A concise total synthesis of (±)-anthecularin

Article abstract of DOI:10.1039/b819454h

A total synthesis of the novel sesquiterpene anthecularin 1, isolated from Greek Anthemis auriculata, based on an intramolecular [5+2] (1,3-dipolar) cycloaddition involving the oxidopyrylium ion 12 derived from the furanmethanol 9, is described.

Full text of DOI:10.1039/b819454h

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A concise total synthesis of ( )-anthecularin†
Yi Li, Christopher C. Nawrat, Gerald Pattenden* and Johan M. Winne
Received 4th November 2008, Accepted 4th December 2008
First published as an Advance Article on the web 19th December 2008
DOI: 10.1039/b819454h
A total synthesis of the novel sesquiterpene anthecularin 1,
isolated from Greek Anthemis auriculata, based on an in-
tramolecular [5+2] (1,3-dipolar) cycloaddition involving the
oxidopyrylium ion 12 derived from the furanmethanol 9, is
described.
quaternary carbon centres. The origin of the “non-regular” C15–
terpenoid carbon framework in anthecularin is not immediately
obvious. However, the isolation of the substituted lactone 2 as a
co-metabolite in A. auriculata3 had led to the proposal that the
cyclohexene ring in anthecularin is derived from 2 in vivo by way
of an intramolecular Diels–Alder reaction involving the methylene
lactone unit in 2 as a key step.1 In this paper we describe a
conceptually distinct synthetic approach to anthecularin, whereby
the entire carbon framework is elaborated in one step, from the
acetoxypyranone-substituted butenolide 11 using an intramolec-
ular [5+2] (or 1,3-dipolar) cycloaddition process4,5 involving the
oxidopyrylium ion 12.6
Anthecularin 1 is a new and unusual sesquiterpene which was
recently isolated from Anthemis auriculata.1 Interestingly, anthecu-
larin originates from the same family of plants, i.e. Asteraceae, that
produce the well-known anti-malarial compound artimisinin.2
Indeed, anthecularin does exhibit anti-malarial activity, but the
level is low in comparison with artimisinin. Anthecularin inhibits
two of the key enzymes of the plasmodium fatty acid synthase
enzyme complex, which has suggested that the natural product
could be a valuable lead compound for the design of new
antimalarial drugs.1
The compact tetracyclic structure of anthecularin 1 accom-
modates a core oxabicyclo [3.2.1] octane ring system which is
fused to a cyclohexene and to a butyrolactone via two contiguous
Thus, treatment of the known alcohol 3a7 containing a terminal
Z-alkenyliodide with iodine–triphenylphosphine first gave the cor-
responding di-iodide 3b in 85% yield (Scheme 1). Deprotonation of
2-phenylthiobutyrolactone 4, using LDA–HMPA at 0 ◦C, followed
by alkylation of the resulting enolate with the di-iodide 3b next
gave the adduct 5, whose formation was accompanied by the
School of Chemistry, The University of Nottingham, University Park,
Nottingham, England NG7 2RD. E-mail: gp@nottingham.co.uk; Tel: +44
115 951 3530
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra for compounds 1, 8 and 13. CCDC reference number 707835. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/b819454h
Scheme 1 Reagents and conditions: (i) Ph3P, I2, THF/CH3CN, rt, 85%; (ii) LDA, HMPA, THF, 0 ◦C to rt, 23%; (iii) m-CPBA, CH2Cl2, 0 ◦C, 30 min,
then toluene, reflux, 2 h, 91%; (iv) Pd(OAc)2, CuI, AsPh3, DMF, rt, 2 h, 85%; (v) NaBH4, MeOH, -10 ◦C, 30 min, 99%; (vi) m-CPBA, CH2Cl2, -20 ◦C,
1 h; (vii) Ac2O, pyridine, DMAP(cat.), CH2Cl2, 0 ◦C to rt, 51% over two steps.
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product of dehydroiodination of 3b. Oxidation of the phenylsulfide
5, using m-CPBA at 0 ◦C, followed by dehydrosulfinylation of
the resulting sulfoxide in refluxing toluene then produced the
substituted butenolide 6 in 91% yield over the two steps.
A Stille coupling reaction between the Z-alkenyliodide 6
and 3-methyl-5-trimethylstannylfurfural 7,8 using Pd(OAc)2, CuI,
and Ph3As in DMF at room temperature, gave the substituted
