermediate 3 is outlined in Scheme 2. The
required arylboronic acid 6 was conveniently synthesised
from commercially available 1,2-dimethoxy-4-methyl-
benzene 55). Thus, 5 was subjected to regioselective
In connection with our studies on the synthesis of herber-
tanes, we have explored a new approach towards these
Scheme 1.
Keywords: terpenes; Suzuki reactions; rearrangements; cyclopropanes.
Corresponding author. Tel.: 134-96-3864509; fax: 134-96-3864328; e-mail: antonio.abad@uv.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020501)00987-5

9728
A. Abad et al. / Tetrahedron 57 12001) 9727±9735
Scheme 2. Reagents and conditions: 5a) iPr2EtN, Tf2O, CH2Cl2, 278 to 2408C, 95%; 5b) BuLi, THF rt, then B5OMe)3, then 5% aq HCl, 67%; 5c) BuLi, THF,
rt, then Me3SnCl, 08C, 65%; 5d) Pd5PPh3)4, aq. Na2CO3, dioxane, re¯ux, 98%; 5e) Pd25dba)3´CHCl3, NMP, rt, 60%; 5f) DIBAL-H, CH2Cl2, 2788C, 98%.
Scheme 3. Reagents and conditions: 5a) Et2Zn, CH2I2, CH2Cl2, rt, 93%; 5b) Et3N, MsCl, CH2Cl2, 08C, 56%; 5c) 5COCl)2, DMSO, CH2Cl2, 2608C then Et3N,
90%; 5d) Li, NH3±THF, 2788C, 80%.
metallation with BuLi and was then quenched with
B5OMe)3 and ®nally hydrolysed with aqueous HCl to afford
6 in 67% yield. The Suzuki cross-coupling of the aryl-
boronic acid 6 with the enol tri¯ate 7, prepared in 95%
yield from 2-methylcyclopentane-1,3-dione 54) and tri¯ic
anhydride-N,N-diisopropylethylamine,9 in the presence of
the Pd5PPh3)4/aqueous Na2CO3 catalyst system10 in dioxane
at re¯ux afforded the enone 8 in very high yield. Previously
to the above described Suzuki reaction, we also examined
the preparation of 8 via the palladium50)-catalysed reaction
of vinyl tri¯ate 7 with aryl trimethylstannane 9,11 prepared
from 5 in 65% yield by transmetallation of the organo-
lithium derived from 5 with trimethyltin chloride. Although
we investigated the optimisation of reaction conditions
by varying catalyst, solvent, reaction temperature, running
time and additives, the coupling between 7 and 9 was not
completely satisfactory. The best conditions [5%
Pd25dba)3´CHCl3, N-methyl-2-pyrrolidinone 5NMP), rt]12
provided a moderate 60±65% yield of 8, always accom-
panied by varying amounts of methyl transfer and stannane
homocoupling products 52,3-dimethylcyclopent-2-enone
and 2,3,20,30-tetramethoxy-5,50-dimethylbiphenyl, respec-
tively).
diisobutyl aluminium hydride 5DIBAL-H) in CH2Cl2 at
2788C.
²
Having completed the synthesis of alcohol 3, our attention
was turned towards the elaboration of the vicinal quaternary
centres on the ®ve-membered ring. Our initial synthetic
strategy for the construction of the ®rst quaternary carbon
atom was based on the cyclopropanation of the double bond
of 3 followed by regioselective exocyclic cleavage of a
cyclopropyl carbinyl radical.13 Towards this end, we set
out to transform 3 into thiocarbamate 11 5Scheme 3).
Although the double bond of 3 was stereoselectively cyclo-
propanated in high yield through a hydroxyl directed
Simmons±Smith cyclopropanation reaction,14 all attempts
to transform the resulting cyclopropyl alcohol 10 into the
thiocarbonyl imidazolide derivative 11 resulted in extensive
²
The complete sequence described here has been realized with racemic
alcohol 3 and, although only one enantiomer is represented, all the chiral
compounds that appear in the schemes are in fact racemic mixtures. The
application of this approach to the preparation of herbertenediol in opti-
cally active form should require enantiopure 5S)-3. This indeed was
prepared in 92% yield and 85±88% ee by the chiral-oxazaborolidine-
catalyzed borane reduction of ketone 8 5see Section 3). The enantioselec-
tive synthesis of 5S)-3 and the successful conversion of 5^)-3 into 5^)-2
described here, together establish a route for the enantioselective total
synthesis of herbertenediol in natural form.
Completion of the synthesis of allylic alcohol 3 was effected
in 98% yield by reduction of cyclopentenone 5 with

A. Abad et al. / Tetrahedron 57 12001) 9727±9735
9729
Scheme 4. Reagents and conditions: 5a) KH, THF, 08C then Me3SnCH2I, rt, 95%; 5b) BuLi, hexane, 2788C to 2108C, 55% of 16, 14% of 17, 21% of 3 and 4%
of 18; 5c) Et2Zn, CH2I2, CH2Cl2, rt, 76%; 5d) 5COCl)2, DMSO, CH2Cl2, 2608C then Et3N, 85%; 5e) NH2NH2, O5CH2CH2OH)2, NaOH, 1608C, 75%; 5f) H2,
PtO2, AcOH±NaOAc, 80%; 5g) BBr3, CH2Cl2, 08C, 82%.
Scheme 5.
formation of the ole®n 12. Thus, only a 27% of thiocarba-
mate 11 was obtained by reaction of cyclopropyl alcohol 10
and 5Im)2CvS under standard conditions.15 Similar results
were obtained when the formation of other derivatives of the
hydroxyl group of 10 was attempted 5e.g. the ole®n 12 was
the only compound identi®ed in the reaction of 10 with
mesyl chloride and triethylamine at 08C). The easy forma-
tion of 12 in these reactions is probably the result of the very
high stability of the benzylic tertiary cation originated upon
endocyclic opening of the cyclopropane ring and loss of the
leaving group.
occupied orbital,16 is completely altered in the case of the
cyclopropyl ketone 13 probably due to the presence of the
2,3-dimethoxy-5-methylphenyl substituent. Such thermo-
dynamic fragmentation has been previously reported for
other substituted cyclopropyl carbinyl radicals.17
In view of the above results, an alternative approach for the
construction of the quaternary benzylic carbon atom based
on a [2,3]-sigmatropic Still±Wittig rearrangement was
explored.18 Towards this end, the alcohol 3 was transformed
into the allyl stannylmethyl ether 15 by deprotonation with
potassium hydride followed by alkylation with iodomethyl-
trimethyltin 5Scheme 4).19
In view of the dif®culties we found in the preparation from 3
of a suitable precursor of the cyclopropyl carbinyl radical,
we examined the cyclopropane ring cleavage of the cyclo-
propyl ketone 13. Oxidation of 10 with oxalyl chloride
and DMSO afforded the ketone 13 in 90% yield together
with minor amounts 5up to 5%) of the cyclohexadiene 12.
