A stereocontrolled total synthesis of (±)-zizaene

Article abstract of DOI:10.1016/S0040-4020(02)00063-7

A stereocontrolled approach to the construction of the tricyclo[6.2.1.0^1,5]undecane ring system related to the sesquiterpene zizaene is delineated. Starting from an indanone, a bromophenol was prepared in a straightforward manner. An intramolecular anionic cyclisation then afforded a tricyclic dienone which was stereoselectively converted into a mesylate through various intermediates. Base induced rearrangement furnished a trans-fused ketone as the sole product which was converted into (±)-zizaene through Wittig olefination.

Full text of DOI:10.1016/S0040-4020(02)00063-7

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1773±1778
A stereocontrolled total synthesis of (^)-zizaene
Lokesh Chandra Pati, Arnab Roy and Debabrata Mukherjeep
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Calcutta 700032, India
Received 26 September 2001; revised 12 December 2001; accepted 10 January 2002
AbstractÐA stereocontrolled approach to the construction of the tricyclo[6.2.1.01,5]undecane ring system related to the sesquiterpene
zizaene is delineated. Starting from an indanone, a bromophenol was prepared in a straightforward manner. An intramolecular anionic
cyclisation then afforded a tricyclic dienone which was stereoselectively converted into a mesylate through various intermediates. Base
induced rearrangement furnished a trans-fused ketone as the sole product which was converted into (^)-zizaene through Wittig ole®nation.
q 2002 Elsevier Science Ltd. All rights reserved.
Zizaene (1), a tricyclic sesquiterpene hydrocarbon, was
isolated1 from vetiver oil and possesses1c,2
tri-
1. Results and discussion
a
cyclo[6.2.1.01,5]undecane skeleton. The structure 1 of
zizaene was secured through correlation1d,2,3 with zizan-
12-ol (2), the stereostructure of which was conclusively
established by single crystal X-ray crystallography4 of the
corresponding p-bromobenzoate 3. In view of its novel
structural features, zizaene has attracted considerable
attention5±10 as a challenging synthetic target. Besides the
construction of the tricyclo[6.2.1.01,5]undecane framework,
the total synthesis of zizaene must address the following
problems: (i) control of the stereochemistry of the four
asymmetric centres, (ii) introduction of gem-dimethyl
groups at C-7, and (iii) installation of an exocyclic methyl-
ene unit at C-6. The total synthesis of (^)-zizaene (1) has
been successfully accomplished by Coates et al.5 and
Wiesner et al.6 Several formal total syntheses of 1 have
also been reported in the literature.7±10 We describe herein
a highly stereocontrolled total synthesis of (^)-zizaene
(Fig. 1).
Our synthesis of zizaene (1) from 3,3-dimethyl-5-methoxy-
indan-1-one (4) is outlined in Scheme 1. The indanone 4
was prepared from 3-methoxyacetophenone following a
procedure reported11 in the literature. Having a convenient
route to 4, we turned our attention to convert 4 into the
bromophenol 11. The indanone was alkylated with methyl
bromoacetate using LDA as the base to give the keto-ester 5
in 73% yield which on hydrolysis furnished the keto-acid 6.
This was reduced to the corresponding benzylic alcohol
with NaBH4 in aqueous NaOH following a procedure
reported by House et al.12 Catalytic hydrogenolysis of the
crude benzylic alcohol in acetic acid containing a few drops
of perchloric acid furnished the crystalline acid 7 in high
yield. The methyl ester 8, prepared from 7, was reduced
with LiAlH4 and the resulting primary alcohol 9 was treated
with a mixture of Ph3P and CBr4 to give the bromoether 10.
Demethylation of 10 with BBr3 in CH2Cl2 provided the
desired bromophenol 11 in excellent yield.
In order to effect an intramolecular anionic cyclisation13 of
the bromophenol 11, a dilute solution of 11 in dry t-BuOH
was heated with t-BuOK (1equiv.) at 80 8C for 10 h. The
dienone 12 was isolated as a crystalline compound as the
only neutral product of the reaction in 73% yield. The IR, 1H
NMR, and 13C NMR spectra of the dienone were in full
accord with structure 12. Conjugate addition of LiMe2Cu
to 12 at 08C was highly regioselective and stereoselective
providing a single enone 13 in 85% yield. The stereo-
chemical assignments at C-1, C-2 and C-8 of 13 followed
from subsequent transformations leading to the cis-diol 16,
the stereostructure of which was established by single-
crystal X-ray crystallography. The enone 13 was converted
into the corresponding thioacetal 14 in near quantitative
yield. Desulfurisation of the thioacetal 14 was accomplished
ef®ciently with Na and EtOH in liquid ammonia14 to provide
Figure 1.
