A short and efficient regioselective approach to the C-6 to C-19 segment of bifurcaranes and a formal total synthesis of β-microbiotene, microbiotol and cyclocuparanol

Article abstract of DOI:10.1039/a908033c

Employing an epoxide rearrangement based ring contraction reaction, a short and efficient regioselective approach to the C-6 to C-19 segment of the toluquinol substituted diterpenes bifurcaranes, and its extension to a formal total synthesis of the sesquiterpenes (±)-β-microbiotene, (±)-microbiotol and (±)-cyclocuparanol are described. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a908033c

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A short and efficient regioselective approach to the C-6 to
C-19 segment of bifurcaranes and a formal total synthesis
of ꢀ-microbiotene, microbiotol and cyclocuparanol
A. Srikrishna* and S. Anitha Nagamani
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received (in Cambridge, UK) 6th October 1999, Accepted 25th October 1999
Employing an epoxide rearrangement based ring contrac-
tion reaction, a short and efficient regioselective approach
to the C-6 to C-19 segment of the toluquinol substi-
tuted diterpenes bifurcaranes, and its extension to a formal
total synthesis of the sesquiterpenes ( )-ꢀ-microbiotene,
( )-microbiotol and ( )-cyclocuparanol are described.
and efficient regioselective approach to the C-6 to C-19 carbon
framework of bifurcaranes, and its extension to a formal total
synthesis of the cyclocuparanes mentioned in the title.
It was anticipated that the Lewis acid catalysed rearrange-
ment of an epoxide derived from a trimethylcyclohexene could
generate a 1,2,2-trimethylcyclopentyl ketone selectively [eqn.
(1)] if the substituent Z on the epoxy carbon was an electron
Bifurcaranes (1a–e) are
a small group of methylhydro-
withdrawing group.5 The 1,3,3-trimethylcyclohexene system
present in the readily available β-ionone 6 was exploited. The
sequence is depicted in Scheme 1. To begin with, reaction of
β-ionone 6 with m-chloroperbenzoic acid (MCPBA) regio-
specifically generated the epoxide 7 in 90% yield. For the key
step, boron trifluoride–diethyl ether was chosen as the Lewis
acid. Treatment of a 0.5 M methylene chloride solution of the
epoxide 7 with three equivalents of boron trifluoride–diethyl
ether at Ϫ70 ЊC for one hour, cleanly furnished the ring
contracted product, enedione 8, in 94% yield, in a highly regi-
oselective manner.6 A catalytic hydrogenation reaction trans-
formed the enedione 8 into the dione 9. Regiocontrolled
Grignard reaction of the diones 8 and 9 with methylmagnesium
iodide at 0 ЊC furnished the keto alcohols 10† and 11, which
contain the C-6 to C-19 carbon framework of bifurcaranes 1a
and 1b. Replacement of one of the tertiary methyl groups in the
starting material 6 by a suitable side chain, e.g. an allyl group,
will lead to compounds suitable for further elaboration to
bifurcaranes. The structures of the compounds 10 and 11 were
established from their spectral data (1H and 13C NMR spectra)
in comparison with the bifurcaranes.
