Enantioselective synthesis of herbertane sesquiterpenes: Synthesis of (-)-α-formylherbertenol

Article abstract of DOI:10.1016/S0957-4166(00)00079-3

The synthesis of 4-hydroxy-3-[(1S)-1,2,2-trimethylcyclopentyl]benzaldehyde [(-)-α-formylherbertenol 1], a herbertane-type sesquiterpene isolated from the leafy liverwort Herberta adunca, from β-cyclogeraniol is described. The synthesis is based on the previously described preparation of an enantiopure 1,2,2-trimethylcyclopentane synthon from which the characteristic aromatic moiety of 1 is elaborated, using a Robinson annulation and a palladium-catalysed methoxycarbonylation of an aryl triflate as key synthetic steps. The synthesis of the natural sesquiterpene (-)-α-herbertenol, also a natural sequiterpene, using the same methodology is also described. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00079-3

Tetrahedron: Asymmetry 11 (2000) 1607±1615
Enantioselective synthesis of herbertane sesquiterpenes:
synthesis of (^)-a-formylherbertenol
Antonio Abad,* Consuelo Agullo, Ana C. Cunat and Remedios H. Perni
Â
Departamento de Quõmica Organica, Facultad de Quõmicas, Universidad de Valencia C/Dr. Moliner 50,
Â
Â
E-46100 Burjassot, Valencia, Spain
Received 16 February 2000; accepted 23 February 2000
Abstract
The synthesis of 4-hydroxy-3-[(1S)-1,2,2-trimethylcyclopentyl]benzaldehyde [(^)-a-formylherbertenol 1],
a herbertane-type sesquiterpene isolated from the leafy liverwort Herberta adunca, from b-cyclogeraniol is
described. The synthesis is based on the previously described preparation of an enantiopure 1,2,2-tri-
methylcyclopentane synthon from which the characteristic aromatic moiety of 1 is elaborated, using a
Robinson annulation and a palladium-catalysed methoxycarbonylation of an aryl tri¯ate as key synthetic
steps. The synthesis of the natural sesquiterpene (^)-a-herbertenol, also a natural sequiterpene, using the
same methodology is also described. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
(^)-a-Formylherbertenol 1 constitutes one of the few examples of herbertanes, a group of aro-
matic sesquiterpenoids characterised by a 1,2,2-trimethyl-1-m-tolylcyclopentane structure that
have been isolated from Herbertus species and other liverworts,1,2 functionalised at the methyl
aromatic group. This compound, isolated from the methanolic extracts of the leafy liverwort
Herberta adunca (Dicks.) S. Gray, shows a strong antifungal activity.3 Other related herbetane-
type sesquiterpene phenols recently isolated are 1,2-dihydroxyherberten-12-al 2,4 methyl 1,2-
dihydroxyherberten-12-oate 34 and the bis-side-chain coupled analogue mastigophorene D 4.5
* Corresponding author.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00079-3

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A. Abad et al. / Tetrahedron: Asymmetry 11 (2000) 1607±1615
The interesting biological properties of the herbertanes and their unique carbon framework, in
particular the two adjacent quaternary carbon atoms, have stimulated extensive synthetic e€orts
from many research teams.6 In recent years we have developed a general approach to the
enantioselective synthesis of herbertane-type compounds. This approach, based on the enantio-
selective preparation of the 1,2,2-trimethylcyclopentane nucleus from readily available b-cyclo-
geraniol 5 followed by elaboration of the aromatic six-membered ring (Scheme 1), has been
successfully used for the preparation of two representative members of this group of sesqui-
terpenes, (^)-herbertene 7 and (^)-a-herbertenol 8.7 In connection with this work we describe in
this paper a new and more ecient procedure for the elaboration of the aromatic moiety of these
systems which has allowed us to complete very eciently the ®rst enantioselective synthesis of
(^)-a-formylherbertenol 1y and opens an alternative way to the preparation of other related
herbertanes.
Scheme 1.
2. Results
As in the previous synthesis, the enantiomerically pure ketone 6 was prepared from b-cyclo-
geraniol in three synthetic steps (Sharpless asymmetric epoxidation, benzylation of the hydroxyl
group and pinacollic rearrangement) in 67% overall yield. Michael addition of the sodium
enolate, obtained by treatment of 6 with N-sodiohexamethyldisilazane (NaHMDS), to a-(tri-
methylsilyl)vinyl ketone followed by KOH promoted intramolecular aldol reaction a€orded
cyclohexenone 9 in 65% overall yield, as an equimolecular mixture of epimers at C-4 (Scheme 2).