Unfortunately, reductive cleavage of the cyclopropyl ketone
moiety of 13 with lithium in liquid NH3 afforded exclusively
the product of the endocyclic cyclopropane ring opening,
the a-methyl cyclohexenone 14 as a 2:1 mixture of epimers
in 80% yield. It is obvious from the above result that the
usually favoured kinetic exocyclic bond cleavage of cyclo-
propanes fused to another ring, which has been attributed to
the better overlap of this bond with the adjacent singly
Treatment of 15 with BuLi in hexane at 2788C generated
the a-lithioether that underwent a smooth [2,3]-sigmatropic
rearrangement upon warming to 2108C overnight to deliver
the homoallylic alcohol 16 in 55% overall yield after
column chromatography, together with a 3:2mixture of
allylic alcohol 3 and the product of [1,2]-rearrangement
17 in 35% yield, and a small amount of the methyl ether
18 5up to 5%).20³ It should be mentioned that the formation
of the [1,2]-rearrangement product in this reaction was not
³
The result of this reaction was very little different when the reaction was
done with the 5tributylstannanyl)methyl allyl ether 515, RvOCH2SnBu3).

9730
A. Abad et al. / Tetrahedron 57 12001) 9727±9735
Scheme 6. Formation of 23.
unexpected in view of the results which are often observed
in the rearrangement of related b-substituted cyclic allylic
systems18a,21 and the presumably stability of the radical
intermediate through which this rearrangement takes places
5e.g. radical i±ii in Scheme 5).22
In conclusion, we have developed a new approach to the
construction of the bicyclic herbertane system, based on a
Suzuki cross-coupling reaction and a [2,3]-sigmatropic
Still±Wittig rearrangement, which has culminated in the
synthesis of herbertenediol 52) and may be easily adapted
for the synthesis of other natural herbertanes and related
sesquiterpenes.
In any case, completion of the synthesis of the herbertane
system was effected as follows. First 16 was submitted to
Simmons±Smith cyclopropanation conditions to cyclopro-
panate the double bond, an indirect way of introducing the
geminal dimethyl group at C-2of the herbertane system.
Thus, treatment of 16 with diiodomethane and diethyl zinc
under the same conditions used previously for the con-
version of 3 into 10 afforded the cyclopropane 19 in 76%
yield. Although irrelevant from the synthetic point of view,
the cyclopropanation reaction of 16 also took place stereo-
selectively, syn to the homoallylic hydroxyl group, as shown
by the NOE observed between the hydrogen of the cyclo-
propane ring at d 0.50 ppm and the hydroxymethyl group at
3.93 ppm.
3. Experimental
3.1. General experimental details
Melting points were determined using a Ko¯er hot-stage
apparatus and are uncorrected. Optical rotations were deter-
mined using a 5 cm path length cell. [a]D values are given in
1
units of 1021 deg cm2 g21. All H spectra were recorded in
CDCl3 at 300 or 400 MHz, and all 13C at 75 MHz. Complete
assignment for compounds 10, 19 and 23 was made on the
basis of a combination of HMQC, HMBC and NOE experi-
ments. Mass spectra were obtained by electron impact 5EI)
at 70 eV. IR spectra were measured as KBr pellets or liquid
®lms. All reactions were carried out under an inert atmos-
phere of dry argon using oven-dried glassware and freshly
distilled and dried solvents. Column chromatography refers
to ¯ash chromatography and was performed on Merck silica
gel 60, 230±400 mesh.
Swern oxidation of 19 under standard conditions23 provided
the aldehyde 20, which upon Huang±Minlon reduction24 of
the formyl group to methyl afforded the cycloherbertane 21
in ca. 64% overall yield. The following step, the opening of
the cyclopropane ring into a gem-dimethyl group, proved to
be more problematic than initially expected, and appropriate
conditions had to be found. The best results were obtained
by stirring a solution of 21 in AcOH±NaOAc and 3 equiv.
of PtO2 under an atmosphere of H2 51.6 atm.) at room
temperature for several days. Under these conditions, the
cyclopropane hydrogenation proceeded very smoothly,
less than 10% of products originated from reduction of the
aromatic moiety were formed and the compound 22 was
obtained in 80% yield after chromatographic puri®cation.
The use of the acetate buffer was crucial for the success of
the above hydrogenolysis, since in the absence of NaOAc it
was not possible to avoid the over-reduction of the aromatic
ring and the formation of complex diastereoisomeric
mixtures of products.25§
3.1.1. Tri¯uoromethanesulfonic acid 2-methyl-3-oxo-
cyclopent-1-enyl ester /7). N,N-Diisopropylethylamine
50.356 mL, 2.051 mmol) was added to a suspension of dike-
tone 4 5100 mg, 0.892mmol) in anhydrous CH 2Cl2 56 mL).
The resulting pale orange solution was cooled to 2788C and
treated dropwise with tri¯ic anhydride. 50.175 mL, 1.043
mmol). The mixture was allowed to warm to 2408C over
1 h before being quenched with water and extracted with
CH2Cl2. The combined organic extracts were washed with
brine, dried 5Na2SO4) and then evaporated in vacuo.
Chromatography of the residue on silica gel using
hexane±CH2Cl2 51:1) as eluent gave the tri¯ate 7
5208 mg, 95%) as a pale brown oil: IR nmax 5®lm) 1725,
1682, 1429, 1384, 1245, 1216 1139 cm21 1H NMR
;
Final conversion of dimethyl ether 22 into herbertenediol
was easily effected by removal of the methyl groups with
BBr3 as described in previous syntheses.7
5300 MHz, CDCl3) dH 2.9±2.8 52H, m, H2-5), 2.7±2.6
52H, m, H2-4), 1.77 53H, dd, Jˆ2.4, 1.8 Hz, Me-2); 13C
NMR 575 MHz, CDCl3) dC 203.1 5C3), 172.1 5C1), 130.0
5C2), 118.3 5q, Jˆ319 Hz, CF3), 34.8 5C4), 26.9 5C5), 6.6
5Me-2); MS 5EI) 5relative intensity): 244 5M1, 100), 175
519), 111 527) and 69 561); HRMS, calcd for C7H7O4F3S
244.0017, found 244.0015.
§
We also attempted the hydrogenolysis of the cyclopropane ring of 19 to
form the gem-dimethyl group before the conversion of the hydroxymethyl
group into the methyl group. The hydrogenation of 19 with PtO2 as
catalyst and AcOH as solvent afforded a mixture of products from
which the bridged ether 23 5see Scheme 6) was identi®ed as the main
product formed 548% yield). The structural assignment of 23 was based
on a detailed spectroscopic study that included NOE experiments. Spec-
troscopic data and experimental details for the preparation of 23 are given
in Section 3.
3.1.2. /2,3-Dimethoxy-5-methylphenyl)boronic acid /6).
