Rapid stereoselective access to the tetracyclic core of puupehenone and related sponge metabolites using metal-free radical cyclisations of cyclohexenyl-substituted 3-bromochroman-4-ones

Article abstract of DOI:10.1016/j.tetlet.2008.04.114

The tetracyclic nucleus of puupehenone, 15-oxopuupehenol and other sesquiterpene-phenol natural products can be assembled stereoselectively in three steps, the last of these being the 6-endo-trig cyclisation of an alpha-keto radical generated from a substituted 2-(2-cyclohexenyl)ethyl 3-bromo-4-chromanone under metal-free conditions.

Full text of DOI:10.1016/j.tetlet.2008.04.114

Tetrahedron Letters 49 (2008) 4156–4159
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Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Rapid stereoselective access to the tetracyclic core of puupehenone
and related sponge metabolites using metal-free radical cyclisations
of cyclohexenyl-substituted 3-bromochroman-4-ones
*
Robin G. Pritchard, Helen M. Sheldrake, Isobel Z. Taylor, Timothy W. Wallace
School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The tetracyclic nucleus of puupehenone, 15-oxopuupehenol and other sesquiterpene–phenol natural
products can be assembled stereoselectively in three steps, the last of these being the 6-endo-trig cycli-
sation of an alpha-keto radical generated from a substituted 2-(2-cyclohexenyl)ethyl 3-bromo-4-chroma-
none under metal-free conditions.
Received 26 March 2008
Accepted 21 April 2008
Available online 24 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Sesquiterpene–phenol
Merosesquiterpene
Benzo[a]xanthene
Puupehenone
Radical cyclisation
6-endo-Trig
a-Bromoketone
Lauroyl peroxide
Marine organisms are an important resource in the search for
molecules of therapeutic value, providing a steady stream of novel
structures with potentially useful biological activity.1 One particu-
lar series in this category is based on a fusion of sesquiterpene and
phenolic moieties, and includes the puupehenones 1–3, whose iso-
lation from a sponge later identified as Heteronema sp. was re-
ported in 1979.2,3 The parent compound (+)-puupehenone 1 has
since been isolated from other sponges, mainly of the orders
Verongida and Dictyoceratida,4–11 often accompanied by derived
dimers.4,6b,9 Other members of the series include the formal 1,6-
addition products 46 and 5,8b (ꢀ)-8-epi-chromazonarol 6,12 (ꢀ)-
15-oxopuupehenol 7,7,11 the dehydro systems 87 and 9,9 (+)-
puupehedione 106b and (ꢀ)-kampanol A 11, which, exceptionally,
is a fungal metabolite of terrestrial origin.13 A diastereoisomeric
series include both antipodes of chromazonarol 1214 as well as
cyclospongiaquinone-1 1315 and (+)-hongoquercin A 14.16
inhibitor of Ras protein farnesyltransferase, making it a potential
lead compound for new anticancer agents.13b The electrophilic
nature of puupehenone 1 has been exploited in the formation of
antigenic peptide conjugates for use in tumour immunotherapy
studies.20
The widespread interest in these structures has prompted vari-
ous studies directed towards their synthesis. A route to ( )-1 from
farnesyl bromide and sesamol was reported by Trammell in
1978,21 the key step being an acid-mediated stereoselective clo-
sure of the C-ring (41% de). Homochiral materials have generally
been obtained by the elaboration of commercial sesquiterpenes
such as (ꢀ)-sclareol 16, (+)-manool 17 or (+)-sclareolide 18,18,22
although a formal synthesis of 10 and 15 from (R)-(ꢀ)-carvone
has also been described.23 In alternative approaches to this series
based on polyene cyclisations, Yamamoto and coworkers devel-
oped enantioselective routes to (ꢀ)-chromazonarol 12 and (+)-8-
epi-puupehedione 15 from aryl polyenes,24 ( )-hongoquercin A
14 was obtained from a geranylated chromene derivative,25 and
titanocene-catalysed radical cyclisations of epoxypolyenes were
used in formal syntheses of ( )-10 and ( )-15.26
The biological activity observed within this series is diverse,
with antitumour,6–8 antimalarial,7,8b antiviral,6 antifungal,2,6b,8
antibacterial,2,6a,8,16 antituberculosis17 and immunomodulatory6b
properties having been reported. Additionally, compounds 1, 2
and
9
are lipoxygenase inhibitors,10a various derivatives of
Our interest in this series and the need for new antimalarials led
us to focus on the tetracyclic benzo[a]xanthen-12-one nucleus of
15-oxopuupehenol 7, whose functionality makes it potentially use-
ful as a precursor of other members of the series and a variety of
synthetic analogues. We established that a C(4a)–C(12a) lactone-
bridged variant of this tetracyclic nucleus could be assembled in
puupehedione 10, especially the synthetic (+)-8-epi-puupehedione
15,18 inhibit angiogenesis,19 and (ꢀ)-kampanol A 11 is a specific
* Corresponding author. Fax: +44 0 161 275 4598.
