The first syntheses of (±)-SDEF 678 metabolite and (±)-speciosins A-C

Article abstract of DOI:10.1002/ejoc.201001402

The epoxyquinone natural products SDEF 678 metabolite, speciosin A, speciosin B and speciosin C have been prepared for the first time via a short synthetic route based around the palladium-catalysed coupling of a halogen-substituted 1,4-benzoquinone monoketal, a Diels-Alder/retro-Diels-Alder sequence and a diastereoselective epoxidation process. The quinone monoketal 13, which was obtained via oxidation of 3-iodophenol, has been converted over six steps into the epoxyquinone natural products SDEF 678metabolite (2) and speciosin A (4), which were subsequently converted into speciosin C (3) and speciosin B (5), respectively.

Full text of DOI:10.1002/ejoc.201001402

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001402
The First Syntheses of (؎)-SDEF 678 Metabolite and (؎)-Speciosins A–C
Daniel R. Hookins,[a] Alan R. Burns,[a] and Richard J. K. Taylor*[a]
Keywords: Natural products / Quinones / Speciosins
The epoxyquinone natural products SDEF 678 metabolite,
speciosin A, speciosin B and speciosin C have been prepared
for the first time via a short synthetic route based around the
palladium-catalysed coupling of a halogen-substituted 1,4-
benzoquinone monoketal, a Diels–Alder/retro-Diels–Alder
sequence and a diastereoselective epoxidation process.
Epoxyquinone natural products are widely distributed in
nature and are of continuing interest due to their many and
varied biological properties.[1] The highly functionalised
and challenging structures present in the epoxyquinone
family have stimulated the synthetic chemistry community
for many years now,[1] and our own group have made con-
tributions in this area [bromoxone, aranorosin, epi-epoxy-
don, harveynone (1), tricholomenyn A, LL-C10037α, alisa-
mycin, manumycins, preussomerins, etc.].[2] The majority of
the epoxyquinone natural products, including (–)-harvey-
none (1),[3] contain disubstituted epoxides. We were there-
fore excited when Ghisalberti and co-workers described the
isolation of the plant growth promoting, anti-fungal metab-
olite 2 from an ectotrophic Australian fungus, SDEF 678;[4]
compound 2 is isomeric with harveynone but contains a
trisubstituted rather than a disubstituted epoxide (Fig-
ure 1). Then in 2009, Jiang et al. described the isolation
of eleven new natural products from the Chinese fungus
Hexagonia speciosa which they named speciosins, six of
which (3–8) were epoxyquinones also containing a trisubsti-
tuted epoxide.[5] As can be seen, speciosin C (3) is simply
the reduced form of the SDEF 678 metabolite (2), whereas
speciosin A is closely related but contains a 2-(but-1-en-3-
ynyl) side-chain rather than the methylated version found
in compounds 1–3. The additional oxidation observed in
speciosins B (5) and D–F (6–8) is also noteworthy.
Figure 1. Representative epoxyquinone natural products.
Given the structural novelty of compounds 2–8, we em-
barked on their synthesis. Having completed the first total
synthesis of harveynone,[2e] we commenced this study by
considering a retrosynthetic analysis (RSA) for the isomeric
compound, SDEF metabolite (2). We also chose a route
which would be easily adaptable to prepare the speciosins
(Scheme 1). The key elements of this RSA are (i) the use of
a Diels–Alder/retro-Diels–Alder sequence (as pioneered by
the groups of Ichihara, Takano and Ogasawara)[6] to pro-
tect the less-substituted quinone alkene and to direct epox-
idation and reduction, and (ii) the palladium-catalysed cou-
pling of a halogen-substituted 1,4-benzoquinone monoketal
(as pioneered in our harveynone synthesis[2e]).
The initial synthetic studies are summarised in
Scheme 2.[7] The requisite starting material, 3-iodo-4,4-di-
methoxycyclohexa-2,5-dienone (13), was prepared from
either 2-bromo-1,4-dimethoxybenzene by electrochemical
oxidation followed by lithiation/iodination and subsequent
regioselective ketal hydrolysis as we originally de-
scribed,[2d,8] or via the direct double oxidation of 3-iodo-
phenol using hypervalent iodine reagents with methanol as
[a] Department of Chemistry, University of York,
Heslington, York, YO10 5DD, UK
Fax: +44-1904-434523
E-mail: rjkt1@york.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001402.
