Synthesis of (±)-aculeatins A and B

Article abstract of DOI:10.1039/b200740a

The first synthesis of two new antiprotozoal and natural products was performed using concomitant deprotecting dithiane-phenolic oxidative reactions to form in one-step the 1,7-dioxadispiro [5.1.5.2]pentadecane core.

Full text of DOI:10.1039/b200740a

Synthesis of ( )-aculeatins A and B
Yung-Sing Wong
Laboratoire de Transformations et Synthèse de Substances Naturelles, Faculté de Pharmacie de Reims
Champagne-Ardenne, UMR CNRS 6013, 51, rue Cognac-Jay, F-51096 Reims, France.
E-mail: ys.wong@univ-reims.fr; Fax: +33 3 26 91 80 29; Tel: +33 3 26 91 81 84
Received (in Cambridge, UK) 21st January 2002, Accepted 15th February 2002
First published as an Advance Article on the web 4th March 2002
The first synthesis of two new antiprotozoal and natural
products was performed using concomitant deprotecting
dithiane–phenolic oxidative reactions to form in one-step the
1,7-dioxadispiro[5.1.5.2]pentadecane core.
transformation into ( ) aculeatins A and B along two concomi-
tant PIFA reactions. Furthermore, the opportunity to keep a
ketone protected by a 1,3-dithiane group until its removal at the
final key step simplified the overall synthetic approach.
Starting from commercially available 4-hydroxyphenyl pro-
pionic acid 2, the corresponding b-ketoester 3 was readily
obtained according to Doherty’s procedure.10 Deprotection of
the phenol followed by protection of the ketone gave the b-
1,3-dithiane ester 4 in 88% yield. Selective reduction was
carried out using DIBAL-H to form the aldehyde 5 (73%).
Concurrently, the synthesis of the silyl enol ether 6 was
achieved in three steps from commercially available myristoyl
chloride. The aldol reaction between aldehyde 5 and silyl enol
ether 6 furnished under BF3·Et2O catalysis the b-hydroxy
ketone rac-7 in 68% yield. Highly diastereoselective reduction
using sodium borohydride–triethylborane in THF–MeOH (4+1)
at 280 °C11 provided the syn 1,3-diol rac-8 in moderate yield
(63%).12 Finally, as expected, syn 1,3-diol rac-8 was readily
converted with 2.5 equivalents of PIFA in MeCN–H2O (6+1) at
0 °C for 5 min into ( )-aculeatins A and B in isolated yields of
44% and 15%, respectively.13 All our spectroscopical data are
in agreement with those reported previously.1 It is noteworthy
that no protection was required for the remaining hydroxy
group. During the intramolecular cyclisations, the construction
In 2000 Heilmann and co-workers disclosed the isolation and
structures of aculeatins (Fig. 1), a novel biologically active
group, from Amomum Aculeatum rhizomes.1,2 Aculeatins A, B,
and D appear to be potent antiprotozoal agents. Aculeatin D
displays in addition some antibacterial activities. Interestingly,
these compounds hold a unique dispiro skeleton including a
spiroketal ring system connected with a cyclohexadienone
moiety. Spiro or bis-spiro-ketal structures have attracted
growing attention with respect to their generation within
molecular edifices of biological importance such as polyether
ionophores.3
Fig. 1 Relative configurations of aculeatins A, B, and D.
Considering that aculeatins A and B are spiro epimers, a
concise synthetic approach to their 1,7-dioxadispiro-
[5.1.5.2]pentadecane skeleton4 should arise from the bio-
synthetic proposal (Scheme 1) involving two intramolecular
cyclisations initiated by a phenolic oxidation of the plausible
bioprecursor 1. In connection with recent efforts to obtain new
cyclohexadienone derivatives,5 we became aware that phenyl-
iodonium(III) bis(trifluoroacetate) (PIFA) can prove in this case
to be the reagent of choice since it has been commonly used to
perform phenolic oxidations6 and also deprotection of dithiane
groups7 among other useful transformations.8 Uenishi and co-
workers have described the use of PIFA for simultaneous
activations of ethyl enol ether and deprotection of 1,3-dithiane
to form substituted cyclohexenones.9
In this context, we wish to report our results on the
preparation of the intermediate rac-8 (Scheme 2) and its direct
Scheme 2 Reagents and conditions: i, H2, 10% Pd/C, EtOAc then propane-
1,3-dithiol, BF3·Et2O, CH2Cl2, 25 °C, 88%; ii, DIBAL-H, toluene, 280 °C,
73%; iii, BF3·Et2O, CH2Cl2, 25 °C, 68%; iv, Et3B, NaBH4, THF–MeOH
(4:1), 280 °C, 63%; v, PIFA, MeCN–H2O (6+1), 0 °C, 5 min.
Scheme 1 Plausible synthetic pathway for the formation of aculeatins A and
B from precursor 1.
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CHEM. COMMUN., 2002, 686–687
This journal is © The Royal Society of Chemistry 2002