Keywords: terpenes; cyclisation; hydroxylation; rearrangement; Wittig
reaction.
p
Corresponding author. Fax: 191-33-4732805;
e-mail: ocdm@mahendra.iacs.res.in
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00063-7

1774
L. C. Pati et al. / Tetrahedron 58 (2002) 1773±1778
Scheme 1. Reagents and conditions: (i) LDA, BrCH2CO2Me, THF, 2108C to rt, 73%; (ii) KOH, MeOH, re¯ux, 6 h, H3O1, 92%; (iii) NaBH4, aq. NaOH, rt,
24 h, H3O1; H2, 10% Pd±C, AcOH, 89%; (iv) CH2N2, Et2O, 08C, 94%; (v) LAH, Et2O, re¯ux, 4 h, 95%; (vi) Ph3P, CBr4, Et2O, rt, 5 h, 80%; (vii) BBr3,
CH2Cl2, 08C to rt, 16 h, 92%; (viii) t-BuOK, t-BuOH, 808C, 10 h, 73%; (ix) LiMe2Cu, Et2O, 08C, 2 h, 85%; (x) HSCH2CH2SH, MeOH, BF3´Et2O, rt, 20 h,
94%; (xi) Na, EtOH, liq. NH3, 86%; (xii) OsO4, C5H5N, rt, 5 days, 85%; (xiii) MsCl, C5H5N, rt, 15 h, 90%; (xiv) t-BuOK, t-BuOH, 208C, 10 min, 88%; (xv)
t-AmOK, (C6H5)3 P1CH3Br2, toluene, 90±928C, 6 h, 64%.
the ole®n 15 in 87% yield. Dihydroxylation of 15 with OsO4
in pyridine at room temperature afforded the cis-diol 16 in
high yield and this on treatment with MeSO2Cl in pyridine
furnished the corresponding monomesylate 17 as a crystal-
line compound in 90% yield. As mentioned before, the
relative stereochemistries at C-1, C-2, C-5, C-6 and C-8 of
the diol 16 were determined by X-ray crystallography
(Fig. 2).15 The bonds a and b of the mesylate 17 are anti-
periplanar and therefore the monomesylate rearranged16
smoothly on treatment with t-BuOK (1equiv.) in t-BuOH
at 208C to provide the ketone 1817 as the sole product in high
yield. The spectral data of the present compound agreed
very well with those reported for (^)-norzizanone 18 in
the literature (Scheme 1).5,6,10
In order to complete the desired synthesis of 1, the last step
to be carried out was the introduction of the exocyclic
methylene group at C-6. Wittig ole®nation of the ketone
18 under appropriate experimental conditions18 employing
potassium t-amylate as the base proved successful. The
Wittig reagent methylenetriphenylphosphorane was
generated at 88±908C using a ®vefold excess of methyl-
triphenylphosphonium bromide and an equimolar amount
of potassium t-amylate in the minimum amount of toluene
to bring the mixture to homogeneity. The ketone 18 was
added to the solution of the reagent at 908C and the reaction
was allowed to proceed at 90±928C for 6 h. Chromato-
graphy of the crude product over silica gel and elution
with pentane afforded pure (^)-zizaene (1) in good yield.
The identity of the present compound was secured through
1H NMR, 13C NMR, IR, and microanalytical data. The
spectral data of our synthetic zizaene are also in good agree-
ment with those reported3,5,6 in the literature.
In conclusion, in the present work a stereocontrolled total
synthesis of the sesquiterpene hydrocarbon (^)-zizaene has
been achieved using a base induced pinacol type rearrange-
ment as a key step.
Figure 2. Single-crystal X-ray structure of the diol 16 (an ORTEP drawing).

L. C. Pati et al. / Tetrahedron 58 (2002) 1773±1778
1775
2. Experimental
ArOMe), 3.02±2.92 (2H, m), 2.58±2.48 (1H, m), 1.52
(3H, s, Me), 1.19 (3H, s, Me); dC (75 MHz, CDCl3) 204.1,
177.7, 165.9, 165.8, 126.8, 125.7, 115.2, 107.0, 55.7, 55.7,
41.8, 31.3, 27.8, 27.0.
2.1. General
The compounds described as having asymmetric centres are
all racemates. Melting points and boiling points are
uncorrected. IR spectra were recorded on a Shimadzu
2.1.4. 1,1-Dimethyl-2-carboxymethyl-6-methoxyindane
(7). To a stirred solution of the keto-acid 6 (3.2 g,
12.9 mmol) in aqueous NaOH (1.5N, 16 mL) was added
NaBH4 (0.57 g, 15 mmol) in small portions during 20 min.
The mixture was stirred at room temp. for 24 h, cooled to
08C and acidi®ed with 3N HCl. Extraction with ether
afforded a gummy material (3 g) which was dissolved in
AcOH (25 mL) and hydrogenated over Pd±C (10%, 0.6 g)
in the presence of a few drops of HClO4. Uptake of hydro-
gen ceased after 1h. The mixture was ®ltered, diluted with
water (50 mL) and extracted with CHCl3 (3£60 mL). The
organic extract was washed with brine, water and dried.
