Structure and total synthesis of benzylthiocrellidone, a novel dimedone-based vinyl sulfide from the sponge Crella spinulata

Article abstract of DOI:10.1039/a901323g

A concise synthesis of the yellow pigment benzylthiocrellidone 1, based on a Michael addition-elimination of dimedone 2 to the ketene thioacetal 7 derived from dimedone, benzyl bromide and carbon disulfide, is described. The synthetic pigment had an X-ray

Full text of DOI:10.1039/a901323g

View Article Online / Journal Homepage / Table of Contents for this issue
Structure and total synthesis of benzylthiocrellidone, a novel
dimedone-based vinyl sulfide from the sponge Crella spinulata
Hon Wai Lam,a Paul A. Cooke,a Gerald Pattenden,*a Wickramasinghe M. Bandaranayakeb
and Wasantha A. Wickramasingheb
a School of Chemistry, Nottingham University, Nottingham, UK NG7 2RD
b Australian Institute of Marine Science, PMB No.3, Cape Ferguson, Townsville,
Queensland 4810, Australia
Received (in Cambridge) 17th February 1999, Accepted 17th March 1999
A concise synthesis of the yellow pigment benzylthio-
crellidone 1, based on a Michael addition–elimination of
dimedone 2 to the ketene thioacetal 7 derived from
dimedone, benzyl bromide and carbon disulfide, is
described. The synthetic pigment had an X-ray crystal
structure identical to that measured for the natural
product.
Benzylthiocrellidone is the name given to a novel and
unprecedented sulfur-containing yellow pigment isolated from
the brightly red coloured sponge Crella spinulata found on the
Great Barrier Reef in Australia.1 The molecule has a structure,
viz. 1, based on two dimedone (5,5-dimethylcyclohexane-1,3-
O
S
OH
Fig. 1
O O
1
O
O
CHO
O
dione) rings linked via a benzylthio methylidene bridge at their
C-2 positions. Benzylthiocrellidone is the first recorded example
of a natural product containing a dimedone (or dimedone
methane) unit.2 The natural product exhibits strong absorption
O
3
2
in both the ultraviolet A (λmax 345 nm; ε 18 500 dm3 molϪ1 cmϪ1
)
and ultraviolet B (λmax 295 nm; ε 16 000 dm3 molϪ1 cmϪ1) regions
which may indicate a biological role in providing protection for
the sponge from the deleterious effects of ultraviolet radiation.
The structure of benzylthiocrellidone followed from extensive
analysis of its spectroscopic properties in conjunction with an
X-ray crystal structure determination (Fig. 1).1 In pursuance of
our interests in the synthesis of novel heteroatom containing
natural products of biological significance from marine organ-
isms, we now describe a short and concise total synthesis of
benzylthiocrellidone.
We examined two conceptually similar synthetic approaches
to the structure 1, both using dimedone 2 and benzyl derivatives
as starting materials, but differing in the source of the one
carbon unit making up the methylidene residue joining the two
dimedone rings to the benzylthio moiety. Thus, formylation of
dimedone 2, using ethyl orthoformate in the presence of acetic
anhydride, first led to the known 2-formyl derivative 33 which
was next reacted with a second equivalent of dimedone under
acid catalysis4 in the presence of phenylmethanethiol pro-
ducing the symmetrical adduct 4 in 43% yield; the by-product
from this reaction was the vinyl sulfide 5 (34% yield). In spite of
several attempts however, using a range of reagents (e.g. DDQ,
MnO2, NBS), we were unable to selectively oxidise the adduct 4
to the target molecule 1. The only interesting product to emerge
from this particular study was the formation of the pyran 6
OH
S
OH
O
S
O
O O
5
4
O
S
O
O
6
(37% yield) following treatment of 4 with DDQ in CH2Cl2 at
room temperature for 12 h.
We next turned to an examination of the synthesis of the
J. Chem. Soc., Perkin Trans. 1, 1999, 847–848
847

