Enantioselective synthesis of 1-(R)-hydroxypolygodial and its 9α epimer, 1-(R)-hydroxyisotadeonal

Article abstract of DOI:10.1016/j.tet.2007.04.059

The enantioselective synthesis of 1-(R)-hydroxypolygodial and its epimer at C-9 is described. α-Ionone was the starting material. Key steps of these syntheses included a Corey-Bakshi-Shibata oxazaborolidine-mediated reduction and a stereoselective Diels-A

Full text of DOI:10.1016/j.tet.2007.04.059

Tetrahedron 63 (2007) 6866–6873
Enantioselective synthesis of 1-(R)-hydroxypolygodial
and its 9a epimer, 1-(R)-hydroxyisotadeonal*
Carmela Della Monica,a Giorgio Della Sala,a Irene Izzo,a Luciano De Petrocellis,b
Vincenzo di Marzoc and Aldo Spinellaa,
*
aDipartimento di Chimica, Universitaꢀ di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy
bEndocannabinoid Research Group, Istituto di Cibernetica, C.N.R., Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy
cEndocannabinoid Research Group, Istituto di Chimica Biomolecolare del CNR, Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy
Received 21 December 2006; revised 29 March 2007; accepted 19 April 2007
Available online 25 April 2007
Abstract—The enantioselective synthesis of 1-(R)-hydroxypolygodial and its epimer at C-9 is described. a-Ionone was the starting material.
Key steps of these syntheses included a Corey–Bakshi–Shibata oxazaborolidine-mediated reduction and a stereoselective Diels–Alder reac-
tion. No vanilloid activity was detected for both compounds in assays on VR1 vanilloid receptor in HEK cells transfected with the human
VR1.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
stereoselective synthesis of 2 and its analogue 3 (Fig. 1),
the latter being an epimer of 2 at the carbon C-9. For the
enantioselective construction of the drimane skeleton of 2
and 3 we relied upon the same general concept used in our
previous synthesis, where a Diels–Alder reaction played
the key role in the construction of the bicyclic moiety.
Terpenoid unsaturated 1,4-dialdehydes, such as 1 (Fig. 1),
are often involved in the defensive strategies of terrestrial
and marine organisms against predators. These compounds
are also known for their pungent sensation in the human
tongue.1 Some years ago, it was suggested that biological
activities of these compounds are linked to the dialdehyde
moiety and to reactivity towards nucleophiles.2 Recently, a
vanilloid activity has been reported for polygodial 1 and
other related dialdehydes, but a clear comprehension of their
mode of action is still incomplete.3 In the course of our
investigation on the relationship between structure and va-
nilloid activity of these dialdehydes, we were recently inter-
ested on the influence of hydroxy groups in their skeleton.
Very recently, we published the stereoselective synthesis
of 2.4 In the present paper, we describe in full our
In fact, even though different synthetic strategies to natural
products with this skeleton have been suggested, the use of
an intermolecular Diels–Alder reaction of an appropriate
1,3-diene with dimethyl acetylene dicarboxylate (DMAD)
to construct the drimane skeleton was particularly attractive
(Scheme 1).
OH
1
CHO
9
OH
15
CO2Me
CHO
5
CO2Me
5
2
4
CHO
OH CHO
OH CHO
Scheme 1. Retrosynthetic analysis for 2.
CHO
CHO
CHO
2. Results and discussion
1
2
3
Figure 1.
The appropriate diene for our synthesis contains a hydroxy
group in the ring and we initially decided to investigate the
influence of this substituent on the diastereoselectivity of
the reaction. In fact, it is well known that dienes containing
an allylic heteroatom substituent can control diastereofacial
selectivity in intermolecular Diels–Alder reactions.5
*
This work is dedicated to the memory of Professor G. Sodano.
Keywords: Total synthesis; Diels–Alder reaction; Terpenoids; Polygodial;
Vanilloid activity.
* Corresponding author. Tel.: +39 089 969585; fax: +39 089 969603;
e-mail: spinella@unisa.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.059

C. Della Monica et al. / Tetrahedron 63 (2007) 6866–6873
6867
The Diels–Alder reaction of hydroxydiene (rac)-4, easily
prepared from a-ionone following a known procedure,6 was
first studied. When a neat mixture of DMAD and 4 was
heated at 110 ꢀC for 24 h, a smooth reaction took place
giving a 1.4:1.0 mixture of adducts 6 and 7 (Scheme 2). This
result showed that unprotected hydroxy group was not able
to give marked diastereofacial selectivity. The relative stereo-
chemistry shown in 6 and 7 was consistent with the results
obtained by 1D 1H NMR NOE experiments. In fact, for com-
pound 7 the irradiation of H-1 (d 4.35) led to the enhance-
ment of the signal due to Me-15 (d 1.27) establishing a
syn-relationship between H-1 and Me-15. An NOE experi-
ment conducted on compound 6 did not exhibit any enhance-
ment of Me-15 (d 1.07) after irradiation of H-1 (d 3.85).
stereomer 9 obtained by approach of the dienophile anti to
the allylic substituent. From these results, we concluded
that in order to have good diastereofacial selectivity a bulkier
group should be introduced in the allylic position of the di-
ene. Therefore, we decided to protect the alcoholic function-
ality as dimethyl-tert-butyl-silyl ether. In order to obtain an
enantioselective process, we planned to use the R enantio-
mer of hydroxydiene 4.
Preparation of (R)-2,4,4-trimethyl-3-vinyl-2-cyclohexene-
1-ol (13) started with enantioselective reduction of dienone
12 using (S)-Me-Corey–Bakshi–Shibata [(S)-MeCBS] ox-
azaborolidine-borane reagent,7 which afforded dienol (R)-4
in 94% yield and 93% enantiomeric excess (Scheme 3). Di-
enol (R)-4 was then converted into silyl derivative 13 (98%).
O
The Diels–Alder reaction of 13 with DMAD (5) proceeds
quite slowly (neat, 110 ꢀC, 48 h) affording compound 14
as a major product (40%) together with small amounts of
its diastereomer 15 (5%) and triene 16 (8.5%).8 The reaction
was stopped after 48 h, although unreacted diene 13 was still
present (15%), because longer reaction time favoured the in-
crease of triene 16. As expected, with a bulky silyl group as
the allylic substituent, the facial selectivity of the cycloaddi-
tion was enhanced. Compound 14 was then subjected to a
base catalyzed isomerization followed by partial hydrogena-
tion, following a known strategy.9 DBU catalyzed isomeri-
zation10 of 14 afforded mainly the conjugated diene 17 (90%
OH
CO2Me
CO2Me
O
OH
15
CO2Me
1
a
5
(rac)-6
(rac)-4
(rac)-7
1.4 : 1.0
b
OAc
OAc CO2Me
CO2Me
OAc CO2Me
CO2Me
c
5
1
yield). Once again, H NMR NOE experiments (Fig. 2)
secured the stereochemical assignment of diene 17.
(rac)-9
(rac)-10
(rac)-8
3.3 : 1.0
Hydrogenation of 17 (H2, Pd/C, MeOH) afforded compound
19 (85% yield) (Scheme 4) whose stereochemistry was
established via 1H NMR NOE measurements (Fig. 2). Irradi-
ation of H-1 (d 3.74 ppm) led to the enhancements of the
signals due to H-5 (d 1.17 ppm) and H-9 (d 3.21 ppm).
