Enantioselective Total Synthesis of Terreumols A and C from the Mushroom Tricholoma terreum

Article abstract of DOI:10.1002/anie.201510709

The cytotoxic meroterpenoids terreumol A and C from the grey knight mushroom Tricholoma terreum were synthesized for the first time. The key step of the enantioselective total synthesis of terreumol C is a ring-closing metathesis to form a trisubstituted Z double bond embedded in the 10-membered ring of the [8.4.0] bicycle. Interestingly, the presence of a free hydroxy group in the metathesis precursor prevents cyclization and favors cross metathesis. (-)-Terreumol C was converted into (-)-terreumol A by diastereoselective epoxidation. Starting from 2-bromo-3,5-dimethoxybenzaldehyde, 14 steps with an overall yield of 23 % are needed for the synthesis of (-)-terreumol A. X-ray analysis of the benzoquinone analogue of terreumol A provides independent proof of the absolute configuration.

Full text of DOI:10.1002/anie.201510709

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201510709
German Edition: DOI: 10.1002/ange.201510709
Total Synthesis
Enantioselective Total Synthesis of Terreumols A and C from the
Mushroom Tricholoma terreum
Alex Frichert, Peter G. Jones, and Thomas Lindel*
Dedicated to Professor Henning Hopf on the occasion of his 75th birthday
Abstract: The cytotoxic meroterpenoids terreumol A and C
from the grey knight mushroom Tricholoma terreum were
synthesized for the first time. The key step of the enantiose-
lective total synthesis of terreumol C is a ring-closing meta-
thesis to form a trisubstituted Z double bond embedded in the
10-membered ring of the [8.4.0] bicycle. Interestingly, the
presence of a free hydroxy group in the metathesis precursor
prevents cyclization and favors cross metathesis. (À)-Terreu-
mol C was converted into (À)-terreumol A by diastereoselec-
tive epoxidation. Starting from 2-bromo-3,5-dimethoxybenzal-
dehyde, 14 steps with an overall yield of 23% are needed for
the synthesis of (À)-terreumol A. X-ray analysis of the
benzoquinone analogue of terreumol A provides independent
proof of the absolute configuration.
reported in the single-digit and low double-digit micromolar
range, which is comparable to cisplatin. There is also interest
in mushrooms of the genus Tricholoma because cases of
poisoning by rhabdomyolysis have been reported.[2] Further
research on the biological activities or derivatization will only
be possible if the terreumols can be accessed by total
synthesis.
A few other natural products share the partially aromatic
[8.4.0] bicycle with the terreumols.[3] Among them, the
clavilactones from the basidiomycete Clitocybe claviceps
have received the greatest attention, and several total
syntheses have been developed.[4–7] As part of our work on
diterpenoids, we have shown that [8.4.0] systems with
a benzene partial structure are accessible through intra-
molecular aldehyde/ketone McMurry coupling for closing of
the ten-membered ring.[8] Therefore, we included McMurry
coupling in our retrosynthesis, in addition to ring-closing
metathesis (RCM; Scheme 1). It was unclear, however,
whether the desired trans configuration of the epoxide
moiety in (À)-terreumol C (2) would allow cyclization. Both
routes would start from the same precursors: 3, 4, and 5.
T
he terreumols from the mushroom Tricholoma terreum are
unique meroterpenoids that were described by Liu and co-
workers in 2013.[1] Characteristically, the terreumols contain
an [8.4.0] bicycle with a methoxy-substituted hydroquinone
moiety and a terpenoid ten-membered ring. (À)-Terreumol A
(1, Figure 1) is a bisepoxide, whereas (À)-terreumol C (2)
exhibits only one epoxide partial structure.
To date, little is known about the biological activity of
terreumols, with the exception of cytotoxicity, for which half
maximal inhibitory concentrations (IC50) values have been
Scheme 1. Retrosynthetic analysis of (À)-terreumol C. Position num-
bering according to Ref.[1].
Figure 1. Terreumols A–D from the mushroom Tricholoma terreum.