Evaporation of the solvent followed by crystallisation of
the solid residue from a mixture of ether and light petroleum
afforded the acid 7 (2.69 g, 89%) as white needles, mp 121±
1228C; [Found: C, 71.70; H, 7.85. C14H18O3 requires C,
71.77; H, 7.74%]; nmax (KBr) 1703, 1608 cm21; dH
(300 MHz, CDCl3) 7.08 (1H, d, Jˆ8.8 Hz, 4-ArH), 6.71±
6.68 (2H, m, 5- and 7-ArH), 3.79 (3H, s, ArOMe), 3.11±
3.04 (1H, m), 2.63±2.45 (3H, m), 2.41±2.33 (1H, m), 1.32
(3H, s, Me), 1.00 (3H, s, Me); dC (75 MHz, CDCl3) 179.9,
158.9, 153.6, 132.7, 124.9, 111.8, 108.0, 55.4, 47.3, 45.6,
35.6, 34.8, 26.5, 23.4.
1
FTIR-8300 spectrophotometer. H NMR (300 MHz) and
13C NMR (75 MHz) spectra were recorded in CDCl3 on a
Bruker DPX-300 spectrometer with SiMe4 as internal
standard. The chemical shifts (d ppm) are reported relative
1
to SiMe4 (dH 0.00) for H and the central line of residual
CHCl3 (dC 77.0) for 13C. Moisture sensitive reactions were
carried out using standard syringe-septum technique.
Anhydrous solvents were obtained by standard procedures.
All solvent extracts were dried over anhydrous Na2SO4.
Product purities were routinely checked by TLC. Ether
refers to diethyl ether and light petroleum refers to the
fraction of petroleum ether in the boiling point range
40±608C.
2.1.1. 3,3-Dimethyl-5-methoxyindan-1-one (4). The
indanone 4 was prepared11 from 3-methoxyacetophenone
as a crystalline compound, mp 63±648C (lit.,11 mp 59±
1
608C); IR and H NMR data of 4 are consistent with the
literature values;11 dC (75 MHz, CDCl3) 204.1, 166.8,
165.5, 128.5, 125.1, 114.9, 107.0, 55.5, 53.0, 38.3, 29.8.
2.1.2. 2-Methoxycarbonylmethyl-3,3-dimethyl-5-meth-
oxyindan-1-one (5). To a stirred solution of diisopropyl-
amine (2.53 g, 25 mmol) in dry THF (15 mL) at 2108C
was added under nitrogen BuLi (1.5 M in hexane, 15 mL,
2.1.5. 1,1-Dimethyl-2-methoxycarbonylmethyl-6-meth-
oxyindane (8). The acid 7 (2.6 g) was treated with an
ethereal solution of CH2N2 (excess) at 08C to provide the
methyl ester 8 (2.59 g, 94%) as an oil, bp 135±1378C/
0.4 mm Hg; [Found: C, 72.70; H, 8.22. C15H20O3 requires
C, 72.55; H, 8.12%]; nmax (®lm) 1738, 1610 cm21; dH
(300 MHz, CDCl3) 7.06 (1H, d, Jˆ8.9 Hz, 4-ArH),
6.70±6.66 (2H, m, 5- and 7-ArH), 3.78 (3H, s, ArOMe),
3.70 (3H, s, CO2Me), 3.04±2.97 (1H, m), 2.59±2.44
(3H, m), 2.38±2.29 (1H, m), 1.29 (3H, s, Me), 0.98 (3H,
s, Me); dC (75 MHz, CDCl3) 173.8, 158.9, 153.7, 132.8,
124.8, 111.7, 107.9, 55.3, 51.5, 47.5, 45.5, 35.6, 34.7,
26.5, 23.3.
22.5 mmol). After 20 min, the indanone
4 (3.92 g,
20.6 mmol) in THF (6 mL) was added and the mixture
was stirred at 2108C for 90 min. Methyl bromoacetate
(3.67 g, 24 mmol) was then added dropwise and the result-
ing mixture was stirred at 2108C for 3 h and at room
temperature for 12 h. It was then poured into ice, acidi®ed
with dil. HCl and extracted with ether (3£40 mL). The ether
extract was washed with saturated aqueous NaHCO3
(25 mL), water (2£30 mL) and dried. The residue remaining
upon evaporation of the solvent was distilled to afford the
keto-ester 5 (3.95 g, 73%) as a colourless oil, bath tempera-
ture (bp) 158±1608C/0.5 mm Hg; [Found: C, 68.52; H, 7.03.
C15H18 O4 requires C, 68.69; H, 6.92%]; nmax (®lm) 1738,
1705, 1597 cm21; dH (300 MHz, CDCl3) 7.66 (1H, d,
Jˆ7.9 Hz, 7-ArH), 6.91±6.88 (2 H, m, 4- and 6-ArH),
3.90 (3H, s, ArOMe), 3.76 (3H, s, CO2Me), 3.04±2.90
(2H, m), 2.49±2.41 (1H, m), 1.50 (3H, s, Me), 1.16 (3H,
s, Me); dC (75 MHz, CDCl3) 203.3, 173.3, 165.6, 165.4,
127.0, 125.3, 115.0, 107.0, 55.9, 55.6, 51.8, 41.5, 30.9,
27.9, 26.8.
