Stereoselective synthesis of polyoxygenated atisane-type diterpenoids

Article abstract of DOI:10.1016/S0040-4039(01)01953-0

A new stereoselective approach to polyoxygenated atisane-type diterpenes starting from (S)-(+)-carvone is described. The key steps involve an intramolecular Diels-Alder reaction, an unusual intramolecular diazo ketone cyclopropanation of an unsaturated ketone, and a regioselective endocyclic cleavage of a cyclopropyl carbinyl radical as key synthetic steps. The synthesis of the bioactive polyoxygenated atisanes atis-16(17)-en-3,14-dione (2) and 3R-hydroxy-atis-16(17)-en-2,14-dione (3) following this approach is presented.

Full text of DOI:10.1016/S0040-4039(01)01953-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8965–8968
Stereoselective synthesis of polyoxygenated atisane-type
diterpenoids
Antonio Abad,* Consuelo Agullo´, Ana C. Cun˜at and Ismael Navarro
Departamento de Qu´ımica Orga´nica, Universitat de Valencia, Dr. Moliner 50, 46100-Burjassot Valencia, Spain
Received 30 July 2001; revised 15 October 2001; accepted 17 October 2001
Abstract—A new stereoselective approach to polyoxygenated atisane-type diterpenes starting from (S)-(+)-carvone is described.
The key steps involve an intramolecular Diels–Alder reaction, an unusual intramolecular diazo ketone cyclopropanation of an
unsaturated ketone, and a regioselective endocyclic cleavage of a cyclopropyl carbinyl radical as key synthetic steps. The synthesis
of the bioactive polyoxygenated atisanes atis-16(17)-en-3,14-dione (2) and 3R-hydroxy-atis-16(17)-en-2,14-dione (3) following this
approach is presented. © 2001 Elsevier Science Ltd. All rights reserved.
A large number of diterpenes with the atisane skeleton
(1) have been isolated from different natural sources.1
Many of these tetracyclic diterpenoids, and particularly
those containing several oxygenated functions, display
a wide spectrum of biological activity.
As a continuation of our studies on the synthesis of
tetracyclic diterpenes5 we report here a new approach
towards these compounds from carvone. Explicitly, we
describe the preparation of atisanes 2 and 3 via the
common key intermediate pentacyclic compound 5
(Scheme 1), which is efficiently prepared from carvone
using an IMDA reaction, an unusual intramolecular
diazo ketone cyclopropanation of an unsaturated
ketone, and a regioselective endocyclic cleavage of a
cyclopropyl carbinyl radical as the key synthetic steps.6
Some examples are shown below.2 Compound 3, iso-
lated from the Samoan ethnobotanical tree Homalan-
thus acuminatus, shows AIDS-antiviral activity3 and
compounds 2 and 4 isolated from the Fijian medicinal
plant Euphorbia fidjiana Boiss,4a are active against
L1210 mouse leukaemia.4b
The easy preparation of 5 in enantiomerically pure
form not only allows the synthesis of these and other
related natural atisanes, but also offers an excellent
opportunity for the preparation of other polyoxy-
12
11
13
O
16
15
1
9
14
2
3
10
8
H
H
5
4
7
O
O
O
6
H
H
I
H
H
2
1
RO
RO
H
H
6
5
O
O
OH
O
H
H
O
O
HO
H
H
O
O
H
H
4
3
RO
H
8
7
Keywords: terpene; carvone; atisane; cyclopropanation; Diels–Alder
reaction; radical cleavage.
R = TBDMS
* Corresponding author. Tel.: 34-6-3864509; fax: 34-6-3864328;
e-mail: antonio.abad@uv.es
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01953-0

