Catalytic asymmetric synthesis of (+)-anthecotulide using enyne and Meyer-Schuster rearrangements

Article abstract of DOI:10.1021/ol202425e

The bioactive sesquiterpene lactone (+)-anthecotulide (1) is synthesized for the first time, in a six-step sequence devoid of protecting groups. The key transformations are a novel Rh(I)-catalyzed asymmetric enyne rearrangement of a terminal alkynyl ester

Full text of DOI:10.1021/ol202425e

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5751–5753
Catalytic Asymmetric Synthesis of
(þ)-Anthecotulide Using Enyne and
MeyerꢀSchuster Rearrangements
David M. Hodgson,*,† Eric P. A. Talbot,† and Barry P. Clark‡
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, U.K., and LRL, Eli Lilly and Co. Ltd.,
Erl Wood Manor, Windlesham, Surrey, GU20 6PH, U.K.
david.hodgson@chem.ox.ac.uk
Received September 7, 2011
ABSTRACT
The bioactive sesquiterpene lactone (þ)-anthecotulide (1) is synthesized for the first time, in a six-step sequence devoid of protecting groups. The
key transformations are a novel Rh(I)-catalyzed asymmetric enyne rearrangement of a terminal alkynyl ester (4), to form the R-methylene-γ-
butyrolactone core, and a final-step mild Au(I)-catalyzed MeyerꢀSchuster rearrangement
Anthecotulide (1) is an optically active irregular sesqui-
terpene lactone first isolated in 1969 from Anthemis cotula
L. (stinking chamomile).1 At the time, the structure was as-
signed from analysis of spectroscopic data. In 2005, a more
detailed analysis, which included a NOESY experiment to
determine the configuration of the stereogenic double bond,
corroborated the original structural assignment.2 Antheco-
tulide has attracted interest due to its contact allergen
properties3 (contamination of chamomile preparations by
A. cotula is to be avoided)2 and its unusual biosynthesis for a
sesquiterpene, involving head-to-middle coupling of geranyl
diphosphate and dimethylallyl diphosphate.4 More recently,
anthecotulide demonstrated antibacterial,5 antimalarial,6
trypanocidal, and leishmanicidal activity7 and has been
shown to inhibit the activation pathway of the transcrip-
tion factor NF-kB which regulates pro-inflammatory
mediators (cytokines, nitric oxide, prostaglandins).8
Due to the emerging biological activity profile, and as
part of our ongoing interest in the synthesis of R-methy-
lene-γ-butyrolactones,9 we communicate here the first
synthesis of anthecotulide.
In this synthesis we aimed to address the synthetic
challenge of assembling the sensitive R-methylene-γ-buty-
rolactone10 and deconjugated ketone functionality in an
efficient and stereocontrolled manner. Specifically, we
envisaged accessing the natural product 1 by a Meyerꢀ
Schuster rearrangement from propargylic alcohol 2
(Scheme 1). This alcohol 2 would be derived by Wittig
homologation of aldehyde 3, which was anticipated to be
accessible from cycloisomerization of enyne 4.
† University of Oxford.
‡ Eli Lilly and Co. Ltd.
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234.
So as to examine this chemistry, enyne 4 was first
prepared (83% yield) by DCC coupling11 of commercially
available (Z)-but-2-ene-1,4-diol (6) with propiolic acid (5)
(4) van Klink, J.; Becker, H.; Andersson, S.; Boland, W. Org. Biomol.
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r
10.1021/ol202425e
2011 American Chemical Society
Published on Web 10/07/2011