After successfully demonstrating the applicability of the
epoxide rearrangement for the generation of the C-6 to C-19 of
bifurcaranes, the methodology has been extended to the formal
total synthesis of the cyclocuparanes mentioned in the title,
Scheme 2. Thus, bromoform reaction on β-ionone 6 followed
by esterification of the resulting acid furnished the ester 12 in
95% yield. Regiospecific epoxidation of the diene ester 12 with
MCPBA furnished the epoxide 13† in 98% yield. Rearrange-
ment of the epoxide 13 with boron trifluoride–diethyl ether
furnished, exclusively, the keto ester 14,† in 90% yield, which on
catalytic hydrogenation furnished the keto ester 15 in quanti-
tative yield. Methylenation of the ketone in 15 will lead to the
ene ester 16 which has already been transformed4 into the
cyclocuparanes 2, 3 and 5 via intramolecular cyclopropanation
quinone-substituted monocyclic diterpenes consisting of a
cyclopentane ring containing two vicinal quaternary carbon
atoms. The first member of this class, bifurcarenone 1a
(RЈ = RЉ = H) was isolated1a from the brown alga Bifurcaria
galapagensis and found to inhibit the mitotic cell division in the
urchin Strongylocentrotus purpuratus. Subsequently, bifurcaren-
one 1a and its analogues as well as those derived from an intra-
molecular aldol condensation reaction were isolated from
a variety of brown alga belonging to the genus Cystoseira.1
Bifurcaranes were found to exhibit antifungal and antibacterial
activities, e.g. the mono methyl ether of bifurcarenone 1a
(RЈ = H, RЉ = Me) was shown to possess antifungal activity
against Botrytis cinerea, Fusarium oxysporum sp. mycopersici
and Verticillium alboatrum; and antibacterial activity against
Agrobacterium tumefaciens and Escherichia coli.1e In addition to
the biological properties, presence of two vicinal quaternary
carbon atoms in a cyclopentane ring as in the sesquiterpenes
cuparanes makes bifurcaranes interesting synthetic targets.2 In
a similar manner, cyclocuparanes cyclocuparenol 2, micro-
biotol 3, α- and β-microbiotenes 4 and 5, isolated from
the liverworts Marchantia polymorpha, Cryptothallus mirabilis,
Microbiota dicussata and Mannia fragrans,3 containing a 1,2,2-
trimethylcyclopentyl group attached to a bicyclo[3.1.0]hexane
system and incorporating three contiguous quaternary carbon
atoms are interesting synthetic targets.4 In continuation of our
interest in the synthesis of natural products containing con-
tiguous quaternary carbon atoms, herein we describe a short
J. Chem. Soc., Perkin Trans. 1, 1999, 3393–3394
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ester 16 using Lombardo’s procedure7 employing titanium
tetrachloride, zinc and methylene bromide. The ester 16 was
found to be identical (TLC, IR, 1H and 13C NMR spectra) with
the authentic sample,4 thus constituting a formal total syn-
thesis of ( )-β-microbiotene 5, ( )-microbiotol 3 and ( )-
cyclocuparanol 2.
In conclusion, we have developed a short and efficient regio-
selective approach to the C-6 to C-19 fragment of the marine
diterpenoids bifurcaranes employing an epoxide rearrange-
ment based ring contraction as the key step to generate the
vicinal quaternary carbon atoms in a regiospecific manner,
and extended it to the formal total synthesis of cyclocuparanes
β-microbiotene, microbiotol and cyclocuparanol. The brev-
ity and efficiency highlights the importance of the present
sequence.
Acknowledgements
We thank the C.S.I.R., New Delhi for financial support.
Notes and references
† All the compounds exhibited spectral data consistent with their struc-
ture. IR and NMR spectral data for the keto alcohol 10: νmax/cmϪ1 3430,
1665, 1610. δH (300 MHz, CDCl3 ϩ CCl4) 6.84 (1 H, d, J 15.3 Hz, H-3),
6.62 (1 H, d, J 15.3 Hz, H-2), 2.45 (1 H, m), 1.70–1.40 (6 H, m), 1.37
(6 H, s), 1.16 (3 H, s), 1.09 (3 H, s), 0.84 (3 H, s). δC (75 MHz,
CDCl3ϩCCl4) 203.8 (C), 151.7 (CH), 122.7 (CH), 71.1 (C), 59.0 (C),
44.0 (C), 40.6 (CH2), 34.5 (CH2), 29.7 (2 C, CH3), 25.6 (CH3), 24.7
(CH3), 20.7 (CH3), 19.7 (CH2). For the epoxide 12: νmax/cmϪ1 1720,
1650. δH (300 MHz, CDCl3 ϩ CCl4) 7.11 (1 H, d, J 15.3 Hz), 5.95 (1 H,
d, J 15.3 Hz), 3.72 (3 H, s), 1.90–1.65 (2 H, m), 1.50–1.20 (4 H, m), 1.13
(6 H, s), 0.91 (3 H, s). δC (75 MHz, CDCl3 ϩ CCl4) 166.3 (C), 144.4
(CH), 123.9 (CH), 70.4 (C), 65.5 (C), 51.5 (CH3), 35.7 (CH2), 33.6 (C),
30.0 (CH2), 26.1 (CH3), 26.0 (CH3), 20.9 (CH3), 17.1 (CH2). For keto
ester 14: νmax/cmϪ11730, 1690, 1630, 980. δH (300 MHz, CDCl3) 7.39
(1 H, d, J 15.5 Hz), 6.66 (1 H, d, J 15.5 Hz), 3.80 (3 H, s), 2.50–2.35
(1 H, m), 1.80–1.40 (5 H, m), 1.20 (3 H, s), 1.10 (3 H, s), 0.86 (3 H,
s). δC (75 MHz, CDCl3 ϩ CCl4) 202.4 (C), 165.8 (C), 137.6 (CH), 129.8
(CH), 59.1 (C), 51.9 (CH3), 44.3 (C), 40.4 (CH2), 34.3 (CH2), 25.4
(CH3), 24.6 (CH3), 20.2 (CH3), 19.7 (CH2).