2.1.6. 1,1-Dimethyl-2-(2-hydroxyethyl)-6-methoxyindane
(9). A solution of the ester 8 (2.3 g, 9.26 mmol) in
anhydrous ether (15 mL) was added dropwise at room
temperature to a stirred suspension of LiAlH4 (0.6 g,
15.8 mmol) in ether (25 mL). After the addition, the mixture
was re¯uxed for 4 h and then cooled. Excess of hydride was
carefully destroyed by addition of saturated aq. Na2SO4 and
the mixture was ®ltered through celite. The residue was
washed thoroughly with ether (3£20 mL). The combined
®ltrate was washed with brine, dried and concentrated.
The residue was evaporatively distilled to afford the primary
alcohol 9 (1.94 g, 95%) as a colourless oil, bp 130±1328C/
0.6 mm Hg; [Found: C, 76.50; H, 9.21. C14H20O2 requires C,
76.33; H, 9.15%]; nmax (®lm) 3366, 1610 cm21; dH
(300 MHz, CDCl3) 7.06 (1H, d, Jˆ7.8 Hz, 4-ArH), 6.69±
6.66 (2H, m, 5- and 7-ArH), 3.85±3.66 (2H, m, CH2OH),
3.78 (3H, s, ArOMe), 2.94±2.87 (1H, m), 2.54±2.45 (1H,
m), 2.14±1.54 (4H, m), 1.29 (3H, s, Me), 0.96 (3H, s, Me);
dC (75 MHz, CDCl3) 158.8, 154.6, 133.3, 124.7, 111.5,
107.9, 62.3, 55.3, 48.0, 45.6, 35.5, 32.7, 26.4, 23.4.
2.1.3. 2-Carboxymethyl-3,3-dimethyl-5-methoxyindan-
1-one (6). The ester 5 (3.8 g) was hydrolysed by re¯uxing
for 6 h with a solution of KOH (4 g) in MeOH (32 mL) and
water (3 mL). Usual work-up followed by puri®cation on a
silica gel column using ether±light petroleum (1:4) as eluent
furnished the keto-acid 6 (3.31g, 92%) as an oil; [Found: C,
67.51; H, 6.38. C14H16 O4 requires C, 67.73; H, 6.50%]; nmax
(®lm) 1703, 1699, 1597 cm21; dH (300 MHz, CDCl3) 7.69
(1H, d, Jˆ9.0 Hz, 7-ArH), 6.92 (1H, dd, Jˆ9.0, 2.4 Hz,
6-ArH), 6.92 (1H, d, Jˆ2.4 Hz, 4-ArH), 3.92 (3H, s,

1776
L. C. Pati et al. / Tetrahedron 58 (2002) 1773±1778
2.1.7. 1,1-Dimethyl-2-(2-bromoethyl)-6-methoxyindane
(10). To a stirred mixture of CBr4 (5.44 g, 16.4 mmol) and
the alcohol 9 (1.8 g, 8.2 mmol) in anhydrous ether (35 mL)
at 258C was added Ph3P (4.3 g, 16.4 mmol) in small portions
After stirring at 258C for 5 h, the reaction mixture was
diluted with ether (40 mL) and ®ltered. The insoluble
material was washed with two 20 mL portions of ether.
Evaporation of the ®ltrate followed by puri®cation of
the residue on a silica gel column using ether±light
petroleum (1:49) as eluent afforded the bromide 10
(1.85 g, 80%) as a colourless oil, bp 128±1308C/0.6 mm
Hg; [Found: C, 59.22; H, 6.95. C14H19BrO requires C,
59.37; H, 6.76%]; nmax (®lm) 1610, 1585, 1485, 1242,
1070 cm21; dH (300 MHz, CDCl3) 7.07 (1H, d, Jˆ8.8 Hz,
4-ArH), 6.69 (1H, d, Jˆ2.3 Hz, 7-ArH), 6.68 (1H,
dd, Jˆ8.8, 2.3 Hz, 5-ArH), 3.79 (3H, s, ArOMe),
3.61±3.38 (2H, m, CH2Br), 2.98±2.91(H1, m), 2.52±
2.44 (1H, m), 2.26±1.85 (3H, m), 1.31 (3H, s, Me), 0.97
(3H, s, Me); dC (75 MHz, CDCl3) 159.0, 154.3, 132.7,
124.8, 111.7, 108.0, 55.4, 50.1, 45.6, 34.8, 33.3, 32.8,
26.5, 23.5.