In order to complete the functionalisation of the target herbertane we ®rst proceeded to the
aromatisation of the cyclohexane-ring moiety. Towards this end we set out to transform 9 into
phenol 12 via the tautomeric cyclohexadienone 11. The standard selenium-based methodology
unfortunately gave rise to low yields of 12 (ca. 40% yield after a-selenenylation, oxidation and
loss of benceneselenenic acid). However, 12 was prepared in good yield by a-bromination/dehydro-
bromination of 9. Thus, treatment of 9 with trimethylsilyl tri¯ate and triethylamine, followed by
in situ reaction of the resulting silyl enol ether with N-bromosuccinimide (NBS), yielded the a-bromo-
ketone 10,{ which, upon heating to 110ꢀC in toluene with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and a small amount of hydroquinone, a€orded phenol 12 in 84% overall yield.
y
A preliminary communication of this work was presented at the 16th International Symposium on Synthesis in
Organic Chemistry, Churchill College, Cambridge, UK, July 1999.
{
Reaction of the silyl enol ether with palladium(II) acetate in acetonitrile gave a complex reaction mixture from which
the phenol 12 could be isolated in very low yield.

A. Abad et al. / Tetrahedron: Asymmetry 11 (2000) 1607±1615
1609
Scheme 2. (a) (i) NaHMDS, ^78ꢀC then 3-TMS-buten-2-one; (ii) KOH, MeOH±H2O, 120ꢀC. (b) TMSOTf, Et3N,
Et2O, ^78ꢀC then NBS, THF. (c) DBU, toluene, 110ꢀC. (d) Tf2O, Et3N, CH2Cl2, ^70!^30ꢀC. (e) Pd(OAc)2, dppp,
Et3N, (C8H17)3SiH, CO, DMF, 70ꢀC. (f) Pd/C, H2, EtOH. (g) PdCl2(PPh3)2, LiCl, Me4Sn, DMF, 88ꢀC. (h) Pd(OAc)2,
dppp, Et3N, CO, DMF±MeOH, 70ꢀC. (i) DIBALH, THF, ^78ꢀC. (j) 4-Acetylamino-2,2,6,6-tetramethylpiperidine-1-
oxoammonium perchlorate, silica gel, CH2Cl2
With the phenol 12 in hand, we proceeded to its conversion into aryl tri¯ate 13. This trans-
formation was readily e€ected in excellent yield by treatment of 12 with tri¯ic anhydride in the
presence of triethylamine. Compound 13 was considered a key intermediate in the synthesis of
herbertane sesquiterpenes of the type shown above due to the easy substitution of the tri-
¯uoromethanesulfonate group by formyl, alkoxycarbonyl or alkyl groups through palladium-
catalysed reactions.8 We ®rst examined the formylation of 13. When a mixture of the aryl tri¯ate,
triethylamine, trioctylsilane and catalytic amounts of palladium(II) acetate and 1,3-bis(diphenyl-
phosphino)propane (dppp) in DMF was stirred at 70ꢀC under a carbon monoxide atmosphere,

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A. Abad et al. / Tetrahedron: Asymmetry 11 (2000) 1607±1615
the aldehyde 14 was obtained in 50% yield after chromatographic puri®cation.x Completion of
the synthesis of a-formylherbertenol 1 from 14 only required deprotection of the phenolic moiety.