Reduction of the ester functionalities produced diol 20,
which was then oxidized using Swern conditions
(C2O2Cl2, DMSO, NEt3) to give dialdehyde 21 (87%). The
last step of the synthesis, involving the hydroxy group
Scheme 2. Reagents and conditions: (a) 110 ꢀC, 24 h, (rac)-6: 44%, (rac)-7:
31%; (b) Ac2O, pyridine, DMAP, CH2Cl2, rt, 21 h, 97%; (c) 110 ꢀC, 46 h,
(rac)-9: 53%, (rac)-10: 16%.
The diene 8, obtained after acetylation of 4, was then used
in the Diels–Alder reaction with DMAD (Scheme 2). In
this case a 3.3:1.0 mixture of diastereomers 9 and 10 was ob-
tained. 1H NOE experiments allowed assignment of the rel-
ative stereochemistry of products. The major adduct was the
OH
O
OH
ref. 6
a
b
O
(rac)-4
(R)-4
11
12
OTBS
TBSO
CO2Me
CO2Me
TBSO
CO2Me
CO2Me
CO2Me
CO2Me
d
c
+
+
14
13
15
16
TBSO
CO2Me
CO2Me
TBSO
CO2Me
CO2Me
e
+
17
18
Scheme 3. Reagents and conditions: (a) PDC, CH2Cl2, rt, 1 h, 91%; (b) (S)-MeCBS reagent, BH3$THF (syringe-pump addition: 1.2 mmol/h), THF, 35 ꢀC, 94%,
93% ee; (c) TBSCl, imidazole, CH2Cl2, rt, 12 h, 98%; (d) 5, neat, 110 ꢀC, 48 h, 14: 40%, 15: 5%, 16: 8.5%; (e) DBU, THF, 40 ꢀC, 4 h, 17: 90%, 18: 5%.

6868
C. Della Monica et al. / Tetrahedron 63 (2007) 6866–6873
NOE
NOE
4. Conclusions
TBSO
TBSO
CO2Me
CO2Me
H
H
H
In summary, a total synthesis of 1-(R)-hydroxypolygodial
and its epimer at C-9 has been achieved in a highly stereo-
selective way starting from a-ionone, through a synthetic
strategy involving a Corey–Bakshi–Shibata oxazaborol-
idine-mediated reduction and a stereoselective Diels–Alder
reaction as key steps. Both compounds were devoid of vanil-
loid activity in VR1 assays. Further evaluation of biological
activity of these compounds is now in progress and results
will be given in due course.
H
CO2Me
CO2Me
1
9
5
NOE
H
17
19
Figure 2.
deprotection, proved to be surprisingly complicated. Usual
deprotection with TBAF caused epimerization at C-9,
probably due to the basicity of Fꢁ. We found that the correct
conditions to yield the desired compound, avoiding epimeri-
zation, consisted in using HF in the deprotection step
(Scheme 4).
5. Experimental
5.1. General
All reactions were carried out under a dry argon atmosphere
using freshly distilled solvents, unless otherwise noted. Tet-
rahydrofuran (THF) was distilled from LiAlH4. Dichloro-
methane was distilled from calcium hydride. Glassware
was flame-dried (0.05 Torr) prior to use. When necessary,
compounds were dried in vacuo over P2O5 or by azeotropic
removal of water with toluene under reduced pressure. Start-
ing materials and reagents purchased from commercial sup-
pliers were generally used without purification. Reaction
temperatures were measured externally; reactions were
monitored by TLC on Merck silica gel plates (0.25 mm)
and visualized by UV light and spraying with phospho-
molybdic acid, p-anisaldehyde or Ce(SO4)2 solutions and
drying.
TBSO
TBSO
CH2OH
CH2OH
CO2Me
CO2Me
a
b
17
19
20
TBSO
CHO
OH CHO
CHO
CHO
1
9
d
c
5
21
2
Scheme 4. Reagents and conditions: (a) H2, Pd/C, MeOH, 1 h, 85%; (b) DI-
BAL–H, THF, toluene, ꢁ78 ꢀC/rt, 12 h; (c) Swern conditions, 1 h, 87%
(two steps); (d) 48% HF (aq), CH3CN, rt, 12 h, 79%.
Flash chromatography was performed on Merck silica gel 60
(particle size: 0.040–0.063 mm). Yields refer to chromato-
graphically and spectroscopically (1H and 13C NMR) pure
materials. The NMR spectra were recorded at room temper-
ature on a Bruker DRX 400, a Bruker DRX 300 or a
Bruker AV 250 spectrometer. Chemical shifts are reported
relative to the residual solvent peak (CHCl3: d¼7.26,
13CDCl3: d¼77.0). Assignments were made on the basis of
homonuclear decoupling experiments or 1D correlation
spectroscopic experiments (COSY, HSQC). Relative stereo-
chemical assignments were made on the basis of NOE
experiments. Assignments in the 13C NMR spectra were
confirmed by DEPT spectroscopic experiments. ESIMS
spectra were performed on a Micromass Quattro micro
APIÔ mass spectrometer equipped with an electrospray ion-
ization source operating in positive mode. EIMS spectra
were obtained with a Thermo Finnigan PolarisQ (70 eV)
mass spectrometer operating in positive mode. IR spectra
were obtained at a resolution of 2.0 cmꢁ1 with a Vector 22
Bruker Spectrometer. Optical rotations were measured
with a JASCO DIP-1000 polarimeter.
1H NMR NOE experiments allowed the correct stereochem-
istry of the obtained compound 2 to be deduced. In fact, ir-
radiation of H-1 (d 3.62 ppm) led to the enhancement of the
signal due to H-9 (d 3.20 ppm). Furthermore, irradiation of
H-5 (d 1.25 ppm) caused enhancements of both signals at
d 3.20 ppm (H-9) and at d 3.62 ppm (H-1). Therefore, H-1,
H-9 and H-5 are all in cis-relationship confirming that these
deprotection conditions (48% HF (aq), CH3CN, rt) do not
cause epimerization at C-9.
Easy epimerization of hydroxypolygodial 2 was obtained
after exposition to basic conditions (basic Al2O3, CH2Cl2,
20 h), which afforded the 9a epimer 3 in 82% yield
(Scheme 5).
OH CHO
CHO
a
2
3
Scheme 5. Reagents and conditions: (a) basic Al2O3, CH2Cl2, rt, 20 h, 82%.
5.2. (8RS,8aSR)-8-Hydroxy-5,5,8a-trimethyl-
3,5,6,7,8,8a-hexahydro-naphthalene-1,2-dicarboxylic
acid dimethyl ester (6) and (8aRS,8bRS)-6,6,8b-tri-
methyl-2-oxo-4,6,7,8,8a,8b-hexahydro-2H-naphtho[1,8-
bc]furan-3-carboxylic acid methyl ester (7)
3. Vanilloid activity
Vanilloid activity was evaluated in assays on VR1 vanilloid
receptor in HEK cells transfected with the human VR1. Pre-
liminary results showed that both hydroxy derivatives 2 and
3 were devoid of any significant vanilloid activity.
A mixture of diene (rac)-4 (74.0 mg, 0.264 mmol) and
freshly distilled DMAD (5) (130.0 mL, 1.056 mmol) was
heated in a reacti-vial at 110 ꢀC for 24 h, under a nitrogen

C. Della Monica et al. / Tetrahedron 63 (2007) 6866–6873
6869
atmosphere. After cooling, the reaction mixture was flash-
chromatographed (30–80% diethyl ether in petroleum ether)
to give 36.0 mg (0.117 mmol, 44%) of the major adduct
(rac)-6 and 23.0 mg (0.083 mmol, 31%) of the lactone
(rac)-7, as clear pale yellow oils.