For the synthesis of the pentasubstituted benzene moiety,
2-bromo-3,5-dimethoxybenzaldehyde (6)[9] was converted
into the nitrostyrene, followed by reduction to the imine/
enamine (Fe, HOAc) and hydrolysis to phenylpropanone 7
(Scheme 2). After protection of the ketone as 1,3-dioxolane
(8), the bromo substituent was replaced by a hydroxy function
through Br/Li exchange, conversion into the dimethylboro-
nate, and oxidative hydrolysis with H2O2/Na2CO3 (aq.) to 9
(90%). Surprisingly, attempts at phenol bromination with
either NBS or PhMe3NBr3 afforded the tetrasubstituted
undesired benzofuran 10 in quantitative yield. Bromination
of the aryl ring was still faster than electrophilic ring opening
of the 1,3-dioxolane but did not occur exclusively. The
[*] M. Sc. A. Frichert, Prof. Dr. T. Lindel
Institute of Organic Chemistry
Technical University Braunschweig
Hagenring 30, 38106 Braunschweig (Germany)
E-mail: th.lindel@tu-braunschweig.de
Prof. Dr. P. G. Jones
Institute of Inorganic and Analytical Chemistry
Technical University Braunschweig
Hagenring 30, 38106 Braunschweig (Germany)
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201510709.
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Scheme 3. Synthesis of metathesis precursors 21a,b.
the terreumols seemed impossible. Therefore, we turned to
RCM.
For synthesis of the RCM precursors, ketone 7 was
methylenated (16, 97%, Scheme 3), followed by Br/OH
exchange, oxidative O-demethylation, reduction to the hydro-
quinone, and double silylation to afford compound 18 (59%
over five steps). Bromination (PhMe3NBr3, CH2Cl2/MeOH,
À788C) afforded aryl bromide 19, which was hydroxyalky-
lated after bromine/lithium exchange (tBuLi, 82%) with
epoxyaldehyde 20,[11] which was synthesized through Kat-
suki–Sharpless epoxidation. We obtained diastereomers
21a,b, which could be separated by column chromatography,
in an almost equimolar ratio (7:5).[12] However, when reacting
either 21a or 21b in the presence of substoichiometric
amounts of Grubbs II catalyst (40 mol%) and tetrafluoro-
benzoquinone (80 mol%) for oxidation of the ruthenium
hydride species,[13] we did not observe cyclization to the ten-
membered ring (Scheme 4). Instead, reaction of 21b provided
22 as a mixture of E/Z isomers by cross metathesis. A product
shortened by one methylene group was also formed, despite
the addition of tetrafluorobenzoquinone. Similar observa-
tions have been made in the course of RCM to cyclooctenes
with trisubstituted double bonds,[14] and also in the absence of
quinone additives.[15,16]
Scheme 2. Synthesis and hydroxyalkylation of sterically congested
phenylbromide 12. CAN=ceric ammonium nitrate, Cy =cyclohexyl,
DCM=dichloromethane, NBS=N-bromosuccinimide, PTSA=toluene-
p-sulfonic acid, rf=reflux, TBSOTf=tert-butyldimethylsilyl trifluorome-
thanesulfonate.
phenolic hydroxy group needed to be protected. Treatment of
9 with CAN led to regioselective demethylation an the
p position and formation of the p-benzoquinone, which
afforded bis(TBS) ether 11 after reduction and silylation
(Scheme 2). Bromination in the para position to the remain-
ing OMe group (PhMe3NBr3) afforded the pentasubstituted
benzene derivative 12.
An unexpected problem occurred in the hydroxyalkyla-
tion of 12 with a,b-unsaturated aldehyde 13, which was
prepared in 6 steps from geraniol.[10] After bromine/lithium
exchange (tBuLi, Et2O) and reaction with aldehyde 13, we
isolated the inverted tertiary allylic alcohol 14 (72% yield),
which in CDCl3 underwent elimination to diene 15 and other
products. Conversion to the required epoxy ketone moiety of
The picture changed after oxidation of 21a,b to epoxyke-
tone 23. In this case, 82% yield of the [8.4.0] bicycle 24 was
obtained, together with minor amounts of open-chain mate-
rial, which could be separated by chromatography
(Scheme 4). The natural product (À)-terreumol C (2) was
obtained as yellow crystals after double desilylation of 24
(88%, NEt3·3HF, Scheme 4). The NMR data of the synthe-
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Scheme 5. Oxidation of (À)-terreumol C (2) to (À)-terreumol A (1) and
p-benzoquinone 25, for which an X-ray structure was obtained.
mCPBA=meta-chloroperbenzoic acid.
