The first total synthesis of (±)-grimaldone

Article abstract of DOI:10.1016/S0040-4039(00)00136-2

The first total synthesis of (±)-grimaldone, a tricyclic sesquiterpene containing three contiguous quaternary carbon atoms, and (±)-epigrimaldone along with (±)-α-cuparenone starting from Hagemann's ester is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00136-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2231–2233
The first total synthesis of (±)-grimaldone
A. Srikrishna ∗ and D. B. Ramachary
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 1 December 1999; accepted 14 January 2000
Abstract
The first total synthesis of (±)-grimaldone, a tricyclic sesquiterpene containing three contiguous quaternary
carbon atoms, and (±)-epigrimaldone along with (±)-α-cuparenone starting from Hagemann’s ester is described.
© 2000 Elsevier Science Ltd. All rights reserved.
The tricyclic sesquiterpene grimaldone (1) was first isolated in 1975 from the central European
liverwort Mannia fragrans, which has a pleasant and intensive odour. The stereostructure of grimaldone
was established in 1988 by single crystal X-ray diffraction analysis, and the absolute structure was
established by comparison of the CD spectrum with that of S-cuparenone.1 The presence of an interesting
carbon framework containing trimethyl-cyclopentanone and bicyclo[3.1.0]hexane sub-units and three
contiguous quaternary carbon atoms made grimaldone a challenging synthetic target. Herein, we describe
the first total synthesis of (±)-grimaldone employing an acid catalysed rearrangement of a diazo ketone2
and an intramolecular cyclopropanation of a diazo ketone as key reactions, starting from Hagemann’s
ester 4.
Retrosynthetic analysis readily identified the γ,δ-unsaturated acid 2 as the requisite precursor, which
could be obtained from the bicyclo[4.2.1]nonanedione 3 by a retro-Claisen condensation. Recently,2 we
have described a convenient procedure for the generation of bicyclo[4.2.1]nonane-2,8-diones employing
an acid catalysed regioselective intramolecular diazo ketone insertion reaction. The synthetic sequence
starting from Hagemann’s ester 4 is depicted in Scheme 1. The Hagemann’s ester 4 was converted to
the allyl alcohol 5 in two steps. Johnson’s ortho ester Claisen rearrangement of the allyl alcohol 5 using
triethyl orthopropionate and a catalytic amount of propionic acid furnished the ester 6. Alternatively,
the ester 6 was also obtained, with almost equal efficiency as a mixture of epimers, via the ortho ester
∗
Corresponding author. E-mail: ask@orgchem.iisc.ernet.in (A. Srikrishna)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00136-2
tetl 16416

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Scheme 1. Reagents, conditions and yields: (a) Ref. 2; (b) CH3CH2C(OEt)3, EtCOOH (catalytic), sealed tube 180°C, four days,
78%; (c) CH3C(OEt)3, EtCOOH (catalytic), sealed tube 180°C, four days, 80%; (d) LDA, THF, HMPA, MeI, 0°C, 95%; (e)
LDA, THF, HMPA, MeI, 0°C, 55%; (f) 4 M KOH, EtOH, 85°C, 12 h; 3N aq. HCl, 85% (two steps); (g) (COCl)2, C6H6, rt, 5 h;
CH2N2, Et2O, rt, 6 h, 58%; (h) BF3·Et2O, CH2Cl2, 0°C, 45 min, 89%; (i) 10% NaOH, MeOH, sealed tube, 100°C, 6 h, 100%;
(j) (COCl)2, C6H6, rt, 2 h; CH2N2, Et2O, rt, 2 h, 80%; (k) Cu, CuSO4, c-C6H12, W-lamp, reflux, 5 h, 77%; (l) Ph3P+CH3 I−,
K+ tAmO−, C6H6, rt, 25 min, 82%; (m) MeMgI, Et2O, 0°C, 3 h, 95% (50% conversion); (n) p-TSA, CH2Cl2, rt, 3 h; 53%; (o)
DDQ, C6H6, reflux, 5 h, 78%
Claisen rearrangement of the alcohol 5 with triethyl orthoacetate followed by alkylation with LDA and
methyl iodide. Alkylation of the ester 6 with LDA and methyl iodide in THF–HMPA furnished the ester
7 containing two quaternary carbon atoms. Base catalysed hydrolysis of the ester moiety followed by
acid catalysed hydrolysis of the ketal furnished the hemi-ketal 8.3 The hemi-ketal 8 was converted into
the diazo ketone 9 via the corresponding acid chloride. Treatment of a methylene chloride solution of
the diazo ketone 9 with boron trifluoride etherate furnished the bicyclo[4.2.1]nonanedione 3 in 89%
yield.4 Retro-Claisen condensation of the dione 3 with sodium hydroxide in methanol furnished the
keto acid 2 in a highly regioselective manner, which was then transformed into the diazo ketone 10 via
the corresponding acid chloride. Anhydrous copper sulfate–copper mediated intramolecular cyclopro-
panation of the diazo ketone in refluxing cyclohexane furnished a 1.7:1 mixture of the stereoisomeric
nordiones 11a and 11b,4 which were separated by careful column chromatography on silica gel. The
stereostructures were tentatively assigned and confirmed by conversion of 11a into grimaldone. Finally,
Wittig methylenation of the dione 11a furnished (±)-grimaldone (1), mp 86°C (lit.1 91–92°C), which
1
exhibited H and 13C NMR spectroscopic data identical to that of the natural compound.1 In a similar
manner Wittig methylenation of the dione 11b furnished (±)-epigrimaldone (12), mp 73°C. In another
direction, controlled reaction of a mixture of the diones 11 with methylmagnesium iodide furnished
a mixture of the tertiary alcohols 13. Dehydration of the tertiary alcohol with toluene-p-sulfonic acid
1
followed by aromatisation with DDQ transformed 13 into (±)-α-cuparenone (14), which exhibited H
and 13C NMR spectroscopic data identical to that reported.5