View Article Online
2 For the dimedone–formaldehyde reaction see: (a) E. C. Horning and
M. G. Horning, J. Org. Chem., 1946, 11, 95. For an example of a
naturally occurring prenylated cyclohexane-1,3-dione see: (b) H.
Obara, J. Onodera, Y. Machida and S. Yada, Bull. Chem. Soc. Jpn.,
1989, 62, 3034; (c) M. R. Cann, A. Davis and P. V. R. Shannon,
J. Chem. Soc., Perkin Trans. 1, 1982, 375.
O
S
3 B. D. Akehurst and J. R. Bartels-Keith, J. Chem. Soc., 1957, 4798.
4 K. Fuchs and L. A. Paquette, J. Org. Chem., 1994, 59, 528.
5 (a) A. Z.-Q. Khan and J. Sandström, J. Chem. Soc., Perkin Trans. 1,
1988, 2085; (b) D. Villemin and A. B. Alloum, Synthesis, 1991, 301.
We produced 7 from dimedone using the literature procedure in an
unoptimised 20% yield.
S
2
2
1
O
7
6 Synthetic benzylthiocrellidone was prepared from dimedone and the
ketene dithioacetal 7 as follows: potassium tert-butoxide (42 mg,
0.36 mmol) was added in one portion to a solution of dimedone
(51 mg, 0.36 mmol) in THF (5 ml) and the mixture was then stirred
at room temperature for 30 min. A solution of the ketene dithioacetal
7 (140 mg, 0.35 mmol) in THF (2 ml) was added dropwise over 10
min and the mixture was then left to stir overnight. Ether (10 ml) was
added, and the mixture was extracted with water (2 × 10 ml). The
combined aqueous extracts were acidified with 1 M HCl and the
precipitated yellow solid was collected by filtration. Recrystallisation
from methanol gave benzylthiocrellidone (87 mg, 60%) as yellow crys-
tals, mp 202–204 ЊC; νmax(Nujol)/cmϪ1 2921, 2853, 1687, 1640, 1604,
1461, 1375, 1328; δH(360 MHz, CDCl3), 1.13 (12H, s, 4 × Me), 2.47
(8H, s, 4 × CH2), 3.81 (2H, s, SCH2Ph), 7.25–7.34 (5H, m, C6H5);
δC(90 MHz, d6-DMSO), 28.4 (q), 39.0 (t), 127.7 (d), 128.9 (d), 129.5
(d), 136.6 (s), 171.8 (s) (some peaks not evident due to tautomeric
exchange); m/z (Electrospray) 413.1754, C24H29O4S (MHϩ) requires
413.1787.
ketene thioacetal 7 and the substitution of one of the benzyl-
thio units in 7 with dimedone via a Michael addition–
elimination sequence. The ketene thioacetal 7 is actually a
known compound5a that can be produced when dimedone is
treated with carbon disulfide and benzyl bromide using fluoride
ion as base on an inorganic support of alumina.5b When we
added this ketene thioacetal 7 to the potassium enolate of
dimedone in THF at 25 ЊC, work up and crystallisation gave the
product 1 in 60% yield, as bright yellow crystals, mp 202–
204 ЊC, which showed identical chromatographic behaviour and
spectroscopic data to those of naturally derived benzylthio-
crellidone, mp 211 ЊC.6,7 Further studies are now in progress
to synthesise structures similar to natural 1, with modified
chromophores, and to evaluate their ultraviolet absorbing
properties for potential applications in skin care products.
7 The X-ray structure for synthetic benzylthiocrellidone, shown in
Fig. 1, was identical to the X-ray crystal structure measured for the
natural product isolated from Crella spinulata.1 A crystal of 1 was
encapsulated in a film of RS3000 perfluoropolyether oil and mounted
on a glass fibre before transfer to the diffractometer.
Crystal data. C24H28O4S, M = 412.52, monoclinic, a = 5.939(4),
b = 14.950(7), c = 11.748(7) Å, β = 91.14(6)Њ, U = 1042.9(11) Å3, T =
150(2) K, space group P21 (No. 4), Z = 2, Dc = 1.314 g cmϪ3, µ(Mo-
Kα) = 0.183 mmϪ1, 3195 unique reflections measured and used in all
calculations. Final R1[2171 F ≥ 4σ(F)] = 0.0988 and wR (all F2) was
0.244. CCDC reference number 207/312. See http://www.rsc.org/
suppdata/p1/1999/847 for crystallographic files in .cif format.
Acknowledgements
We thank the EPSRC for a studentship (to H.W.L.) and the
Royal Society of Chemistry for a travel grant (to W.M.B.). We
also thank the Australian Institute of Marine Science for leave
of absence to W. M. B. during his sabbatical stay in Nottingham
during June–September 1998, and Dr A. J. Blake for collabor-
ation with the X-ray crystal structure determination of syn-
thetic benzylthiocrellidone.
Notes and references
1 W. M. Bandaranayake and W. A. Wickramasinghe, Australian
Institute of Marine Science Report, 1995, No. 23 (27 pp.).
Communication 9/01323G
848
J. Chem. Soc., Perkin Trans. 1, 1999, 847–848