Enantioselective synthesis of natural (-)-tochuinyl acetate, (-)-dihydrotochuinyl acetate and (+)-β-cuparenone using both enantiomers of the same building block

Article abstract of DOI:10.1016/j.tet.2004.05.037

The first enantioselective synthesis of tochuinyl acetate and dihydrotochuinyl acetate, two natural marine products isolated from Tochuina tetraquetra and Gersemia rubiformis, has been achieved starting from an enantiopure building block. The key feature of the present synthesis is complete control of two vicinal quaternary stereogenic centers present in the natural products and elucidation of their absolute stereochemistry, which was previously unknown. Furthermore, starting from the enantiomer of the same building block, the applied methodology provided a new approach towards natural (R)-(+)-β-cuparenone.

Full text of DOI:10.1016/j.tet.2004.05.037

Tetrahedron 60 (2004) 5907–5912
Enantioselective synthesis of natural (2)-tochuinyl acetate,
(2)-dihydrotochuinyl acetate and (1)-b-cuparenone using both
enantiomers of the same building block
*
´ ´
Samir Acherar, Gerard Audran, Fabrice Cecchin and Honore Monti
´ ´ ´
Laboratoire de Reactivite Organique Selective, U.M.R. 6180 “Chirotechnologies: catalyse et biocatalyse”,
t
´
´ ˆ
Faculte des Sciences et Techniques de S Jerome, 13397 Marseille cedex 20, France
Received 19 February 2004; revised 5 May 2004; accepted 14 May 2004
Available online 9 June 2004
Abstract—The first enantioselective synthesis of tochuinyl acetate and dihydrotochuinyl acetate, two natural marine products isolated from
Tochuina tetraquetra and Gersemia rubiformis, has been achieved starting from an enantiopure building block. The key feature of the present
synthesis is complete control of two vicinal quaternary stereogenic centers present in the natural products and elucidation of their absolute
stereochemistry, which was previously unknown. Furthermore, starting from the enantiomer of the same building block, the applied
methodology provided a new approach towards natural (R)-(þ)-b-cuparenone.
q 2004 Published by Elsevier Ltd.
1. Introduction
a challenge for numerous organic synthetic chemists.
However, there have only been a few reports on the
enantioselective synthesis of natural (R)-(þ)-b-cuparenone,
(þ)-3, or the enantiomer3 and, to date, only racemic
syntheses of tochuinyl acetate, 1, and dihydrotochuinyl
acetate, 2, have been published4 (the absolute configurations
remain unknown). Starting from an enantiopure building
block for the introduction and determination of the absolute
stereochemistry, we have carried out the first enantio-
selective synthesis of (2)-1 and (2)-2 to determine the
absolute stereochemistry of the two vicinal chiral centers
present in the natural products. Our methodology is depicted
in Scheme 1. Using the enantiomer of the same building
block, the applied methodology allowed a new approach
towards the known (R)-(þ)-b-cuparenone, (þ)-3. Our
synthetic plan is outlined in Scheme 2.
The marine sesquiterpenes tochuinyl acetate (2)-1 and
dihydrotochuinyl acetate (2)-2 were isolated1 from the
dendronotid nudibranch Tochuina tetraquetra and also from
their feed, the soft coral Gersemia rubiformis. (þ)-b-
cuparenone, (þ)-3, was isolated2 from the essential oil of
the ‘Mayur pankhi’ tree. These natural products, belonging
to the aromatic sesquiterpene cuparene class, possess two
vicinal quaternary centers in a cyclopentane ring, both
stereogenic in (2)-1 and (2)-2, and one in (þ)-3 (Fig. 1).
2. Results and discussion
Figure 1. Natural tochuinyl acetate, (2)-1, and dihydrotochuinyl acetate,
(2)-2, are represented with the absolute stereochemistry as determined in
this work.
We recently reported the straightforward synthesis of the
required enantiopure building blocks, (1S,2S,4R)-4-
hydroxy-2-methyl-2-p-tolyl-cyclopentane carboxylic acid
ethyl ester, (þ)-4, and its enantiomer through enzymatic
kinetic resolution of the corresponding racemic alcohol.5
Owing to the difficulty associated with the construction of
the adjacent quaternary centers on the sterically congested
five-membered ring, their stereoselective synthesis has been
The secondary alcohol of (þ)-4 was protected as its tert-
butyldimethylsilyl ether (þ)-5, using the standard method
(Scheme 1).6 Formation of the lithium enolate of the ester
(þ)-5 with lithium diisopropylamide in THF and HMPA,
Keywords:
Total
Enantioselectivity; Cuparane family; Lipases.