E-mail address: tim.wallace@manchester.ac.uk (T. W. Wallace).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.114

R. G. Pritchard et al. / Tetrahedron Letters 49 (2008) 4156–4159
4157
OH
D
OH
OH
OR
O
O
O
R
H
O
R
OH
X
OH
O
X
H
O
12a
O
O
O
H
4a H
A
H
H
H
H
1 R = H
2 R = Cl
3 R = Br
4 R = OH, X = CN
5 R = OH, X = OMe
6 R = X = H
7
8 R = H, X = Cl
9 R = Me, X = H
10
OH
OMe
CO2H
O
O
O
HO
O
H
HO
H
O
O
O
O
O
O
O
H
H
AcO
H
H
H
H
H
11
12
13
14
15
R
O
HO
HO
O
O
R
O
O
OH
i
19
20
H
O
a 94%
b 80%
2
R
R
H
H
H
16
17
18
OH
21
four steps via a manganese(III) acetate-mediated oxidative radical
cyclisation,27 and now wish to describe a novel metal-free variant
of this cyclisation, which provides the functionalised tetracyclic
nucleus in only three steps from commercial materials.
a
b
R = H
R = OMe
a 90%
b 99%
ii
R
R
Our method for assembling the desired tetracycle is illustrated
in Scheme 1. Condensing dihydro-b-ionone 19 with the acetophe-
none 20a using pyrrolidine in toluene28 gave the chroman-4-one
( )-21a,29 which could be brominated efficiently and selectively
at C(3) using copper(II) bromide in ethyl acetate–chloroform30 to
produce a diastereoisomeric mixture of bromoketones 22a (ratio
ca. 3:2 by 1H NMR spectroscopy).29 Heating the mixed bromo-
ketones 22a with two equivalents of dilauroyl peroxide in reflux-
ing 1,2-dichloroethane gave a mixture in which the major product
was identified as the tetracyclic ketone 23a (56%) on the basis of its
mass spectrum (MH+ 311) and distinctive 1H NMR signals at d
5.57 ppm (triplet, J 3.8 Hz) and 2.8–2.4 ppm (two double doublets,
J 3.8 and 19.7 Hz), which could be attributed to the isolated spin
system composed of the three hydrogens attached to C(5) and
C(6).29
R
R
11
11a
O
O
8
iii
12
7a
1
12a
O
O
a 56%
b 67%
H 6a
Br
12
b
4
6
4a
5
23
22
Scheme 1. Reagents and conditions: (i) pyrrolidine, toluene, reflux (Dean–Stark),
3 d; (ii) CuBr2, EtOAc–CHCl3, reflux, 5–14 h; (iii) lauroyl peroxide 24 (2.0 equiv), 1,2-
dichloroethane, reflux, 6–21 h.