Scheme 4. Ring-closing metathesis to give (À)-terreumol C (2).
IBX=o-iodoxybenzoic acid.
obtained in 14 steps and 23% overall yield. There are
surprisingly few examples of the formation of medium-sized
carbocycles by RCM. The formation of a trisubstituted
double bond in a larger medium-sized carbocycle by RCM
has been achieved by Yi and Hale in their formal total
synthesis of the sesquiterpenoid (+)-eremantholide A,[18] by
Harmata and co-workers in their total synthesis of the
terpenoid buddledone A (11-membered ring),[19] and by
Nicolaou and co-workers in their total synthesis of two
floresolides.[20] In the latter case, competing cross metathesis
had occurred. The influence of the distance of hydroxy groups
and alkene moieties on the outcome of RCM has only been
subject to preliminary investigation.[21] For allylic alcohols, the
hydroxy group accelerates RCM, as first analyzed by Hoye
and co-workers.[22] However, for homoallylic alcohols, retar-
dation of ring closing in favor of cross metathesis was
observed by Hoveyda and co-workers and has been con-
sized and isolated natural product in [D6]acetone agreed
completely. NOESY analysis allowed assignment of the
diastereotopic hydrogen atoms and showed that the preferred
conformation in [D6]acetone is the same as in the crystal
structure obtained by Liu et al. The specific optical rotation of
the synthesized product 2 was about 10% smaller than
21
reported for the isolated sample (½aŠ ¼À50.08 (c = 0.17,
D
20
MeOH) compared to ½aŠ ¼À55.58 (c = 0.17, MeOH)). This is
D
probably a consequence of the ee that can be reached by the
Katsuki–Sharpless epoxidation, which was employed for the
synthesis of epoxyaldehyde 20. By GC on a chiral column
(Hydrodex-b-6TBDM, 25 m ” 0.25 mm), we determined an ee
of 89% for the alcohol precursor.
À
With (À)-terreumol C (2) in hand, we wondered whether
(À)-terreumol A (1) would be accessible by diastereoselec-
tive epoxidation of the trisubstituted alkene moiety. There
was a good chance since one face was expected to be buried in
the inner sphere of the ten-membered ring. Indeed, treatment
with mCPBA gave (À)-terreumol A (1) with perfect diaste-
reoselectivity as a crystalline yellow solid (86%, lmax = 202,
249, 291, 372 nm). All NMR data were in agreement with
nected to the formation of an intramolecular O H···Cl-[Ru]
bridge.[23]
Acknowledgements
We thank Merck KGaA (Darmstadt, Germany) for chroma-
tography materials and BASF Group (Ludwigshafen, Ger-
many) for the donation of solvents.
those reported. We measured a specific optical rotation of
22
½aŠ ¼À221.78 (c = 0.29, MeOH) which compares well with
D
20
D
the reported value (½aŠ ¼ = À216.18 (c = 0.29, MeOH)). We
Keywords: medium-sized rings · meroterpenoids ·
natural products · ring-closing metathesis · total synthesis
also isolated an over-oxidized side product (25, 13%,
Scheme 5), which turned out to be the p-benzoquinone. The
absolute configuration of 25, and thus of (À)-terreumol A (1),
was confirmed by X-ray analysis (6R,7S,10R,11S).[17]
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2916–2919
Angew. Chem. 2016, 128, 2969–2972
In summary, we have achieved the first total synthesis of
the fungal natural products (À)-terreumol C (2) and (À)-
terreumol A (1). Starting from 2-bromo-3,5-dimethoxyben-
zaldehyde, 13 steps with an overall yield of 26% were needed
for the synthesis of (À)-terreumol C. (À)-Terreumol A was
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Received: November 18, 2015
Published online: January 14, 2016
(3J12H-13H 6.6 vs. 9.0 Hz). 21a (dC12 = 67.6, d12-H = 4.69, d13-H
=
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