A simple synthetic approach to trachylobane, beyerane, and atisane diterpenoids from carvone

Article abstract of DOI:10.1055/s-2001-11401

A stereoselective general synthetic approach to trachylobane-, beyerane-, and atisane-type polycyclic diterpenoids from carvone is described. Key steps in this approach are an IMDA reaction, an intramolecular diazo ketone cyclopropanation of an unsaturated ketone, and a controlled regioselective opening of a cyclopropyldiketone moiety.

Full text of DOI:10.1055/s-2001-11401

LETTER
349
A Simple Synthetic Approach to Trachylobane, Beyerane, and Atisane
Diterpenoids from Carvone
Antonio Abad,* Consuelo Agulló, Ana C. Cuñat, Ismael Navarro, M. Carmen Ramírez de Arellano1
Departamento de Química Orgánica, Universitat de Valencia, Dr. Moliner 50, 46100-Burjassot (Valencia), Spain
Fax +34(6)3864328; E-mail: Antonio.Abad@uv.es
Received 4 January 2001
The synthesis of these compounds has attracted the atten-
tion of numerous organic synthetic chemists due to the
difficulties associated with the construction of the bridged
carbocyclic system,3b,4 and several synthetic strategies
Abstract: A stereoselective general synthetic approach to trachylo-
bane-, beyerane-, and atisane-type polycyclic diterpenoids from
carvone is described. Key steps in this approach are an IMDA reac-
tion, an intramolecular diazo ketone cyclopropanation of an unsat-
urated ketone, and a controlled regioselective opening of a have been developed for the construction of the tricy-
clo[3.2.1.02,7]-, bicyclo[3.2.1]- and bicyclo[2.2.2]-octane
cyclopropyldiketone moiety.
moieties, characteristic for trachylobanes, beyeranes/kau-
Key words: terpenoids, Diels-Alder reaction, diazo compounds,
ring opening, cyclopropane
ranes and atisanes respectively.5
As part of our research related to the utilization of readily
available chiral building blocks for the synthesis of poly-
cyclic terpenoids,6 we wish to describe in this paper a ste-
reoselective general approach to the carbocyclic skeleton
of trachylobanes, beyeranes and atisanes from the mono-
terpene carvone. As shown in the retrosynthetic analysis
in Scheme 2, the key feature of the synthesis involves the
preparation of a polycyclic diketone 9, containing the tri-
cyclo[3.2.1.02,7]octane moiety incorporated into ring C.
This is prepared by the intramolecular addition of a -di-
azo carbonyl group to the enone double bond of a homo-
chiral phenanthrenone system 8, which, in turn, is
prepared from carvone 7 following the methodology pre-
viously used by us6 and others7 for the preparation of re-
lated systems. The completion of the trachylobane
skeleton from 9 only requires the introduction of the gem-
inal dimethyl group at C-4, while its conversion into the
beyerane and atisane frameworks requires, as in the bio-
genetic route, additional regioselective fragmentation of
the C12-C13 or C13-C16 bond.
Trachylobane-, beyerane-, atisane- and kaurane-type
polycyclic diterpenoids2 constitute an important group of
natural compounds of terrestrial origin that displays a
broad spectrum of biological activity, including antimi-
crobial, antitumor, antifeedant, gibberellin-like, and anti-
HIV properties. All of them are biogenetically related, and
it is now widely accepted that the tetracyclic carbon skel-
etons of beyeranes, atisanes and kauranes arise from the
cyclization of an intermediate pimaranyl cation 1 that pro-
duces the tetracyclic cation 2 (Scheme 1).3 Closure of this
species occurs by either formation of a protonated cyclo-
propane or by loss of a proton forming the pentacyclic tra-
chylobane skeleton 3. The three possible cleavage modes
of the cyclopropane ring lead to the skeletons of kaurane
4 (path a), beyerane 5 (path b) or atisane 6 (path c).
Scheme 2
Scheme 1
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A. Abad et al.
LETTER
alkylated products.8 Removal of the acetal protecting
group with pyridinium p-toluenesulfonate in aqueous
acetone provided the aldehyde 12 in 92% yield. Chemose-
lective homologation of the aldehyde group of 12 by Wit-
tig reaction with ( -formylethylidene)triphenyl phos-
phorane provided stereoselectively the chain extended
, -unsaturated aldehyde 13, which, by subsequent Wittig
methylenation, afforded the 1,3,9-triene 14 in 75% overall
yield.
