Published on Web 08/12/2009
Concise Syntheses of the Natural Products (+)-Sylvaticin and
(+)-cis-Sylvaticin
Timothy J. Donohoe,*,§ Robert M. Harris,§ Oliver Williams,§ Gra´inne C. Hargaden,§
Jeremy Burrows,† and Jeremy Parker‡
AstraZeneca Pharmaceuticals, Department of Medicinal Chemistry R&D, So¨derta¨lje,
S-151 85, Sweden, AstraZeneca, Process R&D AVlon/Charnwood, AVlon Works, SeVern Road,
Hallen, Bristol, BS10 7ZE, U.K., and Department of Chemistry, UniVersity of Oxford, Chemistry
Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K.
Received June 18, 2009; E-mail: timothy.donohoe@chem.ox.ac.uk
Abstract: Two concise syntheses of the natural products cis-sylvaticin and sylvaticin are reported, using
oxidative cyclization methodology as the key step. A sequential solvolysis/hydride shift/intramolecular
reduction cascade was used to establish the trans stereochemistry of one of the THF rings of sylvaticin.
Scheme 1
Introduction
Sylvaticin and its C-12 epimer cis-sylvaticin belong to the
nonadjacent bis-THF subclass of the annonaceous acetogenins.
Sylvaticin was isolated by McLaughlin in 1990 from the dried
fruits of Rollinia sylVatica St. Hil. (Annonaceae).1 Subsequent
isolations were reported in 1993 from Annona purpurea and in
1995 when it was isolated from leaf extracts of Rollinia mucosa
(Jacq.) Baill. together with cis-sylvaticin, bullatalicin, and
muricatetrocin B.2,3 Both cis-sylvaticin and the parent sylvaticin
display potent activity as antitumor agents and exhibit nanomolar
cytotoxicity toward certain human solid tumor cell lines (human
lung carcinoma and human pancreas carcinoma). Their mode
of action is thought to include the inhibition of ATP production
Via the blockage of mitochondrial complex I. The biosynthesis
of these acetogenins is thought to start from a long chain fatty
acid with the terminal γ-lactone functionality initially formed
with the nonadjacent bis-THF core then generated by oxidation
of the unsaturated units present followed by a series of ring-
opening and closing reactions.4
Scheme 2
Both natural products 1 and 2 contain two nonadjacent THF
rings, with sylvaticin bearing the only trans-ring. One THF is
flanked on either side by a hydroxyl group and an alkyl chain,
and the second is flanked by one hydroxyl group and an alkyl
chain ending in a γ-lactone functionality with a hydroxyl group
at the C-4 position (see Scheme 3 for numbering). At the outset
of this work, the structures of 1 and 2 had not been verified by
total synthesis, although the group of McLaughlin had performed
an extremely thorough analysis of both compounds in the
original isolation paper.3 McLaughlin had also shown the precise
positions of the two THF rings (and the hydroxyl groups) by
EIMS of the natural products and their TMS derivatives. The
relative and absolute stereochemistry was determined by various
NMR techniques developed for these acetogenins and included
a full analysis of their di- and tetra-Mosher ester derivatives,
and the structures were finally assigned as shown in Scheme 1.
Previous work in our group culminated in the first synthesis
of (+)-cis-sylvaticin in 2006;5 with Brown and co-workers
subsequently reporting a synthesis of this natural product in
† AstraZeneca Pharmaceuticals.
‡ AstraZeneca, Process R&D.
§ University of Oxford.
(1) Mikolajczak, K. J.; Madrigal, R. V.; Rupprecht, J. K.; Hui, Y. H.;
Liu, Y. M.; Smith, D. L.; McLaughlin, J. L. Experentia 1990, 46,
324.
(2) Felicitas Cepleanu, K. O.; Hamburger, M.; Hostettmann, K.; Gupta,
M. P.; Solis, P. HelV. Chim. Acta 1993, 76, 1379.
(3) Shi, G.; Zeng, L.; Gu, Z.; MacDougal, J. M.; McLaughlin, J. L.
Heterocycles 1995, 41, 1785.
(4) For a review see (a) Bermejo, A.; Figade´re, B.; Zafra-Polo, M.-C.;
Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269.
(b) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1992, 62,
504. (c) Rupprecht, J. K.; Hui, Y. H.; McLaughlin, J. L. J. Nat. Prod.
1990, 53, 237. (d) Saez, J.; Sahpaz, S.; Villaescusa, L.; Hocquemiller,
R.; Cave´, A.; Cortes, D. J. Nat. Prod. 1993, 56, 351. (e) Zafra-Polo,
M. C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochem-
istry 1998, 48, 1087. (f) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.;
Gu, Z. M.; He, K.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275.
(5) Donohoe, T. J.; Harris, R. M.; Burrows, J.; Parker, J. J. Am. Chem.
Soc. 2006, 128, 13704.
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12854 J. AM. CHEM. SOC. 2009, 131, 12854–12861
10.1021/ja9049959 CCC: $40.75 2009 American Chemical Society