synthesis;
Configuration
determination;
*
Corresponding author. Tel./fax: þ33-4-91288862;
e-mail address: honore.monti@univ.u-3mrs.fr
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.05.037

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S. Acherar et al. / Tetrahedron 60 (2004) 5907–5912
compound (þ)-11 (vide infra). Removal of the TBS
protecting group of ester (2)-6 (TBAF, THF) gave the
corresponding alcohol (2)-7 in 98% yield. Barton–
McCombie deoxygenation of (2)-7 proceeded by way of
xanthate (2)-8, which was reduced smoothly with tri-n-
butyltin hydride to provide the derivative (2)-9 in an overall
yield of 94% for the two steps.9 Finally, reduction of ester
(2)-9 to give alcohol (2)-10, followed by acetylation, led to
(2)-tochuinyl acetate, (2)-1, in 95% yield. The high
enantiomeric purity of the compound was verified by chiral
HPLC (.98% ee). On the other hand, Birch reduction of
alcohol (2)-10 furnished the crude dihydroalcohol, which
on acetylation using acetic anhydride and pyridine gave
(2)-dihydrotochuinyl acetate, (2)-2, in an overall yield of
80% for two steps.
The 1H and 13C NMR spectra of (2)-tochuinyl acetate, (2)-
1, and (2)-dihydrotochuinyl acetate, (2)-2, were identical
with those described for the natural isolated products1 and in
the racemic syntheses.4 However, while the specific rotation
of (2)-1 [[a]2D5¼238.0 (c 1.0, CH2Cl2)] agrees with the
value reported in the literature for the extracted product [lit.1
[a]2D5¼242.5 (c 1.09, CH2Cl2)], the one of (2)-2
[[a]2D5¼245.5 (c 1.0, CH2Cl2)] disagrees in the magnitude
[lit.1 [a]2D5¼229.3 (c 1.1, CH2Cl2)].
The enantioselective synthesis of (þ)-b-cuparenone is
depicted in Scheme 2. Starting from (2)-4, the alkylated
ester (þ)-6 was obtained following the same first two steps
as described in Scheme 1 for (2)-6, and reduction of (þ)-6
furnished alcohol (þ)-11 in 95% yield. The stereochemistry
of the three stereocenters in (þ)-11 was confirmed using 1H
NMR NOESY experiments (Fig. 2). The four aromatic
protons of the p-tolyl substituent resonated as an AB system
at dH¼7.22 and 7.10 ppm (J¼8.2 Hz); a NOESY correlation
between the Me–(C6H4), which resonated at dH¼2.31 ppm,
and the pair at dH¼7.10 ppm showed the vicinal proximities
of these protons. Furthermore, strong NOESY correlations
among the other pair of aromatic protons at dH¼7.22 ppm
and H–C(4) and 2H–C(6) which resonated at dH¼4.50 and
3.02 ppm and in addition, strong NOESY correlation among
2H–C(6) and H–C(4) established the cis spatial orientation
among these protons and the p-tolyl group. Subsequent
oxidation of (þ)-11 with catalytic tetrapropylammonium
perruthenate (TPAP)10 and NMO as the co-oxidant in
dichloromethane provided the aldehyde (þ)-12 (98% yield).
Huang–Minlon reduction11 of the formyl group of (þ)-12
to methyl and, under the conditions of the reaction,
removal of the protective TBS group, afforded directly the
alcohol (þ)-13 in one step and 95% yield. Finally,
conversion of alcohol (þ)-13 in (þ)-b-cuparenone, (þ)-3,
was easily effected by TPAP oxidation as described
Scheme 1. Reagents and conditions: (a) TBSCl, Imidazole, DMF, rt, 100%;
(b) LDA, HMPA, MeI, THF, 290 8C!rt, 93%; (c) TBAF, THF, rt, 98%;
(d) NaH, CS2, MeI, THF, 98%; (e) Bu3SnH, AIBN, toluene, 96%;
(f) LiAlH4, Et2O, 98%; (g) Ac2O, pyridine, 95%; (h) Li, NH3, t-BuOH,
THF, 240 8C; (i) Ac2O, pyridine, 80% for two steps.