(41), 133 (98), 105 (100), 91 (67). Anal. Calcd for
C13H20O2: C, 74.96; H, 9.68. Found: C, 74.81; H, 9.62.
5.4. (8RS,8aSR)-8-Acetoxy-5,5,8a-trimethyl-
3,5,6,7,8,8a-hexahydro-naphthalene-1,2-dicarboxylic
acid dimethyl ester (9) and (8RS,8aRS)-8-acetoxy-
5,5,8a-trimethyl-3,5,6,7,8,8a-hexahydro-naphthalene-
1,2-dicarboxylic acid dimethyl ester (10)
Compound (rac)-6: Rf¼0.50 (100% diethyl ether). 1H NMR
(CDCl3, 400 MHz): d 1.07 (3H, s, CH3), 1.12 (3H, s, CH3),
1.35 (3H, s, CH3), 1.38 (2H, m, H-3 and H-30 overlapped),
1.71 (1H, m, H-2), 1.81 (1H, m, H-20), 2.08 (1H, br s,
OH), 2.78 (1H, dd, J¼1.4, 22.6 Hz, H-7), 3.06 (1H, dd,
J¼5.5, 22.6 Hz, H-70), 3.68 (3H, s, CO2CH3), 3.75 (3H, s,
CO2CH3), 3.85 (1H, dd, J¼5.0, 11.4 Hz, H-1), 5.69 (1H,
dd, J¼1.4, 5.5 Hz, H-6). 13C NMR (CDCl3, 75 MHz):
d 20.1 (CH3), 26.5 (CH2), 28.2 (CH2), 30.7 (CH3), 32.1
(CH3), 35.7 (C), 37.3 (CH2), 45.7 (C), 52.0 (CH3),
52.3 (CH3), 72.8 (CH), 118.9 (CH), 125.6 (C), 147.1
(C), 148.4 (C), 166.2 (C), 171.2 (C). IR (CHCl3): n¼3487
(br), 1725 (br) cmꢁ1. ESIMS: m/z 309 [M+H]+. Anal.
Calcd for C17H24O5: C, 66.21; H, 7.84. Found: C, 66.48;
H, 7.79.
A mixture of diene (rac)-8 (387.0 mg, 1.86 mmol) and
freshly distilled DMAD (5) (915.0 mL, 7.44 mmol) was
heated in a reacti-vial at 110 ꢀC for 46 h, under a nitrogen
atmosphere. After cooling, the reaction mixture was flash-
chromatographed (5–50% diethyl ether in petroleum ether)
to give 51.0 mg (0.250 mmol, 13%) of the unreacted diene
(rac)-8, 340.0 mg (0.970 mmol, 53%) of the major adduct
(rac)-9 and 105.0 mg (0.300 mmol, 16%) of the minor
adduct (rac)-10.
Compound (rac)-9: Rf¼0.25 (40% diethyl ether in petro-
1
leum ether). H NMR (CDCl3, 400 MHz): d 1.10 (3H, s,
CH3), 1.16 (3H, s, CH3), 1.43 (2H, m, H-3 and H-30 overlap-
ped), 1.47 (3H, s, CH3), 1.73 (1H, m, H-2), 1.96 (1H, m,
H-20), 2.01 (3H, s, CH3CO), 2.80 (1H, dd, J¼2.2, 22.6 Hz,
H-7), 3.07 (1H, dd, J¼5.6, 22.6 Hz, H-70), 3.69 (3H, s,
CO2CH3), 3.71 (3H, s, CO2CH3), 4.86 (1H, dd, J¼4.7,
11.1 Hz, H-1), 5.75 (1H, dd, J¼2.2, 5.6 Hz, H-6).
13C NMR (CDCl3, 100 MHz): d 21.5 (CH3), 22.0
(CH3), 23.7 (CH2), 26.5 (CH2), 30.7 (CH3), 32.1 (CH3),
35.8 (C), 36.6 (CH2), 43.4 (C), 52.0 (CH3), 52.1 (CH3),
75.6 (CH), 119.5 (CH), 126.0 (C), 146.3 (C), 147.4 (C),
166.0 (C), 169.2 (C), 170.0 (C). IR (CHCl3): n¼2952,
1730 (br) cmꢁ1. EIMS: m/z (%)¼350 (2), 275 (20), 243
(64), 215 (26), 258 (100), 199 (28), 177 (40). Anal.
Calcd for C19H26O6: C, 65.13; H, 7.48. Found: C, 65.35;
H, 7.39.
Compound (rac)-7: Rf¼0.75 (70% diethyl ether in petro-
1
leum ether). H NMR (CDCl3, 400 MHz): d 1.15 (3H, s,
CH3), 1.18 (1H, m, H-2), 1.21 (3H, s, CH3), 1.27 (3H, s,
CH3), 1.44 (1H, ddd, J¼3.7, 13.8, 14.1 Hz, H-3), 1.61
(1H, ddd, J¼3.7, 3.7, 14.1 Hz, H-30), 1.96 (1H, m, H-20),
3.04 (1H, dd, J¼1.2, 21.7 Hz, H-7), 3.18 (1H, dd, J¼5.9,
21.7 Hz, H-70), 3.85 (3H, s, CO2CH3), 4.37 (1H, dd,
J¼4.8, 12.0 Hz, H-1), 5.74 (1H, dd, J¼1.2, 5.9 Hz, H-6).
13C NMR (CDCl3, 100 MHz): d 25.6 (CH3), 27.5 (CH2),
30.3 (CH2), 30.9 (CH3), 33.7 (CH3), 34.8 (C), 35.5 (CH2),
44.5 (C), 52.5 (CH3), 85.1 (CH), 119.1 (CH), 135.1 (C),
139.1 (C), 149.6 (C), 165.4 (C), 167.5 (C). IR (CHCl3):
n¼2869, 1766, 1730, 1692, 1435, 1122 cmꢁ1. ESIMS: m/z
277 [M+H]+. Anal. Calcd for C16H20O4: C, 69.54; H, 7.30.
Found: C, 69.61; H, 7.26.
Compound (rac)-10: Rf¼0.30 (40% diethyl ether in petro-
1
5.3. Acetic acid (RS)-2,4,4-trimethyl-3-vinyl-cyclohex-
2-enyl ester (8)
leum ether). H NMR (CDCl3, 400 MHz): d 1.18 (3H, s,
CH3), 1.21 (3H, s, CH3), 1.26 (1H, m, H-3), 1.52 (3H, s,
CH3), 1.62 (1H, ddd, J¼4.0, 4.0, 13.8 Hz, H-30), 1.81 (1H,
m, H-2), 1.98 (3H, s, CH3CO), 2.03 (1H, m, H-20), 2.81
(1H, dd, J¼2.4, 23.0 Hz, H-7), 3.22 (1H, dd, J¼5.3,
23.0 Hz, H-70), 3.68 (3H, s, CO2CH3), 3.73 (3H, s,
CO2CH3), 4.86 (1H, m, H-1), 5.79 (1H, m, H-6). 13C
NMR (CDCl3, 100 MHz): d 21.2 (CH3), 22.1 (CH2), 26.0
(CH3), 27.1 (CH2), 31.5 (CH3), 32.3 (CH3), 33.4 (CH2),
35.3 (C), 43.2 (C), 52.2 (ꢂ2) (CH3), 74.2 (CH), 117.9
(CH), 128.6 (C), 144.5 (C), 145.5 (C), 166.9 (C), 168.6
To a solution of (rac)-4 (152.0 mg, 0.914 mmol) in dry
CH2Cl2 (20 mL), pyridine (0.222 mL, 2.74 mmol), DMAP
(5.62 mg, 0.046 mmol) and Ac2O (0.173 mL, 1.83 mmol)
were sequentially added at room temperature, under a nitro-
gen atmosphere. The mixture was stirred for 21 h and then
concentrated under reduced pressure. The resulting crude
was directly purified by flash chromatography (0–10%
diethyl ether in petroleum ether) to afford 185.0 mg
(0.889 mmol, 97%) of (rac)-8, as yellow oil.