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D. R. Hookins, A. R. Burns, R. J. K. Taylor
SHORT COMMUNICATION
ids, the reaction proceeded in poor yield, or double addition
occurred giving adduct 15. However, success was achieved
using Corey’s chiral oxazaborolidine/triflic acid adduct
16[11] giving solely the endo adduct 11, as expected, in 87%
yield, although the product was essentially racemic.[12]
In principle, we could have explored the epoxidation at
this stage but given the sterically encumbered nature of ace-
tal 11 it was converted into enone 10 by stereoselective re-
duction followed by acetal removal; it should be noted that
the use of strongly acidic deprotection conditions, pro-
longed reaction times or increased temperature resulted in
the formation of an acid-catalysed rearrangement prod-
uct.[13] Nucleophilic epoxidation of enone 10 was achieved
using hydrogen peroxide in acetonitrile/DBU[14] giving a
mixture of diastereomers from which the major epoxide 9-
anti could be isolated by column chromatography [the anti-
relationship was subsequently confirmed by the conversion
of 9-anti into SDEF 678 metabolite (2)].[4] Finally, the retro-
Scheme 1.
solvent.[9] The conversion of iodide 13 into enyne 12 was Diels–Alder reaction was explored. We were delighted to
achieved in essentially quantitative yield using alkynyl- find that heating compound 9-anti to 250 °C (external tem-
stannane 14 under Stille coupling conditions with catalytic perature) in diphenyl ether gave the SDEF metabolite 2 in
trans-bromosuccinimidylbis(triphenylphosphane)palladium-
45% isolated yield [80% based on recovered starting mate-
(II);[10] Sonogashira coupling was not investigated due to rial (brsm)]. A comparison of spectroscopic data confirmed
the volatility of 3-methyl-but-3-en-1-yne. At this stage we the authenticity of the synthetic material [e.g. δC (CDCl3)
decided to protect the disubstituted quinone double bond 53.3 (C-1), 63.4 (C-5), 66.2 (C-6); ref.[4] δC (CDCl3) 53.3 (C-
using the Diels–Alder reaction with cyclopentadiene. With 1), 63.3 (C-5), 66.2 (C-6)]. In a similar manner, thermolysis
a range of standard conditions and a number of Lewis ac- of 9-syn gave the novel isomer 17 of SDEF metabolite 2.
Scheme 2.
452
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Syntheses of Epoxyquinone Natural Products
With the synthesis of SDEF 678 metabolite 2 complete, internal reaction temperature was above 200 °C. Using
we next looked to utilise the methodology to prepare the these modified thermolysis conditions, anti-epoxide 22 was
speciosins (Scheme 3). First, the novel stannane 18 was re- converted into speciosin A (4) in a gratifying 91% isolated
quired and this was easily prepared from monovinyl- yield. This synthetic material was fully characterised and
acetylene[15] by a deprotonation-stannylation sequence. Stille the NMR spectroscopic data were essentially identical to
coupling with 3-iodo-4,4-dimethoxycyclohexa-2,5-dienone those reported for natural speciosin A (a comparison table
(13) was then investigated and bis(benzonitrile)palladium di- is given in the Supporting Information).[5,17]
chloride/triphenylarsane[16] was found to be the most effec-
Treatment of speciosin A (4) with DMDO in acetone
tive catalyst giving ene-yne 19 in 91% yield. Next, using the gave speciosin B (5) in a modest, but unoptimised, 52%
Diels–Alder protocol employed earlier, adduct 20 was ob- yield as an inseparable 1:1 mixture of epoxide dia-
tained in 92% yield (again, as a racemic mixture). Diastereo- stereomers. Again, the synthetic compound was fully char-
selective Luche reduction and acetal hydrolysis, carried out acterised and the NMR spectroscopic data were consistent
without purification of the intermediate alcohol, then gener- with those published [e.g. δH (CDCl3) 3.46 (dd, J 3.9, 2.7,
ated enone 21 in 73% overall yield (the corresponding hy- H-3); ref.[5] δH (CDCl3) 3.45 (dd, J 4.0, 2.6, H-3); see Sup-
droxy acetal was also isolated in 14% yield). As before, epox- porting Information for full comparison; speciosin B (5)
idation was carried out using hydrogen peroxide/DBU to was isolated as a single diastereomer but the epoxide config-
provide the desired anti-epoxide 22 in 61% isolated yield, uration was not reported].[5]
along with the corresponding syn-isomer 23 (21%).