Scheme 2. Reagents and conditions: (a) LiAlH4, Et2O, 95%; (b) NMO,
TPAP, CH2Cl2, rt, 98%; (c) NH2NH2·H2O, NaOH, diethylene glycol,
160 8C, 95%; (d) NMO, TPAP, CH2Cl2, rt, 97%.
followed by addition of methyl iodide, furnished the
1
alkylated ester (2)-6 as the sole product.7 In the H NMR
spectrum of this enantiomer, the upfield chemical shift of
the ester methylene (d 3.70 ppm), due to the shielding by the
vicinal cis arene, established the stereochemistry at the
newly created quaternary carbon atom in (2)-6 like
precedence.4b,8 This stereochemistry will be confirmed by
a NOESY experiment (not informative with (2)-6) on
Figure 2. High-field 1H NMR analysis and NOESY correlations of (þ)-11.

S. Acherar et al. / Tetrahedron 60 (2004) 5907–5912
5909
1
above. The product showed the same [a]D value, as well as
the spectroscopic data (1H and 13C NMR) as those
reported.3
1031 cm21; H NMR (200 MHz, CDCl3) d 7.29 and 7.11
(AB, 4H, J¼8.3 Hz), 4.33 (quin., 1H, J¼6.5 Hz), 4.10 (m,
2H), 3.04 (dd,1H, J¼10.2, 8.3 Hz), 2.31 (s, 3H), 2.42–2.18
(m, 3H), 1.85 (dd, 1H, J¼13.4, 5.9 Hz), 1.41 (s, 3H), 1.18 (t,
3H, J¼7.1 Hz), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR
(50 MHz, CDCl3) d 173.6 (C), 146.5 (C), 135.2 (C), 128.8
(2£CH), 125.7 (2£CH), 71.4 (CH), 60.1 (CH2), 53.2 (CH),
51.2 (CH2), 47.4 (C), 38.5 (CH2), 25.8 (3£CH3), 25.5
(CH3), 20.8 (CH3), 18.0 (C), 14.2 (CH3), 24.7 (2£CH3–Si).
Anal. Calcd for C22H36O3Si: C, 70.16; H, 9.63. Found: C,
70.40; H, 9.61.
3. Conclusion
In summary, an enantioselective synthesis of two marine
aromatic sesquiterpenes, belonging to the cuparene class,
has been achieved for the first time, and the absolute
configurations of the two vicinal stereogenic quaternary
centers present in the molecules have been fully determined;
we trust that this will enrich the natural products databases.
Furthermore, starting from the enantiomer of the previously
utilized building block, the synthetic strategy was success-
fully applied to a new approach of the known natural
(R)-(þ)-b-cuparenone. The merits of this work are simple
high-yielding reaction steps, secured absolute stereo-
chemistry, and applicability of the methodology to the
synthesis of the unnatural enantiomers of the present target
molecules by reversing the enantiomers of the starting
building block. Morever, our synthetic plan can also be
adapted for the syntheses of other natural products with
related structures in the field of cuparane and herbertane
family.
4.1.2. (1R,2R,4S)-4-(tert-Butyl-dimethyl-silanyloxy)-1,2-
dimethyl-2-p-tolyl-cyclopentanecarboxylic acid ethyl
ester [(2)-6]. To a cold (290 8C) magnetically stirred
solution of LDA [prepared from diisopropylamine
(0.74 mL, 5.28 mmol) and n-BuLi (5.00 mmol, 3.13 mL of
a 1.6 M solution in hexane)] in 10 mL of dry ether was
added HMPA (1.29 mL, 7.44 mmol) followed by a solution
of the ester (þ)-5 (500 mg, 1.33 mmol) in 3 mL of dry THF
over a period of 10 min. The reaction mixture was stirred for
40 min at the temperature. Methyl iodide (1.34 mL,
21.52 mmol) was added to the reaction mixture, slowly
warmed up to 0 8C and stirred for 5 h. The reaction mixture
was partitioned between ether and, sequentially, 5%
aqueous HCl, 10% aqueous NaHCO3. The organic layers
were dried (MgSO4), concentrated, and chromatographed to
give the alkylated ester (2)-6 (486 mg, 93% yield) as an oil;