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A. Abad et al. / Tetrahedron Letters 42 (2001) 8965–8968
genated non-natural atisane-type compounds that may
provide new candidates for evaluation of biological
activity.
ation of its tetrabutylammonium enolate with the 3-
iodopropanaldehyde diethyl acetal, afforded
diastereoselectively the compound 10 in 66% overall
yield. Removal of the aldehyde acetal function of 10
with pyridinium p-toluenesulfonate (PPTS) in aqueous
acetone provided the aldehyde 11 in 92% yield.
Homologation of this aldehyde with the a-phosphonate
carbanion generated from diethyl 2-oxobutane-3-
phosphonate8 and NaH in THF at room temperature
gave the desired (E)-enone 12 in 83% yield after column
chromatography. The synthesis of the IMDA precursor
The synthesis of compound 5 commences with the
preparation of the 1,3,9-triene 13, precursor of the
IMDA reaction that allows the construction of the
ABC rings (Scheme 2).7 Thus, the reaction of the
kinetic enolate of commercial (S)-(+)-carvone (8) with
acetaldehyde, followed by Swern oxidation of the
resulting b-hydroxyketone to the b-diketone 9 and alkyl-
O
O
O
e
f
g
R1
d
O
O
O
H
H
H
O
H
TBDMSO
O
TBDMSO
R2
H
8: R1 = R2 = H
12
7
13
a
9: R1, R2 = COMe, H H
b
10: R1 = COMe; R2 = CH2CH2CH(OEt)2
11: R1 = COMe; R2 = CH2CH2CHO
c
R1
O
O
O
j
R2
i
l
O
O
H
R1
H
H
TBDMSO
TBDMSO
TBDMSO
H
H
H
14: R1 = Me
17: R1 = OH; R2 = H
6: R1 = H; R2 = I
16
O
h
k
15: R1 = CHN2
O
O
H
m
n
H
H
H
TBDMSO
O
O
H
2
H
5
18
o
O
O
q
p
HO
3
H
20
H
O
TBDMSO
H
H
19
Scheme 2. (a) i LDA, THF, −78°C then CH3CHO, ii (ClCO)2–DMSO, CH2Cl2, −30°C then Et3N, 85%; (b) NaH, THF, 0°C then
Bu4NHSO4 and ICH2CH2CH(EtO)2, 78%; (c) PPTS, H2O–acetone, 92%; (d) (EtO)2P(O)C(Na)(Me)COMe, THF, rt; 83%; (e)
Et3N, TBDMSOTf, CH2Cl2, −78°C; 90%; (f) PhMe, propylene oxide, 190°C; 95%; (g) CH2I2, ZnEt2, toluene, 0°C, 89%; (h) i
LiHMDS, THF, −78°C then CF3CO2CH2CF3, ii MsN3, CH3CN, THF–H2O–Et3N, 80%; (i) bis(N-tert-butylsalicylaldimi-
nate)Cu(II), toluene, reflux, 90%; (j) H2, 10% Pt/C, AcOEt, 4 atm, 95%; (k) i MsCl, Et3N, CH2Cl2, rt, ii NaI, acetone, 40°C, 93%;
(l) SmI2, THF–MeOH, rt, 95%; (m) PTSA, CHCl3, reflux, 86%; (n) i NBS, CH2Cl2–MeOH, 0°C, ii: CrCl3–LiAlH4, i-PrOH, DMF,
91%; (o) TBDMSOTf, Et3N, CH2Cl2, −78°C; 98%; (p) m-CPBA, NaHCO3, CH2Cl2, 0°C then (COOH)2, MeOH, rt, 88%; (q) i
(ClCO)2–DMSO, Cl2CH2, −30°C then Et3N, ii TBDMSOTf, Et3N, CH2Cl2, 0°C, iii LiAlH4, THF, −78°C then acid workup, 65%.