2.1.10. (1RS,2RS,8SR)-2,7,7-Trimethyltricyclo[6.2.1.01,6]-
undec-5-en-4-one (13). A solution of LiMe2Cu was
prepared under nitrogen by dropwise addition of MeLi
(1.6 M in ether, 8 mL, 12.8 mmol) to a stirred suspension
of CuI (1.22 g, 6.4 mmol) in anhydrous ether (20 mL) at
08C. A solution of the dienone 12 (0.61g, 3.24 mmol) in
ether (16 mL) was then added over a period of 10 min and
the resultant mixture was stirred at 08C for 2 h. It was then
treated with saturated aqueous NH4Cl (20 mL), stirred for
20 min, diluted with water (20 mL) and extracted with ether
(3£40 mL). The ether extract was washed with water
(2£30 mL), dried and concentrated. The solid residue was
crystallised from pentane to furnish the enone 13 (0.56 g,
85%) as white needles, mp 64±658C; [Found: C, 82.40; H,
9.75. C14H20 O requires C, 82.30; H, 9.87%]; nmax (KBr)
1668, 1640 cm21; dH (300 MHz, CDCl3) 5.69 (1H, s,
CHvC), 2.69±2.62 (1H, m), 2.30±1.98 (2H, m), 1.80±
1.31 (7H, m), 1.13 (3H, s, Me), 1.09 (3H, s, Me), 1.00
(3H, d, Jˆ7.0 Hz, CHMe); dC (75 MHz, CDCl3) 199.4,
182.1, 116.8, 54.9, 46.9, 43.8, 42.6, 39.7, 33.5, 33.2, 26.9,
24.6, 24.4, 17.5.
2.1.8. 1,1-Dimethyl-2-(2-bromoethyl)-6-hydroxyindane
(11). To a stirred solution of 10 (1.7 g, 6.0 mmol) in dry
CH2Cl2 (12 mL) at 08C was added dropwise BBr3 (1.55 g,
6.2 mmol) in CH2Cl2 (3 mL). The mixture was stirred at 08C
for 1h and at room temperature for 16 h. It was then poured
into ice and extracted with CH2Cl2 (3£20 mL). The organic
extract was washed with aqueous NaHCO3, water, and
dried. Evaporation of the solvent followed by chromato-
graphy of the residue on a silica gel column (45 g) using
ether±light petroleum (1:19) as eluent furnished the bromo-
phenol 11 (1.48 g, 92%) as an oil; [Found: C, 57.83; H, 6.46.
C13H17BrO requires C, 58.00; H, 6.37%]; nmax (®lm) 3346,
1614, 1593 cm21; dH (300 MHz, CDCl3) 7.02 (1H, d,
Jˆ8.2 Hz, 4-ArH), 6.62±6.59 (2H, m, 5- and 7-ArH), 4.94
(1H, bs, ArOH), 3.61±3.38 (2H, m, CH2Br), 2.97±2.89 (1H,
m), 2.51±2.42 (1H, m), 2.24±1.85 (3H, m), 1.28 (3H, s,
Me), 0.96 (3H, s, Me); dC (75 MHz, CDCl3) 154.7, 154.6,
132.8, 125.0, 113.3, 109.2, 50.0, 45.5, 34.8, 33.2, 32.8, 26.4,
23.5.
2.1.11.
(1RS,2RS,8SR)-4,4-Ethyelenedithio-2,7,7-tri-
methyltricyclo[6.2.1.01,6]undec-5-ene (14). To a solution
of the enone 13 (0.51g, 2.5 mmol) in MeOH (4 mL) were
added ethanedithiol (1.2 g) and BF3´Et2O (1mL) and the
mixture was stirred at room temp. for 20 h. The reaction
mixture was then poured into ice-cold aqueous NaOH
(10%, 15 mL) and the product was extracted with ether
(3£25 mL). The ether extract was washed with water
(2£20 mL), dried and concentrated. The residue was
evaporatively distilled at 154±1568C/0.1mm Hg to give
14 (0.66 g, 94%) as a colourless oil; nmax (®lm) 1458,
1379, 1360, 1275 cm21; [Found: C, 68.28; H, 8.79. C16H24
S2 requires C, 68.51; H, 8.62%]; dH (300 MHz, CDCl3) 5.42
(1H, s, CHvC), 3.44±3.26 (4H, m, SCH2CH2 S), 2.35±1.15
(10H, m), 1.05 (3H, s, Me), 1.04 (3H, d, Jˆ6.5 Hz, CHMe),
0.99 (3H, s, Me); dC (75 MHz, CDCl3) 155.5, 118.5, 64.3,
52.1, 47.2, 45.8, 41.1, 40.4, 39.0, 38.6, 33.9, 32.9, 28.8,
25.2, 24.7, 17.5.
2.1.12. (1RS,2RS,8SR)-2,7,7-Trimethyltricyclo[6.2.1.01,6]-
undec-5-ene (15). A solution of the thioacetal 14 (0.6 g,
2.14 mmol) in dry ether (15 mL) was added under nitrogen
to distilled liquid ammonia (80 mL). To this mixture was
added Na metal (0.9 g, 39 mmol) with stirring for 2 min.
