Enantiospecific synthesis of 8-epipuupehedione from (R)-(-)-carvone

Article abstract of DOI:10.1016/S0040-4039(01)00153-8

An enantiospecific synthesis of the antitumor marine sponge metabolite puupehedione (2a) and its C₈-epimer 2b as their methylenedioxy derivatives 8a and 8b was achieved through concomitant O-allyl deprotection and electrocyclization of 20 deriv

Full text of DOI:10.1016/S0040-4039(01)00153-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2389–2391
Enantiospecific synthesis of 8-epipuupehedione from
(R)-(−)-carvone
Soumen Maiti, Sujaya Sengupta, Chandana Giri, Basudeb Achari and Asish Kr. Banerjee*
Department of Medicinal Chemistry, Indian Institute of Chemical Biology, Calcutta 700 032, India
Received 17 November 2000; revised 10 January 2001; accepted 25 January 2001
Abstract—An enantiospecific synthesis of the antitumor marine sponge metabolite puupehedione (2a) and its C8-epimer 2b as their
methylenedioxy derivatives 8a and 8b was achieved through concomitant O-allyl deprotection and electrocyclization of 20 derived
from (−)-carvone. © 2001 Published by Elsevier Science Ltd.
Puupehenone (1), puupehedione (2a), puupehediol (3),
15-cyanopuupehenol (4), 15-oxopuupehediol (5), 15-a-
methoxypuupehenol (6), 21-chloropuupehediol (7) and
their derivatives belong to a group of recently charac-
terized marine sponge metabolites of mixed biogenetic
origin featuring a sesquiterpene unit joined to a C6-
shikimate moiety.1 These compounds have been
reported to display a wide range of important biologi-
cal properties including cytotoxic, antiviral, antifungal,
antitumor and antimalarial activities.2 Moreover, a few
of them have been shown3 to inhibit topoisomerase II
activity, cholesteryl ester transfer protein (CETP) prop-
erties as well as replication of the HIV virus, further
heightening the interest in this class of compounds. The
unique structural features and biological activities of
these compounds has prompted chemists to study their
synthesis.
The first synthesis of ( )-puupehenone (1) starting from
farnesyl bromide and sesamol was reported in 1978 by
Trammel.4 Recently, total syntheses of both the enan-
tiomers of 15-oxopuupehenol (as their methylenedioxy
Scheme 1.
* Corresponding author. Tel.: (91-33) 4735197/4733493; fax: (91-33) 4735197/4730284; e-mail: basish@hotmail.com
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00153-8

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S. Maiti et al. / Tetrahedron Letters 42 (2001) 2389–2391
derivatives) starting from (+)- and (−)-driminal, pre-
pared from farnesol, have been described.5 More
recently, Barrero et al. have published enantiospecific
synthetic routes to puupehenone (1), puupehedione (2a)
and 8-epipuupehedione (2b) from (−)-sclareol.6 Signifi-
cantly, 2b was found to be the most antitumor-active
compound against the cell lines P388, A-549, HT-29
and MEL-28.6 The key element of most of the reported
syntheses is the electrophilic cyclization of phenolic
intermediates B to the respective tetrahydropyrans C
with varying degrees of stereoselectivity (Scheme 1).
The intermediate B is generated from the corresponding
o-quinomethane A, prepared in several steps via the
condensation of a bicyclic aldehyde with an appropri-
ately functionalized O-TBS protected aryllithium.
However, the recently disclosed6b acid-induced electro-
cyclization of A to a 1:4 mixture of the isomeric dihy-
dropyrans 8a (C8-Mea) and 8b (C8-Meb), via the
conjugated dienone D, is the most attractive synthetic
route to 2b.
methylenedioxypyrans 8a and b in a one-pot process
using RhCl3·3H2O in ethanol (Schemes 2 and 3).
The aromatic synthon 12 was obtained in high yield
from sesamol (9) via allylation to 10, electrophilic
bromination to give the O-allylbromoether 11, and
formylation of the in situ generated lithio anion with
DMF (Scheme 2). A minor amount of the chromato-
graphically separable regioisomeric aldehyde 13 was
also obtained in the reaction.7
The (−)-trans-decalone 16 was prepared from natural
(R)-(−)-carvone (14) by modification of a reported
procedure8 through catalytic hydrogenation of the vinyl
bromo ketone 15 in the presence of Pd–C (10%) con-
taining PdCl2 (5 mol%) in EtOH (Scheme 3). Addition9
of the vinyl lithium species 18, generated by exposure of
the tosylhydrazone 17 to an excess of n-BuLi in THF,
to 12 afforded a mixture of the unstable allyl alcohol 19
and the diene 20. Treatment of the crude condensation
product with silica gel in CH2Cl2 for 3–4 h at room
temperature produced the diene 20 quantitatively.
Finally, cleavage of the O-allyl ether of the diene 20 in
refluxing EtOH containing a catalytic amount of
RhCl3·3H2O led to spontaneous cyclization,10 possibly
through the intermediate dienone D (Scheme 1), afford-
We describe herein a simple synthetic entry to 8-epipuu-
pehedione (2b) along with puupehedione (2a) involving
the key O-allyl protected intermediate 20, which was
readily derived by coupling the aldehyde 12 with the
vinyl anion 18, and its conversion to the desired
Scheme 2. (i) K2CO3, allyl bromide, acetone, rt, 12 h, 99%; (ii) NBS, CH3CN, −15°C, 30 min, 98%; (iii) n-BuLi (1.6 M), −78°C,
30 min, then DMF, −78°C, 6 h.
Scheme 3. (i) Pd–C, EtOH, PdCl2 (5 mol%), 95%; (ii) p-TsNHNH2, MgSO4, pTsOH (cat.), THF, reflux, 72 h, 93% based on
recovered starting ketone; (iii) (a) n-BuLi (1.6 M), −78°C (3 h) to −5°C (6 h), to rt (2 h); (b) −78°C, 12, 5 h, 59%; (iv) RhCl3·3H2O,
EtOH, reflux, 7 h, quantitative.