Repeating the sequence with the acetophenone 20b as the start-
ing material gave good yields of the expected intermediates 21b
and 22b, and heating the latter with lauroyl peroxide gave the tet-
racyclic ketone 23b in 67% yield, together with some unreacted
bromoketone 22b (13%).31 Comparison of the respective 1H and
13C NMR spectra indicated that the structures of 23a and 23b were
analogous. The relative stereochemistry of ketone 23b was con-
firmed by X-ray crystallography (Fig. 1).32
22a by the undecanyl radical 26, the latter being generated via the
thermolysis of lauroyl peroxide 24 (Scheme 2). Related processes
involving the abstraction of iodine have been described by Renaud
and co-workers,33 but we are not aware of any bromoketones
being used in this way. The presence of 1-bromoundecane 27
among the by-products of the reaction was confirmed by 1H
NMR spectroscopy. The 6-endo-trig cyclisation of 28, leading to
29 in which the C(6a) and C(12b) methyl groups have a trans rela-
tionship, is consistent with our earlier observation of this type of
Mechanistically the transformation of 22a into 23a can be inter-
preted in terms of the initial abstraction of the bromine atom from

4158
R. G. Pritchard et al. / Tetrahedron Letters 49 (2008) 4156–4159
elaboration. We are currently exploring this possibility and various
mechanistic aspects of the cyclisation reaction.
Acknowledgements
We are grateful to the EPSRC for their financial support of this
work, and we thank Val Boote and Steve Kelly for assistance with
MS and NMR measurements. We also wish to acknowledge the
use of the EPSRC’s Chemical Database Service at Daresbury.35
Supplementary data
X-ray crystallographic data for 23b. Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.04.114.
References and notes
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ring closure27 and the stereoselection is assumed to be conforma-
tionally driven. The pathways linking the radical 29 with the final
product 23a are open to speculation. Lauroyl peroxide can partici-
pate in one-electron oxidations34 and the cation 30 is presumed to
be the immediate precursor of the alkene 23a, but it is unclear
whether the laurate ester 33 is involved. Lauric acid 32 was also
identified among the by-products of the reaction by 1H NMR
spectroscopy.
In summary, the tetracyclic nucleus of puupehenone, 15-
oxopuupehenol and related sesquiterpene–phenol natural prod-
ucts can be assembled stereoselectively in three steps, the last of
these being the peroxide-induced 6-endo-trig cyclisation of an
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a substituted 2-(2-cyclo-
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hexenyl)ethyl 3-bromo-4-chromanone. The cyclisation process is
terminated oxidatively with the formation of an olefinic bond,
which should render the tetracyclic system amenable to further
22a
23a
CO2
heat
R
RCO2
(RCO2)2
R =
n
-C11H23
RCO2H
26
25
24
32
RBr