Scheme 1 Reagents, conditions and yields: (a) MCPBA, NaHCO3,
CH2Cl2, 0 ЊC, 3 h, 90%; (b) BF3ؒEt2O, CH2Cl2, Ϫ78 ЊC, 1 h, 94%; (c) H2,
10% Pd–C, EtOH, 12 h, 100%; (d) MeMgI, Et2O, 5 min, 65% for 10 and
81% for 11.
1 (a) H. H. Sun, N. M. Ferrara, O. J. McConnel and W. Fenical, Tetra-
hedron Lett., 1980, 21, 3123; (b) V. Amico, F. Cunsolo, M. Piattelli
and G. Ruberto, Phytochemistry, 1984, 23, 2017; (c) V. Amico,
F. Cunsolo, M. Piattelli and G. Ruberto, Phytochemistry, 1985, 24,
1047; (d) V. Amico, G. Oriente, P. Neri, M. Piattelli and G. Ruberto,
Phytochemistry, 1987, 26, 1715; (e) A. Bennamara, A. Abourriche,
M. Berrada, M. Charrouf, N. Chaib, M. Boudouma and F. X.
Garneau, Phytochemistry, 1999, 52, 37.
2 So far there is only one approach reported for the synthesis of
bifurcaranes, see: K. Mori and T. Uno, Tetrahedron, 1989, 45, 1945;
K. Mori, T. Uno and M. Kido, Tetrahedron, 1990, 46, 4193.
3 Y. Asakawa, M. Toyota, H. Bischler, E. O. Campbell and S. Hattori,
J. Hattori Bot. Lab., 1984, 57, 383; Y. Asakawa, M. Tori, T. Masuya
and J. -P. Grahm, Phytochemistry, 1990, 29, 1577; D. S. Rycroft and
W. J. Cole, J. Chem. Res. (S), 1998, 600; V. A. Raldugin, V. G. Storo-
zhenko, A. I. Resvukhin, V. A. Pentegova, P. G. Gorovoj and V. I.
Baranov, Khim. Prir. Soedin., 1981, 163; A. V. Tkachev, M. M. Shaki-
rov and V. A. Raldugin, J. Nat. Prod., 1991, 54, 849; S. Melching,
A. Blume, W. A. Konig and H. Muhle, Phytochemistry, 1998, 48, 661.
4 So far there is only one approach reported for the synthesis of
cyclocuparanes, see: A. Srikrishna and D. B. Ramachary, Tetrahedron
Lett., 1999, 40, 6669.
Scheme 2 Reagents, conditions and yields: (a) NaOH, Br2, dioxane,
0 ЊC, 2 h; MeOH, H2SO4, reflux, 5 h; 95%; (b) MCPBA, NaHCO3,
CH2Cl2, 0 ЊC, 2 h, 98%; (c) BF3ؒEt2O, CH2Cl2, Ϫ78 ЊC, 1 h, 90%; (d) H2,
10% Pd–C, EtOH, 12 h, 100%; (e) TiCl4, CH2Br2, Zn, CH2Cl2, 0 ЊC, 2 h,
60%; (f) ref. 4.
5 Y. Yamano, C. Tode and M. Ito, J. Chem. Soc., Perkin Trans. 1, 1998,
2569.
6 B. Frei, H. Eichenberger, B. v. Wartburg, H. R. Wolf and O. Jeger,
Helv. Chim. Acta, 1977, 60, 2968.
7 L. Lombardo, Tetrahedron Lett., 1982, 23, 4293; S. H. Pine, in
Organic Reactions, ed. L. A. Paquette, 1993, vol. 43, pp. 1.
of the diazo ketone derived from the keto ester 16 followed by
addition of the fifteenth carbon to the resulting norcyclo-
cuparanone 17. Since conventional Wittig methylenation was
not successful, the keto ester 15 was transformed into the ene
Communication 9/08033C
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J. Chem. Soc., Perkin Trans. 1, 1999, 3393–3394