Unfortunately, under a variety of reaction conditions hydrogenolysis of the benzyl group of 14
always took place with simultaneous reduction of the aldehyde group followed by hydrogenolysis
of the resulting benzylic alcohol, thus also a€ording the natural a-herbertenol 8. In fact, conver-
sion of 14 into 8 could be e€ected in very high yield by hydrogenation using Pd on carbon in
EtOH.{
In order to circumvent this problem we decided to e€ect a methoxycarbonylation of the tri¯ate
13 as an indirect way to arrive at 1. Treatment of 13 with triethylamine and catalytic amounts of
palladium acetate(II) and dppp in MeOH and DMF at 70ꢀC under carbon monoxide atmosphere
for two days resulted in the isolation of the methyl ester 16 in excellent yield (95%). Hydro-
genolysis of the benzyl group of 16, using palladium on carbon in EtOH, cleanly a€orded the
phenol-ester 17. Final reduction of the ester moiety to an aldehyde group was e€ected in two
steps. First, the ester moiety of 17 was reduced in nearly quantitative yield to the benzylic alcohol
18 by treatment with DIBALH in THF at low temperature. Subsequent oxidation of 18 with
4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium perchlorate9 in CH2Cl2 in the
presence of silica gel provided, after column chromatography, the target compound 1 in 80% yield.k
The spectroscopic properties of the synthetic material were identical in all respects with those of
the naturally occurring compound.3b The overall yield of (^)-a-formylherbertenol 1 from b-cyclo-
geraniol 5 was 20±21% in 12 synthetic steps.
3. Experimental
3.1. General
Melting points were determined using a Ko¯er hot-stage apparatus and are uncorrected.
Optical rotations were determined using a 5 cm path length cell. [ꢀ]D Values are given in units of
1
10^1 deg cm2 g^1. All H spectra were recorded in CDCl3 at 300 or 400 MHz, and all 13C at 75
MHz. Carbon substitution degrees were established by DEPT pulse sequence. Mass spectra were
obtained by electron impact (EI) at 70 eV. IR spectra were measured as KBr pellets or liquid
®lms. All reactions were carried out under an inert atmosphere of dry argon using oven-dried
glassware and freshly distilled and dried solvents. Column chromatography refers to ¯ash chrom-
atography and was performed on Merck silica gel 60, 230±400 mesh.
x
Given the diculties found for the transformation of 14 into 1, see below, this formylation was e€ected only once
and so the yield is not optimised.
An alternative and more ecient synthesis of 8 from aryl tri¯ate 13 was also completed using a palladium-catalysed
{
Stille coupling reaction to introduce the methyl group. Thus, coupling of 13 with Me4Sn in the presence of LiCl and a
catalytic amount of PdCl2(PPh3)2 in DMF a€orded the compound 15 (see Scheme 2) in 80% yield, which, upon
hydrogenolysis of the benzyl group using Pd on carbon in EtOH, gave a-herbertenol 8 in 92% yield. This enantio-
selective synthesis of a-herbertenol from b-cyclogeraniol via aryl tri¯ate 13 (11 steps, ca. 23% overall yield) constitutes
the most ecient enantioselective synthesis described so far for this compound.
k
The use of the oxoammonium salt as oxidant in this transformation was essential. Attempts to run the reaction with
other oxidants a€orded a much lower yield of 1 (e.g. TPAP 43%, PCC on alumina 50%) or even complex reaction
TM
mixtures (Magtrieve , BaMnO4 or Swern oxidation) from which 1 could not be isolated.

A. Abad et al. / Tetrahedron: Asymmetry 11 (2000) 1607±1615
1611
3.2. 4-Benzyloxy-6-bromo-3[(1S)-1,2,2-trimethylcyclopentyl]-2-cyclohexen-1-one 10
To a solution of diastereomeric ketones 97 (591 mg, 1.89 mmol) in anhydrous Et2O (12 mL)
were added triethylamine (0.79 mL, 5.68 mmol) and TMS tri¯ate (0.55 mL, 3.03 mmol) at ^78ꢀC.
The reaction mixture was stirred at the same temperature for 2 h and then treated with a solution
of recently puri®ed NBS10 (1.35 g, 7.58 mmol) in THF (10 mL). The reaction mixture was
allowed to warm to ^30ꢀC over 30 min and then poured into 5% hydrochloric acid and extracted
with ethyl acetate. The organic extracts were washed with 5% aqueous NaHCO3 solution and
brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under vacuum
a€orded an oily residue which was chromatographed on silica gel, using hexane:ethyl acetate 9:1
as eluent, to give the bromoketone 10 as a mixture of four diastereomers (708 mg, 95%).
Although this mixture was directly used in the next reaction (see below), the diastereomers could
be partially separated by MPLC and their spectroscopic data were determined independently.