Finally, we investigated the reduction of SDEF 678 me-
We were now in a position to investigate the retro-Diels– tabolite (2) in order to prepare speciosin C (3) (Scheme 4).
Alder processes (Scheme 3). First, we explored the use of The use of NaBH4/CeCl3 gave reduction in quantitative
high temperature kugelröhr distillation using syn-epoxide yield but epi-speciosin C (25) was obtained as the major
23; although the isolated yield was disappointing, we were isomer (3/25 = 1:8). However, as anticipated,[18] Super-Hy-
able to obtain the novel epi-speciosin A (24) (25%). In order dride® reduced the ketone from the opposite face to the
to prepare speciosin A (4) we therefore went back to the epoxide with complete stereoselectivity giving speciosin C
1
diphenyl ether procedure and found that much higher yields (3) in 92% yield. Again, the high field H and 13C NMR
could be obtained by using a dilute solution of the starting spectroscopic data matched those in the literature[5] (see
material (0.03 m) in diphenyl ether, and by ensuring that the Supporting Information for more details).
Scheme 3.
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D. R. Hookins, A. R. Burns, R. J. K. Taylor
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Scheme 4.
In summary, a concise synthetic sequence has been devel-
oped which has been applied to prepare the epoxyquinone
natural products SDEF 678 metabolite (2), speciosin A (4),
epi-speciosin A (23), speciosin B (5), speciosin C (3) and
epi-speciosin C (25) all for the first time. Ongoing research
is concentrating on the development of an enantioselective
route to the speciosin family.
Supporting Information (see also the footnote on the first page of
this article): Full experimental and characterisation data for all
novel compounds, as well as NMR spectra for the natural products
2–5.
[7] All compounds were fully characterised spectroscopically and
by HRMS.
[8] E. C. L. Gautier, N. J. Lewis, A. McKillop, R. J. K. Taylor,
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9992–9993; For a review see: E. J. Corey, Angew. Chem. 2002,
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[12] Variation of the reaction conditions and the use of modified
substrates (e.g. replacing the methyl acetal by cyclic acetals)
failed to give usable enantiomeric excesses; the best ee (40%)
was obtained using the Mikami reduced TiIV-binol catalyst (see
ref.[11] and K. Mikami, Y. Motoyama, M. Terada, J. Am. Chem.
Soc. 1994, 116, 2812–2820).
Acknowledgments
The authors thank the Engineering and Physical Sciences Research
Council (EPSRC) (DRH, EP/03456X/1), the Biotechnology and
Biological Sciences Research Council (BBSRC, ARB, BB/D527034/
1) for Ph.D. studentship funding, Professor E. L. Ghisalberti (Uni-
versity of Western Australia) for kindly supplying NMR spectra of
SDEF metabolite (2), Professor J.-K. Liu (Kunming Institute of
Botany, PRC) for clarification of the NMR spectroscopic data of
speciosin A (4) and Dr K. Heaton for assistance with mass spectro-
scopic studies.
[13] M. Eipert, C. Maichle-Mössmer, M. E. Maier, J. Org. Chem.
2002, 67, 8692–8695.
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[17] The NMR solvent used for speciosin A was wrongly reported
in ref.[5] (personal communication from M.-Y. Jiang and J.-K.
Liu); see Supporting Information for a full spectroscopic com-
parison.
[18] C. Li, J. A. Porco Jr., J. Org. Chem. 2005, 70, 6053–6065.
Received: October 14, 2010
Published Online: December 14, 2010
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