Butyl lithium 51.6 M in hexane, 17.2mL, 27.59 mmol)
was added to a solution of 1,2-dimethoxi-4-methylbenzene

A. Abad et al. / Tetrahedron 57 12001) 9727±9735
9731
55) 53.0 g, 19.71 mmol) in THF 518 mL) at 08C. The mixture
was stirred for 1 h at room temperature. The white slurry
was slowly transferred into a solution of B5OMe)3 54.4 mL,
39.42mmol) in THF 59 mL) at 2788C. The resulting
mixture was allowed to warm to room temperature and
stirred overnight and then HCl 55%, 22 mL) was added to
the mixture and stirred for 15 min. It was then poured into
H2O and extracted with CH2Cl2. The extract was washed
with brine and dried 5Na2SO4). Evaporation of the solvent
furnished a solid residue which was chromatographed using
hexane±ethyl acetate 58:2) as eluent to give arylboronic acid
6 52.58 g, 67%) as colourless crystals; mp 123.5±124.88C
5from hexane±ethyl acetate); IR nmax 5KBr) 3429, 3344,
5from hexane±ether); IR nmax 5KBr) 3072, 2997, 2966,
2938, 2841, 1692, 1644, 1584, 1481, 1352, 1120, 1062,
1
1007 cm21; H NMR 5300 MHz, CDCl3) dH 6.75 51H, brs,
H-60), 6.53 51H, brs, H-40), 3.87 and 3.67 53H each, each s,
2£MeO), 2.89±2.82 52H, m, H2-4), 2.53±2.48 52H, m,
H2-5), 2.33 53H, s, Me-50), 1.71 53H, t, Jˆ2.1 Hz, Me-2);
13C NMR 575 MHz, CDCl3) dC 210 5C1), 167.5 5C3), 152.7
5C20), 144.0 5C30), 138.4 5C2), 134.0 5C50), 131.0 5C10),
0
120.4 5C60), 113.6 5C40), 61.25MeO-2 ), 55.8 5MeO-30),
34.4 5C5), 30.8 5C4), 21.3 5Me-50), 9.4 5Me-2); MS 5EI)
m/z 5relative intensity) 246 5M1, 100), 231 58), 203 520),
189 566), 175 56); HRMS, calcd for C15H18O3 246.1256,
found 246.1251.
1
1583, 1475, 1432, 1405, 1349, 1271, 1043 cm21; H NMR
5300 MHz, CDCl3) dH 7.21 and 6.86 51H each, each s, H-4
and H-6), 6.77 52H, brs, 2£OH), 3.91 and 3.87 53H each, s
each, 2£OMe), 2.33 53H, s, Me-5); 13C NMR 575 MHz,
CDCl3) dC 152.1 and 151.1 5C2 and C3), 134.4£2
5C1 and C5), 127.4 5C6), 116.6 5C4), 61.4 5MeO-C2),
55.6 5MeO-C3), 21.1 5Me-5); MS 5EI) m/z 5relative
intensity) 196 5M1, 100), 195 526), 181 548), 153 538),
149 550); HRMS, calcd for C9H13BO4 196.0907, found
196.0906.
From 7 and 9. Tri¯ate 7 5603 mg, 2.47 mmol) and
Pd25dba)3´CHCl3 5116 mg, 0.112mmol) were dissolved in
anhydrous degassed NMP 510 mL). After 10 min, a
degassed solution of stannane 9 5705 mg, 2.24 mmol) in
NMP 54 mL) was added and the mixture was stirred at
room temperature for 3 h. The resulting brownish reaction
mixture was poured into water and extracted with CH2Cl2.
The combined organic extracts were washed with water then
brine and dried 5MgSO4). The solution was concentrated
under reduced pressure and the residue obtained puri®ed
by ¯ash chromatography using hexane±ether 57:3) as eluent
to afford, in order of elution, 40.5 mg 56%) of the homo-
coupling product 2,3,20,30-tetramethoxy-5,50-dimethyl-
biphenyl and 454.8 mg of a 5:1 mixture of 8 and
2,3-dimethylcyclopent-2-enone as a semisolid. This mixture
was suspended in cold pentane and ®ltered off to afford
nearly pure 8 5329.7 mg, 60%) as a white solid.
3.1.3. /2,3-Dimethoxy-5-methylphenyl)trimethylstannane
/9). A solution of 5 5500 mg, 3.28 mmol) in THF 53.5 mL)
was treated with BuLi 51.6 M in hexane, 2.66 mL,
4.26 mmol) as above. The resulting suspension was cooled
to 08C and treated with a solution of Me3SnCl 51.05 g,
5.25 mmol) in THF 51.9 mL). The mixture was left stirring
at ambient temperature for 2h, poured into saturated
aqueous NH4Cl solution and extracted with CH2Cl2. The
combined extracts were washed with brine and dried
5Na2SO4). Evaporation of the solvent followed by ¯ash
chromatography, using 95:5 hexane±ethyl acetate contain-
ing 1% Et3N, gave the stannane 9 5671 mg, 65%) as a
3.1.5.
3-/20,30-Dimethoxy-50-methylphenyl)-2-methyl-
cyclopent-2-enol /3). Preparation of 5^)-3. To a solution
of enone 8 5104 mg, 0.423 mmol) in CH2Cl2 52mL), cooled
to 2788C, DIBAL-H 50.634 mL, 0.634 mmol of 1 M in
cyclohexane) was added. The solution was stirred at
2788C for 1 h and then water was added and the mixture
was extracted with CH2Cl2. Workup and ¯ash chroma-
tography 51:1 hexane±ether) afforded the alcohol 3
5102.5 mg, 98%) as a colourless oil; IR nmax 5®lm) 3407,
2934, 2855, 1583, 1481, 1464, 1425, 1349, 1230, 1127,
1
colourless oil; H NMR 5300 MHz, CDCl3) dH 6.75 and
6.73 51H each, each s, H-4 and H-6), 3.85 and 3.81 53H
each, s, 2£MeO), 2.33 53H, s, Me-5), 0.29 59H, s,
Me3Sn); 13C NMR 575 MHz, CDCl3) dC 151.3 and 151.0
5C2and C3), 135.3 and 134.25C1 and C5), 127.7 5C6),
114.2 5C4), 60.8 5MeO-2), 55.3 5MeO-3), 21.1 5Me-5), 8.9
5Me3Sn); MS 5FAB) m/z 5relative intensity) 316 5M1, 33),
301 5100), 286 512), 271 54), 256 52); HRMS, calcd for
C12H20O2Sn 316.0485, found 316.0476.
1
1012cm 21; H NMR 5300 MHz, CDCl3) dH 6.66 51H, brs,
H-60) 6.53 51H, brs, H-40), 4.74 51H, m, H-1), 3.85 53H, s,
MeO-20), 3.68 53H, s, MeO-30), 2.31 53H, s, Me-40), 1.71
53H, t, Jˆ2.1 Hz, Me-2); 13C NMR 575 MHz, C6D6)] dC
153.1 5C20), 145.7 5C30), 138.0 5C3), 136.8 5C2), 132.9
5C50), 132.8 5C10), 122.6 5C60), 112.7 5C40), 80.9 5C1),
60.4 5MeO-20), 55.3 5MeO-30), 35.1 5C4), 33.6 5C5), 21.1
5Me-50), 12.5 5Me-2); MS 5EI) m/z 5relative intensity) 248
5M1, 68), 230 5100), 233 580), 215 538); HRMS, calcd for
C15H20O3 248.1412, found 248.1403.
3.1.4.