However, unequivocal assignment of each set of data to a particular diastereomer was not pos-
sible. We give here the spectroscopic data of the main diastereomer. IR (KBr): 2958, 2873, 1681,
1
1610, 1063, 698, 449 cm^1; H NMR ꢁ 7.5±7.3 (5H, m, H5-Ar), 6.10 (1H, s, H-2), 4.85 (1H, d,
0
J=10.4 Hz, OCH2), 4.48 (1H, dd, J=5.6 and 2.7 Hz, H-6), 4.38 (1H, d, J=10.4 Hz, OCH2 ), 4.32
(1H, dd, J=2.8 and 2.7 Hz, H-4), 3.04 (ddd, J=16, 2.8 and 2.7 Hz, H-5), 2.46 (ddd, J=16, 5.6
and 2.8 Hz, H-50), 1.16 (3H, s, Me-10a), 1.01 and 0.78 (3H each, each s, Me-20a and Me-20b); 13
C
NMR ꢁ 192.65 (C1), 168.19 (C3), 137.14 (C100), 128.49, 128.35 and 127.79 (C200/C600, C300/C500
and C400), 126.21 (C2), 71.07 (OCH2), 70.71 (C4), 52.66 (C10), 45.07 (C20), 40.13 (C6), 40.11 (C30),
36.69 (C50), 31.84 (C5), 26.40 (Me-10), 25.15 (Me-20b), 21.50 (Me-20a), 19.37 (C40); MS (EI) m/z
393 (M++2, 2), 391 (M+, 2), 312 (2), 286 (2), 285 (15), 283 (14), 221 (12), 207 (18), 206 (17), 205
(47), 91 (100); HRMS calcd for C21H28BrO2: 391.1273; found: 391.1270.
3.3. 4-Benzyloxy-3-[(1S)-1,2,2-trimethylcyclopentyl]phenol 12
A solution of the above mixture of bromoketones 10 (384 mg, 0.98 mmol), DBU (0.58 mL,
3.88 mmol) and a few crystals of hydroquinone in anhydrous toluene (10 mL) was heated at 105±
110ꢀC in a sealed tube for 2 h. The reaction mixture was poured into 5% hydrochloric acid and
extracted with ethyl acetate. The combined organic extracts were washed with 5% aqueous
NaHCO3 solution and brine, dried over anhydrous sodium sulfate and evaporated under
vacuum. Chromatography of the residue, using hexane:ethyl acetate 85:15 as eluent, yielded
19
phenol 12 (259 mg, 84%) as a colourless oil. ‰ꢀŠ ^48.7 (c 1.2, CHCl3); IR (KBr) 3349, 1211,
D
1
1023, 803, 741, 697 cm^1; H NMR ꢁ 7.5±7.3 (5H, m, H5-Ar), 6.87 (1H, d, J=3.1 Hz, H-2), 6.77
(1H, d, J=8.6 Hz, H-6), 6.60 (1H, dd, J=8.6 and 3.1 Hz, H-5), 5.0 (2H, s, OCH2), 4.41 (1H, s,
OH), 2.52 (1H, m, H-50), 1.39, 1.05, 0.74 (3H each, each s, Me-10, Me-20a and Me-20b); 13C NMR
ꢁ 152.5 (C4), 148.7 (C1), 137.8 (C3), 137.7 (C100), 128.4 and 127.5 (C300/C500 and C200/C600), 127.6
(C400), 116.6, 113.9 and 112.5 (C2, C5 and C6), 71.2 (OCH2), 51.4 (C10), 44.5 (C20), 41.5 (C30),
39.7 (C50), 20.4 (C40), 27.3, 25.8 and 23.2 (Me-10, Me-20a and Me-20b); MS (EI) m/z 310 (M+,
100), 219 (43), 91 (84); HRMS calcd for C21H26O2: 310.1933; found: 310.1935.