(C), 170.6 (C). IR (CHCl3): n¼2952, 1722 (br) cmꢁ1
.
ESIMS: m/z 373 [M+Na]+.
Compound (rac)-8: Rf¼0.45 (10% diethyl ether in petro-
1
leum ether). H NMR (CDCl3, 400 MHz): d 0.99 (3H, s,
5.5. 2,4,4-Trimethyl-3-vinyl-cyclohex-2-enone (12)
CH3), 1.04 (3H, s, CH3), 1.41 (1H, m, H-3), 1.60 (1H, m,
H-30), 1.67 (3H, s, CH3), 1.72 (1H, m, H-2), 1.90 (1H, m,
H-20), 2.07 (3H, s, CH3CO), 5.03 (1H, dd, J¼2.4, 17.8 Hz,
HHC]CH), 5.21 (1H, t-like, J¼4.4 Hz, H-1), 5.31 (1H,
dd, J¼2.4, 11.4 Hz, HHC]CH), 6.19 (1H, ddd, J¼0.9,
11.4, 17.8 Hz, H2C]CH). 13C NMR (CDCl3, 100 MHz):
d 17.9 (CH3), 21.3 (CH3), 25.1 (CH2), 26.8 (CH3), 28.5
(CH3), 34.0 (C), 34.3 (CH2), 72.2 (CH), 119.2 (CH2),
125.4 (C), 134.4 (CH), 144.5 (C), 170.9 (C). IR (CHCl3):
n¼2965, 2927, 2856, 1720 cmꢁ1. EIMS: m/z (%)¼148
To a solution of the alcohol (rac)-4 (0.543 g, 3.26 mmol) in
˚
dry CH2Cl2 (17 mL), 4 A molecular sieves (1.09 g) and PDC
(2.45 g, 6.52 mmol) were added at room temperature under
a nitrogen atmosphere. The mixture was stirred for 1 h, then
diluted with diethyl ether (100 mL) and allowed to stir for
additional 1 h. Filtration through a short pad of silica gel
(particle size 0.063–0.200 mm) and CaSO4 (10% in weight)
afforded a solution, which was concentrated in vacuo. The
residue was flash-chromatographed (10–40% diethyl ether

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C. Della Monica et al. / Tetrahedron 63 (2007) 6866–6873
in petroleum ether) to afford pure enone 12 (0.488 g,
2.97 mmol, 91%) as a colourless oil.
crude product was flash-chromatographed (0–30% ethyl
ether in petroleum ether) to afford 2.39 g (8.52 mmol,
98%) of pure colourless oil 13.
Compound 12: Rf¼0.56 (30% diethyl ether in petroleum
ether). 1H NMR (CDCl3, 400 MHz): d 1.14 (6H, s,
(CH3)2C), 1.81 (3H, s, CH3C]), 1.84 (2H, t, J¼6.7 Hz,
H-3 and H-30 overlapped), 2.50 (2H, t, J¼6.7 Hz, H-2 and
H-20 overlapped), 5.17 (1H, dd, J¼1.9, 17.8 Hz,
HHC]CH), 5.49 (1H, dd, J¼1.9, 11.8 Hz, HHC]CH),
6.33 (1H, dd, J¼11.8, 17.8 Hz, H2C]CH). 13C NMR
(CDCl3, 100 MHz): d 13.3 (CH3), 27.2 (ꢂ2) (CH3), 34.3
(CH2), 35.2 (C), 37.2 (CH2), 120.7 (CH2), 129.8 (C),
133.9 (CH), 161.5 (C), 199.6 (C). IR (CHCl3): n¼2964,
2929, 1660 cmꢁ1. EIMS: m/z (%)¼164 (100), 149 (4), 107
(15). Anal. Calcd for C11H16O: C, 80.44; H, 9.82. Found:
C, 80.32; H, 9.87.
Compound 13: Rf¼0.62 (0.5% diethyl ether in petroleum
ether). 1H NMR (CDCl3, 400 MHz): d 0.08 (3H, s, CH3Si),
0.09 (3H, s, CH3Si), 0.91 (9H, s, (CH3)3CSi), 0.96 (3H, s,
CH3), 1.02 (3H, s, CH3), 1.37 (1H, ddd, J¼3.1, 9.8, 13.0 Hz,
H-3), 1.59–1.68 (2H, m, H-30 and H-2 overlapped), 1.72 (3H,
s, CH3), 1.80 (1H, m, H-20), 4.01 (1H, t-like, J¼5.6 Hz, H-1),
5.00 (1H, dd, J¼2.6, 17.7 Hz, HHC]CH), 5.26 (1H, dd,
J¼2.6, 11.3 Hz, HHC]CH), 6.18 (1H, dd, J¼11.3,
17.7 Hz, H2C]CH). 13C NMR (CDCl3, 100 MHz): d ꢁ4.6
(CH3), ꢁ4.2 (CH3), 18.1 (CH3), 18.2 (C), 26.0 (ꢂ3) (CH3),
28.1 (CH3), 28.2 (CH3), 29.3 (CH2), 34.2 (C), 35.3 (CH2),
71.2 (CH), 118.5 (CH2), 130.7 (C), 135.3 (CH), 140.7 (C).
[a]2D5 +2.4 (c 1.0, CHCl3). Anal. Calcd for C17H32OSi:
C, 72.79; H, 11.50. Found: C, 72.46; H, 11.36.
5.6. (R)-2,4,4-Trimethyl-3-vinyl-cyclohex-2-enol (4)
A solution of BH3$THF (1 M in THF, 1.87 mL, 1.87 mmol)
was slowly added (1.2 mmol/h by syringe pump) to a warm
solution (35 ꢀC) of dienone 12 (342.0 mg, 2.08 mmol) and
(S)-methyl-oxazaborolidine (1 M in toluene, 2.29 mL,
2.29 mmol) in 2.1 mL of dry THF, under a nitrogen atmo-
sphere. After the completion of the addition, TLC analysis
showed the disappearance of the starting material. The reac-
tion mixture was then cooled and quenched with water at
0 ꢀC. Then THF was removed in vacuo and (R)-4 was ex-
tracted with diethyl ether (3ꢂ10 mL). The combined organic
extracts were dried (MgSO4), filtered and evaporated in va-
cuo. Flash chromatography of the crude (20–60% diethyl
ether in petroleum ether) afforded pure (R)-4 (324.0 g,
1.95 mmol, 94%) as a white amorphous solid.