[a]2D5¼217.6 (c¼1.0, CHCl3); IR (film) n 3042, 1752, 1258,
4. Experimental
1
1015 cm21; H NMR (200 MHz, CDCl3) d 7.12 and 7.03
4.1. General experimental procedures
(AB, 4H, J¼8.4 Hz), 4.68–4.55 (m, 1H), 3.65 (m, 2H), 2.91
(dd, 1H, J¼14.0, 7.7 Hz), 2.62 (dd, 1H, J¼14.1, 7.7 Hz),
2.27 (s, 3H), 1.81 (dd, 1H, J¼13.8, 1.7 Hz), 1.65 (dd, 1H,
J¼13.9, 2.5 Hz), 1.55 (s, 3H), 1.41 (s, 3H), 0.85 (partially
overlapped t, 3H, J¼7.0 Hz), 0.85 (s, 9H), 0.06 (s, 6H); 13C
NMR (50 MHz, CDCl3) d 176.4 (C), 143.2 (C), 135.4 (C),
128.3 (2£CH), 126.3 (2£CH), 71.4 (CH), 59.9 (CH2), 57.2
(C), 51.4 (C), 49.1 (CH2), 47.5 (CH2), 25.8 (3£CH3), 25.2
(CH3), 20.7 (CH3), 20.5 (CH3), 17.9 (C), 13.5 (CH3), 24.8
(2£CH3–Si). Anal. Calcd for C23H38O3Si: C, 70.72; H,
9.80. Found: C, 70.49; H, 9.78.
1H and 13C NMR spectra were recorded in CDCl3 solution
with Bruker AM-200 and Bruker AM-300 spectrometers.
Infrared spectra were obtained as film using a Perkin–Elmer
1600 FT-IR spectrophotometer. Routine monitoring of
reactions was performed using Merck Silica gel 60 F254
,
aluminum supported TLC plates. Column chromatography
was performed with Silica gel 60 (230–400 mesh) and
gradients pentane/ether as eluent, unless otherwise stated.
GC analyses were carried out on a Chrompack 9001 using a
WCOT fused silica column (25 m£0.32 mm i.d.; CP-Wax-
52 CB stationary phase; N2 carrier gas: 50 kPa). Enantio-
meric excess determinations were carried out using a
commercial column from Daiser: CHIRALCEL OD-Hw
(250£4.6 mm; 10 mm) with hexane/iPrOH (98:2, v/v) and a
flow rate of 1 mL/min. Specific rotations were recorded on a
Perkin–Elmer 341 polarimeter. Microanalyses were per-
formed on a ThermoFinnigan EA 1112 analyzer at our
University. Unless otherwise stated, the solutions were dried
over magnesium sulfate and evaporated in a rotary
evaporator under reduced pressure.
4.1.3. (1R,2R,4S)-4-Hydroxy-1,2-dimethyl-2-p-tolylcyclo
pentanecarboxylic acid ethyl ester [(2)-7]. To a solution
of (2)-6 (480 mg, 1.23 mmol) in dry THF (15 mL), tetra-n-
butyl ammonium fluoride (1.0 M in THF, 2.5 mL,
2.50 mmol) was added dropwise. The reaction mixture
was stirred at rt for 4 h. Cold water was added and the
resultant mixture was extracted with ether. The combined
organic extracts were washed with brine, dried, filtered, and
concentrated. The residual oil was chromatographed to
afford 332 mg (98%) of pure alcohol (2)-7; [a]2D5¼224.2
(c¼1.0, CHCl3); IR (film) n 3405, 3034, 1741, 1191 cm21
;
4.1.1. (1S,2S,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-
methyl-2-p-tolyl-cyclopentanecarboxylic acid ethyl
ester [(1)-5]. The alcohol (þ)-4 (675 mg, 2.58 mmol)
was dissolved in DMF (10 mL), imidazole (530 mg,
7.78 mmol) and tert-butyldimethylsilyl chloride (590 mg,
3.91 mmol) were added, and the mixture was stirred for 1 h
at rt. The solution was poured into water and extracted with
ether. The combined organic extracts were washed with
water, brine, dried, filtered, and concentrated. Column
chromatography gave 970 mg (100%) of (þ)-5 as an oil;
[a]2D5¼þ49.2 (c¼1.0, CHCl3); IR (film) n 3041, 1749, 1256,
1H NMR (300 MHz, CDCl3) d 7.13 and 7.04 (AB, 4H,
J¼8.3 Hz), 4.74 (m, 1H), 3.68 (m, 2H), 3.01 (dd, 1H,
J¼14.4, 7.9 Hz), 2.71 (dd, 1H, J¼14.4, 7.9 Hz), 2.28 (s,
3H), 1.85 (dd, 1H, J¼14.3, 2.3 Hz), 1.68 (dd, 1H, J¼14.4,
3.0 Hz), 1.56 (s, 3H), 1.44 (s, 3H), 0.88 (t, 3H, J¼7.2 Hz);
13C NMR (75 MHz, CDCl3) d 176.1 (C), 142.7 (C), 135.6
(C), 128.4 (2£CH), 126.2 (2£CH), 71.1 (CH), 60.0 (CH2),
57.3 (C), 51.5 (C), 48.6 (CH2), 46.7 (CH2), 25.3 (CH3), 20.7
(CH3), 20.6 (CH3), 13.6 (CH3). Anal. Calcd for C17H24O3:
C, 73.88; H, 8.75. Found: C, 74.17; H, 8.72.