3.4. 4-Benzyloxy-3-[(1S)-1,2,2-trimethylcyclopentyl]phenyl tri¯uoromethanesulfonate 13
A solution of 12 (386 mg, 1.25 mmol) in CH2Cl2 (4 mL) was treated with Et3N (0.39 mL, 2.8
mmol). After cooling to ^70ꢀC tri¯uoromethanesulfonic anhydride (0.246 mL, 1.46 mmol) was

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A. Abad et al. / Tetrahedron: Asymmetry 11 (2000) 1607±1615
added dropwise. The reaction mixture was stirred for 1 h from ^70 to ^30ꢀC, poured into 5%
hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with 5%
aqueous NaHCO3 solution and brine, and dried over anhydrous sodium sulfate. Column
chromatography of the residue left after evaporation of the solvent, using hexane:ethyl acetate
19
8:2, a€orded the tri¯ate 13 (495 mg, 90%) as a colourless oil. ‰ꢀŠ ^40 (c 2.1, CHCl3); IR (KBr)
D
1
2960, 2876, 1489, 1423, 1248, 1212, 1143, 1059, 1012, 866, 807 cm^1; H NMR ꢁ 7.4±7.3 (5H, m,
H5-Ar), 7.24 (1H, d, J=2.7 Hz, H-2), 7.04 (1H, dd, J=2.7 and 9.0 Hz, H-6), 6.89 (1H, d, J=9.0
Hz, H-5), 5.06 (2H, s, OCH2), 2.46 (1H, m, H-50), 1.39, 1.03 and 0.71 (3H each, each s, Me-10,
Me-20a and Me-20b); 13C NMR ꢁ 157.4 (C4), 142.8 (C1), 136.4 (C3), 138.6 (C100), 128.6 and 127.6
(C200/C600 and C300/C500), 128.1 (C400), 122.1 (C6), 119.1 (C2), 118.8 (q, J=319 Hz), 113.1 (C5),
71.0 (OCH2), 51.6 (C10), 44.7 (C20), 41.3 (C30), 39.7 (C50), 20.2 (C40), 26.9, 25.6 and 22.8 (Me-10,
Me-20a and Me-20b); MS (EI) m/z 442 (M+, 19), 351 (33), 91 (100); HRMS calcd for
C22H25O4F3S: 442.1426; found: 442.1425.
3.5. 4-Benzyloxy-3-[(1S)-1,2,2-trimethylcyclopentyl]benzaldehyde 14
A mixture of the tri¯ate 13 (90.6 mg, 0.205 mmol), Pd(OAc)2 (9 mg, 0.04 mmol) and dppp (16
mg, 0.04 mmol) in DMF (1 mL) was heated at 70ꢀC. Carbon monoxide was bubbled into the
solution over 15 min and then Et3N (72 mL, 0.52 mmol) and trioctylsilane (189 mL, 0.42 mmol)
were added dropwise. The reaction mixture was stirred under a CO balloon at the same tem-
perature overnight, diluted with water and extracted with ether. The organic extracts were
washed with 5% NaHCO3 aqueous solution and brine and dried over anhydrous sodium
sulfate. Column chromatography of the residue left after evaporation of the solvent, using
hexane:ether 9:1 as eluent, gave the aldehyde 14 (33 mg, 50%) as a colourless solid. Mp 81±82ꢀC
20
D
(from pentane); ‰ꢀŠ ^56 (c 1.7, CHCl3); IR (KBr) 2866, 2722, 1687, 1593, 1246, 808, 746, 699
1
cm^1; H NMR ꢁ 9.91 (1H, s, CHO), 7.95 (1H, d, J=2.4 Hz, H-2), 7.72 (1H, dd, J=8.4 and 2.4
Hz, H-6), 7.5±7.3 (5H, m, H5-Ar), 7.05 (1H, d, J=8.4 Hz, H-5), 5.19 (2H, s, OCH2), 2.65 (1H, m,
H-50), 1.43 (3H, s, Me-10), 1.08 and 0.74 (3H each, each s, Me-20a and Me-20b); 13C NMR ꢁ 191.4
(CHO), 163.1 (C4), 137.0 (C3), 136.0 (C100), 130.8 and 130.1 (C2 and C6), 129.3 (C1), 128.7 and
127.8 (C200/C600 and C300/C500), 128.2 (C400), 112.4 (C5), 70.7 (OCH2), 51.4 (C10), 44.4 (C20), 41.7
(C30), 39.9 (C50), 27.3, 25.9 and 22.8 (Me-10, Me-20a and Me-20b), 20.3 (C40); MS (CI) m/z 322
(M+, 39), 231 (91), 215 (30), 149 (72), 91 (100); HRMS calcd for C22H26O2: 322.1933; found:
322.1928.