5.8. (8R,8aS)-8-(tert-Butyl-dimethyl-silanyloxy)-5,5,8a-
trimethyl-3,5,6,7,8,8a-hexahydro-naphthalene-1,2-di-
carboxylic acid dimethyl ester (14)
A mixture of the diene 13 (187.0 mg, 0.667 mmol) and
freshly distilled DMAD (5) (369.0 mL, 3.00 mmol) was
heated in a reacti-vial at 110 ꢀC for 48 h, under a nitrogen
atmosphere. After cooling, a first flash chromatography of
the reaction mixture (2–40% ethyl acetate in petroleum
ether) furnished 28.0 mg (0.100 mmol, 15%) of the starting
material 13, 13.0 mg (0.031 mmol, 5%) of the minor adduct
15 as an oil, a mixture of the major adduct 14 and DMAD (5)
and 16.4 mg (0.057 mmol, 8.5%) of the pure triene 16. The
fraction containing the major adduct 14 was re-purified (5–
40% diethyl ether in petroleum ether). Pure 14 (114.0 mg,
40%) was obtained as pale yellow oil.
Compound (R)-4: Rf¼0.35 (30% diethyl ether in petroleum
1
ether). H NMR (CDCl3, 400 MHz): d 0.99 (3H, s, CH3),
1.02 (3H, s, CH3), 1.41 (1H, m, H-3), 1.43 (1H, br s, OH),
1.63 (1H, m, H-30), 1.71 (1H, m, H-2), 1.81 (3H, s,
CH3C]), 1.90 (1H, m, H-20), 3.98 (1H, m, H-1), 5.01
(1H, dd, J¼2.5, 17.7 Hz, HHC]CH), 5.29 (1H, dd, J¼2.5,
11.4 Hz, HHC]CH), 6.19 (1H, dd, J¼11.4, 17.7 Hz,
H2C]CH). 13C NMR (CDCl3, 100 MHz): d 18.2 (CH3),
27.1 (CH3), 28.4 (CH2), 28.7 (CH3), 34.2 (C), 34.4 (CH2),
70.0 (CH), 118.8 (CH2), 129.2 (C), 134.8 (CH), 142.1 (C).
[a]2D5 +43.1 (c 1.0, CHCl3). EIMS: m/z (%)¼166 (8), 149
(100), 148 (50), 133 (9), 90 (20). Anal. Calcd for
C11H18O: C, 79.46; H, 10.91. Found: C, 79.32; H, 10.60.
Compound 14: Rf¼0.40 (20% diethyl ether in petroleum
ether). 1H NMR (CDCl3, 400 MHz): d 0.06 (3H, s,
CH3Si), 0.09 (3H, s, CH3Si), 0.89 (9H, s, (CH3)3CSi), 1.08
(3H, s, CH3), 1.16 (3H, s, CH3), 1.31 (3H, s, CH3), 1.34
(1H, m, H-3), 1.47 (1H, ddd, J¼4.5, 4.5, 13.6 Hz, H-30),
1.73–1.79 (2H, m, H-2 and H-20 overlapped), 2.78 (1H,
dd, J¼2.1, 22.4 Hz, H-7), 3.04 (1H, dd, J¼5.8, 22.4 Hz,
H-70), 3.69 (3H, s, CO2CH3), 3.78 (3H, s, CO2CH3), 4.17
(1H, dd, J¼5.8, 8.4 Hz, H-1), 5.70 (1H, dd, J¼2.1, 5.8 Hz,
H-6). 13C NMR (CDCl3, 100 MHz): d ꢁ3.0 (CH3), ꢁ2.6
(CH3), 18.9 (C), 21.7 (CH3), 26.4 (ꢂ3) (CH3), 26.8 (CH2),
28.5 (CH2), 31.3 (CH3), 32.2 (CH3), 35.4 (C), 36.1 (CH2),
46.3 (C), 51.9 (CH3), 52.5 (CH3), 74.1 (CH), 119.0 (CH),
126.6 (C), 148.0 (C), 148.8 (C), 166.4 (C), 169.2 (C). [a]D25
ꢁ50.7 (c 0.95, CHCl3). IR (CHCl3): n¼2954, 2930, 1729
(br) cmꢁ1. ESIMS: m/z 423 [M+H]+. Anal. Calcd for
C23H38O5Si: C, 65.36; H, 9.06. Found: C, 65.84; H, 9.04.
HPLC conditions for ee determination: column: Chiralcel
OD; solvent: 1% propan-2-ol in hexane; flow rate: 1 mL/
min; detector: UV detector (254 nm); retention time: (R),
10.37 min; (S), 9.21 min.
5.7. (R)-tert-Butyl-dimethyl-(2,4,4-trimethyl-3-vinyl-
cyclohex-2-enyloxy)-silane (13)
Compound 15: Rf¼0.80 (20% ethyl acetate in petroleum
ether). 1H NMR (CDCl3, 400 MHz): d 0.03 (3H, s,
CH3Si), 0.04 (3H, s, CH3Si), 0.80 (9H, s, (CH3)3CSi), 1.14
(3H, s, CH3), 1.16 (1H, m, H3), 1.19 (3H, s, CH3), 1.42
(3H, s, CH3), 1.58 (1H, m, H-2), 1.82 (1H, ddd, J¼3.8,
13.1, 13.1 Hz, H-30), 2.01 (1H, dddd, J¼1.6, 3.8, 14.0,
14.0 Hz, H-20), 2.89 (1H, dd, J¼2.8, 23.3 Hz, H-7), 3.03
(1H, dd, J¼4.6, 23.3 Hz, H-70), 3.70 (3H, s, CO2CH3),
3.71 (3H, s, CO2CH3), 4.14 (1H, br s, H-1), 5.68 (1H, dd,
To a solution of (R)-4 (1.45 g, 8.72 mmol) in dry CH2Cl2
(18 mL) were sequentially added, at room temperature, imid-
azole (1.78 g, 26.1 mmol) and TBSCl (3.93 g, 26.1 mmol).
The resulting mixture was left stirring overnight and then di-
luted with H2O. The separated aqueous layer was extracted
with CH2Cl2 (3ꢂ40 mL) and the combined organic phases
were dried (MgSO4), filtered and evaporated in vacuo. The

C. Della Monica et al. / Tetrahedron 63 (2007) 6866–6873
6871
J¼2.8, 4.6 Hz, H-6). 13C NMR (CDCl3, 100 MHz): d ꢁ5.5
(CH3), ꢁ3.4 (CH3), 18.2 (C), 25.1 (CH2), 25.2 (CH3), 25.8
(ꢂ3) (CH3), 27.9 (CH2), 31.4 (CH3), 33.2 (CH3), 33.9
(CH2), 35.5 (C), 45.6 (C), 51.7 (CH3), 51.9 (CH3), 72.3
(CH), 116.7 (CH), 131.4 (C), 142.9 (C), 144.6 (C), 168.3
(C), 168.5 (C). [a]D30 ꢁ29.4 (c 1.0, CHCl3). IR (CHCl3):
n¼2950, 2929, 1717 (br), 1095 cmꢁ1. ESIMS: m/z 445
[M+Na]+.
1.15 (3H, s, CH3), 1.17 (3H, s, CH3), 1.41–1.52 (2H, m,
H-3 and H-30 overlapped), 1.65 (1H, m, H-2), 1.76 (1H, m,
H-20), 3.58 (3H, s, CO2CH3), 3.76 (3H, s, CO2CH3), 3.78
(1H, s, H-9), 3.93 (1H, dd, J¼4.8, 11.2 Hz, H-1), 5.96
(1H, d, J¼6.0 Hz, H-6), 7.06 (1H, d, J¼6.0 Hz, H-7). 13C
NMR (CDCl3, 100 MHz): d ꢁ5.3 (CH3), ꢁ3.6 (CH3), 18.1
(C), 18.4 (CH3), 25.8 (ꢂ3) (CH3), 27.8 (CH2), 30.7 (CH3),
32.0 (CH3), 35.4 (C), 36.7 (CH2), 44.4 (C), 47.5 (CH),
51.3 (CH3), 51.7 (CH3), 74.0 (CH), 117.2 (CH), 122.5 (C),
135.4 (CH), 162.0 (C), 167.0 (C), 172.0 (C). [a]2D8 ꢁ325.2
(c 0.7, CHCl3). IR (CHCl3): n¼2954, 2927, 1735,
1716 cmꢁ1. ESIMS: m/z 445 [M+Na]+.