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S. Acherar et al. / Tetrahedron 60 (2004) 5907–5912
4.1.4. (1R,2R,4S)-1,2-Dimethyl-4-methylsulfanylthio
carboxyoxy-2-p-tolyl-cyclopentanecarboxylic acid ethyl
ester [(2)-8]. To a suspension of sodium hydride (63 mg,
1.30 mmol, 50% dispersion) in 5 mL of THF at 0 8C was
added alcohol (2)-7 (180 mg, 0.651 mmol). After the
mixture was stirred for 30 min at 0 8C, carbon disulfide
(303 mg, 241 mL, 2.61 mmol) and iodomethane (741 mg,
325 mL, 5.22 mmol) was added. The resulting mixture was
stirred for another 1 h, carefully poured into ice, and
extracted with ether. The organic layer was separated,
dried (MgSO4), filtered, and concentrated under reduced
pressure to an oily residue, which was column chromato-
graphed to provide 234 mg (98%) of xanthate (2)-8;
[a]2D5¼229.9 (c¼1.0, CHCl3); 1H NMR (300 MHz,
CDCl3) d 7.15 and 7.07 (AB, 4H, J¼8.5 Hz), 6.12 (tt, 1H,
J¼8.1, 2.7 Hz), 3.70 (m, 2H), 3.20 (dd, 1H, J¼15.1,
8.1 Hz), 2.88 (dd, 1H, J¼15.1, 8.3 Hz), 2.75 (s, 3H), 2.56
(s, 3H), 2.29 (s, 3H), 2.10 (dd, 1H, J¼15.0, 1.7 Hz),
1.93 (dd, 1H, J¼15.2, 2.7 Hz), 1.53 (s, 3H), 1.44 (s, 3H),
0.89 (t, 3H, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3) d
214.8 (C), 175.5 (C), 141.8 (C), 135.9 (C), 128.6 (2£CH),
126.1 (2£CH), 84.4 (CH), 60.3 (CH2), 56.9 (C), 51.2
(C), 45.0 (CH2), 43.3 (CH2), 24.9 (CH3), 20.8 (CH3), 20.1
(CH3), 19.0 (CH3), 13.6 (CH3). Anal. Calcd for
C19H26O3S2: C, 62.26; H, 7.15; S, 17.50. Found: C, 61.99;
H, 7.18; S, 17.69.
(CH3). Anal. Calcd for C15H22O: C, 82.52; H, 10.16. Found:
C, 82.86; H, 10.13.
4.1.7. (1R,2R)-Tochuinyl acetate [(2)-1]. To a magneti-
cally stirred solution of the alcohol (2)-10 (65 mg,
0.298 mmol) in pyridine (3 mL) was sequentially added
acetic anhydride (185 mg, 200 mL, 1.81 mmol) and a
catalytic amount of DMAP. The reaction mixture was
stirred for 4 h at rt, then poured into 6 mL of 5% aqueous
HCl and extracted with CH2Cl2 (3£10 mL). The combined
organic phase was washed with 10% aqueous NaHCO3
solution and brine, and dried (MgSO4). Evaporation of the
solvent and purification of the residue on a silica gel column
furnished tochuinyl acetate (2)-1 (74 mg, 95%) which
exhibited 1H and 13C NMR spectra identical to those of the
natural product; [a]D25¼238.0 (c¼1.0, CH2Cl2); IR (film) n
3040, 1741, 1240, 1030 cm21; 1H NMR (300 MHz, CDCl3)
d 7.22 and 7.07 (AB, 4H, J¼8.3 Hz), 3.59 and 3.35 (AB, 2H,
J¼10.9 Hz), 2.53–2.41 (m, 1H), 2.30 (s, 3H), 1.93 (s, 3H),
1.90–1.69 (m, 4H), 1.60–1.49 (m, 1H), 1.31 (s, 3H), 1.11
(s, 3H); 13C NMR (75 MHz, CDCl3) d 171.0 (C), 142.9 (C),
135.3 (C), 128.5 (2£CH), 126.7 (2£CH), 70.5 (CH2),
49.8 (C), 47.4 (C), 37.5 (CH2), 34.8 (CH2), 24.9 (CH3),
20.8 (CH3), 20.7 (CH3), 20.2 (CH2), 19.5 (CH3). Anal.
