Stereoselective Total Synthesis of Atractylodemayne A, a Conjugated 2(E),8(Z),10(E)-Triene-4,6-diyne

Article abstract of DOI:10.1021/acs.orglett.6b00274

The first total synthesis of the polyacetylene natural product atractylodemayne A is reported. Stereoselective construction of the conjugated 8(Z),10(E)-diene moiety was achieved through a tethered ring-closing metathesis approach, comprising a Ru-catalyz

Full text of DOI:10.1021/acs.orglett.6b00274

Letter
pubs.acs.org/OrgLett
Stereoselective Total Synthesis of Atractylodemayne A, a Conjugated
2(E),8(Z),10(E)‑Triene-4,6-diyne
Bernd Schmidt* and Stephan Audorsch
̈
Universitaet Potsdam, Institut fuer Chemie (Organische Synthesechemie), Karl-Liebknecht-Strasse 24-25, D-14476 Potsdam-Golm,
Germany
S
* Supporting Information
ABSTRACT: The first total synthesis of the polyacetylene natural
product atractylodemayne A is reported. Stereoselective con-
struction of the conjugated 8(Z),10(E)-diene moiety was achieved
through a tethered ring-closing metathesis approach, comprising a
Ru-catalyzed RCM followed by a base-induced elimination. A Pd-
catalyzed Cadiot−Chodkiewicz coupling was used for the synthesis
of the diyne. Overall, atractylodemayne A was synthesized in nine
steps for the longest linear sequence.
olyacetylenes1 constitute a large family of natural products
physiological functions, an important role in inflammatory
processes and may have pro- and anti-inflammatory effects.
However, an overproduction of NO will result in a preponderant
pro-inflammatory effect, and inhibition of iNOS could therefore
be a potential therapeutic concept for the treatment of
inflammatory diseases.12
2−4
Pisolated from diverse biological sources such as plants,
fungi,3,4 bacteria,3 or marine organisms.3,5 In particular, edible
plants, such as vegetables, herbs,6,7 and medicinal plants,8 are rich
sources of polyacetylenes. While this has been considered to be
potentially problematic due to the known harmful effects of some
polyacetylenes on human health, such as allergenicity and
neurotoxicity,8,9 or their contribution to the bitter off-taste of
certain processed vegetable products,10 more recently, the
beneficial effects of polyacetylene phytochemicals have been
emphasized. In addition to antifungal, antibacterial, and cytotoxic
activities,4 antiinflammatory activity has been established for
several polyacetylenes. A particularly well-investigated poly-
acetylene in this regard is falcarindiol (Figure 1), which was
found to inhibit the activity of inducible nitric oxide synthase
(iNOS), thereby leading to a modulation of the endogeneous
NO production.11 Nitric oxide plays, apart from many other
Atractylodes is a genus of the flowering plant of the Asteraceae
family. The rhizomes of several species have been used in
traditional Chinese medicine as remedies against various
diseases. During pharmacological evaluation of crude drug
extracts of some species, anti-inflammatory activity was detected;
however, this activity was not correlated to specific secondary
metabolites.13 Three polyacetylenes were isolated from the
species Atractylodes macrocephala Koidz.14 In vivo tests revealed
that they did indeed contribute to the anti-inflammatory
activity.15 Very recently, this species was reinvestigated using a
bioactivity guided approach with the aim of identifying additional
antiinflammatory compounds which act by inhibition of NO
production in macrophages.16 Seven new and eight known
polyacetylenes were isolated during this study. They all share a
linear 14-carbon chain and a 2-ene-4,6-diyne-8,10-diene arrange-
ment of the C−C multiple bonds. The seven new compounds
were named atractylodemaynes A−G.16
A fully conjugated diene−diyne sequence, as highlighted in the
structural formulas of atractylodemayne A and the previously
described virol A,17 is not an uncommon structural element in
polyacetylene natural products (Figure 1). In most cases, the
diene moiety is E,E-configured. In this regard, the secondary
metabolites isolated from A. macrocephala are remarkable, as five
out of 15 polyacetylenes have an 8Z,10E configuration, as shown
Figure 1. Diene−diyne polyacetylenes falcarindiol, atractylodemayne A
and virol A.