Heating a solution of this compound in toluene and a
small amount of propylene oxide in a sealed tube at 185
C for 6 days afforded stereoselectively the tricyclic com-
pound 15 in very high yield. Having efficiently completed
the preparation of the ABC-ring system common to the
target diterpenes, the stage was now set for the construc-
tion of the tricyclo[3.2.1.02,7]octane moiety of key inter-
mediate 9. Treatment of the lithium enolate of 15 with
2,2,2-trifluoroethyltrifluoroacetate, followed by diazo-
transfer reaction using mesylazide as reagent, provided
the tricyclic -diazoketone 8 in 87% overall yield for the
two steps. Intramolecular addition of the -diazoketone to
the enone double bond was accomplished in 95% yield us-
ing bis(N-tert-butyl salicylaldiminate) copper(II) as the
catalyst.9 In order to complete the construction of the
characteristic geminal dimethyl group at the C-4 position
of the diterpene skeleton, the A-ring double bond was ste-
reoselectively cyclopropanated, using standard Simmons-
Smith cyclopropanation conditions. This reaction cleanly
and stereoselectively afforded the key intermediate 9 in
94% yield, the structure of which was firmly established
by an X-ray crystallographic analysis (Figure 1).10
Scheme 3 (a) i: LDA, THF, -78 ºC then CH3CHO; ii: (ClCO)2-
DMSO, Cl2CH2, -30 ºC then Et3N, 85%; (b) NaH, THF, 0 ºC then
Bu4NHSO4 and ICH2CH(EtO)2, 78%; (c) PPTS, H2O-acetone, 92%;
(d) Ph3P=C(Me)CHO, benzene, ref, 86%; (e) Ph3P=CH2, THF, -78
ºC, 87%; (f) toluene, 185 ºC, propylene oxide, 6 days, 89%; (g) i:
LiHMDS, THF, -78 ºC then CF3CO2CH2CF3; ii: MsN3, CH3CN,
H2O-Et3N, 87%; (h) bis(N-tert-Butyl salicylaldiminate) Cu(II), to-
luene, ref, 95%; (i) CH2I2, ZnEt2, toluene, 0 ºC, 94%; (j) H2, PtO2,
AcOH, 4 atm, 95% for 17 and 83% for 20; (k) Li, NH3-THF, -78 ºC,
83%; (l) SmI2, THF-MeOH, -78 ºC, 75%.
The synthesis of the key intermediate 9 commences with
the preparation of -diketone 10 from commercial (S)-
(+)-carvone (7) (Scheme 3). This was made by reaction of
the kinetic enolate of carvone with acetaldehyde and fol-
lowed by Swern oxidation of the resulting -hydroxyke-
tone. The -diketone 10 is thus obtained in 85% overall
yield as a mixture of inseparable epimers. Alkylation of its
tetrabutylammonium enolate, obtained by treatment of
10, first with two equivalents of NaH in THF and then
with Bu4NHSO4, with 3-iodopropanaldehyde diethyl
acetal, afforded diastereoselectively compound 11 in 78%
yield. Direct alkylation of the sodium enolate of 10 under
different reaction conditions always afforded a much low-
er yield of 11, together with significant amounts of O-
Figure 1 Thermal ellipsoids plot of 9 (50% probability levels)
This compound was then directly converted into the tra-
chylobane-type compound 17 through regioselective cy-
clopropane hydrogenolysis on stirring under H2 (4 atm)/Pt
in AcOH at room temperature.11 This treatment not only
releases the latent geminal dimethyl group at C-4 but also
produces the stereoselective reduction of the C-15 carbon-
yl group, thus facilitating the eventual elaboration of the
peripheral substitution patterns of the trachylobane sys-
tem.
Synlett 2001, No. 3, 349–352 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Simple Synthetic Approach to Diterpenoids
351
Washington, DC; American Chemical Society: Washington,
1992; ORGN 35.
(8) This procedure represents a simple alternative for the
generation of tetrabutylammonium enolates of -dicarbonyl
compounds. See, Shono, T.; Kashimura, S.; Sawamura, M.;
Soejima, T. J. Org. Chem. 1988, 53, 907.
(9) Although the addition of -ketocarbenoids to olefinic bonds
has extensively been used in synthesis, very few examples
have been reported of addition to conjugated ketones (see :
Davies, H. M. L. In Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol.
4 (Semmelhach, M. F. Ed.), Chap. 8, p 103). To our
knowledge this is the first example that utilizes this reaction
for the construction of a natural polycyclic framework. The
high yield obtained in the cyclopropanation reaction of 8
contrasts with the poor results obtained in the few examples of
this reaction described so far (see: Burke, S. D.; Grieco, P. A.