Calcd for C17H24O2: C, 78.42; H, 9.29. Found: C, 78.72; H,
9.33.
4.1.5. (1R,2R,4S)-1,2-Dimethyl-2-p-tolylcyclopentane
carboxylic acid ethyl ester [(2)-9]. To a solution of
xanthate (2)-8 (188 mg, 0.513 mmol) and AIBN (15 mg) in
toluene (5 mL) was added tri-n-butyltin hydride (252 mg,
230 mL, 0.866 mmol), and the reaction mixture heated
under reflux for 40 min, cooled, and concentrated in vacuo.
The resulting oily residue was chromatographed on column
to provide 128 mg (96%) of (2)-9; [a]2D5¼221.4 (c¼1.0,
CHCl3); IR (film) n 3094, 3039, 1749, 1168 cm21; 1H NMR
(300 MHz, CDCl3) d 7.21 and 7.06 (AB, 4H, J¼8.3 Hz),
3.70 (m, 2H), 2.66–2.54 (m, 1H), 2.40–2.31 (m, 1H), 2.29
(s, 3H), 2.03–1.75 (m, 3H), 1.66–1.56 (m, 1H), 1.40 (s,
3H), 1.34 (s, 3H), 0.90 (t, 3H, J¼7.0 Hz); 13C NMR
(75 MHz, CDCl3) d 176.6 (C), 143.6 (C), 135.3 (C), 128.3
(2£CH), 126.3 (2£CH), 59.8 (CH2), 56.5 (C), 51.4 (C), 38.0
(CH2), 36.0 (CH2), 24.5 (CH3), 21.1 (CH2), 20.7 (CH3), 20.5
(CH3), 13.6 (CH3). Anal. Calcd for C17H24O2: C, 78.42; H,
9.29. Found: C, 78.71; H, 9.31.
4.1.8. (1R,2R)-Dihydrotochuinyl acetate [(2)-2]. To a
solution of lithium (78 mg, 11.2 mmol) in 50 mL of freshly
distilled ammonia was added dropwise, a solution of the
alcohol (2)-10 (60 mg, 0.275 mmol) and tert-butanol
(0.5 mL) in 5 mL of dry THF over a period of 10 min.
The reaction mixture was stirred overnight and then
quenched with ammonium chloride. Ammonia was evap-
orated, the reaction mixture was diluted with water and
extracted with ether (3£10 mL). The ether extract was
washed with brine and dried (MgSO4). Evaporation of the
solvent furnished 55 mg of crude dihydro alcohol, which
was immediately used for the acetylation step. To a
magnetically stirred solution of the dihydro alcohol
(55 mg, 0.251 mmol) in pyridine (3 mL) was sequentially
added acetic anhydride (200 mL, 1.81 mmol) and a catalytic
amount of DMAP, and stirred for 4 h at rt. The reaction
mixture was then quenched with 10% aqueous HCl (6 mL)
and extracted with CH2Cl2 (3£10 mL). The combined
organic phase was washed with saturated aq. NaHCO3
solution and brine, and dried (MgSO4). Evaporation of the
solvent and rapid purification of the residue on a silica gel
column furnished the dihydrotochuinyl acetate (2)-2
4.1.6. (1R,2R)-(1,2-Dimethyl-2-p-tolyl-cyclopentyl)-
methanol [(2)-10].