3.6. 1-Benzyloxy-4-methyl-2-[(1S)-1,2,2-trimethylcyclopentyl]benzene 15
A mixture of previously dried LiCl (26.0 mg, 0.61 mmol), PdCl2(PPh3)2 (28.8 mg, 0.04 mmol)
and a few crystals of 2,6-ditert-butyl-4-methylphenol under argon was dissolved in degassed
DMF (1.4 mL). To this mixture was added Me4Sn (113 mL, 0.82 mmol) followed by a solution of
the tri¯ate 13 (90.5 mg, 0.205 mmol) in the same DMF (1.2 mL) and the mixture was heated at
88ꢀC during 1 h. The resulting black mixture was poured into 10% hydrochloric acid and
extracted with ether. The organic extracts were washed with brine, dried over anhydrous magnesium
sulfate and evaporated. Chromatography on silica gel, using pentane:ether 9:1 as eluent, a€orded
compound 15 (50.5 mg, 80%) as an oil. IR (®lm) 2956, 2972, 1604, 1497, 1463, 1223, 802, 736,
696 cm^1; 1H NMR ꢁ 7.5±7.3 (5H, m, H5-Ar), 7.15 (1H, d, J=2.1 Hz, H-3), 6.93 (1H, dd, J=8.3
and 2.1 Hz, H-5), 6.79 (1H, d, J=8.3 Hz, H-6), 5.03 (2H, s, OCH2), 2.55 (1H, m, H-50), 2.28 (3H, s,

A. Abad et al. / Tetrahedron: Asymmetry 11 (2000) 1607±1615
1613
Me-Ar), 1.40 (3H, s, Me-10), 1.05 and 0.73 (3H each, each s, Me-20a and Me-20b); C NMR ꢁ
156.0 (C1), 137.7 (C100), 135.9 (C2), 129.8, 128.4, 127.6, 127.5 and 127.0 (C3, C5, C200/C600, C300/C500
and C400), 129.0 (C4), 112.8 (C6), 70.6 (OCH2), 51.2 (C10), 44.4 (C20), 41.6 (C30), 39.7 (C50), 27.3,
25.8 and 23.3 (Me-10, Me-20a and Me-20b), 20.9 (Me-4), 20.4 (C40). MS (CI) m/z 308 (M+, 23),
223 (16), 217 (38), 161 (20), 135 (49), 91 (100); HRMS calcd for C22H28O: 308.2140; found:
308.2141.
13
3.7. 4-Methyl-2-[(1S)-1,2,2-trimethylcyclopentyl]phenol (a-herbertenol 8)
A mixture of 10% palladium on carbon (7 mg) and the benzyl ether 15 (35 mg, 0.11 mmol) in
absolute EtOH (2 mL) was stirred vigorously at rt under an atmosphere of hydrogen overnight.
Removal of the palladium catalyst by ®ltration through Celite, followed by evaporation of the
19
®ltrate, a€orded compound 8 (22.7 mg, 92%) as a colourless oil: ‰ꢀŠ ^48 (c 5.9, CHCl3) (lit.3b
D
1
[ꢀ]D ^55); IR (®lm) 3525, 1665, 1507, 810 cm^1; H NMR ꢁ 7.1 (1H, s, H-3), 6.86 (1H, d, J=7.9
Hz, H-5), 6.57 (1H, d, J=7.9 Hz, H-6), 4.63 (1H, s, OH), 2.26 (3H, s, Me-4), 1.41 (3H, s, Me-10),
1.18 (3H, s, Me-20b), 0.76 (3H, s, Me-20a); 13C NMR ꢁ 152.2 (C1), 138.0 (C2), 133.0 (C4), 130.0
(C5), 127.2 (C3), 116.70 (C6), 50.9 (C10), 44.6 (C20), 41.2 (C30), 39.4 (C50), 26.9 (Me-10), 25.5 and
23.9 (Me-20a and Me-2 b), 20.8 (Me-Ar), 20.3 (C40); MS (CI) m/z 218 (M+, 88), 203 (11), 161 (8),
149 (11), 148 (26), 111 (100); HRMS calcd for C15H22O: 218.1671; found: 218.1667.