After 5 min, EtOH was added dropwise until the blue colour
disappeared. The ammonia was allowed to evaporate. The
residue was diluted with water (25 mL) and extracted with
ether (3£30 mL). The ether extract was washed with water
(2£25 mL), dried, and concentrated. The residue was
evaporatively distilled to afford 15 as a colourless oil
(0.35 g, 86%), bp 98±1008C/4 mm Hg; [Found: C, 88.28;
H, 11.46. C14H22 requires C, 88.35; H, 11.65%]; nmax (®lm)
1377, 1360 cm21; dH (300 MHz, CDCl3) 5.16 (1H, t,
Jˆ3.5 Hz, CHvC), 1.97±1.84 (3H, m), 1.78±1.59 (3H,
m), 1.53±1.11 (6H, m), 1.03 (3H, s, Me), 0.96 (3H, s,
Me), 0.87 (3H, d, Jˆ7.0 Hz, CHMe); dC (75 MHz, CDCl3)
154.4, 111.1, 52.9, 47.3, 41.4, 39.5, 35.3, 32.3, 29.0, 26.8,
25.7, 25.2, 21.1, 16.2.
2.1.9. 7,7-Dimethyltricyclo[6.2.1.01,6]undeca-2,5-dien-4-
one (12). A solution of the bromophenol 11 (1.4 g,
5.2 mmol) in t-BuOH (5 mL) was added dropwise under
nitrogen to a stirred solution of t-BuOK [prepared from K
(0.21g, 5.38 mmol)] in t-BuOH (400 mL) at 808C. The
mixture was stirred at 808C for 10 h and then ca. 200 mL
of t-BuOH was removed under reduced pressure. The
residue was diluted with water (250 mL) and extracted
with ether (3£200 mL). The ether extract was washed
with water (2£100 mL), dried and concentrated. The
residue was evaporatively distilled at 1108C/0.4 mm Hg to
afford a colourless oil which crystallised from light
petroleum to give the dienone 12 (0.71g, 73%) as colourless
plates, mp 72±738C; [Found: C, 82.83; H, 8.71. C13H16
O
;
requires C, 82.94; H, 8.57%]; nmax (KBr) 1655, 1626 cm21
dH (300 MHz, CDCl3) 7.04 (1H, d, Jˆ9.6 Hz,
CHvCHCO), 6.27 (1H, dd, Jˆ9.6, 1.5 Hz, CHvCHCO),
6.03 (1H, d, Jˆ1.5 Hz, COCHvC), 2.20±1.25 (7H, m),
1.19 (3H, s, Me), 1.13 (3H, s, Me); dC (75 MHz, CDCl3)
187.6, 181.4, 149.7, 130.6, 118.1, 53.8, 48.6, 42.3, 42.1,
33.8, 28.0, 28.0, 24.2.
2.1.13. (1RS,2RS,5RS,6SR,8SR)-2,7,7-Trimethyltricyclo-
[6.2.1.01,6]undecane-5,6-diol (16). A solution of the ole®n

L. C. Pati et al. / Tetrahedron 58 (2002) 1773±1778
1777
15 (0.3 g, 1.6 mmol) and OsO4 (0.41g, 1.6 mmol) in
pyridine (6 mL) was stored at room temp. for 5 days. A
saturated aqueous solution of sodium hydrogen sul®te
(20 mL) was then added to the stirred reaction mixture,
and stirring was continued at room temperature for 3 h.
Water (20 mL) was added and the product was extracted
with ether (3£40 mL). The ether extract was washed with
dilute HCl (3N, 2£15 mL), water (2£25 mL), and dried.
The solid residue remaining upon evaporation of the solvent
was crystallised from light petroleum to furnish the diol 16
(0.3 g, 85%) as colourless rods, mp 116±1178C; [Found: C,
75.18; H, 11.02. C14H24O2 requires C, 74.95; H, 10.78%];
nmax (KBr) 3470, 3395 cm21; dH (300 MHz, CDCl3) 3.85
(1H, dd, Jˆ10.5, 5.2 Hz, CHOH), 2.27±1.01 (14H, m), 1.19
(3H, s, Me), 0.97 (3H, s, Me), 0.88 (3H, d, Jˆ6.4 Hz,
CHMe); dC (75 MHz, CDCl3) 80.0, 72.3, 57.2, 49.7, 43.6,
32.2, 31.5, 31.5, 31.1, 27.3, 24.8, 24.8, 23.0, 17.4.
(1mL) and the mixture was stirred at 90±92 8C for 6 h. It
was then cooled, diluted with water (15 mL) and extracted
with ether (3£20 mL). The combined ether extract was
washed with water (2£15 mL), dried and concentrated.