A solution of (2)-9 (90 mg,
0.346 mmol) in dry ether (5 mL) was slowly added to a
stirred slurry of LiAlH4 (30 mg, 0.790 mmol) in dry ether
(4 mL) at 0 8C. The solution was allowed to rise to rt. After
1 h, Celite (1 g) and Na2SO4·10H2O (1 g) were added and
the solution was stirred for a further 30 min. The mixture
was filtered through a pad of MgSO4 and concentrated. A
column chromatography of the oil afforded 74 mg (98%) of
pure (2)-10; [a]2D5¼250.1 (c¼1.0, CHCl3); IR (film) n
3409, 3041, 1043 cm21; 1H NMR (300 MHz, CDCl3) d 7.29
and 7.12 (AB, 4H, J¼8.3 Hz), 3.12 and 3.05 (AB, 2H,
J¼11.3 Hz), 2.52–2.42 (m, 1H), 2.31 (s, 3H), 1.89–1.66
(m, 4H), 1.61–1.50 (m, 1H), 1.30 (s, 3H), 1.11 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 143.4 (C), 135.4 (C), 128.8
(2£CH), 126.6 (2£CH), 69.3 (CH2), 49.4 (C), 49.2 (C), 37.4
(CH2), 34.8 (CH2), 25.0 (CH3), 20.7 (CH3), 20.2 (CH2), 19.3
1
(58 mg, 80% from the alcohol (2)-10) which exhibited H
and 13C NMR spectra identical to those of the natural
product; [a]2D5¼245.5 (c¼1.0, CH2Cl2); IR (film) n 3051,
1744, 1238, 802 cm21; 1H NMR (300 MHz, CDCl3) d 5.52
(br s, 1H), 5.37 (br s, 1H), 3.80 and 3.72 (AB, 2H,
J¼10.9 Hz), 2.75–2.65 (m, 2H), 2.62–2.53 (m, 2H), 2.18
(dt, 1H, J¼12.8, 9.3 Hz), 2.00 (s, 3H), 1.79–1.56 (m, 3H),
1.63 (s, 3H), 1.48–1.39 (m, 2H), 1.05 (s, 3H), 1.02 (s, 3H);
13C NMR (75 MHz, CDCl3): d¼171.4 (C), 138.5 (C), 130.5
(C), 119.1 (CH), 119.0 (CH), 70.0 (CH2), 50.3 (C), 46.9 (C),
36.9 (CH2), 35.3 (CH2), 31.9 (CH2), 28.3 (CH2), 22.7 (CH3),
22.6 (CH3), 21.0 (CH3), 20.1 (CH3), 19.5 (CH2). Anal.
Calcd for C17H26O2: C, 77.82; H, 9.99. Found: C, 77.59; H,
9.97.

S. Acherar et al. / Tetrahedron 60 (2004) 5907–5912
5911
4.1.9. (1S,2S,4R)-[4-(tert-Butyl-dimethyl-silanyloxy)-1,2-
dimethyl-2-p-tolyl-cyclopentyl]-methanol [(1)-11].
J¼13.8, 8.0 Hz), 1.84–1.79 (m, 1H), 1.78–1.74 (m, 1H),
1.46 (s, 3H), 1.18 (s, 3H), 0.57 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 143.7 (C), 134.9 (C), 128.3 (2£CH), 126.7
(2£CH), 70.4 (CH), 50.8 (CH2), 50.3 (C), 47.6 (CH2), 44.9
(C), 26.5 (CH3), 25.7 (CH3), 24.5 (CH3), 20.7 (CH3). Anal.
Calcd for C15H22O: C, 82.52; H, 10.16. Found: C, 82.41; H,
10.12.
A
solution of (þ)-6 (260 mg, 0.666 mmol) in dry diethyl
ether (50 mL) was slowly added at 0 8C to a stirred slurry of
LiAlH4 (51 mg, 1.34 mmol) in dry ether (5 mL). The
solution was allowed to warm to rt. After 1 h, Celite (2 g)
and Na2SO4·10H2O (2 g) were added and the solution was
stirred for a further 30 min. The mixture was filtered
through a pad of MgSO4 and concentrated. Column
chromatography of the oil afforded 220 mg (95%) of pure
(þ)-11; [a]2D5¼þ30.2 (c¼1.0, CHCl3); IR (film) n 3412,
3039, 1261, 1083 cm21; 1H NMR (300 MHz, CDCl3) d 7.22
and 7.10 (AB, 4H, J¼8.2 Hz), 4.50 (m, 1H), 3.02 (d, 2H,
J¼6.1 Hz), 2.84 (dd, 1H, J¼14.1, 7.9 Hz), 2.31 (s, 3H), 2.15
(dd, 1H, J¼14.0, 7.9 Hz), 1.77 (dd, 1H, J¼14.1, 1.5 Hz),
1.62 (dd, 1H, J¼14.1, 3.3 Hz), 1.46 (s, 3H), 1.19 (s, 3H),
0.88 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3) d
143.2 (C), 135.4 (C), 128.8 (2£CH), 126.5 (2£CH), 70.6
(CH), 69.2 (CH2), 49.7 (C), 49.5 (C), 48.6 (CH2), 46.6
(CH2), 26.2 (CH3), 25.8 (3£CH3), 20.8 (CH3), 19.6 (CH3),
17.9 (C), 24.7 (2£CH3–Si). Anal. Calcd for C21H36O2Si:
C, 72.35; H, 10.41. Found: C, 72.09; H, 10.38.