Z-vinylfuran 8 in 85% yield. Reduction of the furfural 8, using
NaBH4 in MeOH at -10 ◦C, next led to the corresponding
furanmethanol 9 (99%). Treatment of the furanmethanol 9 with
m-CPBA in CH2Cl2 at -20 ◦C resulted in oxidative cleavage of
the furan ring and simultaneous tautomerisation, producing the
hydroxypyranone 10. The hydroxypyranone 10 was then treated
with Ac2O–DMAP leading to the corresponding stable acetate 11
in 51% yield over the two steps.
When a solution of the acetoxypyranone 11 in toluene con-
taining DBU was heated under reflux for 1 h, the anticipated
intramolecular [5+2] (1,3-dipolar) cycloaddition involving the
oxidopyrylium ion intermediate 12 took place, leading to the
crystalline tetracyclic product 13 in 15–20% yield (Scheme 2).9 The
tetracycle displayed 1H and 13C NMR data which were consistent
with the structural assignment, i.e. 13, and its relative stereochem-
istry was confirmed by X-ray crystallography (Fig. 1).†10
Fig. 1 X-ray structure of 13.
AlBN followed by chromatography gave ( )-anthecularin 1 in 65%
yield.11 The synthetic anthecularin showed 1H and 13C NMR
spectra which were superimposable on those recorded for the
natural product isolated from Anthemis auriculata.
In summary, a concise and convergent 10 step synthesis of
anthecularin 1, from readily available starting materials, has
been achieved using an intramolecular oxidopyrylium ion–alkene
cycloaddition involving the species 12 as a key step.
Acknowledgements
We thank the EPSRC (Fellowship to J.M.W.) and AstraZeneca
together with Merck (support to Y.L.) for funding towards this
project.
Notes and references
1 A. Karioti, H. Skaltsa, A. Linden, R. Perozzo, R. Brun and
D. Tasdemir, J. Org. Chem., 2007, 72, 8103–8106.
2 For a recent overview, see: M. Schlitzer, Arch. Pharm. Chem. Life Sci.,
2008, 341, 149–163.
3 R. Theodori, A. Karioti, A. Rancˇic´ and H. Skaltsa, J. Nat. Prod., 2006,
69, 662–664.
4 (a) For some earlier examples of the use of intramolecular
oxidopyrylium–alkene cycloaddition reactions in the synthesis of
natural products, see: S. M. Bromidge, P. G. Sammes and L. J. Street,
J. Chem. Soc., Perkin Trans. I, 1985, 1725–1730; (b) P. Wender, K. D.
Rice and M. E. Schnute, J. Am. Chem. Soc., 1997, 119, 7897–7898, and
references therein; (c) P. Magnus and L. Shen, Tetrahedron, 1999, 55,
3553–3560.
5 For a recent review of cycloaddition reactions involving oxidopyrylium
species in synthesis, see: V. Singh, U. M. Krishna Vikrant and G. K.
Trivedi, Tetrahedron, 2008, 64, 3405–3428.
6 For some of our contemporaneous studies and those of others, see:
B. Tang, C. D. Bray and G. Pattenden, Tetrahedron Lett., 2006, 47,
6401–6404; P. A. Roethle, P. T. Hernandez and D. Trauner, Org. Lett.,
2006, 8, 5901–5904.
7 S. Ma and E.-i. Negishi, J. Org. Chem., 1997, 62, 784–785.
8 P. A. Roethle and D. Trauner, Org. Lett., 2006, 8, 345–347, see also:
F. Roschangar, J. C. Brown, B. E. Cooley, M. J. Sharp and R. T.
Matsuoka, Tetrahedron, 2002, 58, 1657–1666.
9 The yield of 15–20% is not optimised, and is consistent with the yields
recorded for similar cycloaddition reactions involving oxidopyrylium
ions and but-2-enolides; see reference 6.
10 We thank Dr. William Lewis of The School of Chemistry at Nottingham
for this X-ray crystal structure determination.
11 A small amount (10–15%) of the dihydropyran positional isomer,
corresponding to anthecularin, was produced concurrently; it was easily
separated by chromatography.
Scheme 2 Reagents and conditions: (i) DBU, toluene, reflux, 1 h, 15–20%;
(ii) NaBH4–CeCl3, MeOH, rt, 20 min, 95%; (iii), NaH, CS2, MeI, THF, rt,
85%; (iv) Bu3SnH, AIBN, toluene, reflux, 20 min, 65%.
Treatment of the tetracyclic enone 13 with NaBH4–CeCl3 in
MeOH at room temperature next gave the allylic alcohol 14a, as
a single diastereoisomer, which was then smoothly converted into
the corresponding methyl xanthate 14b. Finally, treatment of a
solution of the xanthate 14b in refluxing toluene with Bu3SnH–
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