Received: January 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00274
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Letter
for atractylodemayne A. It is in line with the predominant E,E-
configuration of the natural products that most synthetic efforts
have also addressed this configuration.18 For example, (E)-
dihaloethenes have been elaborated into E,E-configured diene−
diynes with retention of the configuration through successive Pd-
catalyzed cross-coupling reactions.17,19−21 A rare example for the
stereoselective synthesis of an E,Z-diene−yne sequence was
published by Taylor and co-workers in the course of a synthesis
of the marine polyacetylene metabolite carduusyne A. Con-
struction of the E,Z-diene was achieved through a sequence of
nucleophilic addition to a pyrylium salt and electrocyclic ring
opening.22
Herein, we report a highly stereoselective total synthesis of
atractylodemayne A using a Ru-catalyzed tethered ring-closing
metathesis23 for the simultaneous and stereoselective con-
struction of both C−C-double bonds and a Pd/Cu-catalyzed
Cadiot−Chodkiewicz coupling24,25 for connecting both alkyne
moieties. The tethered RCM reaction used here was recently
developed by us. It requires allylbutenoates 1 as starting
materials, which undergo RCM to lactones 1a and a base-
induced elimination (1b → 1c) in a one-pot fashion to yield, after
protonation of the carboxylates 1c, 2(Z),4(E)-dienecarboxylic
acids 2.26−28 This transformation differs from other tethered
RCM reactions, e.g., silicon-29,30 or phosphate-tethered31 RCM.
Insofar as the tether remains in the molecule as a useful
functional group, the double bond generated through olefin
metathesis is shifted to an adjacent position, and a second double
bond is generated via elimination (Scheme 1). Methods for the
carboxylate 1c with a suitable alkyl electrophile. To this end, the
original sequence required some modification, but eventually
cyclization of 7 was accomplished in CH2Cl2 with second-
generation Grubbs’ catalyst39 (A) followed by deprotonation−
ring opening induced by NaHMDS at ambient temperature and
finally alkylation of the sodium carboxylate using Meerwein’s
salt.40 Other alkylating agents were found to be inefficient. The
desired ethyl ester 8 was isolated in good overall yield and as a
single 2Z,4E isomer. The undesired 2E,4E isomer was not
observed. Next, the aldehyde 9 was required as a starting material
for a Corey−Fuchs-type homologation41 to give diene−yne 10.
Conversion of 8 to 9 was accomplished in two steps by reduction
of 8 with DIBAl-H to the corresponding primary alcohol and its
subsequent oxidation to the aldehyde 9. The primary alcohol was
found to be surprisingly unstable when attempts to purify the
crude product were made. In particular, double-bond isomer-
ization appeared to be a major problem. For these reasons, the
crude alcohol was immediately oxidized to dienal 9 using Dess−
Martin periodinane.42 Remarkably, this aldehyde is chemically
and configurationally sufficiently stable to be isolated and fully
characterized. In CDCl3, a slow isomerization to the E,E isomer,
presumably acid catalyzed, occurs, which is quantitative after 3
weeks. In the next step, the aldehyde to alkyne homologation was
investigated. After some experimentation, we found that optimal
results were obtained using Wolkoff’s reagent43 [Ph3PCHBr2]Br·
CH3CN in combination with KOBut as a base. Isolation of the
gem-dibromoalkene intermediate could be circumvented by
adding additional KOBut to the reaction mixture immediately
after completion of the dibromomethylenation.44 In spite of the
strongly basic conditions, the diene−yne 10 was isolated in good
yield and without concomitant double-bond isomerization or
notable polymerization (Scheme 2).
Scheme 1. Tethered RCM Ring Opening
For the construction of the diyne part, we envisaged a Cadiot−
Chodkiewicz coupling of the C6−C14 fragment 10 and
iodoacetylene 12a. The latter had previously been synthesized
Scheme 2. Synthesis of C6−C14 Fragment
stereoselective synthesis of conjugated dienes have recently been
reviewed.32 An example for a stereoselective approach to
2(Z),4(E)-dienecarboxylic acids based on electrocyclic ring
opening of cyclobutenes has been developed by Maulide and co-
workers.33−35
Our synthesis of atractylodemayne A starts from 1,4-
butanediol (3), which was first protected as the monosilyl
ether 4. Several protocols for the oxidation of 4 to the
corresponding aldehyde were tested, but only Anelli’s
TEMPO-bromide-catalyzed oxidation with hypochlorite as
oxidant gave satisfactory results.36,37 Other oxidation methods,
such as Swern oxidation, Dess−Martin reagent, or TPAP/NMO
turned out to be impractical because isolation of the volatile
aldehyde was required. Because of its instability and volatility, the
aldehyde was not purified and characterized but reacted with
vinylmagnesium bromide immediately after workup to give the
allyl alcohol 5. Steglich esterification38 of 5 with carboxylic acid 6
resulted in the formation of allylbutenoate 7, the precursor
required for the tethered RCM−ring-opening sequence. We had
previously synthesized 2(Z),4(E)-diene carboxylic acids via this
sequence26 but thought that for synthetic applications involving a
reduction of the carboxyl group it might be more convenient to
use esters instead of carboxylic acids. For these reasons, we
investigated a modification of the original tethered RCM−ring-
opening protocol that involved a trapping of the intermediate
B
DOI: 10.1021/acs.orglett.6b00274
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Letter
from the enyne 11, which is commercially available, or can be
synthesized in five steps from methylpropiolate.45 One reported
method for the synthesis of 12a from 11 proceeds by
electrophilic iodination/elimination, using iodine in the presence
of KOH.45 In our hands, these conditions led to a complex
mixture of products with formation of trace amounts of the
diiodocompound 13. Treatment of 11 with iodine in the
presence of morpholine17 resulted again in the formation of 13,
but this time in isolable quantities, albeit in extremely low yield.