3.8. Methyl 4-benzyloxy-3-[(1S)-1,2,2-trimethylcyclopentyl]benzoate 16
A mixture of tri¯ate 13 (213 mg, 0.483 mmol), Et3N (0.40 mL, 2.90 mmol), Pd(OAc)2 (32 mg,
0.145 mmol), dppp (60 mg, 0.145 mmol) in DMF (3.5 mL) and MeOH (2 mL) was purged for
several minutes with carbon monoxide. The reaction mixture was heated with stirring in a 70ꢀC
oil bath under a CO balloon for two days. After this time, the reaction mixture was cooled down
and then quenched with brine and extracted with ether. Usual work up followed by column
chromatography of the residue on silica gel, using hexane:ether 9:1 as eluent, gave unreacted
starting material 13 (10 mg, 6%) followed by methyl ester 16 (153 mg, 90%) as a colourless oil.
25
D
1
‰ꢀŠ ^55 (c 1.9, CHCl3); IR (®lm) 1717, 1600, 1495, 1256, 1121, 771, 745, 699 cm^1; H NMR ꢁ
(400 MHz) 8.08 (1H, d, J=2.3 Hz, H-2), 7.84 (1H, dd, J=8.8 and 2.3 Hz, H-6), 7.4±7.3 (5H, m,
H5-Ph), 6.91 (1H, d, J=8.8 Hz, H-5), 5.1 (2H, s, OCH2), 3.9 (3H, s, CO2CH3), 2.60 (1H, m, H-50),
1.38, 1.03 and 0.69 (3H each, each s, Me-10, Me-20a and Me-20b); 13C NMR ꢁ 167.3 (CO2), 161.7
(C4), 136.4 and 136.0 (C3 and C100), 128.6 and 127.8 (C200/C600 and C300/C500), 130.8, 129.1 and
128.0 (C2, C6 and C400), 121.8 (C1), 111.9 (C5), 70.5 (OCH2), 51.8 (CO2CH3), 51.3 (C10), 44.4
(C20), 41.6 (C30), 39.8 (C50), 27.3, 25.9 and 22.9 (Me-10, Me-20a and Me-20b), 20.3 (C40); MS (EI)
m/z 352 (M+, 17), 261 (71), 179 (47), 91 (100); HRMS calcd for C23H28O3: 352.2038; found:
352.2044.
3.9. Methyl 4-hydroxy-3-[(1S)-1,2,2-trimethylcyclopentyl]benzoate 17
A mixture of 16 (112.1 mg, 0.318 mmol) and 10% palladium on carbon (20 mg) in ethanol (4
mL) was shaken at rt under an H2 atmosphere overnight. Removal of the palladium catalyst by
®ltration through a pad of silica gel followed by evaporation of the ®ltrate under reduced pres-
sure a€orded the phenol 17 (75 mg, 90%) as a white solid. Mp 193.7±194.7ꢀC (from benzene±
20
D
ether); ‰ꢀŠ ^49 (c 1.9, CHCl3); IR (KBr) 3373, 1694, 1601, 1512, 1288, 1262, 827, 769 cm^1;

1614
A. Abad et al. / Tetrahedron: Asymmetry 11 (2000) 1607±1615
1H NMR ꢁ 8.06 (1H, d, J=2.4 Hz, H-2), 7.77 (1H, dd, J=8.1 and 2.4 Hz, H-6), 6.70 (1H, d,
J=8.1 Hz, H-5), 5.4 (1H, s, OH), 3.9 (3H, s, CO2CH3), 2.64 (1H, m, H-50), 1.41, 1.20 and 0.74
(3H each, each s, Me-10, Me-20a and Me-20b); 13C NMR ꢁ 167.0 (CO2), 158.8 (C4), 133.3 (C3),
131.6 and 129.0 (C6 and C2), 122.0 (C1), 116.7 (C5), 51.8 CO2Me), 51.0 (C10), 44.7 (C20), 41.3 (C30),
39.5 (C50), 26.9, 25.5 and 22.6 (Me-10, Me-20a and Me-20b), 20.2 (C40); MS (EI) m/z 262 (M+, 38),
247 (5), 192 (100), 179 (50), 161 (3); HRMS calcd for C16H22O3: 262.1569; found: 262.1569.