A. Abad et al. / Tetrahedron Letters 42 (2001) 8965–8968
8967
13 was completed in 90% yield by treatment of the
enone 12 with TBDMS triflate and triethylamine in
dichloromethane at −78°C. The dienol silyl ether 13
underwent a stereospecific IMDA reaction upon heat-
ing in toluene and a small amount of propylene oxide
at 190°C for seven days to give the trans–anti–trans
fused adduct 7 in 95% yield.
a-hydroxy ketone 20. Final isomerization of the a-
hydroxycarbonyl moiety of 20 was executed by an
adaptation of the method of Mori.13 This involved,
Swern oxidation of 20 to the corresponding triketone,
protection of C-2 and C-14 carbonyl groups by conver-
sion into the corresponding tert-butyldimethylsilyl enol
ethers under the conventional silylation conditions,
stereoselective reduction of the carbonyl group at C-3
with lithium aluminum hydride and acid workup. The
whole sequence could be effected without purification
of intermediates affording compound 3 in 65% overall
yield after chromatographic purification.
Having accomplished the synthesis of the ABC-ring
system, attention was turned towards the construction
of the bicyclo[2.2.2]octane moiety. First, 7 was submit-
ted to Simmons–Smith cyclopropanation conditions to
afford stereoselectively the tetracyclic compound 14 in
89% yield.9 Treatment of the lithium enolate of 14 with
2,2,2-trifluoroethyltrifluoroacetate, followed by a diazo-
transfer reaction using mesylazide as reagent,10 pro-
vided the tetracyclic a-diazoketone 15 in 80% overall
yield for the two steps. Cooper(II)-catalyzed
intramolecular addition of the a-diazoketone moiety of
15 to the enone double bond afforded the hexacyclic
compound 16 in 90% yield. Transformation of the
tricyclo[3.2.1.02,7]octane system of 16 into the bicy-
clo[2.2.2]octane moiety of key intermediate 5 was
effected using a radical ring opening of the cyclo-
propane ring.11 Accordingly, the carbonyl group at
C-15 of diketone 16 was chemo- and stereoselectively
hydrogenated to give the a-hydroxyketone 17, which in
turn was converted into the b-iodoketone 6 via the
corresponding mesylate, in an overall yield for the three
steps of 88%. Finally, samarium(II)-mediated regiose-
lective cleavage of the C13ꢀC16 bond of the cyclo-
propane moiety of 6 occurred smoothly to afford
compound 5 in very high yield.
The synthetic samples of 2 and 3 have physical and
spectral characteristics completely identical to those
previously reported for the natural products. The only
difference was in the sign of the optical rotation, which
establishes that the natural compounds have the abso-
lute stereochemistry antipodal of that represented here
(e.g. for natural 2: 5S,8S,9S,10R,12R; for natural 3:
3S,5S,8S,9S,10R,12R).14
In conclusion, we have developed a stereoselective
approach to polyoxygenated atisane diterpenes starting
from (S)-(+)-carvone, which has allowed the efficient
preparation of atisanes 2 and 3 in enantiomerically pure
form. Work is currently in hand to further elaborate
the key intermediate of the syntheses (5) towards other
natural and unnatural more highly functionalised ati-
sane-type compounds.
Acknowledgements
After successful synthesis of the pentacyclic diketone 5,
which incorporates the requisite atisane skeletal frame-
work, the stage was set for further elaboration into the
naturally occurring compounds. Thus, treatment of 5
with p-toluenesulfonic acid (PTSA) in refluxing chloro-
form promoted concomitant ring cleavage of the cyclo-
propane moiety and hydrolysis of the tert-butyl-
dimethylsilyl protecting group to afford the tetracyclic
diketone 18 in 86% yield.
Financial support from the Direccio´n General de Ense-
n˜anza Superior e Investigacio´n Cient´ıfica (Grant PB98-
1421-C02-01) is gratefully acknowledged. We are
grateful to the Conselleria d’Educacio´ i Cie`ncia de la
Generalitat Valenciana for providing a research fellow-
ship to I.N.
References
Completion of the synthesis of the less functionalised
atisane 2 from 18 only required isomerization of the
endocyclic double bond to the less substituted position.
This was achieved very efficiently by a sequence of
allylic bromination, by reaction of 18 with N-bromo-
succinimide (NBS) in a MeOH–CH2Cl2 medium, and
chromium(II)/i-PrOH reduction.12 The global yield for
this conversion was 91%.
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2. The absolute configuration illustrated in structures 2, 3
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3. Gustafson, K. R.; Munro, M. H. G.; Blunt, J. W.;
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presence of NaHCO3 in CH2Cl2 at 0°C and methanolic
oxalic acid giving rise to a 88% overall yield of the

8968
A. Abad et al. / Tetrahedron Letters 42 (2001) 8965–8968
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13. Yajima, A.; Mori, K. Eur. J. Org. Chem. 2000, 4079.
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de Arellano, M. C. Synlett 2001, 349.
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and HRMS. Selected data of more significant compounds
are given. Compound 2: mp 153.5–155°C (from ethyl
ether); [h]2D5 −5.5 (0.7, CHCl3); 1H NMR (300 MHz,
CDCl3): l 4.89 (1H, br s), 4.68 (1H, bs), 2.73 (1H, m),
2.57 (1H, ddd), 2.17–2.38 (6H, m); 1.95 (1H, m), 1.08
(3H, s), 1.01 (3H, s), 0.87 (3H, s). Compound 3: mp
164–164.5°C (from cold ethyl ether); [h]2D6 +14 (1.0,
CHCl3); 1H NMR (400 MHz, C6D6): l 4.75 (1H, dd),
4.55 (1H, dd), 3.64 (1H, dd), 3.60 (1H, d), 2.33 (1H,
dddd), 2.17 (1H, quint.), 2.01 (1H, d), 1.97 (1H, dt), 1.85
(1H, dd), 1.79 (1H, dt), 1.34 (1H, br d), 1.08 (3H, s), 0.61
(3H, s), 0.47 (3H, s). Compound 5: mp 213.5–215.5°C
1
(from MeOH); [h]2D0 −50.8° (1.3, CHCl3); H NMR (300
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dt), 2.14 (1H, dt), 1.99 (1H, dd), 1.77 (3H, d), 1.00 (3H,
s), 0.85 (9H, s), 0.66 (3H, s), 0.49 (1H, dd), 0.24 (1H, d),
0.09 (3H, s), 0.04 (3H, s). Compound 7: [h]1D8 +60.5 (0.5,
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s), 1.72 (3H, s), 1.54 (3H, s), 0.93 (9H, s), 0.71 (3H, s),
0.10 (3H, s), 0.09 (3H, s). Compound 16: mp 186.5–188°C
(from MeOH); [h]D25 +40 (2.1, CHCl3); 1H NMR (300
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