3-/20,30-Dimethoxy-50-methylphenyl)-2-methyl-
cyclopent-2-enone /8). From 6 and 7. To a mixture of
boronic acid 6 5964 mg, 4.92mmol) and Pd5PPh 3)4
5106 mg, 0.092mmol) in degassed dioxane 530 mL), an
aqueous solution of Na2CO3 52M, 4.5 mL, 9.02mmol),
which has been previously purged with nitrogen, and the
tri¯ate 7 51.32g, 5.41 mmol) were added. The resulting
mixture was rigorously degassed by the freeze±thaw
process and then heated at re¯ux for 3 h. The reaction
mixture was cooled down to 108C, and 35% H2O2 512
drops) was added carefully. When the gas evolution ceased,
the reaction mixture was poured into water and extracted
with CH2Cl2. The organic layer was washed successively
with water and brine, and dried 5Na2SO4). Evaporation of
the solvent and puri®cation of the residue over a silica gel
column, using CH2Cl2±ether 59:1) as eluent, furnished the
enone 8 51.185 g, 98%) as a white solid; mp 109.2±110.38C
Preparation of 52)-5S)-3. A solution of BH3´THF in THF
51 M, 0.113 mL, 0.113 mmol) was added to a solution of
5R)-2-methyl-CBS-oxazaborolidine in toluene 51 M, 0.225
mL, 0.225 mmol) at 08C.26 After stirring at room tempera-
ture for 20 min, the mixture was cooled again to 08C and a
solution of the enone 8 527.7 mg, 0.113 mmol) in THF
51.2mL) was added over 2.30 h. After 30 min of additional
stirring at the same temperature, the reaction mixture was
quenched with MeOH 50.2mL). The solvents were
evaporated under reduced pressure and the residue was

9732
A. Abad et al. / Tetrahedron 57 12001) 9727±9735
chromatographed on silica gel with hexane±ether 51:1) as
eluent to give 5S)-3 525.1 mg, 90%) as a colourless oil,
575 MHz, C6D6) dC 152.8 5C2), 144.8 5C1), 137.8 5C10),
134.3 5C30), 133.9 and 132.3 5C3 and C5), 123.7 5C40),
122.3 5C4), 118.0 5C20),112.4 5C6), 61.2 5MeO-2), 56.2
5MeO-1), 34.8 5C60), 28.4 5C50), 23.6 5Me-30), 21.7 5Me-
5); MS 5EI) m/z 5relative intensity) 244 5M1, 42), 242 5100),
227 562), 212 541), 179 550), 91 57); HRMS, calcd for
C16H20O2 244.1463, found 244.1462.
25
[a]D ˆ21.58 5c 1.6, CHCl3). The enantiomeric excess
1
5ee) was determined by H and 19F NMR analysis in C6D6
of the 5R)-51)-a-methoxy-a-tri¯uoromethylphenylacetic
acid ester of 5S)-3.27 Thus, when the 1H NMR was recorded
on a racemic mixture of 3, two peaks corresponding to the
two methyl groups at C-2of both diastereomers were
observed at d 1.57 and 1.68 ppm, allowing an easy measure-
ment of the diastereomeric excess 5de). This NMR analysis
gave a de of 85±88% for the 5R)-MTPA-ester of 5S)-3 and
so an 85±88% ee for 5S)-3. A similar ee was also determined
from the analysis of the 19F NMR, in which the peaks corre-
sponding to the CF3 group at C-2of both enantiomers are
also well differentiated.
3.1.8.
5-/20,30-Dimethoxy-50-methylphenyl)-1-methyl-
bicyclo[3.1.0]hexan-2-one /13). To a stirred, cooled
52608C) solution of oxalyl chloride 518 mL, 0.21 mmol)
in CH2Cl2 50.5 mL), a solution of DMSO 532 ml, 0.45
mmol) in CH2Cl2 50.2mL) was added dropwise. The
mixture was stirred at 2608C for 10 min, followed by
dropwise addition of a solution of 10 549.2mg, 0.19
mmol) in CH2Cl2 50.2mL). After the mixture was stirred
at the same temperature for 30 min, triethylamine 5131 ml,
0.94 mmol) was added and stirring was continued for 5 min.
The mixture was then allowed to warm up slowly to room
temperature over 2h. Saturated aqueous NaHCO 3 was
added to the mixture and extracted with CH2Cl2. The
combined organic layers were washed with brine and
dried. Chromatography of the residue left after evaporation
of the solvent, using hexane±ethyl acetate 575:25) as eluent,
provided the enone 13 544 mg, 90%) as a white solid; mp
94±958C 5from hexane); IR nmax 5KBr) 2966, 2936, 1718,
1585, 1487, 1464, 1427, 1371, 1233, 1143, 1079, 1009,
3.1.6.
5-/20,30-Dimethoxy-50-methylphenyl)-1-methyl-
bicyclo[3.1.0]hexan-2-ol /10). To a cooled 508C) solution
of diethylzinc 51.0 M solution in hexane, 1.64 mL,
1.64 mmol) in CH2Cl2 52mL), diiodomethane 50.132mL,
1.64 mmol) was added. After stirring for 30 min at the same
temperature, a solution of the alcohol 3 581.4 mg,
0.328 mmol) in CH2Cl2 52ml) was added. The mixture
was allowed to warm to room temperature over 2h, before
being quenched with saturated aqueous NH4Cl solution and
extracted with diethyl ether. The organic extracts were
washed with saturated aqueous Na2SO3 solution, water
and brine, dried, and concentrated to give an oil. Flash
chromatography, using hexane±ethyl acetate 51:1) as
eluent, yielded alcohol 10 580.0 mg, 93%) as a solid; mp
76.2±76.88C 5from hexane±ether); IR nmax 5KBr) 3392,
3058, 2956, 2926, 2866, 1585, 1485, 1464, 1462, 1308,
1
838 cm21; H NMR 5300 MHz, CDCl3) dH 6.69 51H, brs,
H-60), 6.60 51H, brs, H-40), 3.84 56H, s, 2£MeO), 2.30 53H,
s, Me-50), 2.27±2.13 54H, m, H2-3 and H2-4), 1.44 and 1.32
51H each, each d, Jˆ4.7 Hz, H2-6), 1.0253H, s, Me-1); 13C
NMR 575 MHz, CDCl3) dC 216.1 5C1), 152.3 5C30), 146.6
5C20), 133.1 and 132.8 5C10 and C50), 123.3 5C60), 112.8
5C40), 61.0 5MeO-20), 55.7 5MeO-30), 40.1 5C5), 38.5 5C1),
32.8 5C4), 29.4 5C3), 25.2 5C6), 21.2 5Me-50), 12.0 5Me-1);
MS 5EI) m/z 5relative intensity) 260 5M1, 100), 245 517),
203 527); HRMS, calcd for C16H20O3 260.1412, found
260.1420.
1
1142, 1095, 1040, 1014 cm21; H NMR 5300 MHz, C6D6):
dH 6.63 51H, brs, H-60), 6.40 51H, brs, H-40), 4.34 51H, m,
CH-2), 3.75 53H, s, MeO-20), 3.30 53H, s, MeO-30), 2.12
53H, s, Me-50), 2.07 51H, m, H-4), 1.85 52H, m, H-3, H-4),
1.11 53H, s, Me-1), 1.1 51H, m, H-3), 1.00 and 0.51 51H
each, each d, Jˆ5.1 Hz, H2-6); 13C NMR 575 MHz, C6D6)
dC 152.7 5C30), 147.7 5C20), 135.3 and 132.3 5C10 and C50),
124.3 5C60), 112.7 5C40), 79.1 5C2), 60.5 5MeO-20), 55.2
5MeO-30), 34.9 and 34.25C5 and C1), 3.24 5C4), 30.5
5C3), 21.1 5Me-50), 17.1 5Me-1), 15.9 5C6); MS 5EI) m/z
5relative intensity) 262 5M1, 77), 244 5100), 229 540), 203
552), 178 536); HRMS, calcd for C16H22O3 262.1569, found
262.1563.
3.1.9.
