A stereocontrolled total synthesis of (±)-norzizanone

Article abstract of DOI:10.1016/S0040-4039(00)01861-X

A stereocontrolled total synthesis of (±)-norzizanone 1 has been efficiently accomplished involving base-induced rearrangement of the mesylate 17 as the key step. Aryl participated intramolecular cyclisation of the bromophenol 11 provided the tricyclic dienone 12, which was stereoselectively converted into the mesylate 17. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01861-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10353–10356
A stereocontrolled total synthesis of ( )-norzizanone
Lokesh Chandra Pati, Arnab Roy and Debabrata Mukherjee*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Calcutta 700 032, India
Received 25 September 2000; accepted 19 October 2000
Abstract
A stereocontrolled total synthesis of ( )-norzizanone 1 has been efficiently accomplished involving
base-induced rearrangement of the mesylate 17 as the key step. Aryl participated intramolecular
cyclisation of the bromophenol 11 provided the tricyclic dienone 12, which was stereoselectively converted
into the mesylate 17. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: terpenes; cyclisation; desulfurisation; hydroxylation; rearrangement.
Norzizanone 1, a norsesquiterpene ketone, possesses the tricyclo[6.2.1.01,5]undecane ring
system characteristic of the zizaane group of sesquiterpenes, and has attracted considerable
attention1–4 as a challenging synthetic target. The ketone 1 has been efficiently converted into the
sesquiterpene zizaene 2 by Coates and Sowerby.1 The total synthesis of 1 presents an interesting
problem in view of the presence of four asymmetric centres and a trans-fused hydroindan ring
junction. We report herein a highly stereocontrolled synthesis of ( )-norzizanone 1 from the
easily accessible (Scheme 1) indane derivative 11. Intramolecular anionic cyclisation of 11
provided the tricyclic dienone 12 in high yield. Using the functional groups in ring A, the
dienone 12 was stereoselectively converted into the cis-diol 16. The corresponding monomesylate
17 rearranged smoothly under appropriate conditions to afford ( )-norzizanone 1 in excellent
yield. The present work constitutes a formal total synthesis of ( )-zizaene 2 (Fig. 1).
Treatment of methyl 3-(4-methoxyphenyl)propanoate5 with MeMgI (4 equiv.) in refluxing
Et2O followed by intramolecular cyclisation of the resulting carbinol with polyphosphoric acid
afforded 1,1-dimethyl-6-methoxyindane 36 in 72% overall yield. Oxidation of 3 with CrO3
furnished the indanone 4 (76%), mp 63–64°C. Alkylation of 4 with ethyl bromoacetate using
LDA (1.1 equiv.) as the base provided the keto-ester 5 (73%), which on hydrolysis yielded the
keto-acid 67 (92%). Reduction of 6 with NaBH4 in aqueous NaOH followed by catalytic
hydrogenation of the crude product furnished the acid 7, mp 121–122°C in 89% yield. The
corresponding methyl ester 8 was reduced with LiAlH4 and the resulting primary alcohol 9
* Corresponding author: Fax: 91-33-4732805; e-mail: ocdm@mahendra.iacs.res.in
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01861-X

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Scheme 1. Reagents and conditions: i, CrO3, AcOH, H2O, 5–20°C; ii, LDA, BrCH2CO2Et, THF, −10 to 20°C; iii,
KOH, MeOH, reflux, H3O+; iv, NaBH4, aq. NaOH, 25°C, H3O+; H2, 10% PdꢀC, AcOH; v, CH2N2, Et2O, 0°C; vi,
LAH, Et2O, reflux; vii, Ph3P, CBr4, Et2O, 25°C; viii, BBr3, CH2Cl2, 0–20°C; ix, t-BuOK, t-BuOH, 80°C; x, LiMe2Cu,
Et2O, 0°C; xi, HSCH2CH2SH, MeOH, BF3·Et2O, 25°C; xii, Na, EtOH, liq. NH3; xiii, OsO4, C5H5N, 25°C; xiv, MsCl,
C5H5N, 10°C; xv, t-BuOK, t-BuOH, 20°C
Figure 1.
(95%) was treated with a mixture of Ph3P and CBr4 to give the bromoether 107 (80%).
Demethylation of 10 with BBr3 provided the bromophenol 11 (92%). Intramolecular anionic
cyclisation8 of 11 using t-BuOK as the base afforded the dienone 12,7 mp 72–73°C in 73% yield.
Conjugate addition of LiMe2Cu to 12 was highly regioselective and stereoselective affording
the enone 13,7 mp 64–65°C in 85% yield. The stereochemical 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 147 in near quantitative yield. Desulfurisation of 14 was effected