RCO2
27
31
RCO2
31
O
O
O
O
6-endo-trig
O
O
O
O
H
H
H
(RCO2)2 RCO2
OCOR
24
25
28
29
30
33
Scheme 2. A possible mechanistic rationale for the formation of 23a from the bromoketone 22a.

R. G. Pritchard et al. / Tetrahedron Letters 49 (2008) 4156–4159
4159
14. (a) Fenical, W.; McConnell, O. Experientia 1975, 31, 1004–1005; (b) Cimino, G.;
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J 16.5 Hz, 3-H), 2.15–2.02 (2H, m, 400-H2), 1.90–1.78 (3H, m, 10-H and 300-H2),
1.74–1.61 (1H, m, 10-H), 1.55–1.47 (2H, m, 20-H2), 1.46 (3H, s, 200-Me), 1.42 (3H,
s, 2-Me), 1.40–1.32 (2H, m, 500-H2), 0.94 (3H, s, 600-Me), 0.87 (3H, s, 600-Me); Rf
0.52 (hexane–EtOAc, 7:3). Compound 22a, yellow oil; mmax/cmꢀ1 (CHCl3) 1704;
dH (400 MHz, CDCl3) (major isomer) 7.89 (1H, dd, J 1.7, 7.8 Hz, 5-H), 7.53 (1H,
ddd, J 1.7, 7.2, 8.3 Hz, 7-H), 7.10–6.95 (2H, m, 6-H, 8-H), 4.46 (1H, s, 3-H), 2.24–
1.78 (4H, m, 20-H2, 300-H2), 1.70–1.30 (6H, m, 10-H2, 400-CH2, 500-CH2), 1.61 (3H, s,
200-Me), 1.33 (3H, s, 2-Me), 0.91 (3H, s, 600-Me), 0.76 (3H, s, 600-Me); (minor
isomer) 4.42 (1H, s, 3-H), 1.61 (3H, s, 200-Me), 1.54 (3H, s, 2-Me), 1.02 (3H, s, 600-
Me), 0.96 (3H, s, 600-Me); Rf 0.48, 0.41 (hexane–EtOAc, 5:1). Compound 22b,
dark yellow oil; mmax/cmꢀ1 (CHCl3) 1680; dH (400 MHz, CDCl3) (major isomer)
7.28 (1H, s, 5-H), 6.47 (1H, s, 8-H), 4.39 (1H, s, 3-H), 3.92 (3H, s, OMe), 3.88 (3H,
s, OMe), 2.20–1.75 (4H, m, 20-H2, 300-H2), 1.65–1.20 (6H, m, 10-H2, 400-CH2, 500-
CH2), 1.61 (3H, s, 200-Me), 1.35 (3H, s, 2-Me), 0.91 (3H, s, 600-Me), 0.79 (3H, s, 600-
Me);(minor isomer) 6.44 (1H, s, 8-H), 4.35 (1H, s, 3-H), 1.61 (3H, s, 200-Me), 1.54
(3H, s, 2-Me), 1.04 (3H, s, 600-Me), 0.99 (3H, s, 600-Me); Rf 0.26, 0.21 (hexane–
EtOAc, 3:1). Compound 23a, pale yellow waxy oil (MH+, 311.2016; C21H27O2
requires 311.2011); mmax/cmꢀ1 (CHCl3) 1680; dH (300 MHz, CDCl3) 7.86 (1H, dd,
J 1.7, 7.8 Hz, 5-H), 7.43 (1H, ddd, J 1.7, 7.1, 8.3 Hz, 7-H), 6.95 (1H, apparent t, J
ca. 7.5 Hz, 6-H), 6.87 (1H, d, J 8.3 Hz, 8-H), 5.57 (1H, t, J 3.8 Hz, 5-H), 2.72 (1H,
dd, J 3.8, 19.7 Hz, 6-H), 2.47 (1H, dd, J 3.8, 19.7 Hz, 6-H), 2.19 (1H, s, 12a-H),
1.80–1.25 (6H, m, 1-CH2, 2-CH2, 3-CH2), 1.34 (3H, s, 6a-Me), 1.14 (3H, s, 4-Me),
1.12 (3H, s, 4-Me), 1.01 (3H, s, 12b-Me); Rf 0.23 (hexane–EtOAc, 3:1).
Compound 23b, mp 165–166 °C (EtOH) (MH+, 371.2213; C23H31O4 requires
371.2222); mmax/cmꢀ1 (CHCl3) 1674; dH (400 MHz, CDCl3) 7.28 (1H, s, 11-H),
6.37 (1H, s, 8-H), 5.56 (1H, t, J 3.8 Hz, 5-H), 3.89 (6H, br s, 2 x OMe), 2.68 (1H,
dd, J 3.8, 19.7 Hz, 6-H), 2.47 (1H, dd, J 3.8, 19.7 Hz, 6-H), 2.13 (1H, s, 12a-H),
1.80–1.25 (6H, m, 1-CH2, 2-CH2, 3-CH2), 1.36 (3H, s, 6a-Me), 1.14 (3H, s, 4-Me),
1.12 (3H, s, 4-Me), 1.02 (3H, s, 12b-Me); Rf 0.27 (hexane–EtOAc, 3:1).
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31. Procedure for the formation of 23b: A solution of the bromoketone 22b (0.520 g,
1.15 mmol) in dry degassed 1,2-dichloroethane (12 mL) was heated to reflux
for 15 min.