3.10. 4-Hydroxymethyl-2-[(1S)-1,2,2-trimethylcyclopentyl]phenol 18
A solution of methyl ester 17 (72.8 mg, 0.278 mmol) in THF (3 mL) was treated with DIBALH
(1.39 mL of a 1 M solution in cyclohexane, 1.39 mmol) at ^78ꢀC. The reaction mixture was stir-
red for 2 h at the same temperature, treated with MeOH (1 mL) and then poured into 5%
hydrochloric acid. Extraction with CH2Cl2 and work up as usual gave a residue which was pur-
i®ed by chromatography using hexane:ethyl acetate 7:3 as eluent to a€ord alcohol 18 (63.7 mg,
24
98%) as an amorphous solid that could not be induced to crystallise. ‰ꢀŠ ^37 (c 1.3, CHCl3); IR
D
1
(KBr) 3316, 1258, 891, 820 cm^1; H NMR ꢁ 7.29 (1H, d, J=2.1 Hz, H-3), 7.06 (1H, dd, J=8.1
and 2.1 Hz, H-5), 6.66 (1H, d, J=8.1 Hz, H-6), 5.1 (1H, br s, OH), 4.6 (2H, s, OCH2), 2.60 (1H,
m, H-50), 1.42 (3H, s, Me-10), 1.19 and 0.75 (3H each, each s, Me-20a and Me-20b); 13C NMR ꢁ
154.4 (C1), 133.6 (C2), 132.2 (C4), 128.9 and 126.1 (C3 and C5), 116.9 (C6), 65.6 (CH2OH), 51.1
(C10), 44.7 (C20), 41.3 (C30), 39.4 (C50), 27.0, 25.6 and 22.8 (Me-10, Me-20a and Me-20b), 20.3
(C40); MS (EI) m/z 234 (M+, 55), 164 (100), 151 (76), 147 (69), 91 (35); HRMS calcd for
C15H22O2: 234.1619; found: 234.1614.
3.11. 4-Hydroxy-3-[(1S)-1,2,2-trimethylcyclopentyl]benzaldehyde (a-formylherbertenol 1)
To a solution of 18 (50 mg, 0.21 mmol) in anhydrous CH2Cl2 (3.2 mL) were added silica gel (70
mg, previously activated at 120ꢀC during 1 h), and 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-
oxoammonium perchlorate9 (70 mg, 0.22 mmol). The bright yellow slurry was stirred at room
temperature for 25 min. The slurry was then ®ltered through a pad of silica gel eluting with
CH2Cl2. The ®ltrates and washings were evaporated under vacuum to give nearly pure 1 (39.5
25
mg, 80%) as a white solid: mp 133±134ꢀC (from benzene±ether) (lit.3b mp 134±135ꢀC); ‰ꢀŠ
D
^72 (c 1.2, CHCl3) (lit.3b [ꢀ]D ^65.8); IR (KBr) 3251, 1667, 1582, 1508, 1423, 1377, 1270, 825
cm^1; 1H NMR ꢁ 9.83 (1H, s, CHO), 7.88 (1H, d, J=2 Hz, H-2), 7.63 (1H, dd, J=8.1 and 2 Hz,
H-6), 6.83 (1H, d, J=8.1 Hz, H-5), 6.1 (1H, br s, OH), 2.65 (1H, m, H-50), 1.43 (3H, s, Me-10),
1.21 and 0.75 (3H each, each s, Me-20a and Me-20b); 13C NMR ꢁ 191.6 (CHO), 160.4 (C4), 134.2
(C3), 132.3 (C2), 129.7 (C6), 129.1 (C1), 117.4 (C5), 51.1 (C10), 44.6 (C20), 41.3 (C30), 39.5 (C50),
27.0, 25.5 and 22.5 (Me-10, Me-20a and Me-20b), 20.2 (C40); MS (EI) m/z 232 (M+, 49), 217 (8),
215 (6), 203 (3), 189 (6), 174 (14), 162 (100); HRMS calcd for C15H20O2: 232.1463; found:
232.1465.
Acknowledgements
Financial support from the Direccion General de Ensenanza Superior e Investigacion Cientõ®ca
(Grants 1FD-97-0705 and PB98-1421-C02-01) is gratefully acknowledged. R.H.P. thanks the
Ministerio Espanol de Educacion y Ciencia for a grant.

A. Abad et al. / Tetrahedron: Asymmetry 11 (2000) 1607±1615
1615
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