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efficiently with Na and EtOH in liquid ammonia9 to give the olefin 157 (87%). Hydroxylation of
15 with OsO4 furnished the cis-diol 167 (85%), mp 116–117°C, which was converted into the
monomesylate 17 (90%). As mentioned earlier, the relative stereochemistries at C-1, C-2, C-5,
C-6 and C-8 of 16 were determined by X-ray crystallography. The bonds a and b of the diol 16
being antiperiplanar, the monomesylate 17 rearranged10 smoothly on treatment with t-BuOK (1
equiv.) in t-BuOH at 20°C to provide the ketone 17 as the sole product in 88% yield. The
spectral data of 1 agreed very well with those reported in the literature.
Acknowledgements
We are grateful to the CSIR, New Delhi, for financial 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.
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7. Selected spectral data for: 6: 1H NMR (CDCl3, 300 MHz) l 1.19 (s, 3H), 1.52 (s, 3H), 2.48–2.58 (m, 1H),
2.92–3.02 (m, 2H), 3.92 (s, 3H), 6.92 (d, 1H, J=2.4 Hz), 6.92 (dd, 1H, J=9, 2.4 Hz), 7.69 (d, 1H, J=9 Hz); 13C
NMR (CDCl3, 75 MHz) l 26.97, 27.82, 31.29, 41.81, 55.66, 55.66, 107.04, 115.22, 125.68, 126.75, 165.79, 165.93,

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1
177.72, 204.09. 10: H NMR (CDCl3, 300 MHz) l 0.97 (s, 3H), 1.31 (s, 3H), 1.85–2.26 (m, 3H), 2.44–2.52 (m,
1H), 2.91–2.98 (m, 1H), 3.38–3.61 (m, 2H), 3.79 (s, 3H), 6.68 (dd, 1H, J=8.8, 2.3 Hz), 6.69 (d, 1H, J=2.3 Hz),
7.07 (d, 1H, J=8.8 Hz); 13C NMR (CDCl3, 75 MHz) l 23.53, 26.50, 32.78, 33.28, 34.80, 45.63, 50.08, 55.39,
107.95, 111.72, 124.85, 132.71, 154.35, 158.95. 12: 1H NMR (CDCl3, 300 MHz) l 1.13 (s, 3H), 1.19 (s, 3H),
1.25–2.20 (m, 7H), 6.03 (d, 1H, J=1.5 Hz), 6.27 (dd, 1H, J=9.6, 1.5 Hz), 7.04 (d, 1H, J=9.6 Hz); 13C NMR
(CDCl3, 75 MHz) l 24.25, 27.97, 27.97, 33.81, 42.10, 42.33, 48.60, 53.82, 118.06, 130.57, 149.73, 181.42, 187.56.
1
13: H NMR (CDCl3, 300 MHz) l 1.00 (d, 3H, J=7 Hz), 1.09 (s, 3H), 1.13 (s, 3H), 1.31–2.69 (m, 10H), 5.69 (s,
1H); 13C NMR (CDCl3, 75 MHz) l 17.49, 24.40, 24.55, 26.94, 33.25, 33.52, 39.66, 42.56, 43.80, 46.86, 54.86,
1
116.83, 182.07, 199.40. 14: H NMR (CDCl3, 300 MHz) l 0.99 (s, 3H), 1.04 (d, 3H, J=6.5 Hz), 1.05 (s, 3H),
1.15–2.35 (m, 10H), 3.26–3.44 (m, 4H), 5.42 (s, 1H); 13C NMR (CDCl3, 75 MHz) l 17.48, 24.70, 25.23, 28.84,
32.90, 33.88, 38.59, 38.98, 40.42, 41.13, 45.85, 47.22, 52.06, 64.34, 118.48, 155.46. 15: 1H NMR (CDCl3, 300
MHz) l 0.87 (d, 3H, J=7 Hz), 0.96 (s, 3H), 1.03 (s, 3H), 1.11–1.97 (m, 12H), 5.16 (t, 1H, J=3.5 Hz); 13C NMR
(CDCl3, 75 MHz) l 16.20, 21.14, 25.16, 25.70, 26.78, 29.00, 32.35, 35.31, 39.52, 41.45, 47.35, 52.87, 111.05,
154.35. 16: 1H NMR (CDCl3, 300 MHz) l 0.88 (d, 3H, J=6.4 Hz), 0.97 (s, 3H), 1.19 (s, 3H), 1.01–2.27 (m, 14H),
3.85 (dd, 1H, J=10.5, 5.2 Hz); 13C NMR (CDCl3, 75 MHz) l 17.40, 22.97, 24.83, 24.83, 27.34, 31.05, 31.51,
1
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22.13, 25.71, 26.79, 30.45, 32.15, 36.15, 41.41, 49.03, 49.98, 54.02, 57.50, 216.51.
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.