The residue was dissolved in pentane and passed through
a short silica gel column to remove the triphenylphosphine
oxide. Further puri®cation was effected by chromatography
on 10 g of silica gel. Elution with pentane afforded (^)-
zizaene (1) (80 mg, 64%) as a colourless oil; nmax (®lm)
3082, 2940, 2860, 1638, 1478, 1375, 891 cm21; dH
(300 MHz, CDCl3) 4.73±4.72 (1H, m, vinyl proton),
4.60±4.59 (1H, m, vinyl proton), 2.52±2.48 (1H, m,
CHCvCH2), 1.97±1.17 (12H, m), 1.08 (3H, s, Me), 1.05
(3H, s, Me), 0.95 (3H, d, Jˆ7.0 Hz, CHMe); dC (75 MHz,
CDCl3) 157.3, 104.9, 54.8, 49.2, 47.2, 40.4, 40.3, 36.1, 32.6,
31.7, 28.6, 26.1, 25.9, 24.8, 20.0. An analytical sample of 1
was prepared by evaporative distillation at 105±1078C/
4 mm Hg; [Found: C, 88.01; H, 11.64. C15H24 requires C,
88.16; H, 11.84%]. [Lit.,5 IR (®lm) 1640, 1480, 1375 and
895 cm21, lit.,5 NMR (CCl4) 4.71and 4.56 (t, 1H each,
Jˆ2 Hz), 1.08 (s, 3H), 1.06 (s, 3H), and 0.96 (d, 3H,
Jˆ7 Hz)].
2.1.14. Preparation of the monomethanesulfonate 17. A
solution of the diol 16 (0.25 g, 1.1 mmol) and methane-
sulfonyl chloride (0.17 g, 1.5 mmol) in pyridine (4 mL)
was left at room temp. for 15 h. The reaction mixture was
then diluted with water (15 mL) and extracted with ether
(3£25 mL). The ether extract was washed with water
(2£20 mL), dried, and concentrated under reduced pressure.
The solid residue was crystallised from a mixture of ether
and light petroleum to afford the monomesylate 17 (302 mg,
90%) as colourless plates, mp 97±988C; [Found: C, 59.44;
H, 8.90. C15H26O4S requires C, 59.57; H, 8.67%]; nmax
(KBr) 3543, 1354, 1167, 939 cm21; dH (300 MHz, CDCl3)
4.97 (1H, dd, Jˆ11.6, 2.4 Hz, CHOMs), 3.05 (3H, s, OSO2
Me), 2.11±1.06 (13H, m), 1.19 (3H, s, Me), 0.98 (3H, s,
Me), 0.88 (3H, d, Jˆ6.5 Hz, CHMe); dC (75 MHz, CDCl3)
86.6, 79.5, 58.5, 50.0, 43.8, 40.9, 32.3, 30.9, 30.5, 28.3,
26.9, 24.8, 24.6, 22.6, 17.2.
Acknowledgements
We are grateful to the CSIR, New Delhi, for ®nancial
support (Grant No. 01(1534)/98/EMR-II). One of us
(L. C. P.) thanks the CSIR for a fellowship. We thank
Professor Animesh Chakraborty, Mr Swarup Kumar
Chattopadhyay and Mr Bharat Baruah of the Department
of Inorganic Chemistry, Indian Association for the
Cultivation of Science, Calcutta for the single-crystal
X-ray structure of the diol 16 and the DST, New Delhi,
for the X-ray diffractometer.
2.1.15.
(1RS,2RS,5RS,8SR)-2,7,7-Trimethyltricyclo-
[6.2.1.01,5]undecan-6-one (18). A solution of t-BuOK
[prepared from K (35 mg, 0.9 mmol)] in t-BuOH (7 mL)
was added under nitrogen to a magnetically stirred solution
of the monomesylate 17 (0.26 g, 0.86 mmol) in t-BuOH
(3 mL) at 208C. The reaction mixture was stirred at 208C
for 10 min and then diluted with water (20 mL). The product
was extracted with ether (3£30 mL). The ether extract was
washed with water (2£20 mL), dried and concentrated.
Puri®cation of the residue on a silica gel column using
ether±light petroleum (1:19) as eluent furnished the ketone
18 (156 mg, 88%) as a colourless oil; [Found: C, 81.65; H,
10.67. C14H22O requires C, 81.50; H, 10.75%]; nmax (®lm)
1707, 1462, 1385, 1151 cm21; dH (300 MHz, CDCl3) 2.93
(1H, t, Jˆ8.0 Hz, CHCO), 2.13±2.00 (2H, m), 1.90±1.80
(3H, m), 1.66±1.15 (7H, m), 1.19 (3H, s, Me), 1.04 (3H, s,
Me), 0.97 (3 H, d, Jˆ6.6 Hz, CHMe); dC (75 MHz, CDCl3)
216.5, 57.5, 54.0, 50.0, 49.0, 41.4, 36.1, 32.1, 30.5, 26.8,
25.7, 22.1, 20.0, 19.2.