Iodoacetylene 12a was eventually obtained by treatment of 11
with N-iodosuccinimide (NIS) in the presence of a catalytic
amount of AgNO3, following a procedure published by Rossi and
co-workers.46 The bromo analogue 12b was synthesized via the
same procedure, using N-bromosuccinimide (NBS), in slightly
higher yield.45,46 All syntheses of haloalkynes 12a,b and their
further transformations should be carried out in the absence of
light (Scheme 3).
fraction which accounts for 24% of the total yield. Pure 14a was
subjected to Steglich esterification with senecioylic acid (15) to
furnish ester 16, which was the starting material for the final
Cadiot−Chodkiewicz coupling. An attempt to synthesize
atractylodemayne A using a Cu-catalyzed coupling17,47 with the
iodoacetylene 12a resulted in no conversion and a recovery of
starting materials. However, with bromoacetylene 12b as the
coupling partner, Pd(OAc)2 as catalyst, and CuI as cocata-
lyst,48,49 the acetylenic coupling proceeded in 43% yield and high
selectivity. In particular, no products resulting from E/Z
isomerization or double-bond migration reactions were detected
(Scheme 4).
Scheme 4. Completion of the Total Synthesis
Scheme 3. Synthesis of Cadiot−Chodkiewicz Coupling
Partners
We decided to remove the TBS protecting group from
compound 10 and replace it by the senecioyl (3-methylbut-2-
enoyl) group required for the target molecule before the Cadiot−
Chodkiewicz coupling. A reversed order of synthetic steps would
require exposure of the fully conjugated diene−diyne−ene
system to nucleophiles or acids to cleave the TBS ether. In
addition, the regioselective introduction of the senecioyl group
would become very difficult due to the presence of two primary
alcohols. We tested first TBAF-trihydrate as a reagent for the
desilylation of 10. Cleavage of the TBS ether was quantitative but
occurred with concomitant partial isomerization of the diene−
yne moiety to 14b. Assignment of the 3Z,5E configuration of 14b
was based on the 3J(H3−H4) value of 10.6 Hz and the 3J(H5−H6)
value of 15.5 Hz. We are currently unable to propose a
comprehensive mechanism for this rearrangement. Attempts to
deprotect 10 with acetic acid to avoid this undesired reaction
resulted in no conversion, while exposure of 10 to acetyl
chloride−methanol resulted in quantitative decomposition. For
these reasons, we returned to the TBAF trihydrate mediated
deprotection and decided to separate 14a and 14b by column
chromatography on silica, which was hampered by very similar
polarities of the products. Eventually, a 45% yield of pure 14a
could be obtained, along with 10% of pure 14b and a mixed
In summary, we describe herein the first synthesis of the
recently discovered polyacetylene natural product atractylode-
mayne A. Our synthesis proceeds in nine steps for the longest
linear sequence and an overall yield of 2.9%. The crucial
8(Z),10(E)-diene moiety was constructed through a tethered
RCM-base induced ring opening sequence, which is highly
stereoselective. Acetylenic coupling to access the diyne was
accomplished under Pd−Cu-co-catalyzed Cadiot−Chodkiewicz
conditions. All analytical data obtained by us for synthetic
atractylodemayne A match those reported by Yao and Yang16 for
the natural product very well.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00274.
Experimental procedures, analytical data, and 1H and 13
C
NMR spectra for all compounds (PDF)
C
DOI: 10.1021/acs.orglett.6b00274
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Letter
(31) Venukadasula, P. K. M.; Chegondi, R.; Maitra, S.; Hanson, P. R.
Org. Lett. 2010, 12, 1556−1559.
AUTHOR INFORMATION
■
Corresponding Author
(32) De Paolis, M.; Chataigner, I.; Maddaluno, J. Top. Curr. Chem.
2012, 327, 87−146.
*E-mail: bernd.schmidt@uni-potsdam.de.
Notes
(33) Souris, C.; Freb
Maulide, N. Org. Lett. 2013, 15, 3242−3245.
̀
(34) Souris, C.; Luparia, M.; Frebault, F.; Audisio, D.; Fares, C.;
́
ault, F.; Patel, A.; Audisio, D.; Houk, K. N.;
The authors declare no competing financial interest.
́
Goddard, R.; Maulide, N. Chem. - Eur. J. 2013, 19, 6566−6570.
(35) Souris, C.; Misale, A.; Chen, Y.; Luparia, M.; Maulide, N. Org. Lett.
2015, 17, 4486−4489.
ACKNOWLEDGMENTS
■
Generous financial support of this work by the Deutsche
Forschungsgemeinschaft (DFG-grant Schm1095/6-2) is grate-
fully acknowledged.
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