4-/20,30-Dimethoxy-50-methylphenyl)-2-methyl-
cyclohexanone /14). To a cooled 52788C) solution of
lithium 510 mg, 1.5 mmol) in liquid NH3 55 mL), a solution
of 13 526.6 mg, 0.1 mmol) in THF 51.5 mL) was added over
a period of 15 min. After 15 min, NH4Cl was added to the
reaction mixture and the solvent was removed. The residue
was dissolved in water and extracted with EtOAc. The
organic layer was washed with water and brine, dried
5MgSO4), and evaporated. Puri®cation by chromatography,
using hexane±ethyl acetate 575:25) as eluent, furnished the
ketone 14 521.2 mg, 80%) as a 3:1 mixture of epimers at
C-2; IR nmax 5KBr) 2960, 2931, 2861, 1713, 1589, 1489,
1464, 1429, 1377, 1324, 1305, 1228, 1147, 1066, 1011,
834 cm21; 1H NMR 5300 MHz, CDCl3) dH 5major isomer):
6.61 51H, brs, H-60), 6.57 51H, brs, H-40), 3.85 and 3.84 53H
each, each s, 2£MeO), 3.55 51H, m, H-2), 2.29 53H, s,
Me-50), 1.06 53H, d, Jˆ6.4 Hz, Me-2); 13C NMR
575 MHz, CDCl3) 5major isomer): dC 213.0 5C1), 152.3
5C30), 144.1 5C20), 137.8 5C10), 133.8 5C50), 118.7 5C60),
3.1.7. 1,2-Dimethoxy-5-methyl-3-/30-methylcyclohexa-
10,30-dienyl)benzene /12). Triethylamine 50.11 mL,
0.72mmol) and methanesulfonyl chloride 530 mL, 0.4
mmol) were added to a solution of 10 530 mg, 0.12mmol)
in CH2Cl2 51 mL) at 08C. The mixture was stirred at the
same temperature for 40 min, and water was added. After
extraction with CH2Cl2, the organic layer was washed with
brine and dried over Na2SO4, and the solvent was evapo-
rated under reduced pressure. Flash chromatography, using
hexane±ethyl acetate 53:2) as eluent, yielded diene 12
515.6 mg, 56%) as a colourless liquid; IR nmax 5®lm)
2926, 2854, 2823, 1584, 1482, 1464, 1425, 1341, 1329,
1
1248, 1231, 1148, 1014, 833 cm21; H NMR 5300 MHz,
111.25C4 ), 61.1 5MeO-20), 55.6 5MeO-30), 44.9 5C2), 36.0
0
C6D6) dH 6.65 51H, brs, H-4), 6.60 51H, brs, H-6), 5.78
51H, brs, H-20), 5.45 51H, m, H-40), 3.85 and 3.73 53H
each, each s, 2£MeO), 2.89 54H, m, H2-50 and H2-60),
2.30 53H, s, Me-5), 1.72 53H, s, Me-30); 13C NMR
5C4), 42.8, 41.7 and 34.3 5C3, C5 and C6), 21.5 5Me-50),
14.5 5Me-2); MS 5EI) m/z 5relative intensity) 262 5M1, 100),
247 54), 178 552); HRMS, calcd for C16H22O3 262.1569,
found 262.1567.

A. Abad et al. / Tetrahedron 57 12001) 9727±9735
9733
3.1.10. [3-/20,30-Dimethoxy-50-methylphenyl)-2-methyl-
cyclopent-2-enyloxymethyl] trimethylstannane /15). To
a stirred slurry of pre-washed 5pentane) potassium hydride
540% dispersion oil; 36.3 mg, 0.90 mmol) in THF 51 mL), a
solution of 3 5150 mg, 0.60 mmol) in THF 51 mL) was
added. After the hydrogen evolution had ceased, a solution
of Me3SnCH2I 5329 mg, 1.08 mmol) in THF 50.6 mL) was
added and the mixture was stirred at room temperature for
1 h. The mixture was cooled to 08C and carefully treated
with saturated aqueous NH4Cl solution followed by extrac-
tion with diethyl ether. The organic extracts were washed
with water and brine, dried 5Na2SO4), and concentrated to
give an oil. Flash chromatography, using hexane±ether
59:1) as eluent afforded the stannane 15 5244.2 mg, 95%)
as a yellowish oil; IR nmax 5®lm) 2955, 2932, 2857, 1698,
1583, 1482, 1464, 1351, 1230, 1128, 1052, 1015, 834,
1460, 1344, 1001, 908, 777, 730 cm21; 1H NMR 5400 MHz,
CDCl3) dH 6.63 51H, brs, H-60), 6.51 51H, brs, H-40), 3.85
53H, s, MeO-20), 3.73 51H, dd, 11.7, 12.6 Hz, OCH2), 3.72
51H, dd, 11.7, 11.7 Hz, OCH0 ), 3.68 53H, s, MeO-30), 2.85
2
51H, m, CH), 2.56±2.74 52H, m), 2.1±2.2 51H, m), 1.82±1.9
51H, m), 2.30 53H, brs, Me-50), 1.60 53H, dd, 2.4, 1.6 Hz,
Me-2); 13C NMR 575 MHz, CDCl3) dC 152.38 5C30), 144.30
5C20), 136.33, 134.86, 133.29 and 132.62 5C2, C3, C10 and
C50), 122.12 5C60), 111.80 5C40), 64.84 5CH2O), 60.62
5MeO-20), 55.69 5MeO-30), 52.44 5C1), 36.84 5C4), 26.36
5C5), 21.27 5Me-50), 13.49 5Me-2); HRMS, calcd for
C16H22O3 262.1569, found 262.1558.
For 18: IR nmax 5®lm) 2933, 2873, 2822, 1730, 1585, 1482,
1
1464, 1353, 1231, 1129, 1014, 834, 780 cm21; H NMR
5300 MHz, CDCl3) dH 6.65 51H, brs, H-60), 6.53 51H, brs,
H-40), 4.40 51H, brs, H-1), 3.80 53H, s, MeO-20), 3.70 53H, s,
MeO-30), 3.41 53H, s, MeO-1), 2.8±2.5 52H, m), 2.31 53H, s,
Me-50), 2.20 51H, m), 1.80 51H, m), 1.70 53H, brs, Me-2);
13C NMR 575 MHz, CDCl3) dC 152.4 5C30), 144.6 5C20),
137.6, 135.7, 133.2 and 132.2 5C2, C3, C10 and C50), 122.1
5C60), 111.9 5C40), 89.4 5C1), 60.8 5MeO-20), 55.7
5MeO-30), 55.2 5MeO-1), 35.0 5C4), 28.5 5C5), 21.2
5Me-50), 15.3 5Me-2); MS 5EI) m/z 5relative intensity) 262
5M1, 52), 247 5100), 231 556), 230 550), 77 57); HRMS,
calcd for C16H22O3 262.1569, found 262.1558.