Organic Reactions, Vol. 26, Chap. 2; Dauben, W. G., Ed; John
Wiley & Sons: New York, 1979; p 361).
Completion of the synthesis of the beyerane and atisane
frameworks was also efficiently accomplished from 9 as
follows. Regioselective cleavage of the C12-C13 bond of
17 by lithium-liquid ammonia reduction furnished the
beyerane diterpene 18 in 83% yield. Alternatively, regio-
selective cleavage of the C13-C16 bond of the cyclopro-
pane moiety of diketone 9 with samarium iodide afforded
the compounds 19, from which the atisane-type com-
pound 20 was obtained after cyclopropane hydrogenoly-
sis. As in the catalytic hydrogenation of 9, a selective
reduction of the carbonyl group at C-15 also occurs, but in
this case to give a mixture of epimeric alcohols at this po-
sition.12
In summary, we have developed a highly efficient and ste-
reoselective approach to trachylobane, beyerane and ati-
sane diterpenoids, via common synthetic intermediates,
from carvone. The final diterpene systems prepared by
this approach (e.g. 17, 18 and 20) are potential precursors
of some relevant naturally occurring compounds. Work is
currently in progress in our laboratory for the adaptation
of this approach to the synthesis of more functionalized
members (particularly around A- and B-rings) of this
group of natural products.
It is unknown if the cyclopropanation reaction occurs via a
ketocarbenoid intermediate, an unfavourable process due to
the electrophilic character of this species and the adverse
electron-withdrawing effect of the carbonyl group on the
reactivity of the double bond, or by dipolar cycloaddition of
the diazocarbonyl moiety to the
-unsaturated system
followed by dinitrogen extrusion (see: Doyle, M. P.; Dorow,
R. L.; Tamblyn, W. H. J. Org. Chem. 1982, 47, 4059). In any
case, control experiments showed that the reaction
(conversion of 8 into 16) also takes place in the absence of the
copper catalyst but at 190 °C in toluene and in no useful
synthetic yield.
Acknowledgement
We are grateful to the Ministerio de Educación y Cultura of Spain
for financial support (Project PB98-1421-C02-01). M.C.R.A.
thanks the Generalitat Valenciana for financial support (Project
GVDOC99-22). We also thank Professor M. Doyle for his com-
ments on the addition of diazo compounds to conjugated ketones.
(10) Crystal data for compound 9: colourless plate of
0.62 0.60 0.10 mm size, monoclinic, C2, a = 10.4259(9),
b = 7.8156(6), c = 20.720(2) Å, = 104.004(7)°,
V = 1638.1(2) Å3, Z = 4, 2 max = 56°, diffractometer Nonius
CAD4, Mo K ( = 0.71073 Å), -scan, 5230 reflections
collected of which 3970 (Rint = 0.019) were independent,
refinement on F2 using SHELX97 program (Sheldrick, G.M.,
University of Göttingen, 1997), 201 refined parameters, riding
hydrogen atoms, absolute structure could not be determined,
R1[I > 2 (I)] = 0.0421, wR2 (all data) = 0.1188, residual
electron density 0.30 eÅ-3.
References and Notes
(1) X-ray crystal structure determination (E-mail: mcra@uv.es)
(2) (a) Connolly, J. D., Hill R. A. In Dictionary of Terpenoids, 1st
ed; Chapman and Hall: London, 1991; Vol. 2, pp 906-970. (b)
Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 165 and previous
reviews of this series.
(3) (a) Wenker, E. Chem. Ind. (London) 1955, 282. (b) Goldsmith,
D. In The Total Synthesis of Natural Products, Vol. 8;
Apsimon J., Ed.; John Wiley & Sons: New York, 1992, p 101.
(4) Recent synthesis: (a) Toyota, M.; Wada, T.; Ihara, M. J. Org.
Chem. 2000, 65, 4565. (b) Toyota, M.; Wada, T.; Fukumoyo,
K.; Ihara, M. J. Am. Chem. Soc. 1998, 120, 4916. (c)
Berettoni, M.; De Chiara, G.; Iacoangeli, T.; Lo Surdo, P.;
Bettolo, R. M.; di Mirabello, L. M.; Nicolini, L.; Scarpelli, R.
Helv. Chim. Acta 1996, 79, 2035. (d) Abad, A.; Agulló, C.;
Arnó, M.; Marín, M. L.; Zaragozá, R. J. J. Chem. Soc., Perkin
Trans. 1 1994, 2987.