using [Rh((R)-BINAP)]SbF6 gave (þ)-aldehyde 3 in 73%
yield and 96:4 er by chiral HPLC (Scheme 2).16
Scheme 1. Retrosynthetic Strategy to Anthecotulide (1)
The sense of asymmetric induction in the cycloisome-
rization above using (R)-BINAP was determined by con-
version of (þ)-aldehyde 3 to the trans-lactone 8a17 of pre-
viously established absolute configuration and comparison
of specific rotation values (Scheme 3). Chemoselective
reduction of aldehyde 3 using BH3,18 followed by hydro-
genation of the R-methylene group in lactone 7 and silyla-
tion of the resulting primary alcohol, gave a cisꢀtrans
mixture of lactones 8 from which trans-lactone 8a could be
obtained by careful chromatography. This correlation
established that the R-configured aldehyde 3 was obtained
from enyne 4 when using (R)-BINAP, and this corre-
sponds to the same sense of asymmetric induction ob-
served in Zhang’s and Nicolaou’s studies.14,15
(Scheme 2). Although metal catalyzed Alder-ene reactions
of 1,6-enynes have been well-studied,12 to the best of our
knowledge only a single isolated example to form an R-
methylene-γ-butyrolactone has been reported, using an
achiral ruthenium(I) catalyst (CpRu(NCCH3)3PF6).13
Scheme 3. Configuration of Aldehyde (þ)-3 by Conversion to
trans-Lactone (þ)-8a
Scheme 2. Synthesis and Cycloisomerization of Enyne 4
With a catalytic and highly enantioselective synthesis of
aldehyde 3 established we examined its conversion to the
propargylic alcohol 2 for the projected MeyerꢀSchuster
rearrangement. Structurally related (internal) alkynes have
been recently shown to undergo one-pot cycloisomeriza-
tionꢀWittig reaction.19 In the present case, addition of ylide
920 (1.3 equiv) following the Alder-ene reaction gave the
E-R,β-unsaturated aldehyde 10 (67% from enyne 4,Scheme4).
Considering the prospects for asymmetric catalysis, we
decided to investigate the synthesis of the R-methylene-γ-
butyrolactone core under rhodium(I) catalysis, which was
originally developed by Zhang and co-workers with inter-
nal alkynes.14 Using Zhang’s conditions ([Rh(cod)Cl]2/
rac-BINAP/AgSbF6, (0.025:0.05:0.05), ClCH2CH2Cl, rt,
15 h), enyne 4 gave the desired aldehyde 3, albeit in low
yields (20ꢀ30%) which were difficult to reproduce. On the
basis that polymerization might be a competitive side
reaction, we lowered the reaction concentration from 0.2
to 0.1 M and 0.05 M, but these experiments also gave low
yields (23% and 15%, respectively). However, modifying the
conditions to those used by Nicolaou and co-workers, where
preforming the catalyst [Rh(rac)-BINAP)]SbF6 was found
optimal for the synthesis of R-methylene-γ-butyrolactams,15
gave aldehyde 3 in much improved yield (71%). Finally,
Scheme 4. Synthesis of Propargylic Alcohol 2
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1352.
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126, 15592–15602. The structural correspondence to the R-methylene-γ-
butyrolactone unit in anthecotulide (1) was noted in this paper.
(14) Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 8198–
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(16) See the Supporting Information for details.
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Org. Lett., Vol. 13, No. 21, 2011

1,2-Reduction of aldehyde 10 with Luche’s conditions,21
followedbyanAppelreaction22 using PPh3 and CBr4, gave
allylic bromide 12 (79% yield from 10). Of various proce-
dures examined for the displacement of the allylic bromide
12 by terminal alkynes,23 conditions developed by White
and co-workers were found to work best.24 Propargylic
alcohol 2 was obtained (63%) by addition of the allylic
bromide 12 at 0 °C to the alkynylcopper species from
alkynol 13, prepared by mixing with stoichiometric CuI
and Et3N in a 2:1 mixture of Et2O and DMF.
Scheme 5. Anthecotulide (1) by MeyerꢀSchuster Rearrange-
ment
Mild methods for the conversion of propargyl alcohols
into R,β-unsaturated ketones (MeyerꢀSchuster rearrange-
ments) have recently been developed.25 Akai and co-
workers reported an effective catalytic combination of
MoO2(acac)2 with AuCl(PPh3)ꢀAgOTf, where rearrange-
ment is considered to proceed by [3,3] sigmatropy of an
intermediate molybdate which is facilitated by alkyne coor-
dination to an in situ generated cationic Au catalyst.26 Using
these conditions propargylic alcohol 2 gave (þ)-anthecotu-
lide (1) in excellent yield (87%) (Scheme 5). No isomerization
of the β,γ-trisubstituted alkene into conjugation with the
ketone was observed. The spectroscopic data were in full
agreement with those in the literature,2,16 and the specific
establishes the absolute configuration of the natural product
as R- and provides a strategy for analog synthesis. Aside
from its brevity, which stems from only one oxidation
level change28 and the absence of protecting-group
chemistry,29 the synthesis is noteworthy for the first ex-
ample of an enantioselective enyne cycloisomerization to a
R-methylene-γ-butyrolactone and the tolerance of the
latter functionality to Au(I)-catalyzed MeyerꢀSchuster
rearrangement.
Acknowledgment. We thank Eli Lilly for funding (to
E.P.A.T.), D. Daniels and P. Roth (Oxford) for assistance
with HPLC analysis, and A. Meyer and P. Imming
€
(Martin-Luther-Universitat Halle-Wittenberg) for spectra
and a generous authentic sample of 1.
rotation of synthetic anthecotulide [R]23 þ81.1 (c 0.15,
D
CHCl3) is of comparable magnitude to that reported for
the natural product [R]23D þ76.9 (c 0.032, CHCl3).27
In summary, the first and asymmetric synthesis of (þ)-
anthecotulide (1) has been achieved in six steps from
commercially available materials, which additionally
Note Added after ASAP Publication. The version pub-
lished ASAP on October 7, 2011 contained typographical
errors in two specific rotations related to Scheme 5. The
correct version reposted on October 11, 2011.
€
€
(19) Korber, N.; Rominger, F.; Muller, T. J. J. Synlett 2010, 782–786.
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1, 1431–1434.
Supporting Information Available. Full experimental
procedures and characterization data. This material
is available free of charge via the Internet at http://
pubs.acs.org.
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