1
767 cm21; H NMR 5400 MHz, CDCl3) dH 6.65 51H, d,
0
0
Jˆ2Hz, H-6 ), 6.53 51H, d, Jˆ2Hz, H-4 ), 4.38 51H, brt,
H-1), 3.84 53H, s, MeO-20), 3.66 53H, s, MeO-30), 3.77 and
3.6251H each, each d, Jˆ10.4 Hz, OCH2Sn), 2.7 51H, m),
2.6 51H, m), 2.30 53H, s, Me-50), 2.2 51H, m), 1.8 51H, m),
1.64 53H, s, Me-2), 0.14 59H, s, Me3Sn); 13C NMR 575 MHz,
CDCl3) dC 152.4 5C30), 144.6 5C20), 137.1, 136.0, 133.2and
132.3 5C3, C2, C50 and C10), 122.2 5C60), 111.8 5C40), 91.2
5C1), 60.8 5MeO-20), 58.25O CH2Sn), 55.7 5MeO-30), 35.1
5C4), 28.0 5C5), 21.3 5Me-50), 12.8 5Me-2), 210.3 5Me3Sn);
MS 5EI) m/z 5relative intensity) 425 5M1, 29), 410 57), 395
520), 318 5100); HRMS, calcd for C19H31O3Sn 425.1289,
found 425.1293.
3.1.12. [2-/20,30-Dimethoxy-50-methyl-phenyl)-1-methyl-
bicyclo[3.1.0]hex-2-yl]methanol /19). Cyclopropanation
of cyclopentene 16 596.5 mg, 0.38 mmol) in the same way
as for 3 afforded, after puri®cation by chromatography using
hexane±ethyl acetate 58:2) as eluent, the cyclopropane±
alcohol 19 577.2mg, 76%) as a white solid; mp 80±81 8C
5from hexane); IR nmax 5®lm) 3514, 3059, 2997, 2934, 2868,
2833, 1603, 1582, 1478, 1463, 1414, 1324, 1229, 1147,
3.1.11. [1-/20,30-Dimethoxy-50-methylphenyl)-2-methyl-
cyclopent-2-enyl]methanol /16). A solution of trimethyl-
stannane 15 5145 mg, 0.34 mmol) in hexane 53.3 mL) was
treated dropwise with BuLi 51.6 M in hexane, 0.23 mL,
0.37 mmol) at 2788C. After 2h at the same temperature,
the mixture was allowed to warm slowly to 2108C over-
night. The reaction was quenched with water and extracted
with diethyl ether. The combined organic extracts were
dried 5MgSO4) and then evaporated under reduced pressure.
Flash chromatography of the residue, using hexane±ethyl
acetate 5from 8:2to 6:4) as eluent, gave, in order of elution,
methyl ether 18 53.6 mg, 4%), the [2,3]-rearrangement
1006, 835 cm21 1H NMR 5400 MHz, CDCl3) dH 6.86
;
51H, brs, H-60), 6.64 51H, brs, H-40), 4.11 51H, dd, Jˆ
11.6, 7.1 Hz, CH2O), 3.93 51H, dd, Jˆ11.6, 8.3 Hz,
CH2O), 3.86 53H, s, MeO-30), 3.84 53H, s, MeO-20), 3.19
51H, dd, Jˆ8.3, 7.1 Hz, OH), 2.33 53H, s, Me-50), 2.01 and
1.66 51H each, each m, CH2), 1.43±1.16 53H, m, CH2 and
H-5), 1.13 53H, s, Me-1), 0.50 51H, t, Jˆ5.0 Hz, H-6), 0.37
51H, ddd, Jˆ7.9, 5.0, 0.8 Hz, H-6); 13C NMR 575 MHz,
1
product 16 549.0 mg, 55%) and a 3:2mixture 5 H NMR
0
CDCl3) dC 153.0 5C30), 143.9 5C20), 137.3 and 133.25C5
analysis) of alcohols 3 and the [1,2]-rearrangement product
17 531.1 mg, 35%). Compound 17 was separated from
the above mixture with 3 by MPLC chromatography,
using hexane±ethyl acetate 58:2) as eluent.
and C10), 123.2 5C60), 110.8 5C40), 68.7 5CH2O), 61.3
5MeO-20), 55.6 5MeO-30), 54.4 5C2), 35.2 5C3), 26.6 5C4),
33.1 5C1), 28.2 5C5), 21.9 5Me-50), 19.5 5Me-1), 14.3 5C6);
MS 5EI) m/z 5relative intensity) 276 5M1, 49), 258 546), 245
5100), 231 530), 208 555), 165 558); HRMS, calcd for
C17H24O3 276.1725, found 276.1728.
For 16: colourless oil; IR nmax 5®lm) 3457, 3032, 2934,
2851, 1583, 1480, 1464, 1416, 1316, 1233, 1149, 1012,
1
834, 780 cm21; H NMR 5300 MHz, CDCl3) dH 6.63 51H,
brs, H-60), 6.50 51H, brs, H-40), 5.70 51H, bs, H-3), 3.96 52H,
m, CH2O), 3.84 53H, s, MeO-20), 3.81 53H, s, MeO-30),
2.37±2.00 54H, m), 2.30 53H, s, Me-50), 1.65 53H, m,
Me-2); 13C NMR 575 MHz, CDCl3) dC 152.9 5C30), 145.2
5C20), 142.6 5C2), 137.4 and 133.1 5C10 and C50), 128.8
5C3), 121.2 5C60), 111.5 5C40), 66.9 5CH2O), 60.7 5MeO-
20), 60.0 5C1), 55.6 5MeO-30), 36.8 and 30.5 5C4 and C5),
21.6 5Me-2), 14.1 5Me-50); MS 5EI) m/z 5relative intensity)
262 5M1, 26), 232 533), 231 5100), 200 513), 175 519);
HRMS, calcd for 262.1569 C16H22O3, found 262.1559.
3.1.13. 4-/20,30-Dimethoxy-50-methyl-phenyl)-1,7-dimethyl-
2-oxa-bicyclo[2.2.1]heptane /23). To a solution of cyclo-
propane±alcohol 19 59.5 mg, 0.035 mmol) in AcOH 51 mL)
was added a catalytic amount of PtO2 530 mg), and the
resulting suspension was stirred under a hydrogen atmos-
phere 54 atm.) for 15 h. The catalyst was removed by ®l-
tration and the ®ltrate was concentrated to give the crude
product that was puri®ed by ¯ash chromatography, with
pentane±ether 57:3) as eluent, to give the compound 23
54.6 mg, 48%) as a colourless oil; IR nmax 5®lm) 2963,
2931, 2872, 2837, 1586, 1486, 1463, 1419, 1326, 1274,
1
For 17: IR nmax 5®lm) 3447, 2930, 2853, 1696, 1577, 1480,
1240, 1136, 1038, 1010, 988, 864, 832 cm21; H NMR

9734
A. Abad et al. / Tetrahedron 57 12001) 9727±9735
5300 MHz, CDCl3) dH 6.63 51H, brs, H-60), 6.4251H, brs,
H-40), 4.15 51H, d, Jˆ7.3 Hz, H-3b), 4.05 51H, dd, Jˆ7.3,
2.4 Hz, H-3a), 3.84 and 3.79 53H each, each s, 2£MeO),
2.30 53H, s, Me-50), 2.23 51H, q, Jˆ6.6 Hz, H-7), 1.95±1.70
54H, m, H2-5 and H2-6), 1.30 53H, s, Me-1), 0.85 53H, d,
Jˆ6.6 Hz, Me-7); 13C NMR dC 575 MHz, CDCl3) 152.7
5C60), 111.5 5C40), 84.7 5C1), 74.4 5CH2O), 60.7 5MeO-20),
55.6 5MeO-30), 54.4 5C4), 47.9 5C7), 37.1 and 36.7 5C5 and
C6), 21.4 5C50), 17.4 5Me-1), 8.0 5Me-7); MS 5EI) m/z 5rela-
tive intensity) 276 5M1, 100), 261 54), 247 557), 231 553),
218 545), 203 535), 187 520), 151 55); HRMS, calcd for
C17H24O3 276.1725, found 276.1731.