References
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2.1.16. (^)-Zizaene (1). To a solution of potassium tert-
amylate [prepared from potassium (118 mg, 3 mmol)] in dry
toluene (2.5 mL) at 808C was added under argon methyl-
triphenylphosphonium bromide (1.11 g, 3.1 mmol) and the
mixture was stirred at 88±908C for 30 min. To the resulting
bright yellow solution of Wittig reagent was added at 908C a
solution of the ketone 18 (125 mg, 0.60 mmol) in toluene
8. Pramod, K.; Subba Rao, G. S. R. J. Chem. Soc., Chem.
Commun. 1982, 762±763.
9. Barker, A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1
1983, 1901±1904.
10. Kim, S.; Cheong, J. H. Synlett 1997, 947±949.

1778
L. C. Pati et al. / Tetrahedron 58 (2002) 1773±1778
11. Bhattacharyya, S.; Mukherjee, D. Synth. Commun. 1981, 11,
993±998.
C(3)±C(2) 110.90(2), C(3)±C(2)±C(1) 112.49(14), C(2)±
C(1)±C(11) 118.30(2), C(11)±C(1)±C(10) 100.37(14),
C(11)±C(1)±C(6) 100.40(13), O(1)±C(6)±C(5) 106.25(13),
C(5)±C(6)±C(1) 112.50(13), C(5)±C(6)±C(7) 114.02(13),
C(8)±C(11)±C(1) 94.97(14), C(9)±C(8)±C(7) 111.90(2),
C(13)±C(7)±C(12) 107.40(2), C(12)±C(7)±C(8) 107.50(2),
C(12)±C(7)±C(6) 114.30(2), C(9)±C(10)±C(1) 104.70(2),
O(2)±C(5)±C(6) 107.49(14), C(5)±C(4)±C(3) 109.30(2),
C(3)±C(2)±C(14) 110.60(2), C(14)±C(2)±C(1) 113.70(2),
C(2)±C(1)±C(10) 113.20(14), C(2)±C(1)±C(6) 115.08(14),
C(10)±C(1)±C(6) 107.71(14), O(1)±C(6)±C(1) 107.51(13),
O(1)±C(6)±C(7) 113.39(13), C(1)±C(6)±C(7) 103.14(13),
C(9)±C(8)±C(11) 101.10(2), C(11)±C(8)±C(7) 102.00(2),
C(13)±C(7)±C(8) 113.90(2), C(13)±C(7)±C(6) 112.10(2),
C(8)±C(7)±C(6) 101.68(14), C(8)±C(9)±C(10) 102.70(2).
Final crystallographic coordinates are deposited in Cambridge
Crystallographic Data Centre (CCDC 174746).
12. House, H. O.; Carlson, R. G.; Muller, H.; Noltes, A. W.;
Slater, C. D. J. Am. Chem. Soc. 1962, 84, 2614±2620.
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213±250 and references cited therein.
14. Ireland, R. E.; Wrigley, T. I.; Young, W. G. J. Am. Chem. Soc.
1958, 80, 4604±4606.
15. Crystallographic data of the diol 16/16 crystallises in the
monoclinic C2/c space group with aˆ22.632 (8), bˆ10.945
Ê
(4), cˆ10.194 (2) A; aˆgˆ908, bˆ98.99 (2)8; Vˆ2493.9
Ê 3
(13) A , and zˆ8. The ®nal coordinates were solved by direct
methods and re®ned by full matrix least square method with
Rˆ0.0330 and Rwˆ0.0858, and GOFˆ1.010 for 242 vari-
ables; measured re¯ections 1705, used re¯ectios 1631; Bond
Ê
length ([A] (standard deviation)): C(5)±C(4) 1.510(3), C(5)±
C(6) 1.535(2), C(5)±O(2) 1.436(2), C(4)±C(3) 1.514(3),
C(3)±C(2) 1.522(3), C(2)±C(1) 1.532(2); C(2)±C(14)
1.524(3), C(1)±C(6) 1.564(2), C(1)±C(11) 1.543(2), C(1)±
C(10) 1.548(2), C(11)±C(8) 1.531(3), C(8)±C(7) 1.550(3),
C(8)±C(9) 1.523(3), C(7)±C(6) 1.597(2), C(7)±C(12)
1.535(3), C(7)±C(13) 1.529(3), C(10)±C(9) 1.537(3), C(6)±
O(1) 1.439(2). Bond angles ([8] (standard deviation)): O(2)±
C(5)±C(4) 111.70(2), C(4)±C(5)±C(6) 112.03(14), C(4)±
16. Gutsche, C. D.; Redmore, D. Carbocyclic Ring Expansion
Reactions; Academic: New York, 1968; pp 101±103, and
references cited therein.
17. Preliminary communication: Pati, L. C.; Roy, A.; Mukherjee,
D. Tetrahedron Lett. 2000, 41, 10353±10356.
18. Smith, III, A. B.; Jerris, P. J. J. Org. Chem. 1982, 47, 1845±
1855.