(5) (a) Cory, R. M.; Chan, D. M. T.; Naguib, Y. M. A.; Rastall, M.
H.; Renneboog, R. M. J. Org. Chem. 1980, 45, 1852. (b) Basu,
B.; Mukherjee, D. Tetrahedron Lett. 1984, 25, 4445. (c) Ihara,
M.; Toyota, M.; Fukumoto, K.; Kametani, T. J. Chem. Soc.,
Perkin Trans. 1 1986, 2151. (d) Toyota, M.; Yokota, M.;
Ihara, M. Org. Lett. 1999, 1, 1627.
(6) (a) Abad, A.; Agulló, C.; Castelblanque, L.; Cuñat, A. C.;
Navarro, I.; Ramírez de Arellano, M. C. J. Org. Chem. 2000,
65, 4189. (b) Abad, A.; Agulló, C.; Cuñat, A. C. Llosá, M. C.
Chem. Commun. 1999, 427 and literature cited therein.
(7) (a) Shing, T. K. M.; Jiang, Q. J. Org. Chem. 2000, 65, 7059.
(b) Rawal, V. H.; Iwasa, S. Abstracts of Papers; 204th
National Meeting of the American Chemistry Society,
(11) It should be mentioned that no hydrogenolysis of the other
cyclopropane ring was observed, even under more forcing
hydrogenation conditions.
(12) All compounds were characterised by 1H NMR, 13C NMR, IR
and HRMS. Selected data of more significant compounds are
given. Compound 9: mp 143-144 °C (from MeOH);
[ ]D+73.9° (c 3.3, CHCl3); 1H NMR (300 MHz, CDCl3)
2.56 (1H, d, J = 8 Hz, H-13), 2.44 (1H, ddd, J = 8, 5 and 2 Hz,
H-12),1.39 (3H, H-17), 0.94 (3H, H-19), 0.79 (3H, H-20),
0.59 (1H, m, H-3), 0.4 (1H, dd, J = 9, 4 Hz, H-18 ); -0.05 (1H,
dd, J = 6, 4 Hz, H-18 ); HRMS m/z (M+) calcd 298.1933,
obsd 298.1932.
Compound 17: mp 154-156 °C (from MeOH); [ ]D+49.8° (c
1.3, CHCl3); 1HNMR (300 MHz, CDCl3) 3.61 (1H, br s, H-
15); 1.87 (1H, m, H-12),1.80 (1H, d, J = 8 Hz, H-13), 1.34
(3H, H-17), 0.87 (3H, H-18), 0.819 (3H, H-19), 0.75 (3H, s,
H-20), 0.7 (H-5, dd, J = 13, 4.5 Hz); HRMS m/z (M+) calcd
302.2246, obsd 302.2244.
Compound 18: mp 164-166 °C (from pentane); [ ]D 44° (c
1.0, CHCl3); 1HNMR (300 MHz, CDCl3) : 3.17 (1H, br s, H-
15), 2.25 (1H, d, J = 19 Hz, H-13), 1.87 (1H, d, J = 19 Hz, H´-
13), 1.07 (3H, s, H-17), 0.86 and 0.83 (6H, each s, H-18 and
H-19), 0.80 (3H, s, H-20); HRMS m/z (M+) calcd 304.2402,
obsd 304.2397.
Compound 20. A 2:1 mixture of
and
epimers at C-15 is
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A. Abad et al.
LETTER
obtained in the reduction of 19. Both epimeric alcohols are
easily separable by column chromatograph using hexane:ethyl
acetate 7:3 as eluent; only data of the main epimer (15 -OH)
are given: mp 164.5-166.5 °C (from cold pentane); [ ]D
14.5º (c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3) 3.18
(1H, d, J = 3 Hz, H-14), 2.54 (1H, ddd, J = 13, 4 and 3 Hz, H-
7 ), 2.27 (1H, dd, J = 19 and 3 Hz, H-16), 2.20 (1H, ddd,
J = 19, 5 and 3 Hz, H´-16), 1.16 (3H, d, J = 7 Hz, H-17), 0.85
(3H, H-19), 0.78 (3H, H-18), 0.69 (3H, H-20); HRMS m/z
(M+) calcd 304.2402, obsd 304.2399.
Article Identifier:
1437-2096,E;2001,0,03,0349,0352,ftx,en;L22000ST.pdf
Synlett 2001, No. 3, 349–352 ISSN 0936-5214 © Thieme Stuttgart · New York