A
solution of dilauroyl peroxide (0.921 g, 2.31 mmol) in dry
pressure-
degassed 1,2-dichloroethane (7 mL) was added dropwise via
a
equalising dropping funnel to the refluxing solution over 2.75 h. After the
completion of the addition, heating was continued overnight (18.5 h). The
reaction mixture was cooled to room temperature and filtered through a pad of
basic alumina (5 mm) on top of a pad of silica (20 mm), which was washed
successively with EtOAc–hexane (3:1, 80 mL) and dichloromethane (150 mL).
The combined filtrate was concentrated in vacuo and purified by flash column
chromatography (EtOAc–hexane, 1:9), which gave recovered bromoketone 22b
(0.070 g, 13%) and the title compound 23b (0.287 g, 67%, 78% based on
recovered 22b) as a white solid.
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126, 11122–11123.
32. Crystal data for 23b: Colourless crystals from EtOH, C23H30O4, M = 370.47,
orthorhombic,
a = 7.5154(2),
b = 14.0755(5),
c = 18.5551(6) Å,
U =
1662.81(11) Å3, T = 293(2) K, space group
P
21 21 21, Z = 4, Dc = 1.254
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Org. Chem. 2006, 4115–4127.
27. Crombie, B. S.; Smith, C.; Varnavas, C. Z.; Wallace, T. W. J. Chem. Soc., Perkin
Trans. 1 2001, 206–215.
Mg mꢀ3, k (MoKa) = 0.71073 Å, l = 0.084 mmꢀ1, 14565 reflections measured,
2197 unique (Rint = 0.0874), which were used in all calculations. The final
wR(F2) was 0.0907 (all data). Crystallographic data (excluding structure
factors) for 23b have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 679032. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44-1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk).
28. Method: Kabbe, H.-J.; Widdig, A. Angew. Chem., Int. Ed. Engl. 1982, 21, 247–256.
29. Selected data: 21a, tan oil (MH+, 313.2177; C21H29O2 requires 313.2168); mmax
/
cmꢀ1 (CHCl3) 1684; dH (400 MHz, CDCl3) 7.85 (1H, dd, J 1.7, 8.0 Hz, 5-H), 7.46
(1H, ddd, J 1.7, 7.0, 8.0 Hz, 7-H), 6.96 (1H, apparent t, J ca. 7.5 Hz, 6-H), 6.95 (1H,
d, J 8.0 Hz, 8-H), 2.79 (1H, d, J 16.4 Hz, 3-H), 2.72 (1H, d, J 16.4 Hz, 3-H), 2.20–
2.07 (2H, m, 400-H2), 1.91–1.82 (3H, m, 10-H and 300-H2), 1.76–1.67 (1H, m, 10-H),
1.58–1.50 (2H, m, 20-H2), 1.47 (3H, s, 200-Me), 1.465 (3H, s, 2-Me), 1.40–1.35
(2H, m, 500-H2), 0.97 (3H, s, 600-Me), 0.88 (3H, s, 600-Me); Rf 0.56 (hexane–EtOAc,
3:1). Compound 21b, tan oil (MH+, 373.2388; C23H33O4 requires 373.2379);
mmax/cmꢀ1 (CHCl3) 1673; dH (300 MHz, CDCl3) 7.23 (1H, s, 5-H), 6.39 (1H, s, 8-
H), 3.88 (3H, s, OMe), 3.84 (3H, s, OMe), 2.71 (1H, d, J 16.5 Hz, 3-H), 2.62 (1H, d,
33. (a) Ollivier, C.; Bark, T.; Renaud, P. Synthesis 2000, 1598–1602; (b) Kolly-Kovac,
T.; Renaud, P. Synthesis 2005, 1459–1466.
34. (a) Coppa, F.; Fontana, F.; Minisci, F.; Pianese, G.; Tortoreto, P.; Zhao, L.
Tetrahedron Lett. 1992, 33, 687–690; (b) Gagosz, F.; Moutrille, C.; Zard, S. Z. Org.
Lett. 2002, 4, 2707–2709; (c) Alajarín, M.; Vidal, A.; Ortín, M.-M. Org. Biomol.
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35. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comput. Sci. 1996, 36,
746–749.