3.1.16.
1,2-Dimethoxy-5-methyl-3-/10,20,20-trimethyl-
cyclopentyl)benzene /22). A solution of cyclopropane 21
518.9 mg, 0.07 mmol) and NaOAc 543 mg) in AcOH
51.5 mL) was hydrogenated at room temperature over
PtO2 568 mg) and 1.6±1.8 atm. of hydrogen pressure. The
reaction was monitored by capillary GC 5using a J&R P/N
21
5C30), 145.8 5C20), 134.2and 133.3 5C5 and C10), 120.8
DBw-5 column, 30£0.2 5 m, He at 30 cm s , 100±2508C at
0
158 min21; retention time of 21 11.65 min) and when the
reaction was complete 5ca. 8 days) it was diluted with CCl4
and ®ltered through a short pad of silica gel. Chroma-
tography of the residue left after evaporation of the ®ltrate,
using hexane±ether 58:2) yielded compound 22 515.2mg,
80%) as an oil; 1H NMR 5300 MHz, CDCl3) dH 6.75 51H, d,
Jˆ1.7 Hz, H-6), 6.61 51H, d, Jˆ1.7 Hz, H-4), 3.83 and 3.77
53H each, s, 2£MeO), 2.63 51H, m), 2.29 53H, s, Me-5),
1.36, 1.12, 0.70 53H each, each s, Me-10, Me-20b and
Me-20a); 13C NMR 575 MHz, CDCl3) dC 153.25C1),
146.8 5C2), 140.2 and 131.7 5C3 and C5), 121.8 5C4),
111.25C6), 60.5 5MeO-2), 55.7 5MeO-1), 51.7 5C1 0), 45.1
5C20), 41.1 5C30), 39.1 5C50), 27.0 5Me-10), 25.4 5Me-20a,
24.3 5Me-20b, 21.8 5Me-5), 20.5 5C40).
3.1.14. 2-/20,30-Dimethoxy-50-methyl-phenyl)-1-methyl-
bicyclo[3.1.0]hexane-2-carbaldehyde /20). Swern oxi-
dation of alcohol 19 569.6 mg, 0.25 mmol), as described
above for compound 13, and puri®cation of the product on
silica gel using hexane±ether 57:3) as eluent, furnished the
aldehyde 20 558.7 mg, 85%) as a crystalline solid; mp 75±
768C 5from hexane); IR nmax 5®lm) 3064, 3001, 2962, 2930,
2869, 2831, 2721, 1716, 1586, 1483, 1464, 1325, 1234,
1
1150, 1117, 1055, 1004, 838 cm21; H NMR 5300 MHz,
3.1.17.
1,2-Dimethoxy-5-methyl-3-/10,20,20-trimethyl-
CDCl3) dH 9.81 51H, s, CHO), 6.76 51H, brs, H-60), 6.66
51H, brs, H-40), 3.85 53H, s, MeO-20), 3.58 53H, s, MeO-30),
2.37 53H, s, Me-50), 2.30 51H, m), 2.03 51H, m), 1.74 51H,
m), 1.40 51H, m), 1.22 53H, s, Me-1), 1.15 51H, m), 0.57
51H, dd, Jˆ4.5, 4.3 Hz, H-6), 0.28 51H, dd, Jˆ7.8, 5.3 Hz,
H-6); 13C NMR 575 MHz, CDCl3) dC 198.8 5CHO), 152.5
5C30), 143.3 5C20), 135.7 and 133.6 5C50 and C10), 121.3
5C60), 111.7 5C40), 60.8 5C2), 59.8 5MeO-20), 55.6 5MeO-
30), 29.3 5C3), 25.9 5C4), 29.2 5C1), 26.4 5C5), 21.8 5Me-50),
18.4 5Me-1), 13.6 5C6); MS 5EI) m/z 5relative intensity) 274
5M1, 100), 245 589), 165 556), 93 534); HRMS, calcd for
C17H22O3 274.1569, found 274.1579.
cyclopentyl)benzene [Herbertenediol /2)]. A solution of
BBr3 51 M solution in CH2Cl2; 85 ml, 0.085 mmol) was
added to a solution of 22 515 mg, 0.057 mmol) in CH2Cl2
55 mL) at 08C. After the mixture had been stirred at the same
temperature for 3 h, the mixture was treated with MeOH and
evaporated under vacuum. The residue was chromato-
graphed on silica gel and eluted with hexane±ether 52:1)
to give 2 511 mg, 82%) as a colourless solid; mp 89±908C
1
5from hexane) [lit.4 mp 90±918C]; H NMR 5300 MHz,
CDCl3) dH 6.68 51H, brs, H-6), 6.55 51H, brs, H-4), 5.40
and 5.3251H each, each brs, 2 £OH), 2.66±2.55 51H, m),
2.22 53H, s, Me-5), 1.42, 1.20, 0.77 53H each, s each, Me-10,
Me-20b and Me-20a); 13C NMR 575 MHz, CDCl3) dC 143.4
5C1), 141.0 5C2), 133.6 and 128.6 5C3 and C5), 122.1 5C4),
3.1.15. 2-/20,30-Dimethoxy-50-methylphenyl)-1,2-dimethyl-
bicyclo[3.1.0]hexane /21). A solution of the aldehyde 20
549.8 mg, 0.18 mmol) and hydrazine hydrate 50.2mL,
4.2mmol) in diethylene glycol 51.5 mL) was heated to
1608C for 4 h. The mixture was cooled to room temperature
and treated with powdered sodium hydroxide 5210 mg,
4.5 mmol). The reaction mixture was further heated to
1808C overnight. It was then cooled to room temperature,
poured into ice-cold water and extracted with hexane. The
extract was washed with brine and dried 5Na2SO4). Evapora-
tion of the solvent and puri®cation of the residue by
chromatography, using hexane±ether 58:2) as eluent, fur-
nished the compound 21 540.2mg, 75%) as an oil; IR
nmax 5®lm) 3065, 2954, 2868, 1601, 1584, 1477, 1460,
0
113.5 5C6), 51.25C1 ), 44.9 5C20), 41.1 5C30), 39.3 5C50),
26.9 5Me-10), 25.5 5Me-20a, 22.9 5Me-20b, 21.2 5Me-5),
20.4 5C40).
Acknowledgements
Â
Financial support from the Direccion General de Ensen
Äanza
Superior e Investigacion Cientõ®ca 5Grant 1FD-97-0705 and
Â
Â
PB98-1421-C02-01) is gratefully acknowledged. R. H. P.
Â
thanks the Ministerio EspanÄol de Educacion y Ciencia for
a grant.