5 M.-E. Trân-Huu-Dâu, R. Wartchow, E. Winterfeldt and Y.-S. Wong,
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of the spiro epimer aculeatin A was favoured in a ratio of 3+1
compared to aculeatin B.
Thus, the first and concise total synthesis of ( )-aculeatins A
and B have been achieved using a one-step assembling process
activated by PIFA. This short synthetic route finds some
applications as many racemic analogues should be readily
obtained by simply changing the enol ethers during the aldol
condensation with the aldehyde 5. Moreover, the cyclohex-
adienone moiety also offers the potential to make various
transformations. We are currently investigating the synthesis of
the syn 1,3-diol 8 in optically pure form therefore allowing the
assignment of the aculeatins A and B with their absolute
configurations. The synthesis of aculeatins C1 and D are also
now under way. All these synthetic results will be reported in
due course.
9 J. Uenishi, Y. Kawachi and S. Wakabayashi, Chem. Commun., 1990,
1033.
10 D. G. Doherty, J. Am. Chem. Soc., 1955, 77, 4887.
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Corley and T. M. H. Liu, Tetrahedron Lett., 1985, 26, 2951.
12 The ratio of syn/anti 1,3-diol rac-8 was 97+3 determined by HPLC.
13 The syn 1,3-diol rac-8 (90 mg, 0.17 mmol) diluted in a stirred solution
of MeCN+H2O (6+1, 2 mL) was cooled with an ice bath and PIFA (190
mg, 0.44 mmol) was then added in one portion. After 10 s, the colourless
mixture changed to a clear yellow coloration. After 5 min, a saturated
aqueous solution of NaHCO3 (5 mL) was added at 0 °C and the products
were extracted with EtOAc (3 3 10 mL). The organic layer was dried
(MgSO4) and after evaporation the mixture was separated by flash
chromatography on silica gel (Eluent: AcOEt–cyclohexane) to give
aculeatin A (33 mg, 44%) and aculeatin B (11 mg, 15%).
Notes and references
1 J. Heilmann, S. Mayr, R. Brun, T. Rali and O. Sticher, Helv. Chim. Acta,
2000, 83, 2939.
2 J. Heilmann, R. Brun, S. Mayr, T. Rali and O. Stricher, Phytochemistry,
2001, 57, 1281.
3 For reviews on their synthesis: F. Perron and K. F. Albizati, Chem. Rev.,
1989, 89, 1617; M. Brimble and F. A. Farès, Tetrahedron, 1999, 55,
7661.
4 A previous synthesis of such a skeleton with a saturated six-membered
alkyl ring was reported: R. Whitby and P. Kocienski, Tetrahedron Lett.,
1987, 28, 3619; P. Kocienski and R. Whitby, Synthesis, 1991, 1029.
CHEM. COMMUN., 2002, 686–687
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