Compound 16: Rf¼0.69 (30% diethyl ether in petroleum
1
ether). H NMR (CDCl3, 300 MHz): d 1.17 (3H, s, CH3),
1.25 (3H, s, CH3), 1.40 (3H, s, CH3), 1.82 (1H, dd, J¼6.3,
16.9 Hz, H-3), 1.98 (1H, br d, J¼16.9 Hz, H-30), 2.78 (1H,
dd, J¼1.0, 21.9 Hz, H-7), 3.23 (1H, dd, J¼6.0, 21.9 Hz,
H-70), 3.73 (3H, s, CO2CH3), 3.81 (3H, s, CO2CH3), 5.48
(1H, dd, J¼2.7, 10.0 Hz, H-1), 5.72 (1H, br d, J¼6.0 Hz,
H-6), 5.77 (1H, br dd, J¼6.3, 10.0 Hz, H-2). 13C NMR
(CDCl3, 100 MHz): d 26.6 (CH2), 26.8 (CH3), 28.8 (CH3),
29.5 (CH3), 35.5 (C), 39.4 (CH2), 41.2 (C), 51.9 (CH3),
52.1 (CH3), 116.8 (CH), 126.7 (CH), 126.8 (C), 129.5
(CH), 147.1 (C), 150.3 (C), 166.1 (C), 169.2 (C). EIMS:
m/z (%)¼290 (7.5), 275 (12), 243 (100), 231 (24), 199
(23), 171 (20), 157 (17), 142 (14).
5.10. (1R,4aS,8R,8aS)-8-(tert-Butyl-dimethyl-silanyl-
oxy)-5,5,8a-trimethyl-1,4,4a,5,6,7,8,8a-octahydro-
naphthalene-1,2-dicarboxylic acid dimethyl ester (19)
To a vigorously stirred suspension of 17 (794.0 mg,
1.88 mmol) and a catalytic amount of 10% Pd/C in MeOH
(21 mL), in a conical flask, was introduced H2 gas at room
temperature. After the disappearance of the starting material
(1 h), the reaction mixture was filtered through a CeliteÒ bed
and the filtrate was concentrated in vacuo. The residue was
flash-chromatographed (10–40% diethyl ether in petroleum
ether) affording pure 19 (679.0 mg, 1.60 mmol, 85%) as col-
ourless oil.
5.9. (1R,8R,8aS)-8-(tert-Butyl-dimethyl-silanyloxy)-
5,5,8a-trimethyl-1,5,6,7,8,8a-hexahydro-naphthalene-
1,2-dicarboxylic acid dimethyl ester (17)
Compound 19: Rf¼0.33 (30% diethyl ether in petroleum
ether). 1H NMR (CDCl3, 400 MHz): d 0.04 (3H, s,
CH3Si), 0.09 (3H, s, CH3Si), 0.85 (3H, s, CH3), 0.90 (9H,
s, (CH3)3CSi), 0.91 (3H, s, CH3), 0.99 (3H, s, CH3), 1.17
(1H, dd, J¼6.0, 10.7 Hz, H-5), 1.26 (1H, m, H-3), 1.43
(1H, ddd, J¼3.3, 3.3, 13.6 Hz, H-30), 1.58 (1H, dddd,
J¼3.3, 11.2, 13.4, 13.6 Hz, H-2), 1.71 (1H, dddd, J¼3.3,
4.2, 4.2, 13.4 Hz, H-20), 2.15–2.28 (2H, m, H-6 and H-60
overlapped), 3.21 (1H, m, H-9), 3.61 (3H, s, CO2CH3),
3.66 (3H, s, CO2CH3), 3.74 (1H, dd, J¼4.2, 11.2 Hz, H-1),
7.02 (1H, m, H-7). 13C NMR (CDCl3, 100 MHz): d ꢁ2.9
(CH3), ꢁ2.3 (CH3), 9.2 (CH3), 18.9 (C), 21.8 (CH3), 24.5
(CH2), 26.6 (ꢂ3) (CH3), 28.5 (CH2), 32.5 (C), 32.6 (CH3),
39.4 (CH2), 43.4 (C), 48.1 (CH), 51.6 (CH3), 51.7 (CH3),
56.6 (CH), 80.6 (CH), 129.6 (C), 140.3 (CH), 167.3 (C),
173.3 (C). [a]2D5 ꢁ39.6 (c 1.0, CHCl3). IR (CHCl3):
n¼2952, 1721 (br), 1256 cmꢁ1. ESIMS: m/z 425 [M+H]+.
Anal. Calcd for C23H40O5Si: C, 65.05; H, 9.49. Found: C,
65.13; H, 9.39.
To a solution of 14 (110.0 mg, 0.260 mmol) in dry THF
(2.6 mL) was added DBU (35.0 mL, 0.234 mmol) under a
nitrogen atmosphere. The mixture was heated at 40 ꢀC for
4 h and then cooled at room temperature. The resulting orange
solution was diluted with Et2O and filtered through a pad of
silica gel (particle size 0.063–0.200 mm); the filter cake was
washed thoroughly with Et2O. The combined filtrate and
washings were concentrated in vacuo. The residue was puri-
fied by flash chromatography (15–30% diethyl ether in pe-
troleum ether) affording 17 (99.0 mg, 0.234 mmol, 90%)
and its epimer 18 (5.5 mg, 0.013 mmol, 5%) as colourless
oils.
Compound 17: Rf¼0.23 (20% diethyl ether in petroleum
ether). 1H NMR (CDCl3, 400 MHz): d 0.05 (3H, s,
CH3Si), 0.07 (3H, s, CH3Si), 0.90 (9H, s, (CH3)3CSi), 1.13
(3H, s, CH3), 1.19 (3H, s, CH3), 1.21 (3H, s, CH3), 1.36
(1H, ddd, J¼5.6, 10.6, 12.5 Hz, H-3), 1.58 (1H, ddd,
J¼4.7, 4.7, 12.5 Hz, H-30), 1.68–1.80 (2H, m, H-2 and H-
20 overlapped), 3.48 (1H, br d, J¼2.4 Hz, H-9), 3.68 (3H,
s, CO2CH3), 3.70 (3H, s, CO2CH3), 3.90 (1H, dd, J¼5.2,
8.7 Hz, H-1), 5.98 (1H, d, J¼6.2 Hz, H-6), 6.94 (1H, dd,
J¼2.4, 6.2 Hz, H-7). 13C NMR (CDCl3, 100 MHz): d ꢁ3.4
(CH3), ꢁ3.2 (CH3), 14.6 (CH3), 18.7 (C), 26.3 (ꢂ3)
(CH3), 28.3 (CH2), 31.3 (CH3), 31.8 (CH3), 36.0 (C), 36.5
(CH2), 46.5 (C), 51.6 (CH3), 51.8 (CH3), 53.1 (CH), 77.7
(CH), 118.2 (CH), 125.1 (C), 133.7 (CH), 160.0 (C), 167.3
(C), 173.0 (C). [a]D25 ꢁ87.7 (c 1.0, CHCl3). IR (CHCl3):
n¼2954, 2929, 2858, 1733, 1710, 1279, 1253 cmꢁ1. ESIMS:
m/z 445 [M+Na]+. Anal. Calcd for C23H38O5Si: C, 65.36; H,
9.06. Found: C, 65.24; H, 9.03.
5.11. (1R,4aS,8R,8aS)-[8-(tert-Butyl-dimethyl-silanyl-
oxy)-1-hydroxymethyl-5,5,8a-trimethyl-
1,4,4a,5,6,7,8,8a-octahydro-naphthalen-2-yl]-methanol
(20)
To a stirring solution of 19 (193.0 mg, 0.454 mmol) in 2 mL
of dry THF, cooled to ꢁ78 ꢀC, was added dropwise a solution
of diisobutylaluminium hydride (DIBAL–H) (1.5 M in tolu-
ene, 6.0 mL, 9.0 mmol) under a nitrogen atmosphere. The
solution was allowed to warm to room temperature and stir
overnight. Then, it was cooled to ꢁ78 ꢀC and 5 mL of
MeOH/H2O (1/1) solution was carefully added. The result-
ing mixture was concentrated and dried under high vacuum.
The residue was suspended in MeOH, filtered through a Cel-
iteÒ bed and the pad was thoroughly washed with MeOH.
The filtrate was concentrated in vacuo to afford the crude
Compound 18: Rf¼0.28 (20% diethyl ether in petroleum
ether). 1H NMR (CDCl3, 400 MHz): d 0.05 (6H, s,
(CH3)2Si), 0.91 (9H, s, (CH3)3CSi), 1.13 (3H, s, CH3),

6872
C. Della Monica et al. / Tetrahedron 63 (2007) 6866–6873
diol 20 as a white amorphous solid, which was used without
any further purification. For a complete characterization,
flash chromatography (50–90% diethyl ether in petroleum
ether) of a small aliquot of crude gave pure 20.
ESIMS: m/z 387 [M+Na]+. Anal. Calcd for C21H36O3Si:
C, 69.18; H, 9.95. Found: C, 69.29; H, 9.81.
5.13. (1R,4aS,8R,8aS)-8-Hydroxy-5,5,8a-trimethyl-
1,4,4a,5,6,7,8,8a-octahydro-naphthalene-1,2-dicarb-
aldehyde [1-(R)-hydroxypolygodial] (2)
Compound 20: Rf¼0.20 (40% diethyl ether in petroleum
ether). 1H NMR (CDCl3, 400 MHz): d 0.11 (6H, s,
(CH3)2Si), 0.84 (3H, s, CH3), 0.85 (3H, s, CH3), 0.87 (3H,
s, CH3), 0.92 (9H, s, (CH3)3CSi), 1.15 (1H, dd, J¼4.8,
11.2 Hz, H-5), 1.28 (1H, ddd, J¼3.6, 13.6, 13.6 Hz, H-3),
1.39 (1H, ddd, J¼3.2, 3.2, 13.6 Hz, H-30), 1.51 (1H, dddd,
J¼3.2, 3.6, 4.0, 13.6 Hz, H-2), 1.65 (1H, dddd, J¼3.2,
11.2, 13.6, 13.6 Hz, H-20), 1.91–2.04 (2H, m, H-6 and H-60
overlapped), 2.26 (1H, m, H-9), 2.89 (2H, br s, 2ꢂOH),
3.55 (1H, dd, J¼4.0, 11.2 Hz, H-1), 3.72 (1H, dd, J¼7.2,
10.4 Hz, H-11), 3.92 (1H, d, J¼12 Hz, H-12), 4.30 (1H, d,
J¼12 Hz, H-120), 4.55 (1H, dd, J¼2.4, 10.4 Hz, H-110),
5.80 (1H, m, H-7). 13C NMR (CDCl3, 100 MHz): d ꢁ4.1
(CH3), ꢁ3.6 (CH3), 9.1 (CH3), 18.2 (C), 22.3 (CH3), 23.2
(CH2), 26.1 (ꢂ3) (CH3), 29.1 (CH2), 32.8 (C), 33.1 (CH3),
40.0 (CH2), 41.7 (C), 49.4 (CH), 53.3 (CH), 62.9 (CH2),
67.1 (CH2), 82.9 (CH), 127.0 (CH), 137.9 (C). [a]2D5 ꢁ20.4
(c 1.0, CHCl3). IR (CHC13): n¼3474 (br) cmꢁ1. ESIMS:
m/z 369 [M+H]+. Anal. Calcd for C21H40O3Si: C, 68.42;
H, 10.94. Found: C, 68.54; H, 10.89.
To a solution of 21 (60.0 mg, 0.165 mmol) in acetonitrile
(5.60 mL), in a silicon vessel, 48% aqueous hydrofluoric
acid (1.7 mL) was added at room temperature. The mixture
was stirred at room temperature overnight and then NaHCO3
was carefullyadded untilthe mixturewas neutralized. The or-
ganic solvent was removed in vacuo and the residual aqueous
layer was extracted with ethyl acetate (3ꢂ4 mL). The com-
binedorganicextractsweredried(Na2SO4),filteredandevapo-
rated in vacuo. Flash chromatography of the crude (30–60%
ethyl acetate in petroleum ether) under N2 afforded pure 2
(32.6 mg, 0.130 mmol, 79%) as a white amorphous solid.
Compound 2: Rf¼0.50 (50% ethyl acetate in petroleum
1
ether). H NMR (CDCl3, 400 MHz): d 0.88 (3H, s, CH3),
0.91 (3H, s, CH3), 0.94 (3H, s, CH3), 1.25 (1H, dd, J¼4.9,
11.4 Hz, H-5), 1.36 (1H, m, H-3), 1.51 (1H, ddd, J¼3.2,
3.2, 13.5 Hz, H-30), 1.56–1.66 (2H, m, H-2 and H-20), 2.37
(1H, dddd, J¼2.4, 3.8, 11.4, 20.0 Hz, H-6), 2.45 (1H, m,
H-60), 3.20 (1H, br s, H-9), 3.62 (1H, dd, J¼7.6, 8.2 Hz,
H-1), 7.09 (1H, m, H-7), 9.37 (1H, s, OHCC-8), 9.82 (1H,
d, J¼3.2 Hz, OHCC-9). 13C NMR (CDCl3, 62.5 MHz):
d 9.3 (CH3), 22.0 (CH3), 24.8 (CH2), 27.8 (CH2), 32.7
(CH3), 32.8 (C), 39.6 (CH2), 43.5 (C), 48.5 (CH), 59.8
(CH), 79.8 (CH), 139.5 (C), 153.1 (CH), 192.9 (CH),
203.9 (CH). [a]D25 ꢁ8.2 (c 1.0, CHCl3). IR (CC14):
n¼3513 (br), 2960, 2928, 2873, 2855, 2739, 1722,
1690 cmꢁ1. ESIMS: m/z 273 [M+Na]+. Anal. Calcd for
C15H22O3: C, 71.97; H, 8.86. Found: C, 71.77; H, 8.91.