4.1.12. (4R)-b-Cuparenone [(1)-3]. Tetrapropyl-
ammonium perruthenate (TPAP) (5 mol%, 10 mg,
0.028 mmol) was added in one portion to a stirred mixture
of the alcohol (þ)-13 (58 mg, 0.266 mmol), N-methyl
morpholine oxide (NMO) (63 mg, 0.538 mmol) and
˚
powdered 4 A molecular sieves (180 mg) in CH2Cl2
(5 mL) at rt under argon atmosphere. On completion the
reaction mixture was filtered through a short pad of celite,
eluting with CH2Cl2. The filtrate was evaporated and the
residue was purified by column chromatography on silica
gel to afford 56 mg (97%) of the b-cuparenone (þ)-3 which
exhibited 1H and 13C NMR spectra identical to those of the
natural product; [a]2D5¼þ45.3 (c¼1.0, CHCl3); IR (film) n
3041, 1718, 1031 cm21; 1H NMR (200 MHz, CDCl3) d 7.20
and 7.12 (AB, 4H, J¼8.3 Hz), 3.12 (d, 1H, J¼18.1 Hz),
2.41–2.24 (m, 3H), 2.31 (s, 3H), 1.40 (s, 3H), 1.22 (s, 3H),
0.72 (s, 3H); 13C NMR (50 MHz, CDCl3) d 218.0 (C), 141.2
(C), 135.8 (C), 128.7 (2£CH), 126.5 (2£CH), 52.4 (CH2),
50.6 (CH2), 47.7 (CH), 41.7 (CH), 26.2 (CH3), 24.4 (CH3),
24.1 (CH3), 20.7 (CH3). Anal. Calcd for C15H20O: C, 83.28;
H, 9.32. Found: C, 82.98; H, 9.36.
4.1.10. (1S,2S,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-1,2-
dimethyl-2-p-tolyl-cyclopentanecarbaldehyde [(1)-12].
Tetrapropylammonium perruthenate (TPAP) (5 mol%,
10 mg, 0.028 mmol) was added in one portion to a stirred
mixture of the alcohol (þ)-11 (190 mg, 0.545 mmol),
N-methyl morpholine oxide (NMO) (130 mg, 1.11 mmol)
˚
and powdered 4 A molecular sieves (370 mg) in CH2Cl2
(5 mL) at rt under argon atmosphere. On completion the
reaction mixture was filtered through a short pad of celite,
eluting with CH2Cl2. The filtrate was evaporated and the
residue was purified by column chromatography on silica
gel to afford 185 mg (98%) of aldehyde (þ)-12;
[a]2D5¼þ27.8 (c¼1.0, CHCl3); IR (film) n 3043, 2719,
Acknowledgements
The authors acknowledge Dr. R. Faure for running NOESY
experiments. We are thankful to Prof. C. Roussel (UMR
6180) for chiral HPLC analyses performed in his laboratory.
1
1250, 831 cm21; H NMR (300 MHz, CDCl3) d 8.90 (s,
1H), 7.16 and 7.09 (AB, 4H, J¼8.1 Hz), 4.52 (m, 1H), 2.63
(dd, 1H, J¼13.9, 7.4 Hz), 2.51 (dd, 1H, J¼14.0, 7.7 Hz),
2.30 (s, 3H), 1.82 (d, 1H, J¼14.0 Hz), 1.62 (dd, 1H, J¼13.9,
2.8 Hz), 1.51 (s, 3H), 1.31 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H);
13C NMR (75 MHz, CDCl3) d 206.4 (C), 140.9 (C), 135.9
(C), 129.0 (2£CH), 126.4 (2£CH), 70.5 (CH), 59.4 (C), 49.9
(C), 48.0 (CH2), 44.5 (CH2), 25.8 (3£CH3), 25.4 (CH3),
20.8 (CH3), 17.9 (C), 16.6 (CH3), 24.8 (2£CH3–Si). Anal.
Calcd for C21H34O2Si: C, 72.78; H, 9.89. Found: C, 73.01;
H, 9.86.
References and notes
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`
Pericas, M. A.; Riera, A.; Greene, A. E.; Alvarez-Larena, A.;
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;
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2.96 (dd, 1H, J¼14.4, 8.3 Hz), 2.33 (s, 3H), 2.05 (dd, 1H,

5912
S. Acherar et al. / Tetrahedron 60 (2004) 5907–5912
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