1
1408, 1310, 1268, 1148, 1063, 1012, 828 cm21; H NMR
5300 MHz, CDCl3) dH 6.83 51H, brs, H-60), 6.61 51H, brs,
H-40), 3.84 and 3.79 53H each, each s, 2£MeO), 2.31 53H, s,
Me-50), 1.85 51H, m), 1.61 53H, s, Me-2), 1.46±1.25 54H,
m), 1.10 53H, s, Me-1), 0.46 51H, t, Jˆ4.0 Hz, H-6), 0.16
51H, dd, Jˆ4.6, 7.8 Hz, H-6); 13C NMR 575 MHz, CDCl3)
dC 153.3 5C30), 146.0 5C20), 140.3 5C50), 131.6 5C10), 122.3
5C60), 110.8 5C40), 60.3 5MeO-20), 55.6 5MeO-30), 48.3
5C1), 38.3 5C3), 26.9 5C4), 29.7 5C2), 27.6 5C6), 23.2
5Me-1), 21.8 5Me-50), 18.25Me-)2, 14.0 5C6); MS 5EI)
m/z 5relative intensity) 260 5M1, 100), 245 568) 231 536),
192565), 177 535), 91 538), 77 531): HRMS, calcd for
C17H24O2 260.1776, found 260.1777.
References
1. Asakawa, Y. Progress in the Chemistry of Organic Natural
Products; Herz, W., Kirby, G. W., Moore, R. E., Steglich, W.,
Tamm, Ch., Eds.; Springer: Wien, 1995; Vol. 65, p. 1.
2. 5a) Connolly, J. D.; Hill, R. A. 1st ed; Dictionary of
Terpenoids, Vol. 1; Chapman & Hall: London, 1991 p 299.
5b) Fraga, B. M. Nat. Prod. Rep. 1992, 9, 217. 5c) Fraga, B. M.
Nat. Prod. Rep. 1993, 10, 397. 5d) Fraga, B. M. Nat. Prod.
Rep. 1994, 11, 533. 5e) Fraga, B. M. Nat. Prod. Rep. 1995, 12,
303. 5f) Fraga, B. M. Nat. Prod. Rep. 1996, 13, 307. 5g) Fraga,
B. M. Nat. Prod. Rep. 1997, 14, 145. 5h) Fraga, B. M. Nat.

A. Abad et al. / Tetrahedron 57 12001) 9727±9735
9735
Prod. Rep. 1998, 15, 73. 5i). Fraga, B. M. Nat. Prod. Rep.
1999, 16, 21 see also page 711. 5j) Fraga, B. M. Nat. Prod.
Rep. 2000, 17, 483.
14. Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness,
C. M. Org. React. 1973, 20, 1.
15. Batey, R. A.; Harling, J. D.; Motherwell, W. B. Tetrahedron
1992, 48, 8031.
3. For recent syntheses of herbertane-type compounds, see:
Â
5a) Abad, A.; Agullo, C.; CunÄat, A. C.; Perni, R. H.
16. 5a) Clive, D. L. J.; Daigneault, S. J. Org. Chem. 1991, 56,
3801. 5b) Wong, H. N. C.; Hou, M.-Y.; Tse, C.-W.; Yip,
Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165.
5c) Dauben, W. G.; Wolf, R. E. J. Org. Chem. 1970, 35,
2361. 5d) de Meijere, A. Angew. Chem. Int. Ed. Engl. 1979,
18, 809.
Tetrahedron: Asymmetry 2000, 11, 1607. 5b) Pal, A.; Gupta,
P. D.; Roy, A.; Mukherjee, D. Tetrahedron Lett. 1999, 40,
Â
4733. 5c) Abad, A.; Agullo, C.; CunÄat, A. C.; Perni, R. H.
J. Org. Chem. 1999, 64, 1741. 5d) Tse-Lo, H.; Chang, M. H.
J. Chem. Soc. Perkin Trans. 1 1999, 2479 and references
therein.
17. Maiti, B. C.; Lahiri, S. Tetrahedron 1998, 54, 9111 and
references therein.
4. Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc. Perkin
Trans. 1 1986, 701.
18. 5a) Still, W. C.; Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927.
5b) Nakai, T.; Mikami, K. Org. React. 1994, 46, 106.
5c) Nakai, T.; Tomooka, K. Pure Appl. Chem. 1997, 69,
595. 5d) Hart, S. A.; Trindle, C. O.; Etzkorn, F. A. Org.
Lett. 2001, 3, 1789 and references therein.
5. Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Tetrahedron Lett.
1996, 37, 1261.
6. Fukuyama, Y.; Asakawa, Y. J. Chem. Soc. Perkin Trans. 1
1991, 2737.
19. Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
20. The formation of the allylic starting alcohol and methyl ether
has also been observed during the related [2,3]-sigmatropic
rearrangement of a 5trimethylsilyl)methyl allyl ether; see for
example: Magnus, P.; Roy, G. Organometallics 1982, 1, 553.
21. 5a) Sugimura, T.; Paquette, L. A. J. Am. Chem. Soc. 1987, 109,
3017. 5b) Kress, M. H.; Kaller, B. F.; Kishi, Y. Tetrahedron
Lett. 1993, 34, 8047.
7. For previous syntheses of herbertenediol, see: 5a) Ref. 5.
5b) Fukuyama, Y.; Matsumoto, K.; Tonoi, Y.; Yokoyama,
R.; Takahashi, H.; Minami, H.; Okazaki, H.; Mitsumoto, Y.
Tetrahedron 2001, 57, 7127. 5c) Srikrishna, A.; Rao, M. S.
Tetraherdon Lett. 2001, 42, 5783. 5d) Mukherjee, D.; Roy, A.;
Pal, A.; Gupta, P. D. Tetrahedron Lett. 2000, 41, 7563.
5e) Bringmann, G.; Pabst, T.; Henschel, P.; Kraus, J.; Peters,
K.; Peters, E.-M.; Rycroft, D. S.; Connolly, J. D. J. Am. Chem.
Soc. 2000, 122, 9127. 5f) Degnan, A. P.; Meyers, A. I. J. Am.
Chem. Soc. 1999, 121, 2762.
22. 5a) Kawase, T.; Enomoto, T.; Wei, C.; Oda, M. Tetrahedron
Lett. 1993, 34, 8143. 5b) Maleczka Jr., R. E.; Geng, F. J. Am.
Chem. Soc. 1998, 120, 8551 and references therein.
23. Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem.
1979, 44, 4148.
8. 5a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
5b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
9. Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1994,
35, 2405.
24. Nagata, W.; Itazaki, H. Chem. Ind. 1964, 1194.
25. For a related situation, see: 5a) Tori, M.; Miyake, T.;
Hamaguchi, T.; Sono, M. Tetrahedron: Asymmetry 1997, 8,
2731. 5b) Inouye, Y.; Inomata, S.; Ishihara, Y.; Kakisawa, H.
Bull. Chem. Soc. Jpn 1982, 55, 208.
10. 5a) Fu, J. M.; Snieckus, V. Tetrahedron Lett. 1990, 31, 1665.
5b) Wurstrow, L. D.; Wise, L. D. Synthesis 1991, 993.
5c) Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221.
11. Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1.
26. Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986
and references therein.
12. Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org.
Chem. 1993, 58, 5434.
27. 5a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543. 5b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc.
1973, 95, 512. 5c) Jones, T. K.; Mohan, J. J.; Xavier, L. C.;
Blacklock, T. J.; Mathre, D. J.; Sohar, P.; Jones, E. T. T.;
Reamer, R. A.; Roberts;, F. E.; Grabowski, E. J. J. J. Org.
Chem. 1991, 56, 763.
13. 5a) Rappoport, Z., Ed.; The Chemistry of the Cyclopropyl
Group, Wiley: New York, 1987; Vols. I and II. 5b) Lee,
H. P.; Lee, B.; Lee, J.; Park, S. K. Tetrahedron Lett. 1999,
40, 3427.