S. Maiti et al. / Tetrahedron Letters 42 (2001) 2389–2391
2391
ing a mixture of the isomeric pyrans 8a (C8-Mea) and
8b (C8-Meb) in a ratio of ca. 1:4 (1H and 13C NMR) in
quantitative yield.11 While the desired major isomer 8b
(43%) was separated from the mixture by chromatogra-
phy, the minor natural isomer 8a could only be
obtained in a partially purified form. Since both the
isomers 8a and b have already been transformed to
puupehedione 2a and its epimer 2b, the present work
represents a shorter formal synthesis of these highly
bioactive compounds from natural carvone. The con-
comitant oxaannulation in the RhCl3-induced deprotec-
tion of an O-allylic phenolic group, virtually under
neutral conditions, should emerge as a simple synthetic
entry to this and a number of natural products and
analogs.
8. Gesson, J. P.; Jacquesy, J. C.; Renoux, B. Tetrahedron
1989, 45, 5853–5866.
9. Di Grandi, D. K.; Krol, W. J.; Danishefsky, S. J. J. Org.
Chem. 1993, 58, 4989–4992.
10. For a five-membered oxaannulation through intramolec-
ular Michael addition, under similar conditions, see:
Martin, S. F.; Garrison, P. J. J. Org. Chem. 1982, 47,
1513–1518.
1
11. 17: mp 136–137°C; [h]2D9 +77.1 (c 0.14, CHCl3); H NMR
(CDCl3, 300 MHz): l 7.83 (d, J=8.5 Hz, 2H), 7.30 (d,
J=8.5 Hz, 2H), 7.17 (br s, 1H, exchangeable), 2.75 (m,
1H), 2.43 (s, 3H), 1.89 (d, J=13 Hz, 1H), 1.48–1.59 (m,
6H), 1.26–1.42 (m, 2H), 0.97–1.10 (m, 2H), 1.04 (d,
J=7.6 Hz, 3H), 0.98 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H).
13C NMR (CDCl3, 75 MHz): l 17.2 (CH2), 18.3 (CH2),
18.8 (CH3), 21.5 (CH3), 21.6 (CH3), 21.8 (CH3), 28.0
(CH3), 32.1 (CH2), 33.2 (CH), 33.7 (C), 36.1 (CH2), 41.5
(CH3), 43.2 (C), 52.8 (CH), 128.1 (CH), 129.2 (CH),
135.5 (C), 143.7 (C), 170.8 (C).
Acknowledgements
1
19: H NMR (CDCl3, 300 MHz): l 7.01 (s, 1H), 6.54 (s,
We are grateful to the DST (New Delhi) for financial
support (Grant No. SP/SI/G-4/93), UGC (New Delhi)
for a JRF to S.S., and Professor U. R. Ghatak of our
institute for his suggestions and advice.
1H), 5.60–6.13 (m, 1H), 5.93 (m, 2H), 5.57 (br s, 1H),
5.43 (dd, J=1.2 and 17 Hz, 1H), 5.32 (dd, J=1.2 and 12
Hz, 1H), 4.59 (d, J=4.8 Hz, 2H), 3.29 (br s, 1H), 2.15
(m, 1H), 1.70 (s, 3H), 1.16 (s, 3H), 0.92 (s, 3H), 0.85 (s,
3H), 0.83 (s, 3H). 13C NMR (CDCl3, 75 MHz): l 18.8
(CH2), 18.9 (CH2), 19.8 (CH3), 21.7 (CH3), 22.5 (CH3),
33.3 (CH3), 34.7 (CH2), 35.9 (CH2), 38.9 (C), 41.6 (CH2),
51.9 (CH), 67.4 (CH), 69.9 (CH2), 95.7 (CH), 101.1
(CH2), 109.5 (CH), 118.0 (CH2), 124.3 (C), 132.9 (CH),
133.2 (C), 139.2 (C), 140.8 (C), 147.1 (C), 151.9 (C). One
aliphatic quaternary carbon signal could not be identified
due to overlap.
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