5.12. (1R,4aS,8R,8aS)-8-(tert-Butyl-dimethyl-silanyl-
oxy)-5,5,8a-trimethyl-1,4,4a,5,6,7,8,8a-octahydro-
naphthalene-1,2-dicarbaldehyde (21)
To a stirring solution of oxalyl chloride (377.7 mg,
2.98 mmol, 0.260 mL) in 7 mL of dry CH2C12 cooled to
ꢁ78 ꢀC was added dropwise 464.9 mg (5.95 mmol,
0.549 mL) of DMSO under a nitrogen atmosphere. After
5 min, a solution of 137.0 mg (0.372 mmol) of 20 in
2.5 mL of CH2C12/DMSO (3/1) was added via cannula. Af-
ter 1 h, 1.40 g (13.8 mmol, 1.93 mL) of freshly distilled tri-
ethylamine was added and the resulting mixture was allowed
to stir at ꢁ78 ꢀC for 5 min and then warmed to room temper-
ature. Then it was passed through a short pad of silica gel
(particle size 0.040–0.263 mm) eluting with ethyl acetate,
under N2, and the eluent was concentrated to give a yellow
oil. The oil was purified by flash chromatography (40–
60% diethyl ether in petroleum ether) under N2 to give
118.0 mg (0.324 mmol, 87% for two steps) of 21 as a white
amorphous solid.
5.14. (1S,4aS,8R,8aS)-8-Hydroxy-5,5,8a-trimethyl-
1,4,4a,5,6,7,8,8a-octahydro-naphthalene-1,2-dicarb-
aldehyde [1-(R)-hydroxyisotadeonal] (3)
To a solution of 2 (5.5 mg, 0.022 mmol) in CH2Cl2 (2.5 mL)
basic Al2O3 (10.0 mg) was added at room temperature. The
mixture was stirred for 20 h and then filtered on a short pad
of silica gel. The pad was thoroughly washed with ethyl ace-
tate, under N2, and the filtrate was concentrated in vacuo to
afford a crude mixture containing 3 and 2 in a ratio of 4.4:1
1
(determined by H NMR). The crude was purified by flash
Compound 21: Rf¼0.50 (50% diethyl ether in petroleum
ether). 1H NMR (CDCl3, 400 MHz): d 0.12 (3H, s,
CH3Si), 0.14 (3H, s, CH3Si), 0.83 (3H, s, CH3), 0.90 (9H,
s, (CH3)3CSi), 0.91 (3H, s, CH3), 0.95 (3H, s, CH3), 1.26
(1H, dd, J¼4.9, 11.1 Hz, H-5), 1.33 (1H, ddd, J¼4.2, 13.2,
13.2 Hz, H-3), 1.50 (1H, ddd, J¼3.2, 3.2, 13.2 Hz, H-30),
1.56–1.71 (2H, m, H-2 and H-20 overlapped), 2.26–2.42
(2H, m, H-6 and H-60 overlapped), 3.30 (1H, br s, H-9),
3.65 (1H, dd, J¼4.5, 10.8 Hz, H-1), 7.03 (1H, m, H-7),
9.32 (1H, s, OHCC-8), 10.0 (1H, d, J¼3.6 Hz, OHCC-9).
13C NMR (CDCl3, 100 MHz): d ꢁ3.7 (CH3), ꢁ3.1 (CH3),
9.9 (CH3), 18.3 (C), 22.4 (CH3), 24.6 (CH2), 26.1 (ꢂ3)
(CH3), 28.0 (CH2), 32.6 (C), 32.8 (CH3), 39.8 (CH2), 44.8
(C), 49.0 (CH), 59.4 (CH), 81.7 (CH), 141.2 (C), 152.0
(CH), 192.7 (CH), 201.0 (CH). [a]2D5 +45.3 (c 1.0, CHCl3).
chromatography (30–70% ethyl acetate in petroleum ether)
under N2 to give 4.5 mg (0.018 mmol, 82%) of 3, as white
amorphous solid, and 1.0 mg (0.004 mmol, 18%) of 2.
Compound 3: Rf¼0.57 (50% ethyl acetate in petroleum
1
ether). H NMR (CDCl3, 400 MHz): d 0.91 (3H, s, CH3),
0.93 (3H, s, CH3), 0.95 (3H, s, CH3), 1.20–1.33 (2H, m,
H-3 and H-30 overlapped), 1.49 (1H, dd, J¼5.0, 11.7 Hz,
H-5), 1.62 (1H, dddd, J¼4.0, 4.0, 4.0, 13.0 Hz, H-2), 1.73
(1H, dddd, J¼3.3, 11.2, 11.2, 13.0 Hz, H-20), 2.28 (1H,
dddd, J¼2.4, 2.4, 11.7, 20.5 Hz, H-6), 2.56 (1H, ddd,
J¼5.0, 5.0, 20.5 Hz, H-60), 3.53 (1H, dd, J¼4.0, 11.2 Hz,
H-1), 3.66 (1H, br s, H-9), 7.11 (1H, dd, J¼2.4, 5.0 Hz, H-
7), 9.44 (1H, s, OHCC-8), 9.89 (1H, d, J¼2.5 Hz, OHCC-
9). 13C NMR (CDCl3, 100 MHz): d 14.8 (CH3), 22.1
(CH3), 25.3 (CH2), 27.5 (CH2), 32.3 (CH3), 32.7 (C), 39.6
IR (CHC13): n¼2929, 2856, 1715, 1682, 1255 cmꢁ1
.

C. Della Monica et al. / Tetrahedron 63 (2007) 6866–6873
6873
2. (a) Taniguchi, M.; Adachi, T.; Oi, S.; Kimura, A.; Katsumura,
S.; Isoe, S.; Kubo, I. Agric. Biol. Chem. 1984, 48, 73–78; (b)
Cimino, G.; Spinella, A.; Sodano, G. Tetrahedron Lett. 1984,
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Tetrahedron 1987, 43, 5401–5410.
(CH2), 43.1 (C), 43.6 (CH), 54.9 (CH), 74.7 (CH), 137.5 (C),
152.7 (CH), 192.9 (CH), 203.1 (CH). [a]2D5 ꢁ98.1 (c 0.15,
CHCl3). IR (CHCl3): n¼3467 (br), 2976, 2929, 2896,
1717, 1682 cmꢁ1. ESIMS: m/z 273 [M+Na]+.
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5.15. Vanilloid activity assays
All prepared compounds have been assayed for TRPV1 sen-
sitivity using fluorometric measurements of changes in intra-
cellular calcium concentration. HEK293 (human embryonic
kidney) cells were plated on poly-(D)-lysine and transfected
transiently by using TRPV1 plasmids. After transfection,
cells have been loaded with a cytoplasmic calcium indicator.
[Ca2+]i was determined before and after the addition of
various concentrations of test compounds.
6. Nicolaou, K. C.; Li, W. S. J. Chem. Soc., Chem. Commun. 1985,
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Acknowledgements
7. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551–5553; Corey, E. J.; Helal, C. J. Angew. Chem., Int.
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ꢀ
The authors acknowledge financial support from Universita
di Salerno and from MIUR-COFIN 2004 ‘La chemorece-
zione gustativa: progettazione razionale di nuove molecole,
8. Really, compound 14 could be obtained also by silylation of ad-
duct 6, but when we tried this reaction we found that protection
of 6, as required by the synthetic plan, proved to be very
difficult probably due to the poor accessibility to the hydroxy
function.
ꢀ
modellazione dell’attivita biologica e applicazioni nell’in-
dustria farmaceutica ed alimentare’.
References and notes
9. Jalali-Naini, M.; Guillerm, D.; Lallemand, J.-Y. Tetrahedron
1983, 39, 749–758.
10. Mori, K.; Watanabe, H. Tetrahedron 1986, 42, 273–281.
1. Jansen, B. J. M.; de Groot, A. Nat. Prod. Rep. 2004, 21, 449–
477 and references therein.