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Acknowledgements
We thank Dr. J. D. Connolly and Dr. D. S. Rycroft for providing the authentic spectra of grimaldone.
We are grateful to the C.S.I.R., New Delhi for the financial support and a fellowship to D.B.R.
References
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Bot. Lab. 1975, 39, 215.
2. Srikrishna, A.; Ramachary, D. B. Tetrahedron Lett. 1999, 40, 1605.
3. It is worth noting that hydrolysis of the ketal moiety in the ketal ester 7 followed by treatment of the resulting keto-ester i
with LiOH in refluxing THF furnished the rearranged keto-acid ii, possibly via the dione iii.
4. All the compounds exhibited spectral data consistent with their structures. Selected spectral data for the dione 3: mp 63–65°C.
1
IR: νmax/cm−1 1740, 1700. H NMR (300 MHz, CDCl3+CCl4): δ 4.94 (1H, s), 4.90 (1H, s), 3.46 (1H, dd, J 8.5 and 2.2),
2.70–2.35 (3H, m), 2.30–2.00 (3H, m), 1.27 (3H, s), 1.02 (3H, s), 0.97 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): δ 214.1
(C), 203.5 (C), 152.3 (C), 113.6 (CH2), 61.3 (CH), 52.2 (C), 49.5 (C), 40.9 (CH2), 35.7 (CH2), 31.6 (CH2), 22.5 (CH3), 20.4
(CH3), 18.5 (CH3). For the nordione 11a: mp 145°C. IR: νmax/cm−1 1720. 1H NMR (300 MHz, CDCl3+CCl4): δ 2.45–1.96
(6H, m), 1.80–1.70 (2H, m), 1.62 (1H, dd, J 9.6 and 3.3), 1.30–1.10 (2H, m), 1.09 (3H, s), 1.05 (3H, s), 1.045 (3H, s). 13
C
NMR (75 MHz, CDCl3+CCl4): δ 220.8 (C), 213.1 (C), 53.0 (C), 45.3 (C), 39.1 (C), 33.3 (CH2), 33.0 (CH2), 30.2 (CH), 27.4
(CH2), 25.3 (CH2), 21.5 (CH3), 21.4 (CH3), 19.6 (CH3), 19.3 (CH2). For the nordione 11b: mp 135°C. IR: νmax/cm−1 1720.
1H NMR (300 MHz, CDCl3+CCl4): δ 2.40–1.95 (7H, m), 1.60–1.40 (2H, m), 1.24 (1H, m), 1.15 (3H, s), 1.09 (3H, s), 0.94
(3H, s), 0.92 (1H, dd, J 5.1 and 3.3). 13C NMR (75 MHz, CDCl3+CCl4): δ 221.2 (C), 212.9 (C), 53.0 (C), 45.3 (C), 39.2 (C),
34.0 (CH), 33.2 (CH2), 32.6 (CH2), 29.0 (CH2), 25.0 (CH2), 22.3 (CH3), 21.5 (CH3), 21.0 (CH3), 14.9 (CH2).
5. Chetty, G. L.; Dev, S. Tetrahedron Lett. 1964, 73; Meyers, A. I.; Lefker, B. A. J. Org. Chem. 1986, 51, 1541.